Companion

Animal
Nutrition
Summit
Nutrition for Life
March 27-29, 2014
Austin, Texas
Preprint
The opinions expressed are those of the individual authors and do not necessarily
reflect the views of Nestlé Purina PetCare Company.
Table of Contents

A Healthy Beginning
Epigenetics and Perinatal Nutrition: A Key Factor of the Life Course Model of Public Health
Robert H. Lane, MD, MS .....................................................................................................................................................................1
Programming Food and Flavor Preferences: Impact of Early Experience
Sandra Lyn, PhD...................................................................................................................................................................................9
The Long-Term Health Effects of Spay and Castration for Dogs
Kate E. Creevy, DVM, MS, DACVIM-SAIM ....................................................................................................................................15
The Challenge of Providing Feeding Recommendations for Puppies after Neutering
Laura A. Eirmann, DVM, DACVN ....................................................................................................................................................25
Feeding Management of the Neutered Cat
Jennifer A. Larsen, DVM, PhD, DACVN ..........................................................................................................................................33

Special Concerns for Seniors

Aging and Stroke: The Human Condition
James W. Simpkins, PhD ....................................................................................................................................................................39
Enhancing Cognitive Function Through Diet in Cats
Yuanlong Pan, PhD .............................................................................................................................................................................53
Systemic Illness: The Role of Oxidative Stress and Antioxidant Supplementation
Katrina R. Viviano, DVM, PhD, DACVIM, DACVCP ......................................................................................................................63
Antioxidants for Eye Health
Wei Wang, PhD...................................................................................................................................................................................73

Evolutionary Diet: Optimum or Opportunistic Nutrition

Adapting to a New Diet During Dog Domestication: Implications for the Domestication Process and Dog Health
Erik Axelsson, PhD ............................................................................................................................................................................81
Evolutionary Versus Evidence-Based Diets
Ellen Kienzle, Dr.med.vet.habil., ECVCN .........................................................................................................................................87
Toward Optimizing Feline Nutrition: Insights from the Dietary Nutrient Profile of Feral Cats
Esther A. Hagen-Plantinga, PhD, DVM .............................................................................................................................................93
Raw Meat-Based Diets: Current Evidence Regarding Benefits and Risks
Beth A. Hamper, DVM, PhD, DACVN ..............................................................................................................................................99

Clinical Nutrition: Interactive Session on ‘How I feed …’

How I Feed: The Underweight Senior Cat with Multiple Problems
Catherine E. Lenox, DVM, CVA, DACVN ......................................................................................................................................109
Canine Renal Disease: When Is the Right Time to Strike with Nutritional Therapy
Julie Churchill, DVM, PhD, DACVN ..............................................................................................................................................115
How I Feed: The Diabetic Dog
Lisa P. Weeth, DVM, DACVN .........................................................................................................................................................121
Management of Overweight Dogs and Cats with Cancer
Glenna E. Mauldin, DVM, MS, DACVIM, DACVN .......................................................................................................................127

Appendix
2014 CAN Summit Speakers............................................................................................................................................................135
Epigenetics and Perinatal Nutrition:
A Key Factor of the Life Course Model of Public Health
Robert H. Lane, MD, MS
Medical College of Wisconsin
Department of Pediatrics
Milwaukee, WI
Email: [email protected]

Abstract We subsequently need three things

Preventing disease costs less than Glossary of Abbreviations to approach a solution to health-care
treating disease. This discussion CpG Methylation: A methyl group on the costs, particularly as it relates to a
cytosine of CpG dinucleotides complicated pathophysiology such
explores how an approach to prevent
CYP2B6: A hepatic P450 drug metabolizing
disease must take into account indi- as obesity. First, we need a paradigm
enzyme
vidual and family experiences, as that allows for both an individualized
IGF-1: Insulin Growth Factor-1
well as genetics, by building on the IGF-1 A: Transcripts that do not include exon 5 approach toward obesity and an
concepts of personalized medicine IGF-1 B: Transcripts that do include exon 5 environmental awareness. This para-
and the Life Course Model. A key IGF-1 P1: Insulin Growth Factor-1 Promoter 1 digm exists through the evolution of
time to use this approach is early in IGF-1 P2: Insulin Growth Factor-1 Promoter 2 personalized medicine into the Life
life, when perinatal nutrition strongly IUGR: Intrauterine Growth Restricted Course Model paradigm.
influences future health and disease. MicroRNA: Small Non-Coding RNAs Second, we need a component
Environmental epigenetics provides of the environment that varies yet
the mechanism through which to target this approach. exists as an essential common human experience, while remain-
ing accessible to manipulation. The characteristic of variation
Cost and Health-Care Approach Toward Obesity provides the opportunity to gauge the historical importance
Health care costs too much to be sustainable. In the United of this component of the environment. The characteristic of
States, health care costs approximately $2.6 trillion a year. remaining accessible to manipulation increases the relevance
Obesity significantly contributes to this cost. Obesity owns the of this component in terms of approaching a solution. Such
sobriquet of “public health enemy No. 1” by extracting over a component exists in the common human experience of peri-
$190 billion in health-care expenditures. Obesity also indirectly natal nutrition.
costs public resources. For example, estimates suggest that Third, we need a biological mechanism that allows us to be as
obesity in the United States burns an additional $1 billion in specific as possible with our manipulation of the environmental
gasoline utilization resources. component (perinatal nutrition), thereby allowing for individu-
Unsustainable health-care costs also exist outside the United alization. This biological mechanism must also account for the
States. Over the past two years, health-care expenditures increased complexity and variation inherent in human experiences of the
by approximately 10% worldwide. Surprisingly, health-care environment. This molecular mechanism exists within the field
expenditures from Latin America and Asia significantly contributed of environmental epigenetics.
to this increase. The health-care costs in these developing regions
track concurrently with an increasing incidence of obesity. First: Personalized Medicine & the Life Course Model
No simple or quick solution exists to eradicate obesity either Personalized medicine customizes health care by basing
in the U.S. or worldwide. Moreover, obesity presents through a medical decisions, practices and products on individual
multifactorial and multidimensional series of pathophysiological patient characteristics. Personalized medicine stands on
events, which further contributes to this dilemma. On one hand, the tenant that individualization of health care reduces costs
the nidus for obesity lies within individuals based on their and by minimizing unnecessary medical interventions based on
their family’s environmental exposures, as well as their individual probability. At this time, personalized medicine depends
genetics. This particular nidus, therefore, suggests an individualized heavily on genetics. Our limited knowledge of how the
approach toward obesity. On the other hand, the impetus for obesity genome works necessitates that genetics-based personalized
is embedded within domestic, local, regional, and cultural tradi- medicine focuses on phenotype extremes. Several relevant
tions and environments. This impetus suggests a need for a more examples demonstrate the power of this approach despite our
global approach. present limitations.
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 Genetics-based personalized medicine powerfully succeeds in A key and often ignored intrinsic challenge exists through our
oncology, pharmacogenomics and rare catastrophic genetic disease. lack of understanding in how our genome functions. Our genomes
An example of this success in the oncology field is the present respond dynamically to our environment. Our lack of understand-
approach toward breast cancer. Many institutes now characterize ing can be observed through our present focus on genes that led
breast cancer along several molecular axes. These axes include, to functional proteins. This approach enables perceived direct
but are not limited to, expression profiles of human epidermal comparisons between expression and disease. However, only
growth factor receptors, fibroblast growth factor receptors, 2% of the human genome encodes for protein expression.7
components of the mTOR pathway, estrogen receptors, and In another light, 98% of the human genome does not generate
progesterone receptors.1 An example of success in the field of proteins. Moreover, we actively transcribe 75% of this non-protein
pharmacogenomics includes CYP2B6.2 CYP2B6 functions as a encoding DNA. The fact that the ratio of non-protein encoding
hepatic P450 drug metabolizing enzyme. The pharmacoge- DNA to protein-encoding DNA correlates with biological com-
nomics of CYP2B6 include 37 distinct star alleles and greater plexity belies the importance of the non-protein encoding DNA.
than 30 SNPs. The relevance of the pharmacogenomics of CYP2B6 Although all three of these intrinsic challenges will be overcome
lays in the impact on non-nucleoside reverse transcriptase inhibitors, with time, we are far from approaching an understanding that
which are a first-line treatment for HIV infection. allows us to meet these challenges.
Finally, an example of genomic-based personalized medicine Extrinsic challenges simply arise from the complexity and
succeeding toward catastrophic genetic disease can be seen in a variability that compose human experiences. An elegant descrip-
case report by Worthey et al.3 The child in this case suffered through tion of this challenge exists in an analysis by Smith that details the
four years of atypical severe inflammatory bowel disease, extreme gloomy prospect of randomness.8 A pivotal point in this review
failure to thrive, aggressive immunosuppression, and multiple revolves around a study attempting to predict cancer risk based
surgeries with progressively diminishing results. Exome sequenc- on shared environment and twins. The unexpected findings
ing revealed a hemizygous missense mutation in the X-linked demonstrate that nonshared environmental influences in twins
inhibitor of apoptosis gene. This finding led to a bone marrow account for approximately 60 to 80% of cancer risk. In contrast,
transplant. Within six weeks, the inflammatory bowel disease heritability only accounts for 20 to 40% of cancer risk, and shared
resolved and the child began to thrive. In these three examples environmental influences only account for 20 to 40% of cancer
(oncology, pharmacogenomics and catastrophic genetic disease), risk. Despite these findings, we believe the message of this review
nothing can diminish the impact of the genetics-based personalized is hopeful. The implicit message is that our present approach
medicine approach on these disease processes. contains voids that fail to account for environmental complexity
Unfortunately, many common disease processes, such as obesity, and variability. We believe these voids can be partially filled by
possess characteristics that set up a genetics-based personalized the Life Course Model.
medicine approach for failure. These characteristics include an The Life Course Model, as we interpret it, hypothesizes that
incremental phenotype and the presence of significant environ- health arises through the interaction of genetics and the accumu-
mental risk factors. Characteristics often found in chronic common lation of multifactorial risk factors by individuals and their past
diseases present challenges that expose the limitations of a purely lineage.9 This model, therefore, accounts for the “weathering”
genetics-based approach. We place these challenges into two that occurs to individuals over the course of a lifetime and poten-
categories: intrinsic and extrinsic. tially accounts for the “weathering” that occurs to families across
Intrinsic challenges include the reality that many common generations. Historically, this model has been applied to the
chronic diseases result from gender, tissue and molecular inter- tragedy of racial disparities in the United States. A benchmark
actions. For example, obesity occurs as a result of dysfunction of this disparity is the high infant mortality observed in the U.S.
between multiple systems (e.g., endocrine, gastrointestinal, within the African-American community. This disparity occurs,
nervous) and tissues (e.g., liver, adipocyte). The singular in large part, due to the high incidence of low birth weight (less
pathology of obesity results from multiple combinations of than 2500 g) in the African-American population.
dysfunction from these systems and tissues. Another intrinsic The Life Course Model explains this adverse outcome of low
challenge includes the robustness of biological networks. This birth weight through the high prevalence of multifactorial risk
is well-described in a series of articles by Dipple and McCabe.4-6 factors that accumulate from conception to death in the African-
In essence, every one of us possesses severe single gene defects American population. Many proponents of the Life Course Model
that never rise to the level of clinical relevance because of our also point out the historical accumulation of risk factors on
biological network’s robustness. Single gene disease is the excep- many African-American families over the past 300 to 400 years
tion, not the rule. This robustness occurs because of variation in in the United States. An observation reinforcing this model is that
functional activity thresholds, modifier genes and system dynamics the time span spent homeless over a woman’s lifetime predicts the
that allow for compensation. The celestial design committee risk of low birth weight better than the occurrence of the home-
demonstrates wisdom by building into mammals this biological lessness during pregnancy.10 Another observation reinforcing
safety net. this model is that a maternal grandmother’s exposure to neigh-

2
borhood poverty during pregnancy predicts the risk of low birth
weight in her grandchildren.11 Regression analysis reveals that Key Concepts
this risk exists independent of the mother’s exposure. Indeed, 25% Developmental Origins of Disease: Early life events
predict later life diseases such as obesity.
of low birth weight infants delivered to mothers not born with
Food Desert Areas: Communities that lack access to
a low birth weight can be statistically attributed to generational
affordable healthy foods usually as a result of poverty
residence in low-income neighborhoods. The Life Course Model and not abundance.
also can be applied to important epidemiological events that Life Course Model: The accumulation of a family’s
educate us about the importance of perinatal nutrition as well as and individual’s experiences significantly influences the
provide insight into possible current and relevant interventions, health of the individual.
particularly in terms of the current issue of obesity.
The impact of this famine, therefore, potentially reverberates over
Second: Perinatal Nutrition subsequent generations because insulin resistance and obesity
Perinatal nutrition plays a pivotal role in lifelong health. This during pregnancy predispose toward large-for-gestational-age
truth is a core tenant of the Developmental Origins of Disease infants. As alluded to in the introduction, the social and financial
hypothesis. This truth became concrete within the scientific costs to China and the rest of the world will strain resources,
community’s consciousness through many diverse studies that considering the millions of individuals potentially affected
included multiple countries, cultures and races. Three key char- across generations. Unfortunately, the rest of the world fails to
acteristics exist within the most rigorous of these diverse studies, learn from this experience.
including the Nurse’s Health Study and the Dutch famine of In the U.S., food desert areas represent a lack of insight on our
1944 to 1945. The first characteristic involves a differentiating part and another risk factor for the racial disparities discussed
environmental event, the most common being famine, followed above. Poor access to healthy and affordable food characterizes
by a nondifferentiating environment. The second characteristic food desert areas. Although the phrase “food desert area” suggests
involves the appearance of a significant morbidity that occurs a literal absence of retail food in a defined area, the most common
temporally distant from the initial differentiating environmental meaning in the U.S. is differential accessibility to healthy and
event. The third characteristic involves a comparison cohort not affordable food between social economically advantaged and
afflicted with the morbidity that is genetically comparable. The disadvantaged areas. For example, areas with a high proportion
above-mentioned studies embed rigor into their observations by of African-Americans have fewer supermarkets or chain stores
controlling for confounding factors, such as gestational age, maternal per capita as well as fewer midsized stores.17 Furthermore, the
smoking, socioeconomic status, ethnicity, parental lifestyle, most severe food deserts in New York City are within east and
medical history, maternal diabetes, and physical activity, among central Harlem and north and central Brooklyn, which have the
other things. The incontrovertible conclusion of these cohort highest proportion of African-American residents.18 The most
studies is that poor perinatal nutrition leads to multiple adult favorable areas within New York are on the Upper East Side,
diseases, not the least of which is obesity.12-14 which is predominantly a middle- and upper-income area. Evidence
Obesity becomes a relevant worldwide issue when a relatively exists that better access to supermarkets reduces the risk for
recent and currently relevant famine is taken into account, such obesity, whereas greater access to convenience stores increases
as the Chinese famine. The Chinese famine, which occurred from the risk for obesity. The field requires further work to focus on
1959 to 1961, is among the largest in human history.15,16 The the impact of food deserts relative to pregnancy and long-term
Chinese famine differs from the Dutch famine through spanning health outcomes within the context of the Developmental Origins
a longer period of time, impacting a population already struggling of Disease. However, the presence of food deserts provides a
from chronic undernutrition, varying across regions, and dispro- possible intervention as we look for solutions against obesity. To
portionately affecting rural regions. target individuals (a long-term goal) and to measure the impact
The Chinese famine also differs from the Dutch famine in terms of an intervention, we need a biological mechanism. We believe
of the impact on subsequent generations. In contrast to the Dutch environmental epigenetics represents one such mechanism.
famine, first-generation adults who were in utero during the Chinese
famine suffered from decreased adult height and neurodevelop- Third: Environmental Epigenetics
mental outcome. These adults were, of course, initially charac- Epigenetics regulate planned or programmed gene expression
terized by low birth weight secondary to poor perinatal nutrition. in eukaryotes. Epigenetics determine accessibility of DNA to
In the second generation, in contrast, recent evidence suggests transcription factor machinery to multiple varied mechanisms.
an unanticipated and cross-generational effect. Specifically, A cell cannot express a gene without invoking epigenetics. We
grandchildren of the women impacted by the Chinese famine divide epigenetics into two fields. Developmental epigenetics
demonstrate a predisposition to greater-than-normal birth weight. allow for cells to maintain distinct rigid programs of gene
In other words, these children are large for gestational age, which expression. This includes programs of gene expression that
predisposes them toward adult insulin resistance and obesity. occur during development or that maintain tissue specificity.

3
Nobody needs a hepatocyte to become a neuron by accident. Subsequently, the histone code contains the capacity to act as
Environmental epigenetics allow for cells to adapt and respond a dynamic storage system that records significant interactions
to the environment. We believe this is what occurs within the between your chromatin and the environment. Unfortunately,
Developmental Origins of Disease hypothesis. Broadly speaking, we are still in our infancy of understanding how to interpret the
we believe that your phenotype is a product of your genetics, histone code, but we will get there.
your family’s exposures and your exposures. Other epigenetic mechanisms exist. This includes the 98%
Epigenetics invoke multiple mechanisms. DNA CpG methy- of the genome that does not encode proteins. Other epigenetic
lation is the most well-studied but not necessarily best-understood. mechanisms include microRNA. These are small non-coding
DNA CpG methylation involves putting a methyl group on the RNAs that mediate post-transcriptional regulation of gene
cytosine of CpG dinucleotides. CpG dinucleotides occur dis- expression. MicroRNAs regulate up to 60% of expression of
proportionately in CpG islands. Two-thirds of human promoters our genome. Another epigenetic mechanism includes long non-
are located within CpG islands. Most promoters located within coding RNA. This is a diverse class of transcripts that lack an
these islands stay unmethylated. Although DNA CpG methylation open reading frame. These transcripts appear to regulate gene
associates with gene silencing, initiation of silencing does not expression through both direct and indirect mechanisms. Long
require this event. More likely, DNA CpG methylation functions non-coding RNAs also may function as an interface between
to maintain a repressed state of transcription. the transcriptome and the proteosome.
DNA CpG methylation studies lend themselves to human Animal models provide the best evidence of a relationship
epidemiological studies because they require little sample and between perinatal nutrition and environmental epigenetics.
appear easy to interpret. Studies demonstrate that DNA CpG More specifically, animal models demonstrate that suboptimal
methylation varies with maternal macro- and micro-nutrient perinatal nutrition affects the epigenetic programming of impor-
intake, the mode of conception, the mode of delivery, maternal tant physiological genes and that targeted perinatal nutritional
smoking, paternal habits, and maternal emotional status. Unfortu- supplementation moderates the effects of suboptimal perinatal
nately, we color the interpretation of the studies with our natural nutrition. A common cause of suboptimal perinatal nutrition in
human tendency toward naïve reductionism. A capability to take developed countries involves uteroplacental insufficiency, often
into multiple individual and familial characteristics to predict a caused by diseases of pregnancy-induced hypertension, such
DNA methylation status, let alone a predisposition toward obesity as preeclampsia.
based on DNA methylation status, does not yet exist. This is partly Uteroplacental insufficiency decreases the transfer of nutrients
due to our inability to account for the effects of methylation from the mother to the baby. The suboptimal transfer causes the
across a whole genome as well as the binomial nature of DNA baby to be intrauterine growth restricted (IUGR). Human IUGR
methylation. You are either methylated or unmethylated. The offspring suffer from increased risk toward multiple postnatal/adult
complexity and variability of the human condition rarely fits morbidities including obesity. We use a well-characterized model
within a simple binomial equation. of bilateral uterine artery ligation in the rat to mimic the human
In contrast, histone code inherently allows for that complexity condition. This model results in rat pups that are 25% smaller
and variability, but as a community, we struggle to interpret its than the norm and that develop postnatal obesity.
meaning. Histone proteins make up the nucleosome core that We use this model to study the effect of suboptimal perinatal
DNA wraps around. Histone proteins have N-terminal tails that nutrition on the epigenetic programming of genes implicated in the
extend from the nucleosome core and are subject to covalent development of obesity, such as insulin growth factor 1 (IGF-1).19
modifications. These covalent modifications make up the histone Serum levels of IGF-1 play a role in regulating multiple processes,
code. The histone code performs three basic functions. Some such as adipocyte homeostasis, as well as insulin resistance.
histone codes regulate the charge of histone lysine residues and Hepatic production of IGF-1 determines serum levels of this
thereby moderate charge dependent interactions between nucleo- protein. Our interest in this gene was further piqued by the
somes and DNA. A covalent modification that often leads to this observation that the IGF-1 gene generates multiple transcribed
function is histone acetylation. Other histone codes regulate the products based on differential exon usage. This variation requires
physical accessibility of chromatin regulating and transcription epigenetic manipulation and, as such, suggests vulnerability to
complexes to DNA. A covalent modification that often leads to environmental epigenetic manipulation. Moreover, variation like
this function is histone methylation. Finally, histone codes also can this stands as a key characteristic of mammalian gene expression
regulate charge and affinity simultaneously. A covalent modifica- that allows us to carry fewer genes than simpler organisms, such
tion that often leads to this function is histone phosphorylation. as the worm.
The histone code within a single cell contains over 4×10 the The hepatic IGF-1 gene generates multiple transcribed products.
30th possible permutations. Furthermore, 51 distinct chromatin IGF-1 promoter 1 (IGF-1 P1) may initiate transcription from
states exist based on varying combinations of histone covalent multiple start sites. IGF-1 P1 appears to predominate early in
modifications. These states affect transcription and expression life and in the basal levels of IGF-1 production. IGF-1 promoter 2
based on the specific complex(es) interacting with the chromatin. (IGF-I P2) also contains multiple start sites as well as growth

4
hormone response elements. IGF-1 P2 becomes more active other models and determining if specific epigenetic events appear
after birth and responds to diet as well as growth hormone more vulnerable to suboptimal perinatal nutrition. In collaboration
stimulation. The hepatic IGF-1 transcript may not include the with colleagues at the University of Iowa, we found that maternal
presence of exon 5, which may affect endoplasmic reticulum diabetes in the rat decreased hepatic IGF-1 transcript levels at
processing. Transcripts that do not include exon 5 are designated day of life 21.21 This decrease in hepatic IGF-1 transcript levels
IGF-1 A transcripts. Transcripts that include exon 5 are desig- corresponded well with decreased lysine 36 trimethylation on
nated IGF-1 B transcripts. The length of the IGF-1 poly A tail histone 3 similar to the uteroplacental insufficiency-induced IUGR
also varies significantly from tissue to tissue. In general, tissues, rat findings. The pathways regulating lysine 36 trimethylation on
such as the liver, that produce relatively large amounts of hepatic histone 3 represent the target of our present research program.
IGF-1 transcript use short poly A tails. Tissues, such as the lung, Another target of our research program involves demonstrating
that tightly control paracrine levels of IGF-1 often use long that perinatal nutritional supplementation moderates the effects
poly A tails. of suboptimal perinatal nutrition. A wonderful example of this
In humans, uteroplacental insufficiency decreases fetal and includes the project of Dr. Aagaard-Tillery during her reproductive
early postnatal serum IGF-1 levels. As adults, IUGR humans scientist development program fellowship. Dr. Aagaard–Tillery
also appear to suffer from dysregulation of IGF-1 homeostasis.20 presently serves as an associate professor at the Baylor College
The exact characteristic of this dysregulation appears to vary of Medicine. This project encompassed two hypotheses. The
with the extent of postnatal catch-up growth. Uteroplacental first hypothesis postulates that second-generation rats whose
insufficiency-induced IUGR in the rat similarly decreases serum parents suffered from uteroplacental insufficiency-induced IUGR
IGF-1 levels in the fetus and through weaning. Moreover, decreased develop obesity and other characteristics of the metabolic syn-
levels of hepatic IGF-1 transcripts characterize the IUGR liver.19 drome in adulthood. The second hypothesis postulates that
The timing of the impact of IUGR on specific hepatic IGF transcripts feeding a diet enriched to facilitate methyl donation dampens the
varies. For example, IUGR decreases IGF-1 P1 and IGF-1 A impact of IUGR on the second generation, essentially normal-
transcript levels only at day of life 0. In contrast, IUGR decreases izing the phenotype. To test these hypotheses, the proposal uses
IGF-1 P2 and IGF-1 B transcript levels at both day of life 0 and every possible combination of control versus IUGR cross con-
day of life 21 (weaning). The impact of IUGR upon hepatic IGF-1 currently while comparing control versus enriched diets.
transcripts corresponds with changes in the epigenetic character- Uteroplacental insufficiency-induced IUGR, indeed, leads to
istics of the rat hepatic IGF-1 gene. For example, IUGR enriches obesity and other markers of the metabolic syndrome in second-
hepatic DNA CpG methylation at IGF-1 P2 at day of life 21. The generation rats, lending new meaning to the phrase “fat rat.”
impact of IUGR on IGF-1 P2 DNA CpG methylation appears Moreover, decreased hepatic IGF-1 transcript levels characterize
more robust in males. Gender-specific epigenetic responses the second-generation fat rats. Our findings became most robust
are common. in males with two IUGR parents. In contrast, the enriched diet
Uteroplacental insufficiency-induced IUGR in the rat also significantly minimizes the transmission of the fat rat phenotype
affects the hepatic IGF-1 histone code. Our initial findings con- and increases hepatic IGF-1 transcript levels in the second gen-
fused us. We studied the hepatic IGF 1 promoters and found eration. The increase in IGF-1 cash of levels corresponded to a
enrichment of histone code that usually corresponds with in- decrease in IGF-1 P2 DNA CpG methylation enrichment. We are
creased transcription. Examples of this include increased lysine often asked if the enriched diet should be used clinically, particu-
14 acetylation on histone 3 as well as increased lysine 4 trimethy- larly because of the slimming effects. We strongly advise against
lation on histone 3. Subsequent introspection led us to study it for two reasons. First, such an epigenetically “active” diet
multiple histone codes across the whole length of the gene. We may lead to unforeseen complications in the future. Second, the
found that IUGR significantly decreased lysine 36 trimethylation enriched diet caused the rats to smell so badly that our institution
on histone 3 across the whole gene, and the impact was quite required us to essentially quarantine the animals.
robust toward the 3’ region of the gene. In vitro studies postulate Taken as a whole, studies from us and multiple groups prove
that lysine 36 trimethylation on histone 3 facilitates RNA poly- that environmental epigenetics demonstrate the following:
merase II elongation of the transcript. The studies taught us that 1) allow for tissue and gender specificity; 2) account for the
to understand epigenetic regulation of a gene by focusing on the robustness of biological systems; 3) account for non-protein
promoter and/or 5’ region of the gene leads to a very restricted encoding DNA; 4) allow for the variability and complexity of
understanding. the human condition; and 5) explain the observations associated
A frustrating challenge in the epigenetic field includes our with the Life Course Model.
present inability to make tissue and gene specific changes in Epigenetics stands as the mechanism that regulates interactions
individual epigenetic characteristics, such as histone code. This between our genome and the environment. Perinatal nutrition
limits our ability to test Koch’s postulates. Our approach to exists as one of the most impactful common components of our
temporally moderate this challenge involves collaborating through environment and influencer of population health. Perinatal nutri-

5
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environment. If we are going to improve a population’s health generational Effect of Neighborhood Poverty on Low Birth
and sensibly reduce the cost of health care, we must learn to Weight Among African-Americans in Cook County, Illinois.
prevent disease rather than treat disease. In the big picture, to Am J Epidemiol. 2009;169(6):712-717.
paraphrase Winston Churchill, healthy citizens are the greatest
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phrase my children, you cannot choose your parents, but you After Prenatal Famine: Further Evidence. Arch Gen Psy. 1996;
can choose your environmental epigenetics. 53(1):25-31.

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8. Smith GD. Epidemiology, Epigenetics and the ‘Gloomy 20. Ashton IK, Zapf J, Einschenk I, MacKenzie IZ. Insulin-
Prospect’: Embracing Randomness in Population Health Like Growth Factors (IGF) -1 and -2 in Human Foetal Plasma
Research and Practice. Int J Epidemiol. 2011;40(3):537-562. and Relationship to Gestational Age and Foetal Size During
Midpregnancy. Acta Endocrinol (Copenh). 1985;110(4):558-563.
9. Lu MC, Halfon N. Racial and Ethnic Disparities in Birth
Outcomes: A Life-Course Perspective. Matern Child Health J. 21. Zinkhan EK, Fu Q, Wang Y, et al. Maternal Hyperglycemia
2003;7(1):13-30. Disrupts Histone 3 Lysine 36 Trimethylation of the IGF-1 Gene.
J Nutr Metab. 2012;2012:930364.
10. Stein JA, Lu MC, Gelberg L. Severity of Homelessness and
Adverse Birth Outcomes. Health Psychol. 2000;19(6):524-534.

6
Notes

7
Notes

8
Programming Food and Flavor Preferences:
Impact of Early Experience
Sandra Lyn, PhD
Nestlé Purina Research
St. Louis, MO
Email: [email protected]

Abstract at birth,2-5 after weaning,2,6-11 young

There has been an increased interest Glossary of Abbreviations adulthood,2,12 and adulthood.13
in how early experiences in utero ePHF: Extensive Protein Hydrolsate Formulas Early flavor learning in the context
and/or postnatally shape the brain, of this review refers to prenatal
physiology and behavior of individuals. Infants are not born a learning, or learning in utero, and postnatal learning, or learning
blank slate but, rather, enter the world with information gathered that occurs during the nursing period. Learning that encompasses
in utero that helps to prepare them for challenges in their immedi- both periods is referred to as perinatal flavor learning. Early flavor
ate environment. One such area is the role of the maternal diet in learning is one mechanism for preparing the offspring for foods
shaping the flavor and food preferences of the offspring. This it will encounter in its ecological niche. Learning before and after
review aims to share what is known about perinatal flavor learning birth may serve different adaptive functions for young animals
in cats and dogs and whether this influences later flavor preferences. as will be discussed later.
Although it has been known for some time that early flavor
Introduction learning could alter food and flavor preferences, it was only
Pets’ food preferences and subsequent food intake are largely recently that studies were carried out with cats and dogs to
drive by the sensory properties of the food. Flavor and food understand if early flavor exposure did, indeed, condition flavor
preferences can impact the health of individuals by determining preferences in the newborn and at other ages.
whether they choose to eat healthful or unhealthful foods. It also
can result in overselection of one or more types of food that Early Flavor Learning in Dogs
could result in malnutrition. And lastly, individual flavor and Prenatal flavor learning has been demonstrated in dogs.5,11
food preferences can be so narrowly tuned that it becomes Wells and Hepper5 conducted a study in which bitches were fed
extremely difficult to foster liking or mere acceptance of new twice daily 5 ml aniseed oil in their diets 19-23 days prior to
potentially healthful foods. It is well-known that domesticated whelping. When tested 24 hours after birth, more puppies with
cats and dogs can be quite selective in what they eat, and this prenatal exposure to aniseed significantly preferred (oriented
can make it very difficult to transition them to new foods, such toward that odor) aniseed odor over distilled water than puppies
as therapeutic diets. As such, it is important to understand the whose mothers did not receive aniseed during pregnancy. Puppies
origins of flavor preferences and how to positively influence that had no prenatal flavor exposure did not show a preference
such preferences, especially at an early age to help create habits for either distilled water or aniseed.
of healthful food choices as well as increase the likelihood for To rule out the possibility that the prenatal flavor learning was
acceptance of novel foods. This review will look at only one of a generalized enhanced preference for odors, the researchers then
the mechanisms by which flavor preferences develop, but it is tested a different group of puppies for their preference for an
not assumed that this is the only means by which flavor prefer- unfamiliar odor, vanilla (matching intensity to aniseed) versus
ences develop in cats, dogs and other animals. distilled water. This time there was no difference between the
Flavors from the maternal diet are transmitted to the fetus via puppies from the two groups for their preference for vanilla
the amniotic fluid and to the infant via breast milk. For example, versus distilled water. Since the puppies were tested at 24 hours
Nolte et al.1 showed that human judges could detect garlic odor after birth, it was possible for postnatal flavor learning to occur
in amniotic fluid, allantoic fluid, fetal blood, and maternal blood since the puppies would have had the opportunity to nurse during
collected 100 minutes after a pregnant ewe had ingested 6 ml of that period. To rule out postnatal flavor learning, a further test
garlic oil. Similarly, odors added to queens’ diets were detectable in was done with puppies before the opportunity to nurse for the
their breast milk (by chemical analyses) two hours after ingestion.2 first time. Puppies were tested 15 minutes after birth, and, again,
Young animals from a number of species, including humans, are it was shown that only the puppies in the prenatal aniseed exposure
capable of early flavor learning that influences flavor preferences group showed a preference for the aniseed odor over distilled

9
water. Interestingly, when tested at 15 minutes old, the control versus the same unscented control. Kittens’ preference for an
group that did not have prenatal exposure to aniseed preferentially unfamiliar odor was assessed as was also done in the dog study to
oriented toward water than the aniseed odor, suggesting avoidance ensure that learning was specific to the exposed odor. Newborn
for an unfamiliar odor. These findings show that puppies’ flavor kittens were assessed for their preference for both the familiar odor
preferences shortly after birth were influenced by what was ingested and the unfamiliar odor versus water. Weaned kittens were similarly
by the mother during late gestation. Moreover, the puppies were tested except this time the odor was presented on 2.5g portions of
able to generalize the odor from the fetal environment to a novel minced chicken (treat). Finally, kittens were tested at 6 months
environment (cotton swab), indicating some olfactory continuity. of age with their normal food. Table 2 shows the main findings.
Prenatal learning may be one mechanism by which the neonate11 Newborn kittens, like puppies, exhibited prenatal flavor learn-
is able to quickly identify what is food and to facilitate nursing. ing. However, unlike puppies, kittens with only prenatal flavor
Prenatal flavor learning alone, however, does not appear to be exposure persisted in showing a preference for the familiar odor
enough to see the persistence of learning over time in puppies. at 8-10 weeks as well as at 6 months of age. The cat is not unique
When puppies were tested at 10 weeks old, their preference for in demonstrating a long-term persistence in prenatal flavor learning.
aniseed odor on top of cooked minced chicken versus unscented For example, prenatal-only exposure (50-130th day of pregnancy)
cooked minced chicken was no different from control puppies to oregano oil led to a preference for oregano-supplemented feed
that did not have prenatal exposure to aniseed.11 in lambs tested at 3, 4.5, 6, and 7.5 months of age.15
Hepper and Wells also assessed postnatal and perinatal flavor Interestingly, the tests of newborn kittens with an unfamiliar
learning in 10-week-old puppies.11 To assess postnatal flavor odor versus water showed active avoidance of unfamiliar odors
learning, one group of puppies was exposed to aniseed odor only similar to what was seen with puppies when they were tested at
via their mothers’ milk, while the other group of puppies did not 15 minutes old.5 Thus, prenatal flavor learning appears to condition
receive aniseed odor. The exposure period was 20 days after preference away from avoidance and not merely a neutral response.2
birth. To assess perinatal flavor learning, one group of puppies Similar to puppies, kittens did not exhibit postnatal flavor
received both prenatal (20-25 days, on average) and postnatal learning after weaning. However, they did show a preference for
flavor exposure (20 days after whelping and only via nursing) the postnatal flavor at 6 months of age. The authors explained
to aniseed odor, while the control group received no aniseed that this finding is not unlike that seen with other species in
odor exposure prior to testing. Perinatal learning, but not post- which postnatal flavor exposure via breast or bottle milk often
natal flavor learning, was shown to produce a significant prefer- leads to long-term flavor preferences, and it may be necessary
ence for the aniseed-scented treat over the unscented control. for some time to elapse for generalization of the flavor to other
contexts.2 Weaning stress may also have contributed to a failure
Early Flavor Learning in Cats to observe a conditioned flavor preference at 8-10 weeks old.2
A long-term study was conducted in cats to study the effect Indeed, Oostindjer et al.16,17 showed that perinatal flavor learning
of prenatal, postnatal and perinatal flavor learning on flavor did not result in preference for the pre-exposed flavor in piglets
preferences in newborn, weaned and young adult cats.2 The at the time of weaning, but it did positively influence their growth,
basic design of the study is shown in Table 1. Three groups of food intake, lower occurrence of diarrhea, and their ability to
kittens were exposed to an odor (familiar odor) in one of three cope with the stress of weaning.
conditions: before birth, after birth or at both periods. A fourth Finally, the largest effect on flavor preferences was due to the
group of kittens served as the control and was not exposed to combined effects of pre- and postnatal learning.
the odors before or after birth. Perinatal learning has also been demonstrated in kittens that
Kittens were tested at three different time periods. At each had a cheese flavor 25 days prior to birth (in utero) and 2-25 days
period, they were tested for their preference for the familiar odor after birth (queen’s milk).14 Specifically, kittens with perinatal
versus an unscented control as well as with an unfamiliar odor exposure to the cheese flavor significantly preferred the cheese
flavor over water at 2 days old and a cheese-flavored food over
Table 1. Queens, depending on the group, were fed diets the unflavored control food at 45 days old. The control group of
containing vanillin, 4-ethylguaicaol or no odor 24-27 days kittens with no exposure to cheese flavor before and after birth did
prior to parturition and/or 26 days after parturition. not exhibit a specific preference at either 2 days or 45 days old.

Prenatal Exposure Postnatal Exposure

Sensitive Periods for Flavor Liking and Acceptance
Kitten Group (24-27 days) (26 days )
At least one sensitive period for flavor liking and acceptance
Prenatal Exposure ✓
has been identified in humans. Extensive protein hydrolysate
Postnatal Exposure ✓
formulas (ePHF) are an option for infants with certain types of
Perinatal Exposure ✓ ✓
food allergy. These ePHF formulas are deemed unpalatable both by
Control
their smell and taste by human adults. Mennella and colleagues19

10
 Table 2.
Newborn (48 hrs) Weaned (8-10 wks) 6 Months
N=27 N=98 N=63
Exposure Familiar* Odor Unfamiliar Odor Familiar* Unfamiliar Familiar* Unfamiliar
vs. Water vs. Water Odor vs. Odor vs. Odor vs. Odor vs.
No Odor Treat No Odor Treat No Odor Food No Odor Food
Prenatal Familiar odor Water Familiar odor No preference Familiar odor No preference
Postnatal No preference Familiar odor
Perinatal Familiar odor Familiar odor
Control Water Water No preference No preference

* The control kittens were never exposed to the odors until they were tested, thus all odors were unfamiliar to them.

have shown that if babies are not exposed to ePHF before 3.5 be argued that the prenatal period may also be a sensitive period
months old, it is much more difficult to promote acceptance. for cats to learn to accept novel odors as Hepper et al.2 showed
However, if infants are exposed to ePHF for at least one month in their work that newborn kittens avoided unfamiliar odors.
before they are 3.5 months old, they not only accept and consume Further evidence of a sensitive period for flavor preferences
more of these formulas than infants fed after 3.5 months old but in cats comes from a pilot study22 with kittens that either had
also their facial response while consuming ePHF does not indicate perinatal flavor exposure to only a single food, tuna or beef wet
signs of rejection.18,19 Moreover, infants who had experience cat food, or to a variety of foods, and then later trained on an
with ePHF were more likely to like novel foods that shared a operant task with both foods serving as the reinforcer. The results
flavor profile to ePHF compared to infants fed a milk-based showed tuna was more rewarding than beef flavor regardless of
formula.20 the flavor of single flavor of food received perinatally but only
In the studies on perinatal flavor learning in both dogs and cats, for kittens exposed to only one food perinatally. Those kittens
the stimuli used for pre- and/or postnatal exposure were always often refused to eat the beef-flavored food. Kittens that were
hedonically neutral as determined by adult cats5,11 and dogs.2,14 offered a variety of foods perinatally showed no preference for
No formal study to assess for a sensitive period for flavor accept- one flavor over the other and accepted both products equally
ance of an unpalatable food has been conducted with cats and well. Thus, it is possible that depending on the early experience
dogs. However, Rogers21 made the following observations from with one or more flavors, it may be more difficult to facilitate
nutrition research in his laboratory where it was necessary to adapt acceptance for less palatable flavors. Early variety feeding may
cats to eat unpalatable semi-purified diets. According to Rogers: result in less finicky behavior.23

We were able to observe kittens that received our semi- Conclusion

purified diets before weaning and assimilated them well. Both cats and dogs demonstrate early flavor learning.2,5,11,14
In this way, we were able to exert a lasting influence on They join a long list of other animals that are capable of such
the feeding behavior of the adult animals. If one wants to learning, which indicates an important role for this type of
adapt an animal that had never had to take such an unac- learning in development. The observation of avoidance of a
ceptable diet, then it will take approximately one to two novel odor in newborns suggests that prenatal odor learning
months before a sufficient quantity is taken. Kittens that serves to teach the newborn what is safe to eat, and it also indi-
during and after the lactation period took a semi-synthetic cates that early flavor learning may not only influence flavor
diet showed no acceptance problems in later life, even though preferences and food intake, but also the ability of the young
they have received a commercial diet for a fairly long period animal to cope with new and potentially stressful events.1,16,17
in between. Therefore, I believe that this phase of accept- The research to date indicates both pre- and postnatal learning is
ance for particular foods plays a very important role. One possible, but to influence long-term flavor and food preferences
practical application of this observation: If one wishes to both types of learning are necessary. Furthermore, early flavor
feed an animal a ration that is not easily acceptable, then learning teaches the animal not only about what is safe to eat
it should be given directly after weaning.21 but also can result in affective learning in which the animal
learns not merely to prefer but also to like the flavors to which
Rogers’ observations suggest that there is likely a sensitive it was exposed perinatally. It may be easier to engender accept-
period when cats can learn to like and accept even unpalatable ance for less palatable, but nutritious, foods by exposing cats and
nutritious foods and that this learning persists well into adulthood dogs to such foods while they are young.
and even after sustained periods of no dietary exposure. It could

11
References 13. Haller R, Rummel C, Henneberg S, et al. The Influence of
1. Nolte DL, Provenza FD, Callan R, Panter KE. Garlic in the Early Experience with Vanillin on Food Preference Later in Life.
Ovine Fetal Environment. Physiol Behav. 1992; 52:1091-1093. Chem Senses. 1999;24:465-467.

2. Hepper PG, Wells DL, Millsopp S, et al. Prenatal and Early 14. Becques A, Larose C, Gouat P, Serra J. Effects of Pre- and
Sucking Influences on Dietary Preference in Newborn, Weaning Postnatal Olfactogustatory Experience on Early Preferences at
and Young Adult Cats. Chem Senses. 2012; 37:755-766. Birth and Dietary Selection at Weaning in Kittens. Chem Senses.
2010;35:41-45.
3. Mennella JA, Jagnow CP, Beauchamp GK. Prenatal and
Postnatal Flavor Learning by Human Infants. Pediatrics. 2001; 15. Simitzis PE, Deligeorgis SG, Bizelis JA, Fegeros K. Feeding
107:E88. Preferences in Lambs Influenced by Prenatal Flavor Exposure.
Physiol Behav. 2008;93:529-536.
4. Schaal B, Marlier L, Soussignan R. Human Fetuses Learn
Odors from their Pregnant Mother’s Diet. Chem Senses. 2000; 16. Oostindjer M, Bolhuis K JE, van den Brand H, et al. Prenatal
25:729-737. Flavor Exposure Affects Growth, Health and Behavior of
Newly Weaned Piglets. Physiol Behav. 2010;99;579-586.
5. Wells DL, Hepper PG. Prenatal Olfactory Learning in the
Domestic Dog. Anim Behav. 2006;72:681-686. 17. Oostindjer M, Bolhuis JE, Simon K, et al. Perinatal Flavor
Learning and Adaptation to Being Weaned: All the Pig Needs
6. Hudson R, Distel H. The Flavor of Life: Perinatal Development Is Smell. PLoS ONE. 2011;pe25318.
of Odor and Taste Preferences. Schweiz Med Wochenschr. 1999;
129:176-181. 18. Beauchamp GK, Mennella JA. Early Flavor Learning and
Its Impact on Later Feeding Behavior. J Pediatr Gastroenterol
7. Altbacker V, Hudson R, Bilko A. Rabbit Mothers’ Diet Influ- Nutr. 2009;48:S25-S30.
ences Pups’ Later Food Choice. Ethology. 1995; 99:107-116.
19. Mennella JA, Lukasewycz LD, Castor SM, Beauchamp GK.
8. Galef Jr BG, Henderson PW. Mother’s Milk: A Determinant of The Timing and Duration of a Sensitive Period in Human Flavor
the Feeding Preferences of Weaning Rat Pups. J Comp Physiol Learning: A Randomized Trial. Am J Clin Nutr. 2011;93:1019-1024.
Psychol. 1972;78:213-219.
20. Mennella JA, Kennedy J, Beauchamp GK. Vegetable Accept-
9. Nolte DL, Provenza FD. Food Preferences in Lambs after ance by Infants: Effects of Formula Flavors. Early Hum Dev.
Exposure to Flavors in Milk. Appl An Behav Sci. 1992;32:381-389. 2006;82:263-268.

10. Wuensch KL. Exposure to Onion Taste in Mother’s Milk 21. Mugford RA, Thorne C. Comparative Studies of Meal Patterns
Leads to Enhanced Preference for Onion Diet Among Weanling in Pet and Laboratory Housed Dogs and Cats. In Nutrition of the
Rats. J Gen Psychol. 1978;99:163-167. Dog and Cat. Anderson RS (ed). Pergamon Press, Oxford, UK.
1980:25-50.
11. Hepper PG, Wells DL. Perinatal Olfactory Learning in the
Domestic Dog. Chem Senses. 2006;31:207-212. 22. Stasiak M. The Effect of Early Specific Feeding on Food
Conditioning in Cats. Dev Psychobiol. 2001;39:207-215.
12. Simitzis PE, Bizelis JA, Deligeorgis SG, Fegeros K. Effect
of Early Dietary Experiences on the Development of Feeding 23. Villalba JJ, Catanese F, Provenza FD, Distel RA. Relation-
Preferences in Semi-Intensive Sheep Farming Systems – A Brief ships Between Early Experience to Dietary Diversity, Acceptance
Note. Appl An Behav Sci. 2008:111:391-395. of Novel Flavors, and Open Field Behavior in Sheep. Physiol
Behav. 2012;105:181-187.

12
Notes

13
Notes

14
The Long-Term Health Effects of Spay and Castration for Dogs
Kate E. Creevy, DVM, MS, DACVIM-SAIM
University of Georgia
College of Veterinary Medicine
Department of Small Animal Medicine and Surgery
Athens, GA
Email: [email protected]

Abstract refers to bilateral orchiectomy

Surgical sterilization of pet dogs
Glossary of Abbreviations of males. The term “neuter” is
BPH: Benign Prostatic Hypertrophy
and cats is a routine practice in typically primarily associated
CCLR: Cranial Cruciate Ligament Rupture
the United States. An increasing with males but can also include
OHE: Ovariohysterectomy
research focus on the long-term OVE: Ovariectomy surgical interventions performed
effects of this management choice TNR: Trap-Neuter-Release on females. The term “gonadec-
is emerging. Beneficial effects USMI: Urethral Sphincter Mechanism Incompetence tomy” can be applied to either sex.
on behavior, increases in life- The perioperative and short-term
span, and reduction of unwanted litters are major arguments in risks associated with OHE and castration have been described
support of elective sterilization. Increased risks of obesity, urinary and will not be addressed here.12 When surgical complications
incontinence, neoplasia, and certain musculoskeletal diseases such as retention of an ovarian remnant or cryptorchid testicle
among sterilized dogs and cats raise concerns about this wide- arise, the long-term consequences can include development of
spread practice. Current knowledge on the physiological and neoplasia in the retained gonad.13,14 Neoplasia related to properly
health effects of elective surgical sterilization in dogs and cats performed surgical sterilization is discussed in greater detail below.
is summarized here. Obvious direct medical benefits of surgical sterilization of
female dogs and cats include avoidance of pyometra, metritis,
Introduction unwanted pregnancy, and complications of pregnancy. Obvious
Models for life history evolution assume that investment in direct medical benefits of gonadectomy of males include avoidance
1,2
reproduction comes at the cost of survival. In support of this of unwanted siring of litters, and, in dogs, avoidance of benign
assumption, numerous studies in both invertebrates and vertebrates prostatic hypertrophy (BPH), which is a direct consequence of
have shown that reduced reproductive effort leads to longer chronic testosterone exposure. BPH is not reported in cats.15
3,4
lifespan. Investigations that manipulate levels of reproduction For female dogs and cats, ongoing debate exists over the
in experimental animals typically evaluate survival, with fewer relative merits of OHE compared with ovariectomy (OVE), with
studies addressing other aspects of physiology or health; indeed, some authors arguing that OVE is less-invasive and potentially
16,17
studies in nematodes, fruit flies and mice are poorly suited to less painful. Regardless, OHE remains the technique prefer-
evaluate pathology at the individual level.5-8 Thus, the specific entially taught in U.S. veterinary schools,16 with limited recent
causes of mortality associated with reproductive capability or advent of OVE as an option, and there are few studies that directly
sterilization status have not been elucidated in these species. compare the two techniques. As most literature on long-term
Companion dogs and cats in the United States are often outcomes is retrospective, the majority of female animals studied
electively surgically sterilized by their owners,9-11 and, thus, they have been sterilized by OHE. For purposes of this review, surgical
represent large and accessible populations in which to assess sterilization, gonadectomy or the term “spay” in females will be
diverse effects of reproductive effort. Additionally, these pets may interpreted to mean OHE, unless specifically stated otherwise.
be affected not only by their variable efforts toward reproduction
but also by the very presence or absence of the reproductive tract Optimal Timing
and its hormones. A substantial impact on overall health could Ongoing debate also exists over the optimal timing to perform
be anticipated by the removal of this endocrine axis; curiously, surgical sterilization procedures. Development of mammary
there has been little scientific interest in this feature of the com- cancer (see later) has been convincingly linked to onset, and total
panion animal population until recently. number, of estrous cycles in females, and, thus, a reasonable
recommendation can be made to perform OHE prior to the first
Definitions heat, which occurs around 6 to 12 months of age for many dog
In the United States, the term “spay” nearly exclusively signifies breeds. Veterinarians have typically preferred to recommend
ovariohysterectomy (OHE) of females, and the term “castration” surgical sterilization approximating the anticipated age of sexual
15
maturity and have traditionally resisted suggestions to perform significance was lost, and no animals were reported to have been
prepubertal surgical sterilization despite lack of evidence to resurrendered to shelters because of these behavioral problems.
justify this concern.9,18,19 Four large studies — two in dogs Overall, 26% of studied dogs were overweight, but dogs sterilized
and two in cats — have compared outcomes of prepubertal younger had lower likelihood of overweight body condition than
sterilization with traditional-age sterilization in animals adopted dogs neutered later in life. No association was found between
from humane organizations and surgically sterilized by clinics age at the time of gonadectomy and 43 other specific medical
associated with the humane organizations.20-23 It is important to and behavioral conditions studied.
note that none of these studies included a comparison group of Cumulatively, these studies suggest limited impact on the
animals left intact, so the only comparisons that can be made timing of surgical sterilization related to the general health of
are related to the timing of sterilization and not sterilization as dogs and cats, with noteworthy exceptions in the categories of
a risk factor itself. musculoskeletal and urinary tract problems. These specific
In the first feline study,20 owners of 38% of nearly 700 surgi- conditions are discussed in more detail below.
cally sterilized cats adopted over two and half years responded
to surveys a median of three years postoperatively. No differences Lifespan and Causes of Death
in the number of health problems, types of health problems, number The author’s recent study of canine mortality in veterinary
of behavior problems, or likelihood of surrender were found teaching hospitals24 revealed that sterilized dogs have a 19%
between cats spayed or castrated at a median of 9 weeks or 51 increase in mean lifespan relative to intact dogs. This finding is
weeks of age. In the second feline study,22 owners of 84% of over consistent with most,25-27 but not all,28 prior literature. The latter
1,800 adopted cats that had been surgically sterilized at 12 months study identified a beneficial effect of duration of intact status on
of age or less responded to surveys a median of 3.9 years post- the lifespans of a cohort of female Rottweilers. Several interesting
operatively. There were significant associations between age at explanations for this discrepant finding exist. In contrast to many
neutering and development of human-directed aggression, urine prior studies, this cohort of female Rottweilers was able to be
spraying, abscesses, gingivitis, and asthma, meaning that cats classified by precise age at the time of sterilization. It has been
neutered at younger ages had lower risks of these conditions argued that the more common methodology of classifying dogs
than cats neutered later. Specifically, no association was found as “sterilized” or “intact” at the time of death without knowledge
between age at neutering and development of obesity or feline of when this sterilization event occurred misrepresents the ben-
lower urinary tract disease. eficial effects of maintaining exposure to sex hormones for some
In the first canine study,21 owners of 42% of over 600 surgi- duration of time prior to sterilization.29
cally sterilized dogs adopted over two and a half years were As sterilization removes an entire organ system and its endo-
available for surveys a median of four years postoperatively. Con- crine axis, clearly some information about lifetime physiologic
sidering the number of health problems, types of health problems, experiences of an individual is lost when the timing of the ster-
number of behavior problems, and likelihood of surrender between ilization experience is not known. As cited above, veterinarians
dogs spayed or castrated at a median of 10 weeks or 52 weeks of report that they preferentially sterilize dogs and cats approximately
age, the only identified difference was a higher risk of parvoviral at the age of sexual maturity, so when data on the timing of
gastroenteritis among the prepubertal gonadectomy cohort. This sterilization are absent, the assumption is that the majority of
increased risk of parvovirosis in the prepubertal gonadectomy patients were sterilized at this reportedly preferred time. However,
cohort may be confounded by the fact that parvovirosis is over- this is a testable hypothesis that has not yet been interrogated.
all more prevalent in puppies than adult dogs. As the surgical Ongoing work by the author's collaborators, and other research
sterilization event was typically the earliest age of contact with groups, will document actual timing of surgical sterilization in
each studied dog, it is likely that medical records including the large canine populations that are under prospective study for
months of life where parvovirosis is most prevalent were not global features of health and lifespan.
available for the dogs sterilized after those months of age. Alternate explanations for the finding that this cohort of female
In the second canine study,23 owners of 88% of over 2,000 Rottweilers derived longevity benefits from remaining intact for
adopted dogs that had been surgically sterilized at 12 months of a period of time may result from some features of the Rottweiler
age or less responded to surveys a median of four and a half years breed or some features of the females in the particular lineages
postoperatively. There were significant inverse associations between studied that were known to exhibit atypically long lifespans
age at sterilization and development of human-directed aggression, compared with the breed at large. Since cancer was a significant
barking and growling, sexual behaviors, hip dysplasia, cystitis cause of death overall among these large-breed dogs and sterili-
(in females), and urinary incontinence (in females), meaning zation has repeatedly been shown to exacerbate this risk (see
that dogs neutered at younger ages had higher risks of these below), it also is possible that remaining intact helped these
conditions than dogs neutered later. Behavioral effects (barking, female Rottweilers avoid a cause of death that is particularly
growling and sexual behaviors) were categorized by owners as impactful for the breed.
mild or serious in questionnaires. If “mild” cases were excluded, Beyond lifespan itself, the domestic dog exhibits dramatic

16
breed-based variation in terms of likely causes of death.30 Life- Weight Gain
span is a composite variable of myriad causes of death and the Investigation into obesity in cats consistently identifies an
consequences of sterilization may or may not influence all causes association between sterilization and decreased metabolic rate
of death equally. The author’s recent study of canine mortality resulting in increased body fat for both males and females.43-47
in veterinary teaching hospitals revealed a striking effect of Most, but not all, studies in dogs also identify a risk for obesity
sterilization on cause of death. Sterilized dogs were dramatically among sterilized individuals.33,39,48-51 Interestingly, Lefebvre and
less likely to die of infectious disease, trauma, vascular disease, others found that the timing of surgical sterilization (≤6 months
and degenerative disease. In contrast, sterilized dogs died more of age, >6 months to ≤1 year of age, or >1 year to ≤5 years of
commonly from neoplasia and immune-mediated disease. Effects age) did not impact the likelihood of a diagnosis of overweight
of sterilization were seen both on common causes of death and or obese body condition. Furthermore, the overall risk of over-
more rare causes (e.g., vascular disease). These visible differences weight or obese body condition in sterilized dogs compared with
in causes of death for sterilized and intact dogs persisted, even intact dogs was greatest in the two years following surgical
among cohorts of dogs that died within limited age ranges.24 sterilization, suggesting that targeted client education during
that time may provide significant benefit.51
Impacts on Specific Areas of Development
Behavioral Effects Activity Level and Training
An excellent review article by Root Kustritz15 provides a The racing performances of spayed and intact female Greyhounds
summary of the current literature regarding long-term effects of (excluding the period of 90 days after estrous in intact females,
spay and castration on dogs and cats, including behavioral effects. during which time racing performance has been shown to decline)
Avoidance of undesirable behaviors associated with, or believed were compared. No significant difference was found between
to be associated with, reproductive maturity is one of the more racing performance in the two groups.52 Meanwhile, only limited
common reasons that owners request surgical sterilization of their and breed-specific differences between intact and sterilized dogs
pets. However, not all undesirable behaviors are associated with were found in a separate study of owner-reported trainability.53
sexual behaviors, and not all are modified by surgical sterilization.
Given the opportunity, intact male dogs are more likely than steril- Cortisol Axis
ized dogs to roam, fight with other male dogs and urine-mark, In an interesting study of feral female cats in a trap-neuter-
though the literature is conflicted about the likelihood of aggres- release (TNR) program, the effects of surgical spay on aggressive
sive behaviors in intact versus spayed female dogs.31-34 In male behavior and hair cortisol levels were assessed. Intact female cats
cats, castration reduces urine spraying, roaming, human-directed displayed more instances of aggressive behavior surrounding
aggression, and mounting behaviors, and in female cats, sterili- delivered food sources and had higher levels of hair cortisol
zation reduces displays of competitive aggression.35-37 (suggesting higher cortisol concentrations over preceding weeks
to months) compared with spayed females.35 Ultimately, this
Growth and Musculoskeletal Development study raises more questions than it answers because the cause-
Surgical sterilization of dogs and cats prior to sexual maturity effect relationship, if any, between aggression and hair cortisol
causes delayed closure of growth plates; other than a slight increase concentrations is not known and because chronically elevated
in height, the significance on health of this delay in closure is cortisol itself is known to promote health risks such as changes
unclear.38-40 Development of hip dysplasia and anterior cruciate in body fat composition, decreased immune function and decreased
ligament injury have been compared between sterilized and intact insulin activity.54 The effect of surgical sterilization on baseline
dogs (see below), but the relationship of these conditions to bone and stimulated cortisol concentrations on both dogs and cats in
growth and physeal closure is unclear. diverse settings warrants further investigation.
Growth and development of urogenital organs also is affected
by surgical sterilization. The penises of male dogs and cats steril- Impacts on Specific Diseases
ized prepubertally are smaller than those of intact males or males Neoplasia
sterilized later in life.39,41 The clinical significance, if any, of Many studies in dogs have examined the effects of neuter
smaller penises in these patients is unclear. On the other hand, the status on the diagnosis of neoplasia. However, in many of these
clinical significance of small or recessed vulvas in female dogs studies, the relationship between sterilization and the risk of
could include increased likelihood of recurrent urinary tract infec- death due to a particular disease is confounded with age. Many
tions and perivulvar dermatitis. However, the current literature diseases, such as cancer, in particular, increase in frequency with
is inconclusive regarding whether small or recessed vulvas are age.30 If surgical sterilization increases life expectancy, then a
more prevalent in spayed than intact females or whether the higher occurrence of those late-acting diseases may be noted in
timing of spay is associated with this anatomical finding.39,42 sterilized dogs simply because they are more likely to reach the
age at which such diseases become frequent. In the author’s recent

17
retrospective study of a large cohort of dogs presented to veterinary greater than 3 months of age, but this conclusion is not uniformly
teaching hospitals, though sterilized dogs lived longer overall, accepted in the literature.23,75,76 Additional risk factors include
neoplastic diagnoses remained more prevalent in sterilized versus obesity (which may itself be related to surgical sterilization as
intact dogs at the time of death, even after controlling for the discussed above), breed and size.74,76-78 Interestingly, the syndrome
effects of age at the time of death.24 of USMI is not described in cats.
Cancers of specific organ systems and/or specific breeds have
been studied more closely in dogs, and surgically sterilized dogs Musculoskeletal Disease
have been shown to be overrepresented compared with intact A concern for the development of hip dysplasia in sterilized
dogs for anal gland carcinoma, prostate cancer, osteosarcoma, dogs has been investigated with varying results. In one study,
hemangiosarcoma, and mast cell tumors.55-60 Specifically for prepubertally sterilized male and female dogs of diverse breeds
osteosarcoma, the study of long-lived female Rottweilers identified were shown to have increased risk of development of hip dys-
an inverse relationship between months of age at the time of gonad- plasia compared with dogs sterilized later, but no control group
ectomy and risk of development of osteosarcoma, that is, the longer of intact dogs was available for comparison.22 In a study of
these dogs remained intact, the lower their risk of osteosarcoma.56 Boxers, sterilized male and female dogs had increased risk of
A large study of Golden Retrievers stratified by age at steril- hip dysplasia compared with intact dogs.79 However, in a study
ization (<12 months of age or ≥12 months of age) compared of Golden Retrievers, sterilized male dogs had a greater risk of
with intact dogs evaluated several specific cancer diagnoses. development of hip dysplasia than intact dogs with greatest risk
For lymphoma, early-neutered males had greater risk than late- in the early sterilized group, but no difference in risk was found
neutered or intact males, though sterilization did not appear to between sterilized and intact female dogs.61
affect risk among females. Conversely, late-neutered female Risk of cranial cruciate ligament rupture (CCLR) between
Golden Retrievers had the greatest risk of hemangiosarcoma sterilized and intact dogs has also been investigated. No difference
compared with early-neutered or intact females, and sterilization in risk was identified between prepubertally sterilized dogs of
did not affect the risk in males. Mast cell tumor also occurred diverse breeds and dogs sterilized later, but no control group of
more frequently in sterilized than intact females, with no differ- intact dogs was available for comparison.22 In another study of
ence between sterilized and intact males. Osteosarcoma did not dogs of diverse breeds less than 2 years of age, the risk of CCLR
occur frequently enough in the population to be analyzed.61 was greater in sterilized than intact dogs of both sexes, but dogs
In cats, fewer large surveys of neoplasia among sterilized with CCLR also had higher body condition scores than dogs
versus intact animals have been performed, and/or a predilection without CCRL.80 Another study of diverse breeds identified an
for sterilized versus intact animals cannot be determined for rare increased risk in sterilized versus intact dogs, with no information
tumors.62-66 In both species, mammary cancer remains a reliable about body condition.81 A study of Golden Retrievers revealed
exception to the pattern of increased risk of cancer among steril- the greatest risk of CCLR among males sterilized early, a lesser
ized animals, as it is more prevalent among intact female dogs risk among those sterilized late, and the least risk among those
and cats.67-69 Early work in dogs showed a protective effect of left intact. Conversely, early-sterilized female Golden Retrievers
performing OHE prior to first the estrous, and an increasing risk also had the greatest risk of CCLR, and late-sterilized females
of benign and malignant mammary cancer development associated were not at greater risk than females left intact.61 It is unclear if
with increasing number of estrous cycles experienced up to 2.5 these findings result from changes in stifle angulation due to
years of age.70 It was later shown that even among intact adult prolonged growth, breed or sex-specific features, a tendency
female dogs that had developed a benign mammary tumor, per- toward weight gain in sterilized dogs, or other factors.
forming OHE at the time of tumor resection reduced the risk of
subsequent tumor development by nearly 50% over the two and a Miscellaneous Diseases
half years following tumor resection compared with tumor-bearing No association between surgical sterilization and the diagnosis
female dogs that did not undergo OHE.71 of idiopathic epilepsy could be found in a large cross-sectional
study of Danish Labrador Retrievers.82 One interesting study of
Urethral Sphincter Mechanism Incompetence (USMI) spayed female cats assessed the immunologic impact of an estro-
Urethral sphincter tone is mediated by sympathetic nervous genic dose of the isoflavone, genistein. Although differences were
innervation, and estrogen potentiates nervous action on this found among genistein-treated, estradiol-treated and untreated
muscle group. Spayed female dogs are at higher risk for poor control cats, a clear pattern of immunosuppression by either estro-
urethral tone than intact females, and the mechanism appears to genic compound was not identified. The authors highlight the
involve not only decreased estrogen concentrations but also variable influence on immune parameters caused by treatment
changes in follicle-stimulating hormone and luteinizing hormone with estrogen and estrogen-like compounds among diverse
concentrations.23, 72-74 An effect of timing of spay has been sug- species.83 Sterilized cats of both sexes have been shown to be at
gested, with a decreased risk proposed for bitches spayed when increased risk for development of diabetes mellitus.84

18
Conclusions 9. Kustritz MV. Determining the Optimal Age for Gonadectomy
Surgical sterilization of pet dogs and cats is commonly performed of Dogs and Cats. J Am Vet Med Assoc. 2007(Dec 1);231(11):
in North America for population control and for desirable effects 1665-1675. PubMed PMID:18052800. Epub 2007/12/07. eng.
on behavior. Increasing research interest has focused on the long-
term medical effects of this common practice. It is logical to 10. APPA National Pet Owners Survey 2011-2012. American
anticipate widespread impact on physiology from the removal of Pet Products Association Inc. Greenwich, CT. 2011.
an endocrine organ system, and, indeed, there is growing evidence
that sterilized dogs and cats have different risks of certain diseases 11. Trevejo R, Yang MY, Lund EM. Epidemiology of Surgical
than intact dogs and cats. These diseases for sterilized dogs include Castration of Dogs and Cats in the United States. J Am Vet Med
cancer overall, specific types of cancer, and hip dysplasia, though Assoc. 2011(Apr);238(7):898-904. PubMed PMID:WOS:
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in these risks. For cats, sterilization increases risks of obesity and
diabetes mellitus. Comparative longevity between intact and 12. Tobias KM, Johnston SA. In: Veterinary Surgery: Small
sterilized cats has not been thoroughly investigated; however, Animal. Elsevier-Saunders, St. Louis, MO. 2012;1:2332.
current research strongly supports the finding that sterilized dogs
live longer overall than intact dogs. This finding of increased 13. Ball RL, Birchard SJ, May LR, et al. Ovarian Remnant
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and Length in the Bitch: Relationship to Spaying and Urinary Study of Epilepsy in Danish Labrador Retrievers: Prevalence
Incontinence. J Sm An Pract. 1999(Apr);40(4):180-184. and Selected Risk Factors. J Vet Intern Med. 2002(May-Jun);
PubMed PMID:WOS:000079894000008. 16(3):262-268. PubMed PMID:WOS:000175601700009.

73. Gregory SP, Parkinson TJ, Holt PE. Urethral Conformation 83. Cave NJ, Backus RC, Marks SL, et al. Modulation of Innate
and Position in Relation to Urinary-Incontinence in the Bitch. and Acquired Immunity by an Estrogenic Dose of Genistein in
Vet Rec. 1992(Aug);131(8):167-170. PubMed PMID:WOS: Gonadectomized Cats. Vet Immunol Immunopathol. 2007(May);
A1992JL03900003. 117(1-2):42-54. PubMed PMID:WOS:000246419400005.

74. Reichler IM, Hung E, Jochle W, et al. FSH and LH Plasma 84. Prahl A, Guptill L, Glickman NW, et al. Time Trends and
Levels in Bitches with Differences in Risk for Urinary Inconti- Risk Factors for Diabetes Mellitus in Cats Presented to Veterinary
nence. Theriogenology. 2005(May);63(8):2164-2180. PubMed Teaching Hospitals. J Feline Med Surg. 2007(Oct);9(5):351-8.
PMID:WOS:000228714300008. PubMed PMID:WOS:000249948500001.

22
Notes

23
Notes

24
The Challenge of Providing Feeding Recommendations for
Puppies after Neutering
Laura A. Eirmann, DVM, DACVN
Nestlé Purina PetCare
Email: [email protected]

Abstract some recommendations to consider when

Surgical sterilization has been associated
Glossary of Abbreviations asked the apparently simple question,
AAFCO: Association of American
with weight gain1 and decreased maintenance “What and how much should I feed my
Feed Control Officials
energy requirement in female dogs.2 The puppy now that she’s been spayed?”
BCS: Body Condition Score
importance of maintaining lean body con- NRC: National Research Council
dition for long-term health and longevity WSAVA: World Small Animal Ensuring Appropriate Energy Intake
is well-established.3 Adjusting feeding Veterinary Association When a commercial pet food is formu-
recommendations after this procedure is lated to provide complete and balanced
prudent. However, it is equally imperative to ensure appropriate nutrition for growth, it is assumed that a puppy consuming the
intake of nutrients during the critical growth phase. Several factors appropriate amount of that formulation to meet its energy need,
including the age of the puppy, breed or anticipated mature size, is also consuming the appropriate amount and ratio of all essential
body condition, activity level, and the specific diet formulation nutrients. It is recommended that the veterinarian begin with
must be considered when asked, “How much should I feed my a nutritional assessment of the individual puppy starting with
puppy?” The answer requires individual patient and diet assess- a complete diet history to determine factors such as the current
ment, client education and continued monitoring. caloric intake, source of calories and feeding management.
Several resources provide a more in-depth discussion on nutri-
Introduction tional assessment.9,10
The Humane Society of the United States estimates that 83% When assessing intake, it is imperative to inquire about all
of owned dogs in the United States are spayed or castrated.4 food sources including snacks, table foods, supplements, dental
Surgical sterilization of dogs may be performed for several reasons chews, edible toys, etc. During this life stage, the puppy is likely
including potential medical or behavioral benefits for the individual, receiving food rewards as part of a training program. It is important
prevention of heritable conditions in future generations, and to to determine the type and amount of treats used in training since
combat pet overpopulation.5,6 This procedure is often performed many pet owners do not consider the calories consumed outside
before dogs have reached adulthood. Knowing that ovariectomy the food bowl when thinking about how much their pet is eating.
can lead to significant weight gain in bitches1 and decrease the Although food rewards are important during training, one must
dog’s daily energy requirement,2 veterinarians often recommend ensure that these treats do not lead to excessive caloric intake or
decreasing caloric intake to prevent weight gain. This is important unbalance the overall nutrient intake. Client education regarding
since maintaining lean body condition throughout the course of appropriate “snacking” should start with the first puppy visit.
a pet’s life is associated with increased longevity and delayed The question “How much to feed?” is best answered with
onset of signs of chronic disease.3 Furthermore, excess calorie the response “Feed to a lean body condition.” A 14-year study
intake in large- or giant-breed puppies has been shown to con- in Labrador Retrievers (Purina Life Span Study) showed that dogs
tribute to the development of skeletal disease.7,8 For these breeds fed to a lean body condition (mean body condition 4.6 on a
the goal is to avoid rapid growth and to provide optimal intake 9-point body condition score system11) had a lower frequency of
of nutrients, such as calcium and phosphorus, for the developing hip dysplasia,12 lower prevalence and severity of osteoarthritis,13
skeletal system. All growing puppies have higher requirements delayed onset of chronic disease, and an increased median life
for nutrients compared to adult dogs. Energy requirements for span3 when compared to a control group consisting of paired
young puppies greatly exceed that of adult dogs but decrease littermates with a mean body condition score (BCS) of 6.7/9.
with increasing age as well as following sterilization. Further Teaching clients the importance of maintaining a lean body weight
complicating the issue is the wide range of individual energy and how to body condition score their dog is recommended. This
requirements among puppies of various ages and breeds, and should be reinforced at every veterinary visit. Since overfeeding
the variability of nutrient content and energy density among the large- and giant-breed puppies has been shown to contribute to
plethora of products marketed for growing dogs. This discussion the development of skeletal disease,7,8,12 owners should be told
will explore some of the patient and diet variables and provide that maximal growth is not optimal growth for these puppies.
25
 Knowing the importance of maintaining a lean body condition exponentially followed by a gradual decline until weight reaches
throughout life, the pet owner may ask, “Well, how much food a plateau.19 Therefore, energy requirements change as the puppy
should I give?” This seems like a reasonable and simple question; progresses from weaning to adulthood.
however, there are food and patient variables to consider. Owners Canine studies have constructed growth curves by plotting
do not always measure food, so providing standard measuring body weight against age for various breeds.20-22 The amount of
cups (since most pet owners in the United States feed based on tissue accretion and, therefore, body weight gain during growth
volume measures) and discussing the importance of knowing for a large- or giant-breed dog far exceeds that of a toy breed.
how much the pet is consuming should occur during routine In other words, the scale of difference among larger and smaller
puppy visits. Diets marketed for puppies do not all have the breeds increases throughout growth such that a sevenfold weight
same caloric content, and there can be significant variation when difference noted between neonates of the smallest and largest
comparing kilocalories per cup among products. To provide one breeds evaluated in one study increased to a 35-fold difference
example, there is a 1.4-fold difference in kcal/cup between two by adulthood.23 With regard to age, in the initial post-weaning
puppy formulations within the same brand, so simply instructing period when growth velocity is highest (i.e., the slope of the
a client to feed 1 cup of “Brand X puppy food” without stating growth curve is steepest), energy needs per metabolic body
the specific formulation could in this example result in over- or weight will be greatest.
underfeeding by approximately 140 calories per day. During these first weeks when growth velocity is high and
Although it is important to provide pet owners with feeding body size is relatively small, it is estimated that approximately
guidelines regarding the amount to feed, you also should recog- 50% of total energy intake may be used for growth and the
nize the limitations of any specific “feed X calories per day” remaining 50% for maintenance.24 At the inflection point of the
recommendation. As stated in the National Research Council’s growth curve, daily weight gain is maximal and then begins to
(NRC) 2006 Nutrient Requirements of Dogs and Cats, “At decline with time as the growth rate begins to decline.18,19 Thus,
present, the energy requirements of an individual dog cannot as the puppy ages, the proportion of energy needed for growth
be more than an educated guess and can easily miss the true declines and the proportion of energy used for maintenance
requirement by 50 percent.”14 Even within the rather homoge- increases. The NRC Nutrient Requirements of Dogs and Cats
neous population mentioned in the Purina Life Span study accounts for this by proposing an arbitrary decrease to 1.6 times
(48 dogs of the same age and breed from seven litters divided maintenance when 50% of adult body weight is reached and to
equally into two groups), the investigators detected a 20% vari- 1.2 times maintenance at 80% of body weight to compensate
ation in metabolizable energy requirement.15 Adding differences for the decline in energy required from weaning to adulthood,14
among breeds, ages, genders, and lifestyles can dramatically though not all studies have demonstrated a decrease in the energy
influence deviations in energy needs. requirement during growth on a metabolic body weight basis.16
Equations used to determine energy needs can only serve as Of course, the age at which an individual puppy achieves 50%
guidelines. Dobenecker et al. also reported a range of 0.72-2.34 of mature body weight is dependent on anticipated mature body
times the maintenance energy requirement when comparing energy weight with smaller breeds maturing at a younger age compared
requirements of two different breeds of puppy from weaning to large- and giant-breed dogs.
until 28 weeks of age.16 An initial feeding recommendation based A study by Hawthorne et al. demonstrated a toy breed
on knowledge of current intake and body condition provides just (Papillon) achieved 50% of its adult body weight at a mean age
a starting point. The owner should be taught how to monitor of 11.1 weeks, while a giant breed (English Mastiff) achieved
body condition at home, and the veterinarian should frequently 50% of its adult body weight at a mean age of 22.9 weeks.22 In
re-evaluate the growing puppy’s BCS over time so feeding guide- the same study, toy, small and medium breeds approached adult
lines can be modified to that individual’s needs. weight at ~9-10 months of age, while large and giant breeds
Understanding the derivation of canine growth energy require- approached adult weight at ~11-15 months of age. This study
ments, the variables that influence caloric requirements, and the noted additional breed-specific growth pattern differences in dogs
limitations of any method for calculating energy needs are nec- of similar size. The NRC’s 2006 recommendations provide an
essary when providing recommendations. Energy requirements equation proposed by Blanchard et al. for calculating canine
for growing puppies take into account the puppy’s maintenance energy requirement during the growth continuum by factoring the
energy requirement plus the growth energy requirement (i.e., percentage of realized growth [body weight at time of evaluation
energy required for tissue accretion). Arnold and Elvehjem pre- (kg)/expected mature body weight (kg)] at a given time point.18,25
dicted that growing puppies require about twice the amount of The equation (shown in Table 1) is best-suited for use with
energy per unit of body weight as an adult dog of the same breed.17 computer programs.
However, growth does not occur in a linear fashion as the puppy Other variables including body composition (e.g., lean body
progresses chronologically from weaning to adulthood; it varies mass), temperament/activity level, coat type, and environmental
with growth stage and breed size.18 The typical post-weaning temperature could affect energy requirements.14,22,26 There is
growth pattern follows a sigmoid curve in which growth begins currently insufficient data to determine whether known breed

26
 bitches, ovariectomized bitches with ovarian autotransplants and
Table 1. Daily Metabolizable Energy Requirements for
the sham control dogs when fed a fixed amount of food and exer-
Growth of Puppies after Weaning25
cised regularly.27 In 2004, Jeusette et al. reported a 30% decrease
ME (kcal) = Maintenance amount x 3.2 x [e(-0.87p) - 0.1] in daily energy requirement in four 2-year old adult female
ME (kcal) = 130 x BWa0.75 x 3.2 x [e(-0.87p) - 0.1] Beagles after ovariectomy.2 These dogs were at ideal body con-
Where: dition at the time of sterilization with feeding amounts adjusted
P = BWa/BWm weekly to maintain optimal body weight for the first 26 weeks
BWa = Actual body weight at the time of evaluation (kg) after surgery. The 30% decrease in daily energy required to
BWb = Expected mature body weight (kg) maintain optimal weight is comparable to observations reported
e = Base of natural log ≈ 2.718 in cats.28,29 The study was not designed to determine whether this
observation is due to a decrease in basal metabolic rate or a decrease
differences affecting adult maintenance energy requirements in activity. These same dogs were then offered high-energy food
should be considered during growth.14 However, the NRC’s 2006 for 16 weeks at twice the amount determined to maintain optimal
recommendations note that inactive puppies may have a 10-20% weight to assess the effect of ad libitum feeding. There was no
lower energy requirement and active puppies or puppies of certain intact female control group. Ad libitum feeding induced over-
breeds, such as Great Dane, may have higher energy requirements. consumption that was most marked during week one though the
Rather than relying solely on energy requirement calculations, the increased energy consumption was significant each of the four
NRC recommends that individual large- and giant-breed puppies weeks when compared to the previous controlled consumption.
be fed to achieve certain body weight guidelines at specific ages Dogs gained weight during this period with a 22% increase of
during the growth phase (Table 2) since controlled growth is body weight resulting in all dogs becoming overweight or obese.
essential for proper skeletal development of these puppies.7,14 The authors concluded that “restriction of energy intake seems
One might postulate that gender, including neuter status, necessary in dogs after ovariectomy.”30
could affect growth patterns and subsequent energy requirements. Although the above studies looked at the effect of neutering
For example, Allard studied small, medium and large breeds older dogs, there is limited data looking specifically at the effect
and noted that males sustained a longer growth term compared of energy and nutrient requirements in dogs neutered at an early
to females of the same breed.20 There have been limited studies (prepubertal) age. A 15-month study saw no difference in rate of
evaluating the effect of neutering on voluntary food intake, body growth, food intake, weight gain, or back-fat depth when com-
weight, body composition, and maintenance energy requirements paring male and female dogs neutered at 7 weeks of age, 7 months
following ovariectomy. Houpt et al. reported ovariohysterectomized of age or sexually intact.31 However, growth plate closure was
bitches gained more weight (1.3 kg +/- 0.3 kg) compared to sham delayed in all neutered dogs compared to intact dogs with the
operated controls (0.3 +/- 0.1 kg; P<0.05) by the 90th postoper- greatest delay in dogs neutered at the youngest age. Whether this
ative day when food was offered ad libitum.1 Total food intake has any implication for optimal nutrient intake of micronutrients,
was significantly higher at certain measured time points in the such as calcium or phosphorus, or growth rate is unknown. In
eight ovariohysterectomized bitches compared to sham controls two cohort studies, owners of dogs that underwent prepubertal
over a 15-week study period. Food intake per kilogram of body gonadectomy were no more likely to report their pet was over-
weight tended to be greater in the ovariohysterectomized bitches weight than owners of dogs that underwent traditional-age (i.e.,
and was significant at one measured time point. The authors near anticipated age of sexual maturity) gonadectomy.32,33 In
attributed the weight gain to decreased activity without decreased fact, one of the studies33 reported that dogs undergoing prepu-
food intake, but activity was not measured in this study. bertal desexing (<5.5 months of age) were less likely to become
Another study of adult female dogs observed for 55 weeks overweight later in life compared to dogs desexed >5.5 months
showed no change in body weight among the ovariectomized of age. However, results of owner surveys regarding the reporting

Table 2. Recommendations for Growth of Large- and Giant-Breed Dogs14

Medium Breeds Large Breeds Giant Breeds

(mature weight 20 kg) (mature weight 35 kg) (mature weight 60 kg)

Age (months) BW (kg) % mature BW BW (kg) % mature BW BW (kg) % mature BW

1 1.8 9 2.5 7 3.6 6
2 4.4 22 7.0 20 8.4 14
3 7.4 37 12.3 35 15.6 26
4 10.4 52 16.8 48 22.8 38
6 14.0 70 22.8 65 36.0 60
12 19.0 95 30.8 88 48.0 80

27
of a pet’s body condition must be interpreted with caution since puppy such that when a puppy consumes the proper amount
other studies have observed that pet owners underestimate their of food to meet his energy needs, he has concurrently met his
own pet’s body condition score.34,35 macronutrient and micronutrient requirements as well.
A recent retrospective cohort study set out to determine One can consider that for a puppy with a very low energy
whether gonadectomy or age of gonadectomy was associated requirement, the diet must have a relatively higher nutrient-to-
with the risk of dogs becoming subsequently obese.36 The study calorie ratio to ensure that the puppy consumes the recommended
evaluated electronic medical records data from 1,930 desexed amount of each essential nutrient at a lower-than-average caloric
and 1,669 sexually intact dogs followed over a minimum 10-year intake. This scenario would argue against selecting a product that
period. The relative risk of becoming overweight was assessed has been formulated close to the minimum nutrient recommen-
between desexed and intact dogs according to their age at gonad- dations. Therefore, knowledge of the nutrient profile of the
ectomy [early (<6 months of age), standard (6-12 months of age), specific food that the pet is consuming is required to make this
and late (1-5 years of age)]. The study was limited by the lack assessment. For adult dogs with an unusually low energy intake,
of a standardized body condition scoring system for most of the the NRC’s 2006 recommendations use the dog’s metabolic body
study period. weight to determine the recommended allowance for each specific
Gonadectomized dogs had a greater risk of being diagnosed nutrient.25 This same recommendation is not stated for puppies,
as overweight compared to intact dogs, but this difference was but rather, guidelines exist for calculating the amount of nutrients
only significant during the first two years after surgical sterili- to feed based on a puppy’s calculated energy requirement multi-
zation. No difference in risk of being overweight was detected plied by the recommended allowance for that nutrient.
with respect to age at time of gonadectomy. From a practical There are additional guidelines for the calcium recommenda-
clinical perspective, this study supports the recommendation tion of weaned puppies up to 14 weeks of age with an anticipated
for client education regarding food intake and close monitoring mature body weight >25 kg.25 Calcium requirements for grow-
of body weight and body condition score after neutering. ing puppies require special consideration since both inadequate
Although the evidence is strong to support the recommenda- calcium intake37-40 and excessive calcium intake, particularly
tion that dogs should be kept lean during their entire lifetime, without a concurrent increase in dietary phosphorus,7,37,41-43 are
specific recommendations regarding exactly how much to feed an associated with adverse health effects including skeletal malfor-
individual requires an understanding of all variables that impact mations and stunted growth. In addition, certain breeds appear
energy requirements and an appreciation that the “one size fits all” more intolerant to a wider range of dietary calcium content than
recommendation means feeding the amount necessary to ensure others.43,44 This reaffirms the importance of an individual nutritional
a lean body condition. Teaching clients to properly body condi- assessment in the exam room to recognize a breed that may be
tion score and objectively assess their own pet is recommended. more susceptible to developmental orthopedic disease if energy,
This is especially important at the time of neutering since tradi- calcium and phosphorus intake are not considered.
tional surgical sterilization (around 4-6 months of age) coincides Let’s suppose we are asked to provide a dietary recommen-
with when a puppy’s growth and daily maintenance energy needs dation for a 12-week-old spayed female Newfoundland puppy
subsequently are leveling off. More data are needed specifically in lean body condition that weighs 15.4 kg. Per the NRC’s 2006
regarding the impact of energy requirements in puppies neutered recommendations, a puppy of this expected mature size under
at a much earlier age. 14 weeks should consume not less than 15.4 kg (BW) x 0.54 grams
calcium/kg(BW) = 8.32 grams of calcium per day. Also per NRC,
Ensuring Appropriate Nutrient Intake her estimated daily energy requirement would be 2108 calories
Feeding to maintain a lean body condition means the caloric per day. However, if we assume a Newfoundland puppy would
intake must match the individual’s energy requirement. As dis- have a similar breed-specific lower maintenance component to
cussed above, this can vary significantly between individuals. her energy requirement (105 x kg BW0.75),25,26 her daily energy
Two puppies of similar body weight and body condition, age, requirement may be closer to 1703 Kcal/day. If we further assume
breed, and gender may have different energy requirements. For that the 30% decrease in daily energy requirement required to
example, in young adult dogs, Kienzle and Rainbird found that maintain optimal weight that Jeusette reported in the study eval-
Newfoundlands had a lower and Great Danes had a higher energy uating 2-year-old Beagles2 may also apply to this prepubertal
intake than dogs of other breeds.26 However, all puppies have an ovariohysterectomized dog, perhaps her daily energy intake could
increased need for nutrients during the growth phase. The chal- be even lower (1192 Kcal/day). Therefore, in this hypothetical
lenge is to ensure that the individual consumes the necessary extreme of the range of individual energy requirements, this dog
amount of all essential nutrients when fed the appropriate amount would need to be fed a diet that provided 6.97 g calcium/Mcal
of food to meet energy needs. In other words, the essential nutri- (=697mg/100Kcal) in order to consume 8.32 grams/day. This
ents must be balanced to the caloric density of the diet, and the amount of 6.97 g calcium/Mcal is well above the Association
calorie density of the diet must be balanced to the needs of the of American Feed Control Officials’ (AAFCO) minimum for

28
growth and reproduction (2.9 g/Mcal) and approaching the ing lean body condition throughout life, measuring food intake,
AAFCO maximum (7.1 g/Mcal).45 The veterinarian would and understanding appropriate selection and amount of snacks.
need to determine if this dog would be at risk if less than 0.54 Development of standardized breed-specific growth charts may
g/kg body weight was provided since a commercial puppy diet in the future assist veterinarians and pet owners in determining
most likely would not provide this calcium intake when fed if a specific puppy is growing at the appropriate rate. Since rec-
to provide 1192 Kcal/day. If the nutritionist determined this ommendations are often, at best, an educated guess and should
puppy needed more calcium than the current diet provided, only be considered as a starting guideline, frequent reassessment
options could include recommending a diet with a higher ratio with necessary modifications to the nutrition plan is warranted.
of calcium to energy or careful supplementation for a defined It is not uncommon in some practices for the puppy to be eval-
period of time. uated at 6 months of age (time of neutering) and, if no health
In addition, for a dog with very low metabolic energy expen- problems occur, not to be evaluated again until the next vacci-
diture, owner consultation regarding snacks is imperative. The nations are due after 1 year of age. A veterinary practice might
owner may need to use complete and balanced food rewards for consider implementing veterinarian or veterinary technician well-
training, such as a piece of kibble, since the individual may not ness nutrition recheck appointments so that the puppy can be
have the luxury to consume “treats” that are not concurrently evaluated and the owner can continue to be educated regarding
delivering essential nutrients. proper nutrition.
At the other end of the spectrum is the puppy with a higher- “What food to feed?” can only be answered after the nutri-
than-average energy requirement, such as a Great Dane puppy. tional assessment. Owners can be directed to reputable resources
In this scenario avoiding excess nutrient intake may become a such as the World Small Animal Veterinary Association (WSAVA)
consideration when energy intake is high. Therefore, the same Global Nutrition Committee’s recommendations on selecting pet
nutrient-dense diet selected in the above example could potentially foods (http://www.wsava.org/sites/ default/files/Recommendations
lead to excessive nutrient intake. A diet with a lower nutrient- %20on%20Selecting%20Pet%20Foods.pdf46) to provide general
to-calorie ratio fed to meet the energy requirement for proper guidelines for assessing a pet food. However, the recommenda-
growth rate and maintenance of lean body condition without tion still needs to be tailored to the individual as demonstrated in
leading to overconsumption of a nutrient of concern, such as the Newfoundland puppy example. Since no standard large-breed
calcium, would be an appropriate recommendation. puppy nutrient profile guidelines exist, one cannot rely solely on
the product name to know the caloric content or nutrient profile
Providing a Recommendation for a given “large-breed puppy formula.” Depending on the caloric
The veterinarian providing consultation for growing puppies density and nutrient profile, certain large-breed puppy formulations
must first complete a nutritional assessment of individual patient may meet that puppy’s needs and others may not. An all-life
factors including breed, age, neuter status, body weight, body stage product may, in fact, meet one puppy’s needs better than
condition score, current caloric intake, source of calories, etc., a product marketed as a large-breed puppy diet.
and owner factors including feeding philosophies, level of Some veterinarians may recommend switching a growing
knowledge regarding canine pediatric nutrition, and personal large-breed puppy to an adult food in an attempt to lower energy
needs and desires before providing a recommendation regard- intake. This is probably based on the assumption that an adult
ing what to feed and how much to feed. “How much to feed?” diet will be lower in calories than the puppy diet. This assump-
is answered by feeding to a lean body condition. tion may not be correct because of the range in caloric density
Some general guidelines, such as knowing most dogs have of both adult and growth formulations, e.g., some “adult” foods
achieved 50% of mature weight around 4 months of age, help can contain more calories than some puppy foods. Further, the
provide general recommendations. At this age, energy need puppy may still consume as much or more energy when fed an
expressed as kcal/kg is decreasing such that for many puppies adult formulation if portions are not controlled. In addition, the
the amount of food (i.e., absolute caloric intake per day) is un- adult diet may not meet the specific nutrient requirements for
likely to increase significantly in the coming months. Further- growth. Given the variables of both calories and nutrient/calorie
more, 4 to 6 months of age coincides with the traditional age ratio, the veterinarian must evaluate the nutrient profile of the rec-
for surgical sterilization. This time period is critical for nutri- ommended diet before determining that a specific food will meet
tion consultation and client education. If the puppy is neutered that puppy’s needs. For a puppy with a relatively low-energy
at this age, the amount of food likely will have to be decreased. requirement, products formulated to near-minimum requirements
This is not intuitive to most pet owners who more likely will should be avoided as they will need a greater “safety margin.”
assume the puppy will need to be fed more food in the coming Providing snacks or treats is one way owners interact and
months. Currently, one of the best tools is client education for bond with their puppy. General guidelines such as ensuring
all puppy owners that includes teaching body condition scoring, snacks do not comprise >10% of daily caloric intake are useful.
appropriate growth rate for the breed, importance of maintain- However, this recommendation also should be tailored to the

29
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keep the puppy occupied, such as certain edible chew toys, may 10. Freeman L, Becvarova I, Cave N, et al. WSAVA Nutritional
contribute more calories than the owner realizes. Alternative feeding Assessment Guidelines. J Sm An Pract. 2011;52:385-396.
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challenges and involve a bit more thought when providing a Food Consumption on the Incidence of Hip Dysplasia in Growing
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useful tools we currently have to make dietary recommendations 14. Nutrient Requirements for Dogs and Cats. National Research
for the neutered patient. Council. The National Academies Press, Washington, D.C.
2006;28-48.
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19. Sheffy BE. Nutrition and Nutritional Disorders. Vet Clin
5. Kustritz MV. Determining the Optimal Age for Gonadectomy N Am. 1978;8:7-29.
of Dogs and Cats. J Am Vet Med Assoc. 2007;231:1665-1675.
20. Allard R. The Effect of Breed and Sex on Dog Growth.
6. Hoffman JM, Creevy KE, Promislow DE. Reproductive Comp An Pract. 1988;15-19.
Capability Is Associated with Life Span and Cause of Death
in Companion Dogs. PLoS One. 2013;8:e61082. 21. Helmink SK, Shanks RD, Leighton EA. Breed and Sex
Differences in Growth Curves for Two Breeds of Dog Guides.
7. Hedhammar A, Wu FM, Krook L, et al. Overnutrition and J An Sci. 2000;78:27-32.
Skeletal Disease: An Experimental Study in Growing Great Dane
Dogs. Cornell Vet. 1974;64(Suppl 5):5-160. 22. Hawthorne AJ, Booles D, Nugent PA, et al. Body-Weight
Changes During Growth in Puppies of Different Breeds. J Nutr.
8. Meyer H, Zentek J. Energy Requirements of Growing Great 2004;134:2027s-2030s.
Danes. J Nutr. 1991;121:S35-S36.

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23. Kirkwood JK. The Influence of Size on the Biology of the 35. White GA, Hobson-West P, Cobb K, et al. Canine Obesity:
Dog. J Sm An Pract. 1985;26:97-110. Is There a Difference Between Veterinarian and Owner Percep-
tion? J Sm An Pract. 2011;52:622-626.
24. Debraekeleer J, Gross KL, Zicker SC. Feeding Growing
Puppies: Postweaning to Adulthood. In: Small Animal Clinical 36. Lefebvre SL, Yang M, Wang M, et al. Effect of Age at Gonad-
Nutrition. Hand MS, Thatcher CD, Remillard RL, Roudebush P ectomy on the Probability of Dogs Becoming Overweight. J Am
(eds). Mark Morris Institute, Topeka, KS. 2010;5th ed:311-319. Vet Med Assoc. 2013;243:236-243.

25. Nutrient Requirements for Dogs and Cats. National Research 37. Hazewinkel HA, Van den Brom WE, Van TKAT, et al. Cal-
Council. The National Academies Press, Washington, D.C. 2006; cium Metabolism in Great Dane Dogs Fed Diets with Various
354-370. Calcium and Phosphorus Levels. J Nutr. 1991;121:S99-S106.

26. Kienzle E, Rainbird A. Maintenance Energy Requirement 38. Lauten SD, Goodman SA, Brawner WR. Growth and Body
of Dogs: What Is the Correct Value for the Calculation of Composition of the Large-Breed Puppy as Affected by Diet. In:
Metabolic Body Weight in Dogs? J Nutr. 1991;121:S39-S40. Recent Advances in Canine and Feline Nutrition. Reinhardt GA,
Carey DP (eds). Iams Nutrition Symposium Proceedings. Orange
27. Le Roux PH. Thyroid Status, Oestradiol Level, Work Perform- Frazer Press, Wilmington, OH.1998;2:3-12.
ance and Body Mass of Ovariectomised Bitches and Bitches
Bearing Ovarian Autotransplants in the Stomach Wall. J S Afr 39. Goodman S, Montgomery R, Fitch R, et al. Serial Orthopaedic
Vet Assoc. 1983;54:115-117. Examinations of Gowing Great Dane Puppies Fed Three Diets
Varying in Calcium and Phosphorus. In: Recent Advances in
28. Flynn MF, Hardie EM, Armstrong PJ. Effect of Ovariohys- Canine and Feline Nutrition. Reinhardt GA, Carey DP (eds).
terectomy on Maintenance Energy Requirement in Cats. J Am Iams Nutrition Symposium Proceedings. Orange Frazer Press,
Vet Med Assoc. 1996;209:1572-1581. Wilmington, OH. 1998;2:63-70.

29. Harper EJ, Stack DM, Watson TD, et al. Effects of Feeding 40. Laflamme DP. Effect of Breed Size on Calcium Requirements
Regimens on Body Weight, Composition and Condition Score for Puppies. Compend Contin Educ Pract Vet. 2000;23:66-69.
in Cats Following Ovariohysterectomy. J Sm An Pract. 2001;42:
433-438. 41. Goedegebuure SA, Hazewinkel HA. Morphological Findings
in Young Dogs Chronically Fed a Diet Containing Excess Cal-
30. Jeusette I, Daminet S, Nguyen P, et al. Effect of Ovariectomy cium. Vet Pathol. 1986;23:594-605.
and Ad Libitum Feeding on Body Composition, Thyroid Status,
Ghrelin and Leptin Plasma Concentrations in Female Dogs. J 42. Voorhout G, Hazewinkel H. A Radiographic Study on the
An Physiol An Nutr (Berl.) 2006;90:12-18. Development of the Antebrachium in Great Dane Pups on
Different Calcium Intakes. Vet Rad. 1987;28:152-157.
31. Salmeri KR, Bloomberg MS, Scruggs SL, et al. Gonadectomy
in Immature Dogs: Effects on Skeletal, Physical and Behavioral 43. Dobenecker B, Kasbeitzer N, Flinspach S, et al. Calcium-
Development. J Am Vet Med Assoc. 1991;198:1193-1203. Excess Causes Subclinical Changes of Bone Growth in Beagles
But Not in Foxhound-Crossbred Dogs, as Measured in X-Rays.
32. Howe LM, Slater MR, Boothe HW, et al. Long-Term Out- J An Physiol An Nutr (Berl.) 2006;90:394-401.
come of Gonadectomy Performed at an Early Age or Traditional
Age in Dogs. J Am Vet Med Assoc. 2001;218:217-221. 44. Nap RC, Hazewinkel HA, Voorhout G, et al. Growth and
Skeletal Development in Great Dane Pups Fed Different Levels
33. Spain CV, Scarlett JM, Houpt KA. Long-Term Risks and of Protein Intake. J Nutr. 1991;121:S107-S113.
Benefits of Early-Age Gonadectomy in Dogs. J Am Vet Med
Assoc. 2004;224:380-387. 45. Association of Animal Feed Control Officials. Official
Publication. 2014;162.
34. Singh R, Laflamme DP, Sidebottom-Nielsen M. Owner
Perception of Canine Body Condition Score. J Am Vet Med 46. Recommendations on Selecting Pet Food. WSAVA Global
Assoc. 2002;362. Nutrition Committee. Accessed January 2014 at: http://www.wsava.
org/sites/default/files/Recommendations%20on%20Selecting%
20Pet%20Foods.pdf

31
Notes

32
Feeding Management of the Neutered Cat
Jennifer A. Larsen, DVM, PhD, DACVN
University of California-Davis
School of Veterinary Medicine
Department of Molecular Biosciences
Davis, CA
Email: [email protected]

Neutering is one of the most common seen after neutering. Further, what is
surgical procedures performed on pets in Glossary of Abbreviations the relationship among body mass,
BCS: Body Condition Score
the U.S. There are known effects of neuter- body composition, energy intake, and
IGF-1: Insulin Growth Factor-1
ing on the physiology and behavior of the energy expenditure?
LBM: Lean Body Mass
cat that predispose to obesity, which is the NRC: National Research Council One study showed that neutered cats
most significant sequela from a nutritional RER: Resting Energy Requirement gained more body weight and fat mass
perspective. Proactively addressing these when assessed at one and three months
changes with nutritional management strategies can help prevent postsurgery compared to cats left intact, and that males gained
weight gain and associated negative consequences. Likewise, more weight than females.11 When food intake was measured at
successfully achieving the reversal of obesity in neutered cats the baseline and three-month time points, the authors reported a
may have benefits and should be pursued despite the challenges significant increase only for neutered and not intact males and
of the process. females, with neutered males having higher food intake than
neutered females.11 They also reported that fasting but not rest-
Introduction ing metabolic rate, calculated on a metabolic body weight basis
There are almost one billion owned cats in the United States, (kcal/kg total BW0.75/day), decreased at three months after neu-
and over 90% of those are neutered.1 Epidemiological data have tering in females but not in males despite a smaller mean gain
demonstrated that neutering is a risk factor for obesity in cats, in the females at that time point. The question remained, how-
especially in males.2-5 Obesity is a common and serious problem ever, whether energy expenditure on a lean body mass basis
in domestic cats. Studies have reported that some populations was altered by neutering or by gender, and whether reduced en-
have a prevalence of overweight and obese cats of 28 to 63%.4,6-8 ergy expenditure or increased food intake was driving the gain
Overweight cats are more likely to suffer from many problems, in body mass.
including diabetes mellitus, constipation, orthopedic disease, Another study investigated energy balance in male cats during
altered hemostasis, urinary tract disease, hepatic lipidosis, and the immediate postsurgical period and found that food intake
skin disease.7,9,10 As the majority of feline veterinary patients have increased almost immediately for neutered cats compared to intact
a known risk factor (neuter status) for a disease that is likely to cats, becoming significantly higher at three days after neutering,
result in potentially significant morbidity (obesity), strategies aimed while body weight increases did not become significantly higher
at prevention and, where necessary, intervention are indicated. until seven weeks after neutering.13 The gains in body weight
plateaued at approximately 28% and were primarily due to
Impacts of Neutering on Food Intake, Body Weight increases in fat mass; however, it is interesting to note that energy
and Energy Expenditure expenditure on a lean body mass basis was not different before
The relationships among food intake, body weight and con- and after neutering and that there also was no difference in energy
dition, and energy expenditure after neutering are complex. expenditure between neutered and intact cats in that study.13
However, it seems clear that when cats are fed ad libitum after These findings agreed with a previous study that also reported
neutering, weight gain is likely to occur,11-14 and free availability no change in energy expenditure on a lean body mass due to
of food results in greater body weight and body fat percentage neutering,20 and were also confirmed by more recent data
after neutering of male15 as well as female cats16 compared to demonstrating that postneutering weight gain in adult male cats
restricted access. This effect is even seen in feral cats participating is the result of increased food intake and not a change in energy
in trap-neuter-release programs.17 In addition, greater weight expenditure.21
gain and body fat accumulation is seen after neutering when In contrast, another study showed an increase in heat produc-
energy-dense diets are used.18-19 Many studies have investigated tion in male and female cats neutered at 7 weeks or 7 months
whether an increase in food intake, a decrease in energy expen- compared to those kept intact; however, the calculations used
diture, or both, are responsible for the weight gain commonly absolute body weight, and body composition, weight and body

33
condition of the cats were not reported.22 Assuming that the Mechanisms for Increased Food Intake
neutered cats were heavier throughout the study as well as at the One of the consequences of neutering is a change in the hor-
end point as reported by this author in lecture proceedings,23 if monal milieu including impacts on cholecystokinin response,27
ideal or lean body mass (LBM) had been used to calculate the increases in concentrations of prolactin, IGF-1 and leptin,28 and
heat coefficients, the differences between the intact and neutered decreases in concentrations of sex hormones, such as testosterone
cats would have been smaller and may not have been significant.22 and estrogens. Decreases in sex hormones, are unsurprising; how-
The role of gender, and potential differential effects of neuter- ever, it is noteworthy that significant reductions in estradiol are
ing on females versus males, may also be significant.11,24 One seen in male cats after neutering, with reduction of plasma con-
study showed that calorie intake to maintain body weight in centrations to approximately half the presurgical concentrations.15
neutered females was significantly decreased over time after Previous work has implicated this as a potential major factor
surgery, though there was no significant reduction for neutered influencing the increase in food intake seen with neutering. For
males up to 16 weeks after surgery.24 Gender differences in hor- example, it has been demonstrated that administration of low-dose
monal responses (leptin, insulin, free thyroxin) to neutering were estradiol to overweight, neutered male and female cats signifi-
also noted.24 Similarly, another study showed that significantly cantly reduced food intake.29 In addition, low-dose exogenous
fewer calories were necessary to maintain body weight in ovar- estrogen can prevent the increase in food intake associated with
iohysterectomized versus intact queens.25 These findings agree neutering as well as reduce the degree of accompanying weight
with another study that showed an over 30% restriction in food gain and increase in fat mass.30 Further, plasma concentrations
intake was necessary to maintain body weight in neutered queens; of estradiol were not impacted by food restriction versus free
voluntary activity of the cats was also markedly decreased (60% access, nor with the degree of adiposity, and exogenous injections
and 33% of baseline measurements for the light and dark periods, of estradiol restored presurgical plasma concentrations and resulted
respectively).16 More work is needed to explore these differences in reduced food intake.15
and may help explain varied findings in studies of energy expen- These findings support the role of gonadal estrogens in both
diture of neutered cats. genders. It remains to be seen whether this therapy may be
It should be noted that most studies vary as to when energy clinically useful for the management of cats after neutering and
expenditure is measured after neutering, which may bias the whether long-term treatment would be needed. Since the general
findings when significant body weight and fat mass gains have agreement is that food intake is the key factor underlying weight
occurred in the interim. In addition, the methodology used to gain after neutering, the current focus remains on feeding man-
measure energy expenditure is not standardized. Further, some agement and owner education.
studies rely on estimated energy intake or degree of restriction to
maintain body weight as an indirect measure of energy expendi- Management of Neutered Kittens
ture. When measured using indirect calorimetry in the immediate Cats are commonly neutered at a young age during the period
postneutering period, and normalized for body composition, of growth. Kittens require a specific balance of nutrients to
energy expenditure does not change in adult male cats.13,21 support normal development, so it is important to feed a food
Although most evidence supports that energy expenditure (as designed for growth until approximately 1 year of age. Due to
determined by indirect calorimetry and adjusted for lean mass) the timing of neutering, this presents a challenge for balancing
does not change as a result of neutering regardless of body weight the nutritional requirements of a growing kitten with the need to
change, it has been shown that energy restriction per se results in control food intake and avoid excessive weight gain. As there
a decrease in lean mass-adjusted energy expenditure.26 Further, does not appear to be a difference in obesity risk dependent on
one study showed that energy restriction in overweight neutered age of neuter,22,31 it might be prudent to delay neutering proce-
female kittens to the amount consumed by intact littermates, after dures until after the most rapid growth period is passed, when
a period of ad libitum feeding of 18 weeks postneutering, resulted possible; however, in many circumstances earlier neutering is
in continued accumulation of body fat, increased body weight preferred (or mandated) to address overpopulation issues. In
and increased body condition score (BCS).14 any case, portion-controlled feeding is recommended, and reg-
It also has been demonstrated that body weight gain can be ular monitoring of body weight and body condition is necessary
avoided after neutering provided that food intake is actively to enable adequate and timely adjustment of the amounts fed.
limited, though it seems clear that some cats need fairly severe In addition, although diets formulated for growth tend to be
restriction to maintain preneutering body weight.12,25 Thus, it more energy dense compared to those formulated for adult
appears that the initial effect of increased food intake, when maintenance, there still is a wide range of options with varying
allowed, followed by resultant increases in body weight and fat energy densities in the kitten growth category. An informal and
mass, is probably responsible for the obesity seen in neutered cats.13 limited survey of over-the-counter products by the author revealed
This underscores the role of food intake and feeding management a range of energy density values for dry kitten foods of 3288-
in pet cats after neutering and supports an individualized approach 4420 kcal/kg as fed and for canned kitten foods of 847-1343
to the determination of the necessary degree of restriction. kcal/kg as fed. If food intake cannot be adequately controlled
34
and/or if the necessary volume restrictions are too severe, a Owner Education
growth diet with lower energy density should be used. However, Underestimation of the cat’s overweight condition or a general
this recommendation assumes the volume intake is consistent, unawareness of body condition is common among cat owners
though the drive for increased food intake may overcome the and may contribute to the development of obesity.3 In fact, one
reduction in energy density. Using a canned diet may be an recent study identified owner underestimation of cat body condi-
effective way to limit food intake32 yet still meet the needs of a tion as a main variable influencing obesity in cats.8 Pet owners
growing kitten. However, more active restrictions on food con- should be counseled on appropriate body condition for their indi-
sumption are probably needed in many cases. Further, given vidual pet36 and encouraged to perform body condition scoring at
the marked reduction in voluntary activity in neutered queens,16 home on a regular basis (every two weeks during the growth
it is possible that actively encouraging increased activity may period37).
help offset the effect of neutering such that less-severe restrictions Free feeding is common for cats and is a convenience factor
of food intake are needed. The difficulties in accomplishing that owners sometimes attribute to their preference of pet cats
weight loss in cats in addition to the risk of the cat regaining over dogs. Free feeding is often practiced regardless of body
the weight help emphasize that any factors that help to prevent condition,38 with 80% of pet owners using this method of feed-
obesity are preferable to trying to reverse it. ing.39 Some studies have found no link between feeding practices
and the prevalence of obesity.6,8,40 It is clear that some cats
Energy Requirements for Growth and Maintenance successfully regulate their food intake to maintain ideal body
For adult cats undergoing neutering, energy restriction to weight, though others tend to overeat and become overweight or
prevent increased food intake is less complex, though many obese. For many cases, consideration of the amount fed as well
owners do not already monitor or control their cats intake, in as the energy density of the diet is important. Monitoring the
which case this may require the institution of a new household pet’s BCS and body weight, accompanied by any necessary
routine. If known, the energy intake should be reduced by at least adjustment in the amount and type of food fed, is a critical com-
15% and may need to be restricted over 30%, based on the degree ponent in providing recommendations that meet the needs of
of the increases reported for adult cats by several studies.13,15,16,21,25 individual pets; this process starts with a veterinary assessment
Although not ideal due to the individual variation in energy and is maintained by both the owner and the veterinary team.37
requirements, if the prior intake cannot be determined, reliance
on equations to estimate these needs is necessary. Recommendations for Kittens and Adult Cats
Many studies of the daily energy maintenance requirements after Neutering
of cats have been conducted, with a very wide range of values It is challenging to provide guidance to pet owners for feeding
determined and primarily given on an absolute body weight their neutered kitten. Growing cats have higher requirements for
basis (31-100 kcal/kg BW).33 Many factors likely explain the protein, amino acids, specific fatty acids, and most minerals com-
variation; however, despite a relatively consistent body size and pared to adults,34 and foods intended for growth are necessary.
shape of domestic cats, allometric scaling and the use of metabolic Kitten owners should be counseled to look for the nutritional
body weight are justified. Based on work by Nguyen and agreement adequacy statement on the label, which will indicate whether the
with other data, the National Research Council (NRC) provides food has been formulated or feeding trials conducted for growth or
different equations for lean versus overweight adult cats that all life stages; diets formulated or feeding trials conducted only for
use different coefficients for metabolic body weight:33-34 adult maintenance are not satisfactory options. Although it may
• Lean cats 100 kcal x kg BW0.67 be tempting to switch to an adult diet, these options may not provide
• Overweight cats 130 kcal x kg BW0.4 the appropriate concentrations of nutrients that are essential for
For kittens after weaning, the equation provided is more optimal growth. Although weight gain during growth is normal and
complex and requires estimation of predicted adult body weight; expected, it is important that the pet owner understands how to
this was based on pooled data from many published studies:34 assess body condition and proactively adjusts the amount of food
(100 kcal x kg BW0.67) x 6.7 x [e(-0.189p) – 0.66] offered to prevent gain of body fat. There is very little data provid-
where p = actual body weight/expected mature body ing information on the degree of restriction necessary to avoid
weight and e = base of natural log (~2.718) weight gain after neutering. One study reported that neutered
Many veterinary nutritionists use a simpler equation based on female cats had 17% higher food intake compared to their intact
a growth factor applied to the resting energy requirement (RER) littermates.14 However, individual kittens will vary in the degree
at the current weight:35 of restriction needed, and a gender difference also is possible.
2.5 x RER Cats neutered as adults may require quite dramatic energy
where RER = 70 * kg BW0.75 restriction to avoid weight gain. Studies have reported reductions
Regardless, any equation used is a starting point, and recom- of up to 30-36% to maintain preneuter body weights in adult
mendations for individuals necessitate reassessment and adjust- female cats.16,25 Food intake in adult males increased by 12%
ments as needed to maintain ideal body condition during growth. after neutering in one study, which was modest yet allowed body
35
weight increases of 27-29%.13 Another study showed increases in 9. Scarlett JM, Donoghue S. Associations Between Body Con-
food intake after neutering in 17% of females and 26% of males.11 dition and Disease in Cats. J Am Vet Med Assoc. 1998;212:
Therefore, it seems important to ensure that owners of cats of 1725-1731.
either gender understand the importance of food restriction
immediately after neutering to avoid the development of obesity. 10. Bjornvad CR, Wiinberg B, Kristensen AT. Obesity Increases
Beginning with a restriction of at least 15%, and instituted imme- Initial Rate of Fibrin Formation During Blood Coagulation in
diately after the procedure, seems reasonable. Body weight and Domestic Shorthaired Cats. J An Phys An Nutr (Berl). 2012;
condition should be assessed regularly, with further reductions 96:834-841.
implemented as needed to maintain ideal BCS.
11. Fettman MJ, Stanton CA, Banks LL, et al. Effects of Neu-
Conclusion tering on Body Weight, Metabolic Rate and Glucose Tolerance
Ultimately, evidence supports avoidance of allowing unrestricted of Domestic Cats. Res Vet Sci. 1997;62:131-136.
access to food, consideration for energy density, provision of a
life stage-appropriate diet, and regular monitoring of the body 12. Harper EJ, Stack DM, Watson TDG, et al. Effects of Feeding
condition of neutered cats. Determination of energy needs should Regimens on Body Weight, Composition and Condition Score
be based on prior intake, if known; however, the degree of restric- in Cats Following Ovariohysterectomy. J Sm An Pract. 2001;
tion necessary to avoid weight gain is variable and underscores 42:433-438.
the importance of monitoring and adjustment.
13. Kanchuk ML, Backus RC, Calvert CC, et al. Weight Gain
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Benefits of Early-Age Gonadectomy in Cats. J An Vet Med Assoc.
2004;224:372-379.

37
Notes

38
Aging and Stroke: The Human Condition
Miranda N. Reed, PhD,1,5 Danielle N. Doll, BS,2,5 James W. Simpkins, PhD,3,5 and Taura L. Barr, RN, PhD4,5
West Virginia University Health Sciences Center
1
Department of Psychology
2
Center for Neuroscience
3
School of Medicine, Department of Physiology and Pharmacology
4
School of Nursing
5
Center for Basic and Translational Stroke Research
Morgantown, WV
Email: [email protected]

Abstract Stroke affects about 800,000 Ameri-

Stroke and aging-related cognitive Glossary of Abbreviations cans annually and is estimated to
decline are complex processes that AD: Alzheimer’s Disease cost a total of $72 billion/year.4-6

AMPA: α-Amino-3-Hydroxy-5-Methyl-4-
are interconnected and influenced aMCI: Amnestic Mild Cognitive Impairment Unfortunately, effective preventives
by immune/inflammatory processes. and treatments for these conditions
Isoxazolepropionic Acid
In this paper, we explore the relation- are not available, and the number of
Aβ: Beta-Amyloid Protein
ships among the cardiovascular, young stroke and AD patients is
ApoE: Apolipoprotein E
immune and nervous systems that APP: Amyloid Precursor Protein expected to rise.7
could account for the associated ATP: Adenosine Triphosphate This review considers the effects of
mechanisms between brain aging BACE: Beta-Amyloid Cleavage Enzyme aging and comorbid cardiovascular
and stroke, and describe the influence BBB: Blood-Brain Barrier diseases on cognitive decline and
of the immune system on stroke and DG: Dentate Gyrus stroke. We will describe the normal
aging-related cognitive decline and EC: Entorhinal Cortex course of cognitive aging, the effects
assess the potential that age-related EPSP: Excitatory Postsynaptic Potentials of AD on this process, and the factors
dysfunction in mitochondria may FDG: 18F-fluoreodeoxyglucose that may contribute to the effects of
contribute to both stroke and cognitive ICAM-1: Intercellular Ahesion Molecule 1 aging and stroke on cognition. Recent
IL: Interleukin evidence suggests the relationships
aging. We conclude that comorbid
LTP: Long-Term Potentiation
chronic inflammatory diseases con- among cardiovascular disease, stroke
MCI: Mild Cognitive Impairment
tribute to stroke prevalence and severity and dementia are undeniable.8
MMPs: Matrix Metalloproteinases
and may also contribute to age-related NO: Nitric Oxide
cognitive decline, perhaps by com- OxPhos: Oxidative Phosphorylation Cognitive Aging and
promising mitochondrial function. O2: Oxygen Alzheimer’s Disease
PET: Positron Emission Tomography As life expectancy has increased,
Introduction PSD: Postsynpatic Density the prevalence of age-associated loss
The Greying of America places an ROS: Reactive Oxygen Species of cognitive ability and memory has
enormous stress on our health-care Tg: Transgenic increased. Only a minority of aged
delivery system. The number of TNF-α: Tumor Necrosis Factor-α individuals will experience successful
Americans in the ≥65 and ≥85-year- VCAM-1: Vascular Cell Adhesion Molecule 1 aging, defined here as maintaining
old categories is growing at a rate peak cognitive performance during
faster than younger segments of our population.1 Because we senescence.9 Most individuals above the age of 50 will experience
are living longer, the number of chronic comorbid conditions declines in episodic memory relative to their prior performance.10,11
is increasing in our elderly population and consumes the vast Among individuals in their seventh and eighth decades, a range
majority of health-care resources including doctor visits and of cognitive aging occurs and can be viewed on a continuum
prescription medications.2 Due to their debilitating nature, extending from successful cognitive aging to pathological aging,
Alzheimer’s disease (AD) and ischemic stroke are the diseases with the latter sometimes leading to mild cognitive impairment
contributing most of the health-care burden in elderly populations. (MCI) or even a debilitating and progressive neurodegenerative
AD is the leading cause of dementia and affects 5 million condition, AD. Aging is the greatest known risk factor for AD,
Americans annually at a current cost of $203 billion/year.3 with the likelihood of developing AD doubling every five years

39
after the age of 65.12 Though debated, MCI may represent a
transition state between normal aging and AD13,14; individuals
with amnestic mild cognitive impairment (aMCI) have an annual
conversion rate from MCI to dementia three to six times higher
than that observed in normal aging.13,14 We will highlight age-
related changes in the hippocampus, a critical structure for learn-
ing and memory, and how these abnormalities could contribute
directly to the neurodegenerative process observed in AD.

Normal Course of Cognitive Aging

With aging, cognitive decline occurs in a number of domains,
but some processes remain unimpaired. For example, verbal
skills, implicit (procedural) memory and semantic memory are
often unimpaired.15 Similarly, memories of older events are often Figure 1. The trisynaptic loop of the hippocampus.
rigidly retained,16 but there are notable age-related deficits in In the trisynaptic loop of the hippocampus, flow is largely
executive functioning, attention, spatial learning, working memory, unidirectional. Information enters this loop via axons of layer II
episodic (declarative) memory, and the ability to form complex of the entorhinal cortex (EC), known as the perforant pathway,
associations.17,18 Interestingly, recent evidence suggests a com- and these axons connect to the dentate gyrus (DG) of the
hippocampus. The mossy fibers of the DG, in turn, project to
mon neurobiological source for many of these memory-related
the CA3, and the CA3 connects to the CA1 region via the
deficits, the hippocampus.19 In a range of species, hippocampal
Schaffer collaterals. Outputs of the CA1 project to the subiculum
lesions result in impairments in spatial and episodic memory.20
(SC), where the SC, and to a lesser extent the CA1, project
Similarly, AD is associated with profound neuronal death in the to the EC again, thereby completing the trisynaptic loop. In
hippocampus.21 However, unlike amnestic patients with clear addition to this unidirectional flow, layer III of the EC also directly
hippocampal destruction or AD, hippocampal neurons of species connects to the CA1 and SC (dotted lines), and layer II of the
exhibiting age-associated memory impairment are largely intact.22-24 EC provides direct connections to the CA3 via the perforant
Instead, age-associated memory impairments seem to arise from pathway. CA3 neurons also receive more than 95% of their
alterations in the functional connections of the hippocampus, input from recurrent CA3 collaterals, referred to as “auto-
particularly the cell groups of the trisynaptic loop (Figure 1). associative” tracts.
Compared with young rats, the dentate gyrus (DG) of aged
rats receives a fourth to a third fewer synaptic connections from
the entorhinal cortex (EC),25,26 with the reduction in synaptic rats.33 When the role of CA3 place cells in discriminating spatial
connections correlating with deficits in memory performance.26 representations was examined, young CA3 place cells were almost
The loss of inputs from the EC is consistent with the observation exclusively active in one arena. In contrast, aged CA3 place cells
that stimulation of the perforant path generates less excitation had high activity levels in both environments, suggesting aged
in the DG of aged rats.27 However, although the overall input is CA3 cells failed to rapidly encode changes in the environment.33
lower, the individual synapses become more powerful in older The hyperactivity of the CA3 may be explained by three age-
rats; stronger depolarizing responses are observed in aged granule related changes in hippocampal circuitry.33 First, there is an
cells due to an increase in quantal size.28 Changes in long-term age-associated decrease in hippocampal inhibitory interneurons.34-36
potentiation (LTP), believed to underlie learning and memory, Loss of these inhibitory interneurons may increase the suscepti-
have also been noted in aged mice; in synapses of the DG from bility of the aged hippocampus to hyperexcitability. There also
the perforant pathway, the threshold for LTP induction is elevated is an age-associated decrease in cholinergic modulation from
in memory-impaired aged rats29 and LTP decays more rapidly, with basal forebrain innervation,37,38 which releases the CA3 recur-
faster decays correlating with memory deficits.27 In memory- rent, autoassociation fibers from inhibition, leading to greater
impaired, aged humans, there also is evidence of atrophy of the activity.39 Third, there is diminished input from the EC to the
perforant pathway,30 as well as signal degradation of white mat- DG and CA3,25-27 yet there is no age-associated change in CA3
ter in the region of the perforant pathway.31 Similarly, synapses recurrent, autoassociation synapses.26,40 The loss of EC to DG
in the DG receiving input from the EC via the perforant pathway innervation is particularly important because DG firing increases
are reduced in MCI patients exhibiting memory deficits compared the activation of hilar interneurons, thereby suppressing CA3
to age-matched control subjects with no cognitive impairment.32 pyramidal cells;41 removal of the perforant pathway to the DG
Age-related alterations have also been noted in the CA3 region increases CA3 activity.41 The hyperexcitability of the CA3 is also
of the hippocampus. In memory-impaired aged rats, the firing observed in memory-impaired aged humans; aged individuals
rates of CA3 place cells are higher overall compared to young with poorer memory performance exhibit increased hippocampal

40
activation.42 Furthermore, patients with MCI exhibit greater Neural network hyperactivity may also be permissive for the
hippocampal activation during memory encoding,43-46 and development of AD. A hallmark of AD is the aggregation and
increased activation in MCI is predictive of the degree and accumulation of beta-amyloid (Aβ), a peptide produced by pro-
rate of cognitive decline and for conversion to AD.47 teolytic cleavage of the amyloid precursor protein (APP). Animal
In the CA1 region, age-related memory impairments are not studies suggest increased neural activity increases APP processing
associated with a loss of synapses from either the CA323, 26 or and cleavage by beta-amyloid cleavage enzyme (BACE), leading
EC inputs.26 Rather, aged rats with memory deficits exhibit to increased production of Aβ.65 Thus, the age-related increases
decreased excitatory postsynaptic potentials (EPSPs)48 and a in CA3 activity observed in rats,33 as well as that found in aMCI
30% reduction in the postsynaptic density (PSD) area of CA1 subjects,66,67 may well lead to an increase in Aβ production. Even
synapses.49 These alterations are believed to be due to an increase in the absence of increased neuronal activity, when synaptic
in the number of nonfunctional “silent” synapses, or synapses vesicles undergo exocytosis, extracellular Aβ levels increase.
with no AMPA receptors,50 a hypothesis supported by findings The latter might be particularly relevant for the aged DG cells,
of deficits in LTP induction at the Schaffer collaterals.51 The where overall input from the EC is lower yet individual synapses
number of L-type calcium channels in CA1 cells also increases become more powerful due to increases in quantal size,28 which
with age,52 which could explain the disruption of neuronal calcium typically represents an increase in synaptic vesicle size.68 Addi-
homeostasis observed in aging.53 The increase in L-type calcium tional support comes from mouse models of AD in which Aβ
channels may also explain why CA1 neurons are highly sensitive plaques were found specifically within the vicinity of hyperactive
to excitotoxicity and susceptible to loss in AD.54 Furthermore, neurons.69 Circumstantial human evidence also supports this view;
the age-related excess drive from the CA3 may increase the patients with temporal lobe epilepsy, who exhibit substantially
likelihood of excitotoxicity and subsequent loss of CA1 neurons elevated neuronal activity, develop amyloid plaques as early as
in AD.55 30 years of age.70
These age-related changes in hippocampal circuitry are subtle The relation between hyperactivity and memory impairments
when compared to the massive neuronal loss observed in AD. is more than correlational; reducing hippocampal hyperactivity,
Nevertheless, the impact these abnormal patterns of neural net- either by microinjection of an inhibitory neuropeptide in the
work activity may have on the development of AD could be CA3 or via systemic treatment with antiepileptic agents (sodium
significant and are discussed below. valproate and levetiracetam), dose-dependently improved memory
in aged rats71; despite testing the same range of doses in young
Relation Between Normal Cognitive Aging and rats, levetiracetam had no effect on memory performance, further
Alzheimer’s Disease supporting the view that dampening of hippocampal hyperac-
AD is a neurodegenerative disorder that targets connected tivity, not simply global cognitive enhancement, was responsible
neuronal networks.56 Effective regulation of activity in these for the memory improvement observed in levetiracetam-treated
neural networks is essential; over- or understimulation can aged rats.71 A low dose of levetiracetam also reduced the hippo-
erode synaptic regulation, leading to alterations in learning and campal activation observed in aMCI and improved performance.66
memory and, more concerning, neurodegeneration throughout Together, these studies suggest increased hippocampal activation
vulnerable networks.57 A particularly interesting phenomenon is not merely a compensatory response but a dysfunctional con-
observed in the years preceding AD diagnosis, before notable dition that may be permissive for the development of AD.
neuronal death occurs, is a hyperactivity of the distributed memory
network, composed of the hippocampus, medial temporal lobe Stroke and Aging
and a subset of cortical regions.58 For example, hippocampal Epidemiology of Stroke
activation during memory tasks is abnormally high for middle- Strokes are rare in people under the age of 18 years, then in-
aged and elderly people with the ApoE4 allele, a known genetic crease in prevalence as people age (Figure 2). In both men and
risk factor for AD, and longitudinal assessment indicates the women, prevalence of stroke increases from <0.6% in the age
degree of hippocampal overactivation correlates with declines group of 20-39 years to nearly 14% in the >80 year old group.
in memory.59 Hyperactivity has been confirmed by multiple After the age of 55 years, there is a doubling of stroke prevalence
laboratories examining individuals at genetic or familial risk of with each passing decade of life. This greater than 23-fold
AD,60-63 as well as asymptomatic and minimally impaired older increase in the prevalence of stroke over the life span indicates
individuals with amyloid deposition.64 Although this hyperac- that aging is the greatest risk factor for stroke in our population.
tivity was once believed to be a compensatory response for In the U.S., stroke is more common in the Southeast and
deteriorating circuitry (i.e., greater cognitive effort to achieve Appalachian regions than in the rest of the country. This is
comparable performance),61 more recent evidence suggests this hypothesized to be the result of poor lifestyle choices that
hyperactivity may signify neuronal excitotoxicity and could contribute to poor overall health. The Appalachia and Southeast
represent a therapeutic target. differ from national norms in demographics, socioeconomic

41
 known factors contributing to the age-related increase in the
prevalence of stroke are chronic suppression of the immune
system (See Immune System, Aging and Stroke, below), the lack
13.9 13.8
of adaptation of the autonomic nervous system77 and cardiovas-
Percent of Population

cular system78 with age, and the age-related alterations in the

endocrine system.79 The maladaptation of these four integrative
systems, immune, autonomic, cardiovascular and endocrine,
6.2
6.9 could contribute substantially to the age-related increase in stroke.
However, the relative contributions of each of these systems
to the age-related increase in the prevalence of stroke are not
2.1 2.1 known and the mechanism(s) by which they contribute to the
0.4 0.6 increase in strokes is only now being characterized.
20-39 40-59 60-79 80+
Age (Years) Connection Between Stroke and Dementia
Stroke ranks as the fourth leading cause of death and the
Figure 2. Prevalence of stroke by age and sex. National
Health and Nutrition Examination Survey: 2007–2010.
most common cause of permanent disability in the U.S. Stroke
Source: National Center for Health Statistics and National survivors must cope with ongoing neurological impairment and
Heart, Lung and Blood Institute. sensorimotor functional deficits as well as a decline in cognitive
ability.80 Epidemiological studies have shown that the prevalence
of dementia in ischemic stroke patients is ninefold higher than
characteristics, health status, health care needs, and access to controls at three months81 and four to 12 times higher than controls
care. They have low per capita and household incomes.72,73 It is four years after a lacuna infarct.76 Many of these dementias develop
well-documented that there is a direct correlation between eco- progressively after stroke, suggesting that this cognitive decline
nomic and financial stability and health status, e.g., the more is not a direct consequence of the initial ischemic damage.82
economically disadvantaged a group is, the poorer the health In animal models, we identified a progressive decline in spatial
status of that group.74 Other reasons for poor health status and learning and memory after ischemic stroke that correlates with
outcomes are linked and include a number of characteristics, suppression of hippocampal LTP, an electrophysiological correlate
the impact of which contributes to negative population health of memory.83 Additionally, we have demonstrated that stroke
outcomes. One example of this is documented for the state of induces neuropathological features of AD, including tau hyper-
West Virginia. Two-thirds of its 1.8 million people live in com- phosphorylation,84 BACE1 activity,85 aberrant neuronal cell cycle
munities with fewer than 2,500 residents, and 49 of 55 counties reentry,86 and overproduction of APP.87 As such, patients that
are designated either fully or partly as Health Professional Shortage experience a stroke may be at risk of developing AD-like neu-
Areas and/or Medically Underserved Areas. In 2010, the state ropathology and subsequent cognitive decline.
ranked second worse in the nation in cancer deaths, fourth in No studies have assessed Aβ fibular plaques density or neuro-
heart disease-related deaths, fourth in stroke prevalence, and fibrillary tangles following stroke in human subjects. Such studies
first in overall diabetes prevalence, heart disease and hyperten- are needed to fill a gap in knowledge about post-stroke events that
sion.72 Data from 2010 indicate that 26% of West Virginians may link animal studies demonstrating AD-like neuropathology
smoked cigarettes (second), 32% were obese (fifth), and the and clinical studies showing cognitive decline following stroke.
state ranked first in adult physical inactivity.75 Collectively, these
factors contribute to the unacceptably high prevalence of stroke Immune System, Aging and Stroke
among West Virginians. Other Southeastern states share many of It was once thought that the brain was an immune-privileged
these health outcome characteristics. Rural communities experi- organ that did not produce an inflammatory response to ischemic
ence higher levels of chronic conditions (46.7%) than do urban brain injury.88 However, it is now well-established that cells in the
areas (39.2%), and these populations tend to be understudied brain produce and secrete cytokines, chemokines and adhesion
and underserved. molecules enabling the brain to mount a central and peripheral
The potential contributing factors to this age-related increase inflammatory response to ischemia.89,90 Both central and periph-
in the prevalence of stroke are many and may be linked. Factors eral inflammation contributes to the pathophysiology of stroke91,92
known to be associated with an increase in stroke prevalence are and neurodegenerative disease.93 There is increasing evidence
biological factors, such as hypertension, diabetes, metabolic that peripheral inflammation not only plays a role in the pathology
syndrome, and obesity, and behavioral factors, such as sedate of stroke but also impacts stroke etiology by increasing suscep-
lifestyle, smoking and excess alcohol use. These identified bio- tibility.94 In addition, altering peripheral inflammation during
logical factors are well-known to increase with age.76 Less well- neurodegenerative disease significantly alters disease course.95

42
Risk factors such as atherosclerosis, obesity, diabetes, and hyper- that activate the tissue factor-mediated extrinsic pathway of co-
tension are associated with an increased peripheral inflammatory agulation. Clinical studies have observed in stroke patients with
profile, and the majority of stroke patients have at least one of infections increased platelet activation and decreased concentra-
these risk factors.96 Many of these factors could participate in tions of anticoagulatory molecules, such as antithrombin, activated
regulating interactions between the central and peripheral immune protein C and free protein S.114,115 Preclinical studies confirm
systems, those classically identified as immune-response medi- these findings and demonstrate that systemic administration of
ators and those traditionally unassociated. A further understanding proinflammatory cytokines mimic characteristics of infection.
of the interaction between the immune and nervous systems is Obese animal models and animal models with other comorbid
important to determine the contribution of maladaptive immune diseases, such as diabetic mice and spontaneously hypertensive
responses as a causative factor in both stroke and AD, resulting rats, exhibit larger infarcts and more severe neurological
in disease progression and poor functional outcome. deficits.116,117 These preclinical and clinical studies support the sig-
Stroke most commonly occurs when an atherosclerotic plaque nificance of peripheral inflammation and its impact on stroke, and
ruptures resulting in thromboembolism. The initiation and progres- how the interaction between the immune system and the brain can
sion of plaques are driven by inflammatory cells and mediators, affect neurological dysfunction after an ischemic insult.
such as cytokines and chemokines.97 Dysfunctional endothelial Not only does acute and chronic inflammation preceding
cells of the vascular wall at the site of the atherosclerotic lesion stroke increase susceptibility to stroke and increase brain damage
express adhesion molecules such as VCAM-1 and ICAM-1 that after stroke, but also stroke itself initiates a local inflammatory
recruit macrophages and T cells.98 These immune cells produce response in the brain and peripheral inflammation that can amplify
cytokines and chemokines along with vasoactive molecules that this central inflammatory reaction. Interruption of cerebral blood
activate immune cells and smooth muscle cell proliferation result- flow results in the deprivation of oxygen, glucose and other
ing in the progression of the atherosclerotic lesion.99 The contin- essential nutrients to the brain and leads to a complex, multi-
uous recruitment of immune cells and activation results in the faceted cascade of inflammatory events. Acutely after ischemia,
formation of a mature plaque, and activated macrophages and microglia are activated due to the increase in extracellular ATP
T cells are a significant part of the plaque.100 These activated from the depolarization of neurons and glia, and activated microglia
immune cells secrete matrix metalloproteinases (MMPs), which secrete cytokines and chemokines along with developing phago-
are collagen-degrading proteases that destabilize the plaque and cytic properties.118 Within four to six hours after an ischemic
result in the rupture of the plaque, causing ischemia.101 It is clear insult, peripheral leukocytes migrate and adhere to vessel walls
that inflammation is an essential contributor to the development and infiltrate into the ischemic brain tissue producing deleterious
and progression of atherosclerosis, and numerous preclinical inflammatory mediators.92 Numerous studies have shown that
studies demonstrate that animal models deficient in adhesion neutrophils are the first blood-derived cells from the periphery to
molecules, inflammatory mediators and T cells attenuate the infiltrate ischemic brain tissue, and when neutrophil infiltration
progression of plaque formation and the instability of the is inhibited, infarct size is significantly decreased.119-121 Reper-
plaque.100,102-104 Clinical studies using positron emission tomog- fusion of the occluded vessel generates reactive oxygen species
raphy (PET) have shown patients presenting with transient ischemic (ROS) resulting in further activation of immune and brain cells
attacks have high 18F-fluoreodeoxyglucose (FDG) signals in and oxidative stress, and these activated cells secrete cytokines,
atherosclerotic plaques.105,106 FDG is taken up by macrophages chemokines, MMPs, nitric oxide (NO), more ROS, and adhesion
and indicates the degree of macrophage activation, which further molecules that increase cell death and disruption of the blood-
supports inflammation causing plaque instability.107 brain barrier (BBB).118,122 Moreover, reperfusion and disruption
Increased atherosclerotic burden is a hallmark of obesity and of the BBB leads to further leukocyte infiltration into the brain,
diabetes, and these comorbid diseases cause endothelial dys- amplifying the inflammatory response and enhancing damage.
function through insulin resistance and inflammation.108 Thus, The peripheral and central inflammatory response after ischemia
risk factors such as obesity and diabetes increase stroke suscep- leads to an increase in neuronal death, infarct size and severity
tibility through proatherogenic effects. Furthermore, clinical of stroke.
studies have linked peripheral bacterial infections and increased Adhesion molecules are essential for leukocytes to infiltrate
stroke susceptibility during the first three days after infection.109,110 into the brain after stroke, and notably ICAM-1 and VCAM-1,
Infection is known to increase vascular disease along with increas- the same adhesion molecules that recruit immune cells to ather-
ing inflammatory mediators, such as cytokines, to clear the infec- osclerotic lesions, mediate the interaction between leukocytes
tion, which can promote the formation of plaques and increase and the vascular endothelium.123 Furthermore, both ICAM-1 and
destabilization of the plaque.111,112 Along with the proatherogenic VCAM-1 expression increase after stimulation by cytokines,
effects of infection, infection promotes a hypercoagulable state.113 such as TNF-α and IL-1, which are increased after stroke and
Interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) are in obese, diabetic and atherosclerotic patients.92 An experimental
cytokines that increase during the inflammatory response to infections stroke study in diabetic rats showed higher expression of ICAM-1

43
in diabetic rats after stroke compared to non-diabetic rats, and and the almost exclusive use of mitochondrial oxidative phos-
this increase in adhesion molecules due to comorbid diseases phorylation (OxPhos) for the production of ATP.142 As such,
and infection could contribute to the exacerbation of stroke and even transient reductions in O2 or glucose put neurons at risk of
increase susceptibility to stroke.124 Moreover, using ICAM-1 dysfunction and death.
deficient mice and inhibiting ICAM-1 and VCAM-1 in experi- During aging143,144 and AD,145,146 brain mitochondrial function
mental stroke studies result in smaller infarct sizes.125,126 Clinically, is compromised, expressed as a reduction in OxPhos, transport
increased plasma and cerebral spinal fluid levels of ICAM-1 and of mitochondria from soma to energy-demanding synapses and
VCAM-1 are observed in stroke patients and correlated with excessive mitochondrial fission.146 Thus, both normal aging and
stroke severity.127,128 Thus, peripheral inflammation due to infec- disease aging, like AD, set the stage for limited mitochondrial
tion or other comorbid factors may increase stroke severity and response to ischemia. These mitochondrial defects could be re-
stroke susceptibility by increasing adhesion molecules and other sponsible for the increase in the prevalence of stroke, increase
inflammatory mediators, which produce an environment that in severity of infarcts, and the limited recovery from stroke
enhances leukocyte activation and adhesion. with advancing age.
It is evident that stroke is a vascular disease that results in With age and AD, the brain experiences a reduced capacity
neurological deficits after an ischemic insult, and it is not sur- to take up and utilize glucose as an energy source.143-146 This
prising that the prevalence of stroke increases with age because reduction in glucose utilization in the face of persistent energy
aging affects the vasculature and the immune systems. Capillary demand means that the brain must tap into other sources of
networks and density decrease during aging in the cortex of adult energy to supply its basic functions and to respond to ischemic
humans and animals.129,130 Chronic inflammation and acute infec- events. In the absence of glucose, brain mitochondria use ketone

β-oxidation to supply carbon fragments for OxPhos.147

tion contribute to capillary disruption and cell loss resulting in bodies derived from endogenous sources or dietary lipids through
a leaky BBB, and aged rodents exhibit increased BBB disruption
along with reduced neurogenesis after stroke.131-133 In addition, The use of endogenous sources of fatty acids for fuel for
age-associated immune system dysfunction increases the inci- mitochondria may contribute to the initiation or progression of
dence of acute infections and comorbid factors characterized AD. Landfield et al. reported that both aging148 and AD149 are
by inflammation, such as diabetes and atherosclerosis, and as associated with an upregulation of genes for myelin degradation,
discussed above, these comorbid factors greatly increase sus- suggesting that the aging and diseased brain may autocatabolize
ceptibility to stroke and worsen the outcome after stroke.134 this vital material to generate energy. Additionally, it is now
Aged individuals are in a chronic state of low-grade inflam- recognized in both normal aging and AD, there is a progressive
mation referred to as inflamm-aging, and during inflamm-aging, loss of white matter, a possible reflection of the digestion of
there is a shift in cytokines toward a proinflammatory state pro- myelin for fuel.150,151 Brinton et al.152,153 have shown that trans-
ducing proinflammatory cytokines such as TNF-α and IL-1.135,136 genic (Tg) mice contain mutations in genes for human APP,

ance of β-oxidation in very early in life, arguing that AD muta-

The immune dysregulation theory supports the idea that during presenilins and tau, mitochondrial defects in OxPhos, and appear-

tions cause an early life switch from glucose to β-oxidation of

healthy aging, anti-inflammatory mediators, such as IL-10, inhibit
proinflammatory mediators; however, when the system is chal-
lenged by an acute infection, comorbid factors, genetic predispo- lipids in neurons.
sition and environmental factors, the immune system is unable Inasmuch as both normal aging and AD compromise mito-
to mount an anti-inflammatory response to shift the proinflam- chondrial structure, function and movement, the possibility is
matory state, resulting in an increased incidence of infections, strong that progressive mitochondrial defects contribute to the
stroke and possibly AD.134,137 Thus, understanding the effect of age-related increase in stroke prevalence, severity and lack of
age alone on stroke is difficult because it is likely that age is a recovery. Further, the extent to which factors known to increase
surrogate for increased chronic inflammation associated with the risk of stroke do so by decreasing mitochondrial function is
comorbid diseases. This creates a proatherogenic and procoag- a challenge to the field of stroke research. Finally, methods of
ulable state responsible for the increased incidence of stroke in enhancing mitochondrial functions as a therapeutic target to
the aged. prevent, treat and recover from stroke have not yet been explored.

Mitochondrial Role in Propensity to Stroke Summary and Conclusions

Ischemic stroke represents 87% of all strokes.4 During ischemia, It is clear that nonpathological aging results in cognitive decline,
there is a transient or permanent decrease in blood flow to the primarily through loss of synapses, while cognitive decline in
affected brain regions, resulting in deprivation of oxygen (O2) AD is associated with both synaptic and neuronal losses. Further,
and glucose. The brain represents only 2% of the body mass the age-related increase in stroke incidence and severity is asso-
but consumes >20% of O2 and glucose,138 the result of the ciated with cognitive loss. There are a number of factors that are
high-energy demand of neurons to maintain ion gradients 139-141 common in both stroke and age-related cognitive decline, which

44
suggests that common pathological processes may be at work 9. Rowe JW, Kahn RL. Human Aging: Usual and Successful.
in these diseases. These include chronic inflammation due to Science. 1987;237:143-149.
comorbid factors, such as cardiovascular disease. It is also appar-
ent that chronic inflammation is a consequence of immune system 10. Verhaeghen P, Vandenbroucke A, Dierckx V. Growing Slower
dysfunction with age and stroke, producing an uninhibited proin- and Less Accurate: Adult Age Differences in Time-Accuracy
flammatory phenotype. Finally, we now have evidence that with Functions for Recall and Recognition from Episodic Memory.
aging, mitochondrial structure, function and trafficking in neurons Exp Aging Res. 1998;24:3-19.
is compromised, a condition that could account for part of the
age-related increase in stroke prevalence and severity as well as 11. Small SA, Stern Y, Tang M, Mayeux R. Selective Decline
age-related cognitive decline, and perhaps AD. As such, targeting in Memory Function Among Healthy Elderly. Neurology. 1999;
mitochondria for intervention could be a promising new area 52:1392-1396.
for research.
12. Lindsay J, Laurin D, Verreault R, et al. Risk Factors for
Acknowledgements Alzheimer’s Disease: A Prospective Analysis from the Canadian
The research described herein was supported, in part, by the Study of Health and Aging. Am J Epid. 2002;156:445-453.
following grants: P01 AG022550 (JWS), P01 AG027956 (JWS),
the Robert Wood Johnson Nurse Faculty Scholars Program 13. Luck T, Riedel-Heller SG, Kaduszkiewicz H, et al. Mild
(TLB) and National Institute of General Medical Sciences, Cognitive Impairment in General Practice: Age-Specific Preva-
U54GM104942 (MNR), and the Alzheimer’s Association, lence and Correlate Results from the German Study on Aging,
NIRG-12-242187 (MNR). Cognition and Dementia in Primary Care Patients (agecode).
Dement Geriatric Cogn Disord. 2007;24:307-316.
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Notes

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Enhancing Cognitive Function Through Diet in Cats
Yuanlong Pan, PhD,1 and Norton W. Milgram, PhD 2,3
1
Nestlé Purina Research
St. Louis, MO
2
CanCog Technologies
Toronto, Canada
3
University of Toronto
Department of Pharmacology
Toronto, Canada
Email: [email protected]

In this study, we selected a blend healthy brain aging is to retard brain

of nutrients based on their ability to Glossary of Abbreviations atrophy by reducing or eliminating
either minimize or eliminate risk factors AAFCO: Association of American Feed risk factors associated with brain
associated with brain aging and demen- Control Officials aging and dementia.3 Accelerated
tia, and we tested the effects of the blend AD: Alzheimer’s Disease brain aging and dementia have been
on cognitive functions in middle-aged ANOVA: Analysis of Variance associated with many risk factors,
BPB: Brain Protection Blend
and senior cats. The cats were tested on including increased oxidative stress,
CDS: Cognitive Dysfunction Syndrome
four cognitive test protocols during the chronic inflammation, DHA deficiency,
DHA: Docosahexaenoic Acid
one-year study. The cats fed the test diet DNMP: Delayed-Non-Matching-to-Position Test high homocysteine, low status of
showed significantly better performance EPA: Eicosapentaenoic Acid vitamin B6, vitamin B12 and folic
on three of the four tests. The results FGTA: Feline General Test Apparatus acid, high blood pressure, and cerebral
support our hypothesis that brain Land-0: Landmark 0 Task vascular lesions.14-22
function of cats can be improved by Land-1: Landmark 1 Task Since multiple factors are linked to
the nutrient blend that minimizes or NO: Nitric Oxide accelerated brain aging and dementia
eliminates the risk factors associated RBC: Red Blood Cells risk, we would not expect any single
with brain aging and dementia. nutrient or bioactive compound to
Cognitive dysfunction syndrome (CDS) is a major disease retard brain aging and reduce the risk of dementia. Many risk
in geriatric cats and is clinically associated with disorientation, factors have been identified for higher risk of dementia, including
altered social interactions, sleep-wake cycle disturbance, loss Alzheimer’s disease (AD) in people.14-22 Limited data suggests
of housetraining, and altered activity levels and patterns.1,2 It has that the same risk factors associated with higher risk of AD in
been estimated that CDS affects 28% of 11- to 14-year-old cats people (age, gender, sex hormone deficiency, oxidative stress)
and 50% of cats over 15 years of age.1,2 Severe and irreversible are also linked to higher risk for CDS in pets.23 Therefore, we
loss of brain cells and synapses results in dementia in people and formulated a blend of nutrients, referred to as the Brain Protec-
CDS in pets over the course of aging.3-6 tion Blend (BPB), based on their ability to minimize or eliminate
The brains of aged cats, like both dogs and humans, develop the risk factors associated with accelerated brain aging and
beta-amyloid pathology,7,8 including plaques immunopositive for dementia. The BPB includes fish oil, arginine, B vitamins, and
AB42, but lack senile plaques observed in the human brains.9 selected antioxidants. Fish oil containing DHA and EPA prevents
Although aged cats have also been reported to develop hyper- and corrects DHA deficiency and offers anti-inflammatory
phosphorylated tau protein, they don’t develop neurofibrillary benefits.24,25 Arginine enhances nitric oxide (NO) synthesis,
10
tangles. We have recently reported that neuropsychological test which is involved in circulation, blood pressure control and
performance in cats shows age-dependent changes that parallel cognition.26,27 B vitamins prevent and correct any B vitamin
those seen in dogs and in humans.11 deficiency and minimize the risk of hyperhomocysteinemia.28-30
Dementia in humans and CDS in pets are not curable diseases Antioxidants, including vitamins E, C and selenium, protect both
because brain cells and synapses that die cannot be replaced in brain tissue and blood vessels against oxidation and inflammation-
sufficient quantities to provide normal brain functions.3-5, 12,13 induced damage.31-36
Therefore, a more promising strategy is disease prevention focus- The objective of this study was to determine the effect of BPB
ing on retarding the loss of brain cells and synapses in both humans on cognitive functions in middle-aged and senior cats. The cognitive
and pets. We have hypothesized that the best option to promote evaluation included protocols for assessing landmark discrimination,

53
 reported by Christie et al.39 The size discrimination protocol was
Table 1. Dietary Compositions*
also previously reported for cognitive evaluation of dogs.40,41
Control Test (BPB)** Both the egocentric and size discrimination protocols included
Nutrient Composition (% as fed) reversal learning components, which were intended to provide
Moisture 8.31 8.19 measures of the executive function.41 The initial DNMP test was
Ash 5.75 6.08 used in group stratification.
Crude Protein 40.50 40.90
Crude Fat 17.9 18.6 Materials and Methods
Crude Fiber 1.08 0.87 Cats and Diets
Linoleic Acid (% of total fat) 14.0 13.7 Thirty-two domestic shorthaired cats aged 6.65 ± 0.72 years
Energy Content (range 5.5 to 8.7 years) were enrolled in the study with 16 cats
Calculated ME§(kJ/g) 16.20 16.33
per group. The cats were randomly assigned to either the control
* This table is modified from the original published in a previous paper42 or test group based on their baseline DNMP test results. The study
§ Calculated based on the predictive equation for metabolizable energy in cat foods61
protocol, which was approved by the CanCog Technologies
** BPB = Brain Protection Blend including the addition of DHA, EPA, vitamin C,
and elevated levels of arginine, B vitamins, selenium, and alpha tocopherol Institutional Animal Care Committee, complied with the guide-
lines of the Ontario Ministry of Agriculture and the Nestlé
Table 2. Levels of BPB Ingredients in Diets§
Purina Animal Welfare Guidelines. The cats were group-housed
based on compatibility in rooms with environmental enrichment
Control Test (BPB)* consisting of toys, beds and opportunities to play outside daily.
Eicosapentaenoic Acid (EPA)** 0.04 0.28 The control diet was based on a commercial super-premium
Docosahexaenoic Acid (DHA)** 0.04 0.27 product for adult cats. Both diets, manufactured by Nestlé Purina
Arginine** 1.48 2.30 PetCare (St. Louis, MO), were isoenergetic and contained the
Alpha Tocopherol Acetate(mg/kg) 73.6 550 same levels of protein, fat and carbohydrates, but they differed
Vitamin C (mg/kg) 0 80 regarding the ingredients from the BPB (Tables 1 & 2). Cats were
Selenium (mg/kg) 0.72 1.00 individually fed their assigned diet in sufficient amounts to main-
Thiamine (mg/kg) 37.3 55.0 tain body weight.
Riboflavin (mg/kg) 17.2 30.9
Jugular blood samples were collected at baseline and after
Pantothenic Acid (mg/kg) 26.1 55.4
200 or 345 days of treatment to measure selected folic acid, B12
Pyridoxine (mg/kg) 15.4 18.0
Cyanocobalamin (mg/kg) 0.05 0.09
and homocysteine concentrations, fatty acid profiles in red blood
Folic Acid (mg/kg) 1.6 4.25 cells (RBC), and total antioxidant status.

§ This table is modified from the original published in a previous paper42 Cognitive Testing Apparatus
* BPB = Brain Protection Blend including the addition of DHA, EPA, vitamin C, All cognitive tests were conducted with the Feline General
and elevated levels of arginine, B vitamins, selenium, and alpha tocopherol
** % as fed Test Apparatus (FGTA),43 which has an enclosure with a front
consisting of three adjustable gates and a movable food tray.
The cats stayed in the enclosure for 5 to 15 minutes, depending
Table 3. Cognitive Test Schedule§
on the cognitive tests. The technician was separated from the cat
by a one-way mirror and a hinged door, which could be opened
Cognitive Tests Days
Baseline DNMP Test -12 to -1 for presentation of the food tray. A food reward, consisting of
Egocentric Protocol 31 to 74 approximately 1 gm of canned cat food that was selected based
Landmark Protocol 82 to177 on the individual preference of the cat, was used to motivate the
Size Discrimination Protocol 201 to 281 cat to participate in the tests.
Retest of DNMP 304 to 345 All cognitive tests were administered by trained behavioral
technologists who were blinded with respect to diets. All cog-
§ This table is modified from the original published in a previous paper 42
nitive testing was performed in the morning or early afternoon,
and each cat was tested at about the same time each day.
egocentric discrimination, size discrimination, and visuospatial
memory, or the delayed-non-matching-to-position (DNMP) test. Baseline Cognitive Testing and Randomization
The landmark discrimination learning test was designed to assess All the cats enrolled in this study had previous cognitive testing
visuo-spatial learning and perception, and it had previously been that included, at a minimum, testing on object discrimination
shown to be sensitive to age in dogs.37,38 The egocentric test pro- and reversal learning and on a two-component version of the
tocol was designed to assess egocentric spatial ability as initially DNMP task.44 Twelve cats had been extensively trained on a

54
variety of cognitive tasks and were characterized as an experi- Cats were given the tests daily until they successfully achieved
enced group. The remaining 20 cats had the minimal possible a two-stage learning criterion. The cats completed the first stage
experience and were, therefore, classified as an inexperienced when they either made 11 or more correct choices on one day,
group. The cats were divided into two equal groups based on: 20/24 over two consecutive days, or 29/36 over three consecu-
(1) baseline cognitive performance on the DNMP task over five tive days. To complete the second stage, the cats had to select
consecutive sessions, and (2) extent of previous cognitive expe- correctly on at least 26 of 36 trials over three successive sessions.
rience. After striation, the two treatment groups were equivalent After completion of the egocentric discrimination phase, the
in body weight (4.26±0.27 kg for control and 4.13±0.20 kg for location of reward was switched to the opposite side. Thus, if the
the BPB group), age and cognitive performance. The groups cats were initially rewarded for approaching the object closest to
were then randomly assigned to dietary treatment. After a 30- their left side, they were now rewarded for approaching the
day wash-in period, the cats were evaluated with four cognitive object closest to their right side. After completing the first reversal
test protocols (Table 3). task, the cats were given additional reversal training until they
completed a total of 40 sessions following the egocentric dis-
Cognitive Test Protocols crimination. For the first and second reversal tasks, a two-stage
The delayed-non-matching-to-position task evaluates both learning criterion was used. Completion of these stages used
visuo-spatial learning and short-term visuo-spatial memory, and the same criteria as completion of the egocentric discrimination
the test procedure was based on a protocol originally developed phase. For subsequent reversals, a one-stage criterion was used;
for dogs.44 The cats were presented with a series of trials, in which the cats completed the stage if they either selected correctly on
each contained both a sample phase and a test phase. During 90% or more of the trials on a single day or if they responded
the sample phase, the cat was presented with a single object correctly on 80% of the trials over two successive days.
covering a food reward over either the left or right food well. The landmark discrimination task evaluated allocentric spatial
During the test phase, the cat was presented with two identical learning ability, which entailed utilization of an external landmark
objects covering both the left and right food wells. To obtain the to locate a food reward. The protocol consisted of two parts:
food reward, the cat had to respond to the well that was not Land-0 and Land-1. During Land-0, the landmark (a yellow rod)
covered during the sample phase. All cats had been trained on was attached to the middle of one of two coasters and the cats
the DNMP prior to the study. At baseline, the cats were all had to respond directly to the landmark to obtain the reward. The
given five test sessions, and their performance was used in cats were given 10 trials per day until they either completed a
group randomization. During the test phase, the cats were two-stage learning criterion or failed to complete the criterion
tested for relearning of the DNMP task with the delay between within 30 training days. To complete the first stage, the cats had
the sample and test phase set at 5 seconds. to first select correctly on at least 9/10 trials on a single day or
In the egocentric test, cats were required to locate the food on 16/20 trials over a two-day period. To complete the second
reward by selecting an object based on the proximity to either stage, the cats had to respond correctly on 70% of the trials over
its left or right side.39 The egocentric test protocol consisted of three consecutive days. Thus, it took a minimum of four days
three phases: a one-day preference test phase, an egocentric for the cats to complete the two-stage criterion. Cats that failed
discrimination phase and an egocentric reversal phase. The to complete the task within the 30 days were given a remedial
reversal task is designed to assess executive function including training. If a cat failed to pass Land-0 after remedial training, it
the ability to switch response sets, adapt to new situations, and was not tested further on the subsequent Land-1 task. During the
reason. During the preference test phase, cats received 10 pre- Land-1 test, the landmark was placed 2.5 mm from the edge of the
sentations of identical objects to both the left and right food wells, coaster and the cats had to select the coaster closer to the landmark.
with both objects covering a food reward. Thus, the cats were The size discrimination task measures visual discrimination
rewarded for selecting either object (well). The side that the cat learning ability, which depends on associative learning. The rever-
selected more frequently was designated the preferred side. If sal task assesses executive function. The cats were first trained
both sides were selected equally, the preferred side was decided to respond to one of two identical objects that differed in size.
by a coin toss. The preferred side was used as the correct choice The test protocol started with a one-day preference test, in which
during the egocentric discrimination phase. For example, if the the cats were allowed to respond to either of two objects over
preferred side was the left side, then during the egocentric dis- 10 trials, with both responses associated with reward. The object
crimination phase, the cat was rewarded for selecting the left chosen more frequently was considered the preferred object and
food well covered by an identical object. was used as the correct object associated with reward during the
During the egocentric discrimination phase, the cats received discrimination learning phase. After the preference test, the cats
12 trials per day using two wells for each trial with three possible received up to 40 sessions to complete a two-stage learning cri-
configurations: left versus center, left versus right, or right versus terion on the size discrimination task. After completion of the size
center. Each configuration was given to the cat for four trials. discrimination task, the cats were trained on the reversal learning

55
task. The protocol was identical to that of the size discrimination
Table 4. Performance (% correct) on Egocentric
learning test, except that the correct object associated with the Discrimination and Reversal&§
reward was reversed. The cats were given a maximum of 40
sessions to pass the reversal task. For both phases of the tests, the Control BPB
passing criterion was the same as that used for the landmark test. Mean SE Mean SE
Egocentric Discrimination 75.46 1.37 80.39* 1.66
Statistical Analysis Egocentric Reversal 59.75 1.10 67.02** 0.99
We originally planned to use an error measure as evidence of
§ This table is prepared from the data published in a previous paper42
cognitive performance, with a failure to respond counted as 0.5 BPB = Brain Protection Blend
error. However, a number of cats did not achieve the a priori & n = 16
* Control vs. BPB: p=0.042
learning criterion due to frequent response failures, which arti- ** Control vs. BPB: p=0.002
ficially elevated the total number of errors in individual cats that
normally performed very accurately. Accordingly, we analyzed
the data with a second target variable, which was the percent of The BPB diet did not significantly affect blood vitamin B12,
correct responses of the total attempted responses, ignoring trials homocysteine or total antioxidant capacity; however, cats fed
with response failures. For instance, if an animal responded the BPB diet had significantly (p<0.05) higher fasting blood
correctly on five trials out of five attempted responses but failed levels of folic acid (10.18±1.41 vs. 15.6 ±1.51ng/ml) 200 days
to respond on the other five trials, its score would be 100%. In after the feeding started. Body weights did not differ significantly
addition, it became necessary to remove individual cats from between control and BPB groups at any point.
specific tasks because of too frequent inconsistent responses.
For the BPB group, two cats were removed from the landmark Effect of Diets on Performance of the Egocentric Test
test, two from the size test, and one from the DNMP. The results of analysis revealed highly significant main effects
The data were analyzed using either analysis of variance or of treatment and task. Cats in the BPB group performed signifi-
two-tail t tests. The results were considered statistically significant cantly more accurately on both tests than the cats in the control
if the significance level was ≤0.05. Repeated measures analysis group (Table 4).
of variance was used for determining differences between groups
in body weight, fatty acid profiles of RBCs, vitamin B12, folic Effect of Diets on Performance of the Landmark Test
acid, and total antioxidant status. Values are expressed as means Two of the cats in the BPB group were dropped before com-
± SEM except the cognitive data in the figures. pleting the land-0 task because of inconsistent responding, and
The data for the initial learning and reversal of the egocentric their data were not included in the statistical analysis. The results
test were analyzed with a repeated analysis of variance using task revealed a significant effect of task (p=0.009) and no other sig-
as the within subject variable and both treatment (control versus nificant effects or interactions. Although cats in the BPB group
BPB) and experience as the between subject variables. The data of performed more accurately than the cats in the control group,
size discrimination tests were analyzed with a repeated measures the difference was not statistically significant (Figure 1).
ANOVA using treatment group and experience as between subject
variables and task (size discrimination and reversal) as the within Effect of Diets on Performance of the Size Discrimination
subject variable. The data from landmark tests were analyzed Learning and Reversal Tests
with a repeated measures ANOVA, using treatment group and Analysis revealed a significant effect of group and a margin-
previous experience as between subject variable and task as a ally significant effect of task (Figure 2). The task effect reflects
within subject variable. The data of the DNMP test were analyzed less-accurate performance on the reversal learning phase. The
with a factorial analysis of variance using diet and previous significant group effect was driven by group differences in the
experience as within subject variables. discrimination learning phase, in which the cats in the BPB
group performed significantly better on the size discrimination
Results task (Tukey multiple comparisons; p=0.010) than the cats in the
Effects on Body Weight, Fatty Acid Profile of RBCs, control group.
B Vitamins, and Total Antioxidant Status
The cats in both groups had identical fatty acid profiles at Effect of Diets on Performance of the DNMP Test
the baseline. By the end of the study, the cats in the BPB group The results showed a significant effect of diet (p=0.0149),
had significantly higher DHA, EPA, total n-3 fatty acids, lower and no other significant effects or interactions (Figure 3). The
LA, and total n-6 fatty acids than the cats in the control group. cats in both groups performed at equivalent levels at baseline;
In addition, the cats fed the BPB diet had significantly lower however, cats in the BPB group performed significantly better
omega-6 to omega-3 ratios than the cats fed the control diet. than cats in the control group at the end of the study.

56
 With the exception of the landmark discrimination protocol,
the cats fed the BPB diet showed significantly better performance
than the cats fed the control diet. In the egocentric task, the cats
in the BPB group performed significantly better in both discrim-
ination and reversal tasks than the cats in the control group. The
cats fed the BPB diet performed significantly more accurately on
the size discrimination test. Finally, the cats in the BPB group had
significantly better performance in the DNMP than the cats in
the control group.
Collectively, these data indicate that the BPB diet has either
cognition-enhancing benefits, neuroprotective benefits, or possibly
both. The suggestion that the diet may have cognition-enhancing
properties is supported by the fact that the cats fed the BPB diet
showed significantly better cognitive performance in the ego-
centric tests, which started within a month of the study yet was
Figure 1. Effects of the BPB supplementation on cats’ perform- too short a timeframe to demonstrate neuroprotective effects.
ance in object discrimination (Land-0) and landmark discrim- The suggestion that the diet had neuroprotective effects was
ination (Land-1) learning tasks. The performance was expressed supported by the results of the DNMP test, in which performance
as percent of correct choices. The data are means ± SE, of the cats fed the BPB diet at the end of the one-year study was
n = 16 for controls and n = 14 for BPB group. This figure is
significantly superior to that of the cats fed the control diet. The
prepared from the data published in a previous paper.42
lack of any savings effect in the control cats may be due to an
age-related cognitive decline over the one-year period of the
study. Overall, the results from this study support our hypothesis
that brain aging can be managed successfully by targeting risk
factors associated with accelerated brain aging and dementia.3
Our strategy to test the effects of a nutrient blend was driven by
the assumption that no one single nutrient or bioactive compound
is sufficient for reducing or minimizing multiple risk factors associ-
ated with dementia and AD; we, therefore, selected the ingredients
of the BPB based on their ability to reduce or eliminate multiple
risk factors associated with brain aging and dementia.24-36 The

Figure 2. Effects of the BPB supplementation on cats’ perform-

ance in the size discrimination and reversal learning tasks.
The performance was expressed as percent of correct choices.
The data are means ± SE, n = 16 for controls, and n = 14 for
BPB group. There were statistically significant differences in
the size discrimination test. (*p<0.05). This figure is prepared
from the data published in a previous paper.42

Discussion
The objective of this long-term study was to evaluate the effects
of BPB on cognitive performance in middle-aged and old cats. Figure 3. Effects of the BPB supplementation on cats’ perform-
Baseline cognitive performance was used in dividing the cats ance in the DNMP test. The performance was expressed as
into two cognitively equivalent groups. Over the course of the percent of correct choices. The data are means ± SE, n = 16
one-year study, the cats were tested on four test protocols: (1) for controls, and n = 15 for BPB group. There were statistically
significant differences between the control and BPB groups.
landmark discrimination learning, (2) egocentric learning and
(*p<0.05). This figure is prepared from the data published in
reversal, (3) size discrimination learning and reversal, and (4)
a previous paper.42
relearning the DNMP task.

57
levels of B vitamins and antioxidants in the BPB diet are found Oxidative stress and chronic inflammation are important risk
in commercially available, highly nutrient-dense products for adult factors for brain aging and dementia.19,21 The antioxidants and
cats. With the exception of the inclusion of fish oil and ascorbic EPA in the blend may reduce oxidative stress-induced damages
acid and elevated levels of arginine, B vitamins and antioxidants and low-grade inflammation in the whole body including the
in the BPB diet, the control and BPB diets contained the same brain and cerebrovascular system. Selenium and vitamin E came
levels of protein, fat, carbohydrate, fiber, and essential fatty acid from the food ingredients and exceeded the daily requirements of
(Table 1), calcium, choline, potassium, magnesium, taurine, zinc, adult cats in the control diet; no significant difference in the total
and amino acid profile (data not shown). More importantly, all blood antioxidant capacity was detected between cats fed the
the essential nutrients in the control diet were above the daily control and test diets.
nutrient requirement recommended for cats by the Association Although the control diets were not deficient in any nutrients,
of American Feed Control Officials (AAFCO). all the nutrients included in the BPB were present at levels
The observed beneficial effects of the BPB on brain functions higher in the BPB diet than those in the control diet. For instance,
in cats are consistent with the beneficial effects of a Mediterranean the levels of B vitamins were at least three and half times higher
diet on cognitive function in older adults.46 In fact, all the ingre- than the daily requirements, and arginine was two times higher
dients in the BPB are present in the fruits, vegetables, cereals, than the daily requirement for adult cats in the BPB. Improved
seeds, legumes, vegetable oils, and fatty fish of the Mediterranean cognitive functions in the cats in the BPB group suggest that
diet. More interestingly, all the ingredients of the BPB are also cats need to consume those nutrients at levels much higher than
present in the natural prey of cats,47-51 indicating that cats naturally their daily minimum requirements to protect their brains from
obtain those nutrients from their prey. aging-induced decline in functions.
Low status of DHA has been linked to cognitive decline in In summary, this study confirms that the BPB, containing
both normal elderly subjects and dementia and Alzheimer’s ingredients with the ability to reduce or eliminate the known
disease subjects.52,53 Fish oil supplementation has been reported risk factors for brain aging and dementia, can significantly
to improve cognitive function in people54 and in aged rodents.55 enhance brain functions and retard aging-induced decline in
In humans, maximal cardiovascular protection of DHA and EPA brain functions in normal middle-aged and senior cats.
is achieved with a concentration of 8% erythrocyte fatty acids as
EPA+DHA.56 Coincidentally, the levels of DHA and EPA in the Acknowledgements
nutrient blend resulted in close to 8% of erythrocyte fatty acids The authors wish to thank Wendell Kerr for statistical analysis
as EPA and DHA in the cats. More studies should be conducted of the blood chemical data, Drs. Bruce A. Watkins and Yong Li
to determine the optimal levels of EPA+DHA in erythrocyte for for RBC fatty-acid profile analysis, Ms. Shanon L Byous for the
optimal protection against brain aging and CDS in cats. analysis of blood B vitamins and total antioxidant status, and
Inclusion of elevated levels of B vitamins was further supported Ms. Rachel Anderson for homocysteine analysis.
by a study indicating that B vitamin supplementation not only
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Reduced by Enrichment. Neurobiol Aging. 2008;29:39-50. 2011;162:959-965.

14. Cole GM, Ma QL, Frautschy SA. Omega-3 Fatty Acids and 27. Yamada K, Noda Y, Nakayama S, et al. Role of Nitric Oxide
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Performance, But Not Mood in Women of Various Ages. J Nutr.
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teine and Neurocognitive Function in the Elderly. Am J Clin Nutr.
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57. De Jager CA, Oulhaj A, Jacoby R, et al. Cognitive and Clinical 60. Ast J, Jablecka A, Bogdanski P, et al. Evaluation of the
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Notes

62
Systemic Illness: The Role of Oxidative Stress and
Antioxidant Supplementation
Katrina R. Viviano, DVM, PhD, DACVIM, DACVCP
University of Wisconsin
School of Veterinary Medicine
Department of Medical Sciences
Madison, WI
Email: [email protected]

Abstract enzymes and other essential antioxidants,

In humans, antioxidant depletion and Glossary of Abbreviations cysteine, vitamin E and selenium.
lipid peroxidation are correlated with CCNU: Lomustine All components of the endogenous
disease severity and associated with poor CKD: Chronic Kidney Disease antioxidant network, as well as the cel-
DM: Diabetes Mellitus lular oxidation byproducts produced by
outcomes. Antioxidant supplementation
FIV: Feline Immunodeficiency Virus ROS, are used as biomarkers of oxida-
during illness may reduce mortality. Illness
GPx: Glutathione Peroxidase
in dogs and cats is associated with oxida- tive stress. Some of the more common
GSH: Glutathione
tive stress, however, species differences indirect biomarkers of oxidative stress
IMHA: Immune-Mediated Hemolytic
exist. Dog and cat populations that may Anemia quantified and reported in the literature
benefit from antioxidant supplementation MDA: Malondialdehyde are GSH, vitamins E and C, selenium,
include patients with acute or chronic NAC: N-acetylcysteine and 8-isoprostane concentrations. Due to
hepatopathies, drug-associated toxicosis, ROS: Reactive Oxygen Species the diversity in study design, analytical
heart failure, chronic kidney disease, SAMe: S-adenosylmethionine methods used, and biomarker stability,
chronic inflammatory disease, and dia- SOD: Superoxide Dismutase there is no consensus as to which bio-
betes mellitus. This review highlights the TAC: Total Antioxidant Capacity marker is the most specific or sensitive
need for species and disease-specific TBARS: Thiobarbituric Acid Reactive in the assessment of oxidative stress.3
Substance In most studies, multiple biomarkers are
clinical studies to further assess the role
of oxidative stress during illness and the used to provide a more complete assess-
therapeutic role of antioxidant supplementation. ment of cellular redox status and its impact on the endogenous
antioxidant network. However, antioxidant concentrations are
Introduction often evaluated, as antioxidant supplementation may be a logical
Reactive oxygen species (ROS) are a continuous byproduct next step in the treatment of ill patients with disease-associated
of oxidative metabolism generated as part of both physiologic oxidative stress.
and pathologic cellular processes. These transient, highly reactive Oxidative stress plays a role in the pathogenesis of many acute
ROS oxidize cellular components including lipids, proteins, and chronic systemic diseases in humans.2,4 ROS induce cellular
carbohydrates, and DNA. It is the endogenous antioxidant network injury directly via oxidation and indirectly through cytokines and
that functions to modulate or quench ROS and maintain cellu- proinflammatory gene induction contributing to progressive
1
lar homeostasis and redox balance. When ROS are produced systemic inflammation, tissue injury, cellular oxidative damage,
in excess of the capacity of the endogenous antioxidant network, and mitochondrial dysfunction.5 In critically ill humans, antiox-
increased cellular oxidative products are generated leading to a idant depletion (e.g., glutathione,5,6 ascorbate7,8) correlates with
state of oxidative stress.1,2 severity of illness and survival, is associated with systemic decom-
The antioxidant network is made up of thiol antioxidants (i.e., pensation, and increases susceptibility to infections.6,9-11 GSH
glutathione [GSH], cysteine), scavenger enzymes (i.e., glutathione deficiencies have been reported in many systemic disease9,10
peroxidase, glutathione reductase, superoxide dismutase, catalase), states including diabetes mellitus,12 trauma,13 kidney failure,14
lipids, water-soluble vitamins (i.e., A, C, E, beta-carotene), and retroviral infections,15,16 sepsis,17 liver disease,18 and acute pan-
trace minerals (i.e., selenium, zinc, iron, manganese, copper). creatitis.19 In critically ill patients, decreased GSH concentrations
The endogenous antioxidants function independently and syner- have been associated with decreased survival.4,20 Urine or
gistically to maintain cellular redox balance. GSH is the main plasma 8-isoprostane concentrations, a stable marker of lipid
intracellular antioxidant that is intimately linked to the thiol peroxidation, correlate with disease severity in humans,21,22 are

63
significantly increased in animal models of oxidative injury,22 glutathione peroxidase(GPx), serum selenium or plasma total
and are modulated by antioxidants.23 antioxidant capacity (TAC) concentrations compared to healthy
cats.36 However, the IRIS stage IV cats have increases in plasma
Oxidative Stress: Dogs and Cats GPx compared to healthy cats, suggesting enzyme upregulation
The data reported in humans supports that oxidative stress in cats with more advanced disease. Dogs and cats, like humans
contributes to the clinical outcome in some patient populations, with CKD, have evidence of oxidative stress that may contribute
including the acute and chronically ill as well as the critically ill. to disease pathology, including renal interstitial fibrosis, glomeru-
The available published studies and case reports in dogs and cats losclerosis, glomerular hypertension, renal inflammation, and a
support the state of oxidative stress in association with various decline in kidney function.37
systemic diseases. However, extrapolations across species are
difficult based on differences in diet, metabolism, and disease Cardiovascular Disease
etiologies and pathophysiology. In comparing endogenous anti- Dogs in congestive heart failure due to both chronic valvular
oxidant concentrations in healthy dogs and cats,24 healthy dogs disease and dilated cardiomyopathy have significant increases in
have significantly higher antioxidant concentrations (i.e., GSH, plasma oxidized GSH, ascorbate and isoprostane levels; providing
cysteine and ascorbate), suggesting species differences in anti- evidence of an oxidative state associated with congestive heart
oxidant homeostasis. These interesting but not well-understood failure in dogs.38 In addition, vitamin E concentrations negatively
differences in healthy dogs and cats exemplify the need for ad- correlate with disease severity in dogs with idiopathic dilated
ditional research in understanding the role of oxidative stress cardiomyopathy.39 These altered antioxidant levels are speculated
during illness and the therapeutic role antioxidant supplementa- to be a compensatory adaptation in dogs with cardiac dysfunction
tion plays during illness. and suggests a population of dogs that may benefit from anti-
oxidant supplementation. Studies designed to assess the effects
Systemic Illness of antioxidant supplementation in dogs with naturally occurring
Hospitalized ill dogs experience systemic oxidative stress cardiac disease or with congestive heart failure are lacking.40
including decreased endogenous antioxidants (erythrocyte GSH
and serum vitamin E) and increased urinary isoprostane concen- Neoplasia
trations, a marker of lipid peroxidation.24,25 Compared to healthy The role of ROS in cancer is complex and multifactorial.
cats, systemically ill cats have increased ascorbate concentrations, Recent studies not only support the role of ROS in contributing
suggesting a different endogenous antioxidant profile or response DNA damage and tumorigenesis, but also the impact of ROS on
during illness compared to that of dogs or humans.24 tumor biology through their role in modifying cellular signaling
to promote tumor growth and contributing to metastisis.41 Studies
Liver Disease in humans support increased circulating markers of oxidative
Similar to humans, both dogs and cats with spontaneous liver stress in cancer patients.42 For example, patients with breast,
disease have decreased hepatic GSH levels.26-28 Approximately lung, or oral cancer have increased circulating markers of lipid
50% of dogs and cats with inflammatory liver disease have low peroxidation.43,44
liver GSH concentrations as well as dogs with copper toxicosis Markers of lipid peroxidation, specifically serum MDA, are
and extrahepatic cholestasis.26,27 Studies in humans describe increased in association with many types of cancers in dogs rel-
decreased liver GSH concentrations in naturally occurring liver ative to healthy dogs; consistent with a redox imbalance or oxi-
disease and animal models of induced hepatopathies.29-32 Multiple dative stress in tumor-bearing dogs.45 In this heterogeneous group
mechanisms likely contribute to the low GSH levels including of dogs diagnosed with cancer, the most common tumor types
limited GSH precursors, impaired hepatic synthesis of S-adeno- included mammary gland carcinoma, mast cell tumor and osteo-
sylmethionine (SAMe), increased GSH hepatic efflux, increased sarcoma. Others have reported evidence of oxidative stress in
GSH utilization, and reduced redox recycling of oxidized GSH. dogs with cancer including mammary gland tumors,46 mast cell
tumors47 and lymphoma.48 Dogs with mammary gland tumors
Kidney Disease have unchanged serum markers of lipid peroxidation but have
In humans, chronic kidney disease (CKD) leads to a pro- increased thiobarbituric acid reactive substance (TBARS) and
oxidant environment and oxidative stress.33 In dogs with CKD, decreased vitamin E concentrations within the excised neoplastic
vitamin concentrations (decreased 25-hydroxycholecalciferol tissue.46 At the time of diagnosis, dogs with lymphoma have
and folate and increased ascorbate and vitamin A) are altered reduced vitamin E concentrations and increased levels of oxi-
relative to healthy dogs.34 Azotemic dogs have increased urinary dative markers, including isoprostanes and glutathione peroxidase
markers of oxidative stress and increased urinary malondialdehyde activity, which return to normal following chemotherapy and
(MDA)/creatinine ratio, which correlated with plasma creatinine disease remission.48
concentration and urinary protein/creatinine ratio.35 Cats with CKD, In cancer patients, the benefits and risks of antioxidant supple-
IRIS stage I-IV, do not have significant changes in erythrocyte mentation remain controversial. The role of antioxidant therapy

64
in cancer patients is complicated as traditional chemotherapy and concentrations that normalize following radioiodine therapy.59
radiation therapy are, in part, successful in killing tumor cells Interestingly, endogenous antioxidants, erythrocyte GSH, plasma
via the generation of ROS. This raises the question whether ascorbate, and plasma vitamin E are unchanged in hyperthyroid cats.
concurrent antioxidant therapy in cancer patients reduces the
efficacy of treatment.49-51 Toxicosis
Acetaminophen is a common analgesic and antipyretic used by
Infectious/Inflammatory Diseases owners that is sometimes inappropriately dosed or accidentally
In the few published studies available, both infectious and ingested by dogs and cats leading to toxicity. The mechanism
inflammatory diseases of dogs and cats are associated with for acetaminophen toxicosis in dogs and cats is complicated by
oxidative stress. Dogs experimentally infected with Ehrlichia differences in metabolism between species, but in both species
canis had increased serum concentrations of nitric oxide, TBARS decreased GSH concentrations contribute to toxicity.60-62 The
and glutathione reductase activity, supporting a redox imbalance primary antidote for the treatment of acetaminophen toxicosis is
post-infection.52 Acute gastroenteritis in dogs due to canine par- supplementation with a GSH source. Clinically N-acetylcysteine
vovirus is associated with increased markers of lipid peroxidation (NAC) is most commonly used in dogs and cats.63
(i.e., erythrocyte MDA).53 Relative to healthy dogs, dogs with
immune-mediated hemolytic anemia (IMHA) are reported to Antioxidant Supplementation
experience oxidative stress (i.e., increased plasma MDA levels) Increasing evidence supports the role of oxidative stress in
and reduced antioxidant reserve (i.e., decreased vitamin E serum the pathogenesis of many systemic diseases in humans,2,11 as well
concentrations) during illness.54 as in dogs and cats,24 making antioxidant supplementation a rational
An experimental study in cats infected with feline immuno- therapy to block the formation of ROS, scavenge ROS and augment
deficiency virus (FIV) reported increased whole blood superoxide endogenous antioxidants. Many clinical studies in humans have
dismutase (SOD) and glutathione peroxidase concentrations over evaluated antioxidant supplementation during illness with mixed
the first 9 to 12 weeks of an acute FIV infection with values results, in part, due to the lack of standardization of methodologies,
returning to baseline 16 weeks postexposure.55 In another study, including the type, dose and route of the antioxidant intervention
a group of naturally exposed FIV-positive client-owned cats with and the biomarkers evaluated.64,65 By comparison, much less is
no clinical signs of illness were compared to healthy cats. Despite known about oxidative stress and antioxidant supplementation
no significant change in erythrocyte GSH or plasma cysteine in ill veterinary patients. Most of what is known is limited to
concentrations, these chronically infected FIV-positive cats had experimental studies, case reports and small clinical studies.
increased plasma ascorbate concentrations.24 These small studies
independently support that FIV-positive cats experience oxidative Glutathione Supplementation
stress during the acute as well as the chronic stage of infection. GSH supplementation is a logical approach to treating patients
However, FIV-positive cats have a very different antioxidant with liver disease. The results of human clinical studies assess-
pattern compared to human HIV-positive patients.56 ing antioxidant supplementation in liver disease patients are
difficult to compare as most trials consist of a low number of
Endocrinopathies patients and have a high risk of bias and heterogeneity. However,
Human endocrinopathies are associated with oxidative stress. some reported clinical trials and meta-analyses support the use
A few published studies support a shift toward an oxidative state of GSH precursors (SAMe, NAC and silibinin) to replenish
in dogs and cats with diabetes mellitus (DM) and feline hyper- hepatic GSH concentrations. Extrapolated from human studies,
thyroidism. Cats with DM experience a decrease in plasma SOD the use of antioxidant supplementation in dogs and cats with
concentrations when compared to healthy control cats; consistent liver disease is common despite the paucity of species-specific
with an increase in oxidative stress in cats with DM.57 Following controlled clinical trials or meta-analyses.
a diet change to a high-protein/low-carbohydrate diet, despite S-adenosylmethionine (SAMe): A methyl donor and also a
an increase in glutathione peroxidase, there was no significant precursor to GSH, SAMe is essential for cellular metabolic
change in the plasma SOD concentration over the eight-week processes, detoxification and antioxidant pathways. Adequate
period of dietary intervention. Diabetic dogs, both well-con- concentrations of SAMe and GSH are normally produced in the
trolled and poorly regulated dogs, have increased erythrocyte liver, but in patients with liver disease low GSH concentrations
catalase activity, which relates to disease severity and supports contribute to hepatocyte damage and disease progression.26
that oxidative stress occurs in dogs in association with DM.58 Studies in both dogs and cats support that oral SAMe admin-
Feline hyperthyroidism is an endocrine disorder of geriatric istration increases GSH concentrations. SAMe administration
cats that is most commonly associated with a functional thyroid increased both hepatic and erythrocyte GSH concentrations in
adenoma. Return of the euthyroid state is attained following radio- dogs treated with prednisone66,67 and was successful in increasing
iodine therapy. During the hyperthyroid state, cats experience GSH levels in a dog with acetaminophen toxicosis.68 In healthy
lipid peroxidation identified by increased urinary isoprostane cats, SAMe administration increased hepatic GSH concentrations

65
and decreased markers of systemic oxidative stress.69 SAMe has of dogs and cats have primarily focused on acetaminophen tox-
been reported to be protective in limiting Heinz body formation icosis. NAC remains the standard of care for the treatment and
and erythrocyte destruction, as well as increasing hepatic GSH prevention of the oxidative damage associated with acetamino-
concentrations, in cats with acetaminophen toxicosis.70 In humans, phen-induced hepatoxicity in dogs62,80 and methemoglobinemia
supplementation with SAMe is recommended for the treatment in cats.62
of hepatotoxicity and cholestatic liver disease.71 Clinically, SAMe Recently, a randomized placebo-controlled clinical study
supplementation in dogs and cats parallels that of humans. supplemented GSH-deficient ill dogs with NAC for 48 hours.
Silibinin (milk thistle): A natural product of the flowering The NAC-supplemented dogs stabilized their erythrocyte GSH
plant of the aster family, silibinin functions as an antioxidant, concentrations compared to the control dogs, which had a further
anti-inflammatory and antifibrotic. Silibinin is used as an adjunc- decline in erythrocyte GSH. However, short-term NAC supple-
tive therapy in humans with chronic hepatitis, alcoholic or viral mentation did not resolve the systemic oxidative state, improve
hepatitis, nonalcoholic steatohepatitis, and cirrhosis.72 No random- serum vitamin E concentrations, or impact long-term outcome.
ized clinical trials have evaluated the use of silibinin in dogs and Further studies are needed to investigate whether longer duration
cats with spontaneous liver disease. Veterinary use of silibinin or combination antioxidant therapy would benefit ill dogs.
has primarily been extrapolated from its use in the treatment
of hepatopathies in humans and based on a limited number of Vitamin E
experimental studies in dogs and cats. Decreased vitamin E concentrations are associated with chronic
Experimental studies in dogs support the use of silibinin in liver disease of different etiologies in humans. The overall clinical
the prevention and/or treatment of acute toxicities, including benefits of vitamin E in the treatment of hepatobiliary disease
Amanita mushroom toxicosis and gentamicin-induced nephro- in humans remains controversial.81 However, a recent study
toxicity. Silibinin prevents the phalloidin toxin (the toxic principle supports the use of vitamin E as part of a combination protocol
in Amanita mushroom toxicosis) from binding hepatocytes, in the treatment of nonalcoholic steatohepatitis.82 Decreased
minimizing hepatotoxicity and Amanita mushroom toxicosis.73 vitamin E concentrations and the use of vitamin E in the treatment
In another study, dogs treated with gentamicin for nine days of spontaneous liver disease in dogs and cats is not well-documented.
were concurrently supplemented with silibinin or saline; the Despite the paucity of data, vitamin E supplementation is often
silibinin-supplemented dogs had a reduction in gentamicin-in- pursued empirically in dogs and cats with liver disease. The
duced nephrotoxicity relative to the dogs treated with saline.74 published studies or case reports evaluating vitamin E in dogs
In healthy cats, granulocyte GSH concentrations increase with liver disease are summarized below.
following silibinin administration, and silibinin is reported to Experimental studies suggest that dogs with ischemia-induced
be well-tolerated when administered orally with a bioavailability liver disease may benefit from vitamin E supplementation.
of 6-7%.57 Cats experimentally exposed to acetaminophen and Anesthetized dogs with experimentally induced hypoxia experi-
prophylactically administered silibinin were protected from the ence a time-dependent depletion in plasma and liver vitamin E
development of acetaminophen-induced toxicosis.63 concentrations.83 A single clinical study that used vitamin E in
Denamarin®: A combination product of silibinin and SAMe, dogs with spontaneous liver disease has been published. In a
Denamarin is often used empirically as a GSH source in dogs small group of dogs with chronic inflammatory liver disease,
and cats with liver disease. No published prospective clinical dogs were randomized to treatment with or without vitamin E.
studies are available to assess the efficacy of Denamarin in The vitamin E-supplemented dogs had a significant increase in
dogs and cats with spontaneous liver disease. serum and liver vitamin E concentrations, increased GSH con-
Recently, a heterogeneous group of dogs diagnosed with neo- centrations and decreased ALTs relative to the controls.84
plasia that were treated with lomustine (CCNU) were randomized Vitamin E supplementation may also have a role in treating or
to treatment with CCNU alone or in combination with Denamarin. preventing acute drug toxicities (e.g., acetaminophen, tetracycline,
Only 68% of the Denamarin-treated dogs experienced increases gentamicin). Vitamin E combined with cysteine was used in an
in their liver enzymes associated with CCNU administration experimental study in cats to successfully reduce the oxidative
versus 85% of the dogs treated with CCNU alone.75 The results state induced by acetaminophen.85 In a single case report, vita-
of this study suggest a population of dogs that may benefit from min E combined with selenium was used therapeutically in a
prophylactic GSH supplementation to prevent iatrogenic hepa- cat with a marked increase in ALT suspected to be secondary
toxicity associated with CCNU administration. to a tetracycline-induced hepatotoxicity.86 In an experimental
N-acetylcysteine (NAC): An acetylated variant of L-cysteine, study, dogs treated with gentamicin for nine days were supple-
NAC is used as a thiol source to replenish intracellular cysteine mented with vitamin E during therapy, and, similar to silibinin
and GSH levels. In humans, NAC is used in the treatment of acute administration, the vitamin E-supplemented dogs had a reduction
hepatoxicity,76 nonalcoholic steatohepatitis77,78 and alcoholic in gentamicin-induced nephrotoxicity relative to dogs treated
hepatitis.79 Studies evaluating the use of NAC in the treatment with saline.39

66
Dietary Antioxidants/Vitamins extrapolated from humans and based on a limited number of
The rationale for the use of vitamins/dietary antioxidants (e.g., experimental studies, small clinical studies and case reports.
vitamins A, C, E, beta-carotene, essential fatty acids, and poly- The available evidence-based data in dogs and cats highlight the
phenols) is to provide a balanced dose of antioxidants that directly need for species and disease-specific clinical studies to further
functions as free-radical scavengers to limit oxidative injury but assess the role of oxidative stress during illness and the thera-
also induces endogenous antioxidants and repair enzymes.40,87,88 peutic role of antioxidant supplementation.
A recent meta-analysis of clinical studies evaluating antioxidant
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Summary
As in humans, an altered redox state is associated with illness 7. Bonham MJ, Abu-Zidan FM, Simovic MO, et al. Early
in dogs and cats. In dogs, endogenous antioxidant concentrations Ascorbic Acid Depletion Is Related to the Severity of Acute
during illness more closely resemble the alternations reported Pancreatitis. Br J Surg. 1999;86:1296-1301.
in humans. Unexpectedly endogenous antioxidant concentrations
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Notes

72
Antioxidants for Eye Health
Wei Wang, PhD
Nestlé Research Center
St Louis, MO
Email: [email protected]

Abstract leading cause of vision loss in older

Eyes commonly experience age-related
Glossary of Abbreviations humans, generally affecting people
AAFCO: Association of American Feed age 50 and older. Cataract, a clouding
changes, such as cloudy eyes (nuclear
Control Officials
sclerosis and/or cataract) and retinal of the lens in the eye that affects vision,
AMD: Age-Related Macular Degeneration
degeneration, and leading age-related is another leading cause of vision loss
AREDS: Age-Related Eye Disease Study
eye conditions may result in visual D: Diopter in older humans. By age 80, more
impairments. There are similarities DHA: Docosahexaenoic Acid than half of all Americans either have
among species regarding age-related EPA: Eicosapentaenoic Acid a cataract or have had cataract surgery.
changes in eyes. Our studies, summa- ERG: Electroretinography Globally, the main cause of blindness
rized in this paper, showed that visual La: Anterior Lens Reflection is cataract (51%), though uncorrected
impairment as measured by increasing Lb: Posterior Lens Reflection refractive errors are the major cause
lens reflective dot sizes and refractive of visual impairment (43%), accord-
error is significantly associated with age in dogs. Antioxidant ing to the World Health Organization.1
supplementation in dogs resulted in improvement in retinal/visual Cataracts develop for a variety of reasons, including long-term
response and a reduction in refractive error changes. Antioxidants ultraviolet exposure, exposure to radiation, secondary effects of
can be beneficial for preserving and improving eyesight and visual diseases, such as diabetes, or simply due to advanced age. They
function in dogs as well as humans. are usually a result of denaturation of lens proteins, which then
clump together and cause cloudiness, resulting in blurred vision
Introduction and, potentially, blindness. Free radical damage to the lens and
Traditionally, eye health has been viewed as an issue most retina is a major factor in cataracts and macular degeneration.
important to humans. Most research seeking nutritional interven- Prevention strategies have been centered on using antioxidant
tion for eye benefits has been focused on human applications. supplements to block free radical buildup.2,3
Our eyes are our window to the world. Our eyesight influences the
way in which we view the world. Good eyesight is an important Cloudy Eye in Dogs and Cats
part of well-being and a significant factor in retaining independence Development of cloudy eyes (nuclear sclerosis and/or cataract)
and quality of life as we get older. Contrary to popular belief, loss is common in aging dogs and cats.4 The cloudy lens of older
of vision does not need to be an accepted consequence of aging. dogs or cats is readily visible to the naked eye as an observed
Vision can deteriorate for many reasons, and even when associ- hazy or bluish appearance and often is viewed by owners as
ated with the aging process, many interventions are available. cataract formation. Cloudy eye is one of the common concerns
The World Health Organization estimates that up to 80 percent for owners to bring their pets for a veterinary evaluation.5
of blindness and serious visual loss around the world is avoid- Differences of opinion exist about cloudy lens in veterinary
able through prevention or treatment. 1 and human medicine. The cloudy lens as seen in older dogs or
Eyesight is equally important to dogs and cats. Eyesight is cats is commonly diagnosed as nuclear sclerosis by veterinary
one of the key senses for animals to acquire information from ophthalmologists and considered as part of normal aging.6 In
their outside environment and is critical for hunting for food contrast, nuclear sclerosis is considered a type of cataract in
and daily survival. Although most pet dogs and cats do not hunt human medicine (nuclear cataract or senile cataract).7,8 In vet-
for their food, eyesight is still important to allow them to get erinary ophthalmology, nuclear sclerosis is believed to result
visual cues from their owners for their understanding and social from internal compression and an increased density of the lens
interactions. nucleus, but it is not generally believed to significantly affect vision
in dogs, except in unusually dense or advanced cases. However,
Common Eye Problems in Humans the clinical distinction between advanced nuclear sclerosis and
Age-related macular degeneration (AMD) is a disease that early nuclear senile cataract in dogs is often indistinct.6
gradually destroys the macula, the part of the eye that provides We conducted studies to evaluate age-related changes in the
sharp, central vision required to see objects clearly. AMD is a eyes of dogs and cats at one of our pet care centers. For the canine

73
study, we evaluated eyes for evidence of nuclear sclerosis and methods involving visual targets and feedbacks from the test
cataract in 222 dogs, aged 1 to 17 years, representing Beagles, subjects. It is challenging to evaluate visual impairment in animals.
Labrador Retrievers and English Setters. Lens cloudiness was We have used several new technologies in our recent studies
scored using a 1-5 cloudiness grading scale (Tobias lens cloudi- evaluating eye health in dogs.
ness grading scale).9 Lens cloudiness score was significantly
associated with the age of the dogs (r=0.88, p<0.05). Among the Visual Impairment: Blurry Vision with Aging
182 dogs that were 6 years and older, the prevalence of nuclear We recently conducted a study to determine if the Tobias
sclerosis increased from 60% at age 6-8 years to 100% for dogs cloudiness scale could be used to monitor lens sclerotic changes
9 years and older; 36% of these dogs also had some form of over time associated with aging. Eye examinations were completed
cataract. Cataracts were most prevalent in dogs aged 12 years by a veterinary ophthalmologist, and lens cloudiness scores were
and older. assessed by two veterinarians independently on each eye of 18
We performed eye examinations on 80 cats at our center, healthy Beagles (age mean 6.48±0.30 year; 7 neutered males and
with at least 16 cats per age group representing age groups of 11 spayed females); and 27 Labrador Retrievers (age mean
1-3, 4-6, 7-9, 10-12, and 12+ years of age. Cats started to show 8.29±0.82 year; 14 neutered males and 13 spayed females). Lens
nuclear sclerosis at age 7-9 years, and 100% of cats older than cloudiness score and reflective dot sizes from the anterior (La)
12 years of age showed evidence of nuclear sclerosis. Among and posterior (Lb) of the lens reflection from a penlight were
the 48 cats aged 7 years and older, 13% had some form of cataract assessed repeatedly every year for five years. The reflective dot
in addition to the presence of nuclear sclerosis. size from the anterior (front) and posterior (back) of the lens
Lens cloudiness also was evaluated by Williams et al., using measures how scattered an incoming penlight source may be-
a 0-10 score system.10 The lens cloudiness seemed to increase come when it shines through the back of lens. The more light-
noticeably around 6 years of age. The age at which prevalence scattering of the incoming light in real life would result in a
of cataract was 50% among the 2,000 dogs in their study was more blurry vision from a single light source. Statistical evalua-
9.4±3.3 years.10 Williams et al. also showed that the onset for tions were performed using repeated measures analysis of co-
nuclear sclerosis and cataract in cats begins at about 7-9 years variance with the initial age of the dogs as a covariate.
of age. The age at which prevalence of cataract was 50% among Dogs showed a significant increase in lens cloudiness score
the 2,000 cats in their study was 12.7±3.4 years, but was 5.6±1.7 as well as reflective dot sizes over time (p<0.05) (Figure 1 and
years for cats with diabetes and 9.9±2.5 years for cats with a Figure 2a and 2b). There was no breed difference for progression
history of dehydration crises.11 rate of lens cloudiness, with an average increase of 0.33±0.14
Nuclear sclerosis is an age-related progression of lens cloudi- units for Labradors and 0.28±0.15 units for Beagles per year,
ness in both human and veterinary medicine. Change in lens trans- respectively. The reflective dot sizes increased from ~1 mm to
parency is considered a dynamic phenomenon in aging humans, ~2 mm for anterior reflective dot size and from ~1.5 mm to 3 mm
progressing from nuclear sclerosis to senile cataract.7 In veteri- for posterior reflective dot size over five years for Labradors; and
nary medicine, nuclear sclerosis is a consistent finding in dogs from ~0.5 mm to 1.5 mm for anterior reflective dot size and
greater than 6-7 years of age. Although the clinical appearance from ~1.0 mm to ~2.5 mm for posterior reflective dot size for
and rate of progression of age-related eye clouding in dogs can Beagles. The doubling of the reflective size over five years may
vary, an increase in nuclear opalescence, and punctuate to striate suggest light scattering due to the lens aging, thus a direct re-
opacifications of the adult lens nucleus, are usually observed. sult could be blurry vision.
These changes are generally noted concurrently with, or following
the presence of, dense nuclear sclerosis.6,10 Visual Impairment: Refractive Error Change
Humans affected with nuclear sclerosis/nuclear cataract Over Aging
report visual disturbances resulting from a myopic shift (from Some more objective evaluation methods that have been used
hardening of the lens nucleus), astigmatism, a shift in contrast in human studies could be useful to adapt for companion animal
sensitivity (especially with low-contrast objects), glare, and visual studies. One such method uses an auto-refractor for testing refrac-
acuity reduction.6 A myopic shift in the lens has been reported tive errors in infants and toddlers who cannot yet communicate
in older dogs,12 presumably from a change in refractive status well. The SureSight hand-held auto-refractor has lights and
of the sclerotic lens nucleus. This shift likely affects visual sounds that engage the test subjects’ attention, with minimal
acuity.13 It is possible that other visual alterations occur in the cooperation required, making it ideal for use on young children,
aged dogs as well; however, the ability to detect these subtle the disabled and when there is a language barrier.14,15
visual disturbances, especially in the less-active older dog, has We completed a pilot study to evaluate the auto-refractor for
been limited.6 use in dogs. Spherical equivalent refractive error was measured
using the hand-held auto-refractor (WelchAllyn SureSight) on
Visual Impairment in Dogs 9 Beagle dogs (ages 1-14 years) under both indirect and direct
Visual impairment in humans can be studied using different lighting conditions with five measurements per condition, per eye

74
 Figure 2a. Lens Reflective Dot Size Change
Lens Cloudiness Score Change Over Five Years
over Five Years in Labradors

La and Lb Size (mm)

a
Lens Cloudiness Score

a
a
a a

b b
Age of dogs (years)

Figure 2b. Lens Reflective Dot Size Change

over Five Years in Beagles
Age of dogs (years)

La and Lb Size (mm)

Figure 1. Eighteen healthy Beagles (initial age mean 6.48±0.30
year; 7 neutered males and 11 spayed females) and 27
Labrador Retrievers (initial age mean 8.29±0.82 year; 14
neutered males and 13 spayed females) were followed for
five years. Lens cloudiness score was assessed using Tobias
grading scale each year. Statistics were done using a repeated
measures analysis of covariance with the age of the dogs
Age of dogs (years)
when they started the study as a covariate.
a and b: Differences between later years to year 1 Figure 2a and 2b. Linear correlations between La (anterior
Statistical significance at p<0.05. lens reflective dot size), Lb (posterior lens reflective dot
size), and age of the dogs were analyzed using SAS.
(Figure 3 a-d). Measures were repeated three different days for Significant correlation between La and Lb to age in both
each dog within six weeks. Indirect light condition was set with breeds; r=0.67 (La) and r=0.77 (Lb) for Labradors; r=0.58
an indoor light from an adjacent room coming into a dark room (La) and r=0.72 (Lb) for Beagles, respectively.
with dogs facing the incoming light, and direct light condition Statistical significance at p<0.05.
was set in the same position but with the dark room’s light
turned on. Eyes were tested under indirect light condition first, Each dog participated in three trials while their eyes were fitted
followed by direct light at the same setting. Nonparametric sta- with 0- (plano), +1.50- or +3.00-diopter (D) contact lenses,
tistics were used to detect differences among lighting conditions applied in random order. Retrieval times were significantly faster
and test days, and between eyes. Spearmen correlation assessed with plano lenses than with +1.50- or +3.00-D lenses, but there
the visual measurement outcomes’ association with age. were no significant differences in times between +1.50- and
There was no difference for day-to-day or intra-eye measure- +3.00-D lenses. Judges blinded to the specific treatment assigned
ments. Significantly, Beagles showed a myopic shift with aging the best performance scores to dogs with plano lenses and the
(average spherical equivalent ranged from plano to -3.00 diopters), lowest scores to dogs fitted with +3.00-D lenses. The authors
suggesting that the older the dog, the more nearsighted (r=-0.48 concluded that even mild myopic defocusing, such as -1.5-D, had
and -0.73 under direct and indirect lights; p<0.05 both). Younger a significant negative impact on both the subjective and objective
dogs were able to make larger accommodation changes from assessments of dogs’ performances.16
indirect light to direct light conditions, indicating a more flexible Cloudy lens in older dogs may be more similar to human
lens (r=-0.50, p<0.05). The results of this pilot study show that the nuclear/senile cataracts than previously acknowledged. It appears
hand-held portable human auto-refractor technique is applicable that the cloudiness of the lens in dogs, as with humans, may
to dogs, repeatable and sensitive to light conditions. result in similar vision disturbances, such as blurry vision and
The myopic refractive shift could be expected to compromise refractive error, which may have a negative impact on their daily
dogs’ visual functions with aging. The older dogs in our study activities. Concerning possible developmental mechanism(s), oxi-
had myopic shift close to -2 and -3 diopter (dogs at age 10.2 and dative damage to the lens has been considered an important factor
age 13.7 years of age that had moderate and advanced nuclear in the initiation and progression of age-related cataracts.17
sclerosis). This can be a functionally important difference, as
shown by Ofri et al.16 Antioxidants Benefiting Human Eyes
Ofri et al.16 studied seven Labrador Retrievers and one Balanced nutrition is an integral part of good eye care. Most
Chesapeake Bay Retriever that were trained for field trial com- eye diseases are a result of oxidative damage and/or inflamma-
petition. Dogs were commanded to retrieve targets at 150 yards. tion, which, in turn, produce free radicals, singlet oxygen and

75
 a Refractive Error in Right Eye Under Direct Light
c Refractive Error in Left Eye Under Direct Light

Spherical Equivalent
Spherical Equivalent

Age of dogs (years) Age of dogs (years)

b Refractive Error in Right Eye Under Indirect Light d Refractive Error in Leftt Eye Under Indirect Light
Spherical Equivalent

Spherical Equivalent

Age of dogs (years) Age of dogs (years)

Figure 3a-d. Spherical equivalent refractive error was measured using the hand-held auto-refractor (WelchAllyn SureSight) on
9 Beagle dogs (ages 1-14 years) under both indirect and direct lighting conditions with five measurements per condition, per
eye. Measures were repeated on three different days (test day 1-3) for each dog within six weeks. Indirect light condition was set
with indoor light from adjacent room coming into a dark room with dogs facing the incoming light, and direct light condition was
set in the same position but with the dark room’s light turned on. Eyes were tested under indirect light condition first, followed
by direct light at the same setting.

Nonparametric statistics were used to detect differences among lighting conditions and test days, and between eyes. Spear-
men correlation assessed the visual measurement outcomes’ association with age.

Significant correlation between refractive error to age in both light conditions (r=-0.48 and -0.73 under direct and indirect lights;
p<0.05 both); and accommodation changes from indirect light to direct light conditions to age indicating a more flexible lens
(r=-0.50, p<0.05).

There was no difference for day to day or intra-eye measurements.

Statistical significance at p<0.05.

reactive oxygen species, which lead to the onset of various Building on these results, the National Eye Institute initiated
eye diseases.17 AREDS2 in 2006, modifying its formula by adding 10 mg lutein,
Strong scientific evidence has shown many nutritional factors, 2 mg zeaxanthin, 1000 mg omega-3 fatty acids (650 mg EPA and
such as lutein, zeaxanthin, omega-3 fatty acids (eicosapentaenoic 350 mg DHA), and 25 mg zinc and removing beta-carotene. The
acid [EPA] and docosahexaenoic acid [DHA]), vitamins, and study results, presented in 2013, showed that the modified supple-
minerals, may be protective for age-related eye problems.2,3,18-21 ment had the same overall protective effect on advanced AMD.3
The Age-Related Eye Disease Study (AREDS1), a major Lutein, zeaxanthin and beta-carotene belong to a family of
clinical trial sponsored by the National Eye Institute and pub- phytonutrients known as carotenoids. Lutein and zeaxanthin are
lished in 2001, showed that high levels of antioxidants and zinc yellow plant pigments that are especially enriched in dark leafy
significantly reduced the risk of progression to advanced AMD greens such as spinach, kale or collard greens. Beta-carotene is
by 25% and the risk of moderate vision loss by 19%.2 Specifi- orange plant pigment that is enriched in orange-colored fruits and
cally, the AREDS formula contained 500 mg of vitamin C, vegetables, such as carrots, pumpkins and sweet potatoes. In the
400 IU of vitamin E, 15 mg of beta-carotene, 80 mg of zinc, body, beta-carotene is used to make vitamin A, which is required
and 2 mg of copper.2 by the retina to detect light and convert it into electrical signals.

76
Lutein and zeaxanthin are found in the retina and lens, where
they may act as antioxidants and help absorb damaging, high- a-wave amplitude
energy blue and ultraviolet light.

a-wave amplitude difference

Blue light is the highest energy form of visible light and in-

(post-pretreatment) (mV)
duces photo-oxidative damage by generating reactive oxygen
species. Lutein and zeaxanthin together protect the photorecep-
tor cells and also nervous tissues in the brain from the damage
of reactive oxygen species. They are intimately associated with
omega-3 fatty acids, which are also abundant in nerve cells, and
protect these easily damaged fats from oxidation. Consumption
and serum levels of lutein have been shown to be inversely related
to the risk for ocular diseases, including AMD and cataracts.22,23
ERG protocol light conditions
Long-term supplementation in humans with these carotenoids,
Figure 4. Retinal function a-wave amplitude measured by
including lutein, zeaxanthin and another potent carotenoid
electroretinography.
astaxanthin, can assist in retaining healthy eyesight, visual per-
formance and acuity, as well as aid glare and contrast sensitivity
and support vision in dim light.2,3,18-21 b-wave amplitude

Ab-wave amplitude difference

Vitamin A is an essential fat-soluble vitamin with antioxidant

(post-pretreatment) (mV)
properties best-known for its role in preventing blindness through
the formation of rhodopsin. This photo pigment is responsible for
vision under low light. Vitamins C and E both play important
roles in protecting the eye through their actions as antioxidants.
Zinc is an essential nutrient that acts as a cofactor for more than
100 enzymes. Zinc is also found in high concentrations in the
retina, has been shown to help support healthy night vision, and
ERG protocol light conditions
is essential to the activity of dozens of enzymes important for
vision health.17,24
Figure 5. Retinal function b-wave amplitude measured by
Antioxidant Supplementation in Dogs electroretinography.
It is reasonable to hypothesize that antioxidants beneficial In both Figure 4 and 5, ERG protocol light conditions are shown:
for human eyes would also be beneficial for dog or cat eyes. To S: Scotopic condition
begin to explore this, we completed a study to evaluate the effect S1-S5: Scotopic condition with increasing light intensity
of antioxidant supplementation in dogs on eye function measured Ssd: Scotopic condition with standard light intensity
by full-field flash electroretinography (ERG) and spherical Sh: Scotopic condition with high-light intensity
equivalent refractive error. P: Photopic condition
Twelve Beagles, 6-8 years of age, with normal eyes upon Pc: Photopic condition for cone
indirect ophthalmoscopy and slit lamp biomicroscopy, were age- Pfl: Photopic condition flickering light
and gender-matched and randomly assigned to receive a feed- Statistical analysis was done using t-test comparing changes
ing regimen for six months with or without daily antioxidant (after-before) between two treatments (n=6 per treatment
supplementation. The control diet was formulated to meet all group). Statistical significant at *: p<0.05 or **: p<0.01.
Association of American Feed Control Officials (AAFCO) nutri-
tion requirements. The antioxidant supplement blend included
known antioxidants for human eye health: major carotenoids nificant improvements in the scotopic high and photopic single
(20 mg lutein, 5 mg zeaxanthin, 20 mg beta-carotene, 5 mg flash cone (p<0.05, for both) ERG responses (Figure 4). For the
astaxanthin), 500 IU vitamin E, and 180 mg vitamin C. b-wave amplitudes, all responses were increased similarly, with
Portable mini-Ganzfeld ERG was used with an automated and significant improvements in responses for the scotopic high-light
standardized canine ERG protocol25,26 in the dogs at baseline and intensity stimulation (p<0.05) and for photopic single flash cone
at the end of the supplementation period for ERG measurement. and 30 Hz flicker (p<0.01, for both) recordings (Figure 5).
Hand-held auto-refractor was used under indirect light conditions Scotopic high is for assessing rod photoreceptor function under
at baseline and at the end of the supplementation period for refrac- dark condition. Photopic single-flash cone is for assessing cone
tive error measurement. photoreceptor function under light condition, and photopic 30 Hz
All ERG a-wave amplitudes were increased in the treatment flicker is for cone and rod photoreceptor function under light
group compared to those of dogs in the control group, with sig- condition.25
77
 Refractive Error Changes over Six-Month Supplementation Acknowledgement
The author would like to thank all collaborators for contributing
Refractive Error Spherical Equivalent

to various aspects of the research work presented here. Special

thanks go to Dr. Cecil Moore for all the eye exam evaluations;
to Dr. James Mrkvicka and Dr. Carolyn Cupp for lens cloudiness
scoring; to Dr. Janet Jackson and Dr. Stuart Richer for new
method and technologies; to Dr. Kristina Narfstrom for ERG
measurements; to Wendell Kerr and Xuemei Si for statistical
analyses; and to pet care technicians for carrying out various
studies and tests, especially Jerome Hernandez, Nicholas Whiting,
Harold King, DeAnn Harring, Jennifer Davis, Holly Hendricks,
and Rebecca Peery. Special thanks to Dr. Dorothy Laflamme
Figure 6. Right and left eyes before or after treatment for the critical review of this manuscript,
(n=6 eyes per group).

Change from before to after treatment with all eyes (left and References
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Statistical analysis was done using t-test comparing ness. 2013.
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of High-Dose Supplementation with Vitamins C and E, Beta-
* Statistical significance at p<0.05.
Carotene and Zinc for Age-Related Macular Degeneration and
Vision Loss. AREDS Report No. 8. Arch Ophthalmol. 2001;
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supplemented group compared to the control group. This indicates 3. Chew EY, Clemons TE, Sangiovanni JP, et al. Secondary
that even in healthy dogs with normal eyes, a better retinal response Analyses of the Effects of Lutein/Zeaxanthin on Age-Related
could be obtained with antioxidant supplementation. Macular Degeneration Progression. AREDS2 Report No. 3.
We also observed a marginal but significant difference in the JAMA Ophthal. 2013.
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combined, the control group had a refractive error change of 4. Tobias G, Tobias TA, Abood SK, et al. Determination of Age
-0.56 over the six-month study period, while the treatment group in Dogs and Cats by Use of Changes in Lens Reflections and
had a change of -0.13 (p=0.0495) (Figure 6). Transparency. Am J Vet Res. 1998;59(8):945-950.
Dogs, like humans, experience retinal functional decline and
compromised vision with age. Therefore, antioxidant supplemen- 5. State of Pet Health: 2012 Report. Banfield Pet Hospital. 2013.
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vation and improvement of eye function in dogs. 6. Davidson MG, Nelms SR. Diseases of the Canine Lens and
Cataract Formation. 2007;Ch18:859-887.
Summary
Eyesight is important for the well-being and quality of life of 7. Berliner ML. Nuclear Cataract. 1966;2:1147-1153.
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in dogs and cats. The age-related lens sclerotic changes were 8. Chylack LT, Khu PM. Subjective Classification and Objective
associated with increased lens cloudiness, increased lens reflec- Quantitation of Human Cataract. 2000;3:227-234.
tive dot sizes indicating light scattering and blurry vision, and
increased refractive error toward a myopic shift. All these may 9. Tobias G, Tobias TA, Abood SK, et al. Determination of Age
result in visual impairments that interfere with daily activities of in Dogs and Cats by Use of Changes in Lens Reflections and
dogs and cats. Antioxidants known for human eye health were Transparency. Am J Vet Res. 1998;59(8):945-950.
able to improve retinal responses as measured by ERG and to
slow down the refractive error shifting during a six-month anti- 10. Williams DL, Heath MF, Wallis C. Prevalence of Canine
oxidant supplementation trial in dogs. These results confirmed Cataract: Preliminary Results of a Cross-Sectional Study. Vet
our hypotheses that these antioxidants benefit dog eyes by improv- Ophthal. 2004;7(1):29-35.
ing their retinal and visual functions.

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11. Williams DL, Heath MF. Prevalence of Feline Cataract: 20. Richer S, Stiles W, Statkute L, et al. Double-Masked,
Results of a Cross-Sectional Study of 2000 Normal Animals, Placebo-Controlled, Randomized Trial of Lutein and Antioxidant
50 Cats with Diabetes and 100 Cats Following Dehydrational Supplementation in the Intervention of Atrophic Age-Related
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Antioxidant Supplementation Trial). 2004;75(4):216-230.
12. Murphy CJ, Zadnik K, Mannis MJ. Myopia and Refractive
Error in Dogs. Invest Ophthal Vis Sci. 1992;33(8):2459-2463. 21. Richer SP, Stiles W, Graham-Hoffman K, et al. Randomized,
Double-Blind, Placebo-Controlled Study of Zeaxanthin and
13. Miller PE, Murphy CJ. Vision in Dogs. J Am Vet Med Assoc. Visual Function in Patients with Atrophic Age-Related Macular
1995;207(12):1623-1634. Degeneration. The Zeaxanthin and Visual Function Study (ZVF).
FDA IND #78, 973. 2011;82(11):667-680.
14. Steele G, Ireland D, Block S. Cycloplegic Autorefraction
Results in Preschool Children Using the Nikon Retinomax Plus 22. Brown L, Rimm EB, Seddon JM, et al. A Prospective Study
and the Welch Allyn SureSight. Optom Vis Sci. 2003;80(8):573-577. of Carotenoid Intake and Risk of Cataract Extraction in U.S. Men.
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15. Ying GS, Maguire M, Quinn G, et al. ROC Analysis of the
Accuracy of Noncycloplegic Retinoscopy, Retinomax Autore- 23. Mares-Perlman JA, Fisher AI, Klein R, et al. Lutein and
fractor and SureSight Vision Screener for Preschool Vision Zeaxanthin in the Diet and Serum and Their Relation to Age-
Screening. Invest Ophthal Vis Sci. 2011;52(13):9658-9664. Related Maculopathy in the Third National Health and Nutrition
Examination Survey. 2001;153(5):424-432.
16. Ofri R, Hollingsworth SR, Groth A, et al. Effect of Optical
Defocus on Performance of Dogs Involved in Field Trial Com- 24. Chew EY. Nutrition Effects on Ocular Diseases in the Aging
petition. Am J Vet Res. 2012;73(4):546-550. Eye. Invest Ophthal Vis Sci. 2013;54(14):ORSF42-ORSF47.

17. Taylor A, Jacques PF, Epstein EM. Relations Among Aging, 25. Katz ML, Coates JR, Cooper JJ, et al. Retinal Pathology in
Antioxidant Status, and Cataract. 1995;62(6 Suppl):1439S-1447S. a Canine Model of Late Infantile Neuronal Ceroid Lipofuscinosis.
Invest Ophthal Vis Sci. 2008;49(6):2686-2695.
18. Parisi V, Tedeschi M, Gallinaro G, et al. Carotenoids and
Antioxidants in Age-Related Maculopathy Italian Study: Multi- 26. Narfstrom K, Ekesten B, Rosolen SG, et al. Guidelines for
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2008;115(2):324-333. 105(2):83-92.

19. Piermarocchi S, Saviano S, Parisi V, et al. Carotenoids in

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Results of a Randomized Study. Eur J Ophthal. 2012;22(2):216-225.

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Notes

80
Adapting to a New Diet During Dog Domestication:
Implications for the Domestication Process and Dog Health
Erik Axelsson, PhD
Uppsala University
Department of Medical Biochemistry and Microbiology
Uppsala, Sweden
Email: [email protected]

Abstract this process by capturing wolf pups

Genome-wide comparisons of dogs Glossary of Abbreviations for use in guarding or hunting. Alter-
AMY2B: Pancreatic amylase in the small natively, as humans changed from a
and wolves are offering new perspec-
intestine of dogs that initiates starch digestion
tives on the origin of dogs. We recently nomadic to sedentary lifestyle, wolves
GO: Gene Ontology
used this technique to map selection themselves may have approached
MGAM: Maltase-Glucoamylase responsible
during dog domestication and identi- for the hydrolysis of maltose to glucose waste dumps near human settlements
fied several genes involved in diges- PCR: Polymerase Chain Reaction to scavenge for food.6 Selection for
tion and fat metabolism. In particular, SGLT1: Sodium-Glucose Co-Transporter 1 characteristics that allowed an efficient
selection at three genes responsible YBP: Years Before Present use of this alternative food resource
for the digestion of dietary starch indi- may have resulted in the evolution of
cates that dog domestication was accompanied by a change from a type of scavenger wolf that constituted the proto dog.
a mostly carnivorous to a relatively starch-rich diet. Through
surveys of genetic diversity in these loci in dog populations Genomic Differences Between Dogs and Wolves
from across the globe, we may gain insights into how and where Genome-wide comparisons of domestic and wild relatives at
this adaptation took place as well as how this dietary change a population level recently have started to shed light on several
may affect dog health. domestication processes. Identifying genomic regions where
domestic varieties share a haplotype that is typically absent or
Introduction to Dog Domestication rare in wild relatives can be used to map selection during initial
Dogs were likely the first animal to be domesticated, yet they domestication. Functional characterization of genes in these
still are important today to modern human society. It is not clear regions may then provide insight into traits characterizing
when and where this domestication process started. Fossil remains domestic animals. Such knowledge can, in turn, be used to
of canids in Europe and Russia dating 12,000 to 33,000 years explore the genetic basis for these traits and to extrapolate on
before present (YBP)1,2 suggest that it may have started among the environmental changes that accompanied the transition from
Palaeolithic hunter-gatherers. It is, however, uncertain whether wild to domestic animal, hence, offering a new perspective on
3
these remains represent ancestors to modern dogs, failed domes- the domestication process.
tication attempts or natural morphological variation among Following this reasoning, we recently mapped selection during
wolves.4 Canine remains from Israel that are 12,000 years old early dog domestication by comparing pooled whole-genome
could instead represent the earliest verified dog remains,5,6 sequence data from 12 widely distributed wolves and 60 dogs11
potentially associating dog domestication with the human tran- and identified 36 genomic regions that differ significantly between
sition from a nomadic to sedentary lifestyle. dogs and wolves. By functionally characterizing genes within
Large-scale genetic analyses indicate that dog domestication these regions using gene ontology (GO) analysis, we identified
began between 18,000 to 11,000 YBP,7,8 but as all wolves appear two major themes of functional change during dog domestication.
to be equally closely related to dogs,8 these analyses are less The first theme relates to the GO term nervous system devel-
informative with regard to the location of the domestication opment, which supports the hypothesis that selection for altered
process. On the other hand, worldwide surveys of mitochondrial behavior was important during dog domestication and that muta-
and Y-chromosome haplotype variation in dogs show that Chinese tions affecting developmental genes may underlie these changes.12,13
village dogs harbor unrivaled levels of genetic diversity, suggest- The second theme relates to digestion and includes genes involved
ing that most modern dogs have a Chinese origin.9,10 Adding to in both starch and fat metabolism. In particular, we found evidence
these uncertainties about the origin of dogs, it also is not clear for selection affecting three consecutive steps in the pathway
why and how dogs were domesticated. Humans may have begun responsible for starch digestion and subsequent glucose absorp-

81
tion, indicating that dogs may have adapted to a change from a
mainly carnivorous to a more starch-rich diet.

AMY2B
In dogs, starch digestion is initiated in the small intestine by
pancreatic amylase (AMY2B) catalyzing the breakdown of starch
to oligosaccharides maltose and maltriose.13 Following initial
observations of biased sequence coverage near AMY2B in dog,
we used quantitative polymerase chain reaction (PCR) to show
that repeated gene duplications have resulted in an average
sevenfold AMY2B copy number increase in dogs relative to
wolves (Figure 1).11 We subsequently determined that this dif-
ference is associated with higher pancreatic AMY2B expression Figure 2. a. MGAM mRNA expression levels in the pancreas
(28-fold higher average expression in dog, [Figure 1] as well as of 8 wolves (circles) and 9 dogs (squares). b. MGAM activity
higher serum amylase activity in dog compared to wolf [4.7-fold in serum from 8 wolves (squares) and 7 dogs (circles).11
higher activity in dog, Figure 1]).11 Our observations argue that
AMY2B duplications likely resulted in a selective advantage to some 16 that is highly divergent between dogs and wolves. We
early dogs by increasing the amylase activity. identified several candidate mutations within this locus including
two conservative amino acid substitutions, a 2 bp deletion that
MGAM disrupts the MGAM stop codon in dogs and a mutation in intron
After the initial breakdown of starch to oligosaccharides, 37 that affects a predicted transcription factor-binding site.
maltase-glucoamylase (MGAM) is responsible for the hydrolysis Although we have not been able to determine which of these
of maltose to glucose.14 MGAM is located in a region on chromo- mutations were targeted by selection during dog domestication,
our functional assays concluded that both MGAM expression
and MGAM protein activity have changed during the domesti-
cation process: MGAM is, on average, expressed at ~12-fold
higher levels in dogs compared to wolves, and maltose is con-
verted to glucose at twice the rate in dog compared to wolf
serum (Figure 2).11

SGLT1
After the hydrolysis of starch has been completed, the resultant
glucose is absorbed through the wall of the small intestine by
the sodium-glucose co-transporter 1 (SGLT1).15 SGLT1 resides
in a region on chromosome 26 that also differs markedly in
haplotype frequencies between dog and wolf. All dogs tested
were carriers of a particular haplotype that was completely
absent in 18 of 19 wolves.11 This region includes a conservative
amino acid substitution in SGLT1, though so far we have not
been able to determine that this mutation, indeed, represents the
target of selection in this region.

AMY2B Copy Number and Amylase Activity

Varies Among Dogs
Although our observations argue that dogs, in general, digest
starch more efficiently than wolves (Figure 3), strong variability
in AMY2B copy number (diploid AMY2B copy number range in
dogs 2N=4-30) and widely varying serum amylase activity
Figure 1. a. AMY2B copy number distribution among 35 values among dogs16 indicate that the ability to handle starch
wolves (filled bar) and 136 dogs (open bars). b. Amylase
may vary in a genetically determined manner within the dog
messenger RNA expression levels in the pancreas of 12 wolves
population. By comparing AMY2B copy number and amylase
(circles) and 9 dogs (squares). c. Amylase activity in serum
activity in a diverse set of dogs, we have confirmed that amylase
from 13 wolves (circles) and 12 dogs (squares).11
activity is associated with AMY2B copy number (beta 0.69 per

82
 to traditional feeding habits and whether it could be associated
with susceptibility to metabolic disorders.

Pancreatic Amylase References

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2. Pionnier-Capitan M, Bemilli C, Bodu P, et al. New Evidence

for Upper Palaeolithic Small Domestic Dogs in Southwestern
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3. Thalmann O, Shapiro B, Cui P, et al. Complete Mitochondrial

Genomes of Ancient Canids Suggest a European Origin of
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4. Crockford SJ, Kuzmin YV. Comments on: 1) Germonpre, et

Figure 3. Illustration showing how starch is digested in the
al. Fossil Dogs and Wolves from Palaeolithic Sites in Belgium,
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Illustration courtesy of Maja Arendt. 12,000 Years Ago in Natufian of Israel. Nature. 1978; 276:608-610.

copy; p=0.028, linear regression), arguing that individual dogs, 6. Tchernov E, Valla FF. Two New Dogs, and Other Natufian
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13. Mocharla H, Mocharla R, Hodes ME. Alpha-Amylase Sodium Glucose Transporters. Physiol Rev. 2011;91:733-794.
Gene Transcription in Tissues of Normal Dog. Nucleic Acids
Res. 1990;18:1031-1036. 16. Arendt ML, Fall T, Lindblad-Toh K, et al. Amylase Activity
Is Associated with AMY2B Copy Numbers in Dog: Implications
14. Nichols BL, Avery S, Sen P, et al. The Maltase-Glucoamylase for Dog Domestication, Diet and Diabetes. (Submitted for pub-
Gene: Common Ancestry to Sucrase-Isomaltase with Comple- lication)

84
Notes

85
Notes

86
Evolutionary Versus Evidence-Based Diets
Ellen Kienzle, Dr. med. vet. habil., PhD, ECVCN
Ludwig-Maximilians-Universität
Department of Animal Nutrition and Dietetics
München, Germany
Email: [email protected]

Abstract simplifies nutrition. For the believer, this

Evolutionary diets are diets perceived by
Glossary of Abbreviations feels like taking a shortcut to knowledge in
BARF: Biologically Appropriate
pet owners as mimicking the natural diet nutrition that is then perceived as superior
Raw Food
of the wild ancestors of pets. Evolutionary to science. This naïve simplification is not
NRC: National Research Council
diets may induce serious malnutrition in the unique to nutrition. It leads to unsubstantiated
hands of pseudo-experts in nutrition. Such problems are highly beliefs and prejudices in many situations. In part, it is attributed
unlikely to occur in science-based diets, including balanced to the expansion of human knowledge in general.
evolutionary diets, even though the scientific evidence for pet Individuals cannot possibly keep up with new knowledge in
nutrition is rather limited in many aspects. In view of that, all areas of expertise. This leads to an increase of “not knowing”
scientists should not disregard the traditions and intuitions of in all areas with the possible exception of one’s own specializa-
experienced, observant dog and cat people. tion. Taking a shortcut around the complexity of the scientific
knowledge outside their own expertise and using naïve-simplified
Introduction: Why Scientists Do Not Like ideas relieves the individual from feeling ignorant.3 In social
Evolutionary Diets media, lay people may create a virtual pseudo-expertise around
The mentioning of so-called evolutionary diets, such as BARF such ideas that multiplies the impact of unsubstantiated beliefs
(biologically appropriate raw food), a prominent evolutionary on numerous subjects including nutrition. This kind of pseudo-
diet consisting of bones and raw food, to small animal nutrition expertise if applied in practice in nutrition often leads to severe
scientists induces the same reaction all over the world: eye rolls, malnutrition and the crippling or killing of animals. It is not
contemptive laughter, annoyed and ironic remarks, in short, a surprising that this approach to nutrition annoys the educated
general expression of being fed up with this nonsense. Nutri- nutritionist who goes the opposite way and tries to understand
tionists point out the obvious differences between wolves or wild all the details and complexities of his specialty.
cats and pets in appearance, lifestyle and even metabolism, such
as the development of the ability to digest starch during domes- Definition: What Is an Evolutionary Diet?
tication in dogs.1 We mention the different goals of evolution At first try, it seems rather easy to discriminate between science-
(reproduction) and pet owners (a long, healthy life, mostly based and evolutionary diets. The evidence-based diet takes into
without reproduction). We point out that there is a difference account scientific knowledge on the nutrition of the species and
between nature and paradise and that mortality rates may be life stage of the individuals that are going to eat it. By contrast,
around 30% in the adult wolf population.2 We explain that if the evolutionary diet tries to include certain features of the diet of
there is hardly a free-living wolf with a broken tooth, this is not wolves or wild cats, such as feeding raw and/or to avoid/reduce
due to wolves never breaking teeth but to wolves starving to death certain feeds that are perceived as not being major ingredients
if they do. We refer to the hygienic risks involved, and we report of natural diets. An evolutionary diet for dogs and cats can be
cases of serious malnutrition on such diets. defined as a diet that is perceived by the owner to be as close to
All this came to my mind when I was asked to give this the natural diet of the wild ancestors of our pets. This, however,
presentation. Then, I started wondering why scientists react this does not mean that scientific knowledge cannot be taken into
way. In some cases, the animal suffering by malnutrition of account as well. It is possible to create a complete and balanced
evolutionary diets, such as the induction of skeletal diseases in BARF diet without using a “chemical” supplement. It also is
growing puppies, does not entirely explain the annoyance expressed possible to buy the ingredients for this diet as human food grade
in this context by nutritionists. Why do the myths and beliefs in and to handle them in accordance with scientific hygiene rules.
context with evolutionary diets make us so angry? Nutrition is Such a diet would then be a science-based evolutionary diet.
extremely complex and giving science-based appropriate nutrition Can we transfer the principles of evidence-based medicine
to dogs and cats is short of impossible for lay people. Believing to nutrition? The first step in this approach says: “Formulate a
in a “back to nature — evolutionary — what the wolf eats diet” clear clinical question from a patient’s problem.”4 For dietary

87
treatment of a clinical problem, such as food allergy or chronic that justify meta-analysis. With the melamine contamination,
kidney disease, this works quite well. The same is true for eval- I would rather presume that for a responsible pet food producer
uation of the potential effects of a nutraceutical. But, for a general a phone call from an expert that alerts to a potential problem
nutritional approach, what would be our question? What is the should be sufficient to induce action. In many countries, it would
best diet for dogs or cats? That is too comprehensive. However, be illegal to wait for meta-analysis before starting damage control.
we can break it down into many questions, such as: The same is true when other potentially harmful problems come
• Are energy and nutrient requirement met by the diet? up, such as the lower availability of taurine in canned diets or
• Are there nutrient excesses and, if so, are they safe? adverse effects of nutrients. That means we need a different
• Are there interactions between nutrients or ingredients that approach in evidence-based nutrition with regard to risk man-
alter requirements or tolerance? agement. We need to reformulate the point. If there is a potential
• Are there hygienic risks? risk in a food, then we need excellent scientific evidence that it
• Is there a possibility for feed contamination? is safe before we disregard it.
• Are there effects of industrial processing? Are we losing essen- In evidence-based medicine, there is usually a caution that
tial or functional substances or reducing their availability? even if you apply correctly the rules laid down for this approach,
Are new substances produced, and, if so, what are their effects? you can end up with information that is wrong.6 Good examples
• Is there anything new that we may have overlooked, such as for the truth of this statement are requirement figures, especially
the microbiome or epigenetic effects of nutrition? for companion animals. They are usually the product of a liter-
• Are there behavioral and psychological effects? ature meta-analysis done by a committee of experts in the field.
The second step would be to “search the literature for relevant The results are estimates based on the current scientific knowl-
… articles,” and the third one would be to “evaluate (critically edge. They are prone to change with scientific progress. There are
appraise) the evidence for its validity and usefulness.” For the numerous examples for quite substantial alterations of require-
latter, there are guidelines ranking meta-analysis as highest, ment figures in the National Research Council’s (NRC) 2006
clinical studies second, case reports third, and finally experts’ Nutrient Requirements of Dogs and Cats,7 which are not just of
opinions and experiences. Within these types of evidence, there academic interest. These include zinc requirements of growing
are indicators for quality, such as the inclusion of control groups, dogs eating high-phytate, high-calcium food, taurine requirements
blinding, statistics, and quality of description of treatment. Finally, of cats and certain dog breeds, potassium requirements of cats
we “implement useful findings in clinical practice” or, in our case, eating acidifying diets, and tyrosine requirements for maximal
in feeding practice. black hair color. The individual variation of maintenance energy
The problem of transferring this concept to general nutrition is requirements has not been embraced by science until rather recently.
not just the comprehensive character of the questions. In medi- Another excellent example for scientific progress is the change
cine in many diseases you can treat a problem or you can choose of the paradigm that nutrient requirements are a function of
between treatments. In many cases you can even abstain from body weight and energy and that protein requirements are a
major intervention. The major effects expected from the treatment function of metabolic body weight. We now presume that all
are presumed to be positive. Then, you have to balance potential nutrient requirements are more or less a function of metabolic
risks and side effects against positive effects of the treatment. In body weight. For a Great Dane, this may mean a reduction of
general, nutrition is different; obviously, abstention from feeding maintenance requirements of nutrients by 50%. Another point
or eating is never a long-term solution. The biggest point, how- is the intervals between updating reference books for nutrient
ever, is that nutrition can rarely do more than help an organism to requirements, which in pet nutrition, so far, are in the range of
function to the best of its potential. By contrast, errors in nutrition decades. The number and quality of studies on which require-
can reduce the ability of an organism to function. It is impossible ments and safe upper limits are based is just scary. Like in other
to make a team of Dachshunds win the Iditarod by giving them specialties, looking critically at the scientific evidence on which
optimal nutrition, but it is quite easy to stop the best Husky team we base our nutritional knowledge is a sobering experience.6
from winning by malnutrition. Nutrient deficiencies and excesses, Comparing the gaps in our knowledge and the titles of presen-
insufficient food hygiene, and food contamination can cause tations on recent congresses, I cannot help wonder whether we
life-threatening or crippling diseases. So, in the first place, pick the right questions in our research on pet nutrition.
good nutrition is the absence of the above-mentioned problems
and not the addition of something “healthy.” Another point is Do We Know Enough on the Effects of Processing?
that with foodborne diseases, you may not even know what you With regard to the question of evolutionary diets, the effects
are looking for. There is something new or highly unexpected of food processing need to be discussed. They go way beyond
from time to time, such as the recent melamine problem.5 nutrient availability. At present, there is high interest in the effect
This creates another problem with the evidence-based approach of food on the gut microbiota. Starch of different origins in its
used for medicine. You cannot possibly postpone intervention various stages of processing is an excellent example for very
in the case of a nutritional risk until there are a number of studies different effects of the same nutrient on digestion including the

88
gut microbiota. Although cooked cornstarch is highly digestible by scientifically known for decades, such as calcium or thiamin
amylase, raw cornstarch is more a source of fermentable carbo- deficiency. There are, however, people other than the above-
hydrate and raw potato starch has an extremely low digestibility mentioned pseudo-experts with nonscientific knowledge of
and fermentability in the gut of cats.8 The different starch types nutrition that is based on tradition, experience and intuition. They
altered not only starch digestibility but also digestibility of other are not so easy to beat with scientific knowledge. Such a person
nutrients and fecal parameters indicative of microbial activity, having the intuition, for instance, the gut feeling that something
such as pH. In other species, even smaller differences of feed is wrong, sees an effect without knowing what he or she sees.
processing have been demonstrated to have strong effects on An excellent example is the physical appearance of the
the microbiota. In pigs, altering particle size of the same feed laminitis-prone horse. Experienced horse people can identify
had strong effects on caecal parameters and even the prevalence such a horse just by looking at it, but mostly they do not know
of Salmonella, which was lower in pigs eating feed with larger how they can tell that from the appearance of the horse. In his
particle size.9 In pigs, particle size can interact strongly with the excellent research on insulin resistance in horses, David Kronfeld
effects of probiotics.10 In addition, particle size can have a strong and his working group pointed out that laminitis-prone horses
effect on satiety and glycemic response in humans.11 A counter- have a typical fat distribution with lots of crest fat and stem fat.20
acting effect of home cooking on population obesity is a well-known Laminitis-prone horses are usually easy keepers, a desirable
feature in human nutrition.12 It is presumably multifactorial and quality for hardworking and military horses. There is, in fact, a
includes psychological aspects, but effects of processing, such description of the appearance of the easy keeper by the Greek
as smaller particle size, may be among the factors. The effect of cavalry officer Xenophon that is nearly 4,000 years old.22 Until
home cooking on the incidence of overweight appears to exist in today, traditional judgment of the appearance of a “good” horse
dogs too. There is a surprisingly low incidence of overweight includes this kind of fat distribution. Especially in leisure horses
of 11.5% in dogs eating BARF diets.13 The same was true for that do not work hard, being an easy keeper and laminitis-prone
dogs eating vegetarian diets14 (incidence of overweight 8%), are not good qualities anymore, and the goals of breeding need to
and it also is true in our clients’ dogs that eat predominantly change accordingly. In a changing environment and with chang-
completely or partly home-cooked diets.15 ing lifestyle, science can definitely beat tradition. In scientific
There are strong effects of processing on the interactions of horse nutrition, we often end up with results that confirm old
food with the immune system. Processed foods may lose or military rules on horse feeding, which were obtained by gener-
gain allergenicity. Depending on the individual eating the food, ations of cavalry men.23
both effects are possible in the same food.16 Maillard products The number of people owning dogs or caring for dogs who
(reaction products of amino acids and sugars) have numerous have experience with dogs comparable to the horse sense of
adverse and some beneficial effects in various species,17 but cavalry men is relatively limited to small groups, such as expe-
this has not been investigated predominantly in carnivores. rienced mushers, hound masters, professional dog handlers of
Maillard products are mainly, but not exclusively, produced drug, rescue or police dogs, and some dog breeders. Until very
during heating. Feeding raw or home-cooked food will reduce recently, cats were partly independent from humans feeding
the intake of such products. In this context, it is worthwhile to them, which precludes a long tradition. Cat breeders and tech-
mention that a large number of people feeding BARF diets to nicians in cat colonies or homes for rescue cats may acquire
their dogs and consulting our service tell us that they do so be- lots of experience. The traditional and intuitive knowledge of
cause the dog otherwise shows either gastrointestinal problems such people can be a valuable resource in improving pet nutri-
or skin lesions consistent with food intolerance. Another example tion. It may include positive experiences with some features of
that there may be a difference between eating a “natural” product evolutionary diets. Part of our job is shifting the grain of tradi-
or something “artificial” is antioxidants. Fruits and vegetables tional and intuitive knowledge of experienced animal owners
have been presumed to be healthy foods for a long time, and from the chaff of unsubstantiated myths and beliefs of virtual
scientific data have even confirmed a protective effect against pseudo-experts.
cancer.18 Eating antioxidants, which were perceived as potential
mediators of this effect of fruit and vegetables, did not have the References
same effect and may even promote cancer.19 1. Axelsson E, Ratnakumar A, Lindblad-Toh K, et al. The Ge-
nomic Signature of Dog Domestication Reveals Adaptation to a
The Pet Owners’ Question Starch-Rich Diet. Nature. 2013;495:360-364.
The question for the dog owner when deciding whether to
use a science-based diet is not: “Did the scientists do their best?” 2. Theberge JB, Theberge MT. Wolf-Ecosystem Research
but rather “Can they do a better job than other experts?” As Algonquin Park. The Wolves of Algonquin Park, a 12-Year
mentioned above, it is rather easy to beat pseudo-experts fanta- Ecological Study. Department of Geology Publications, Reports,
sizing about wolves’ diets. Science-based nutrition will certainly Theses. University of Waterloo Publications, Waterloo, Ontario.
not cripple or kill animals by inducing feeding mistakes that are Publication Series No. 56. 2004.

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3. Bergler R. Irrationalitaet und Risiko; Gesundheitliche 13. Dillitzer N, Becker N, Kienzle E. Intake of Minerals, Trace
Risikofaktoren und deren Naturwissenschaftliche und Psychol- Elements and Vitamins in Bone and Raw Food Rations in Adult
ogische Bewertung. Koelner Universitaetsverlag GmbH. Dogs. Br J Nutr. 2011;106.S1:S53-S56.
2000;1:13.
14. Engelhard R. Feldstudie zur Vegetarischen Ernaehrung von
4. Rosenberg W, Donald A. Evidence-Based Medicine: An Hunden und Katzen. Tieraerztliche Fakultaet Muenchen. Thesis.
Approach to Clinical Problem-Solving. Br Med J. 1995;310 1999.
(6987):1122.
15. Thes M, Koeber N, Kienzle E. Metabolizable Energy Intake
5. Brown CA, Jeong K-S, Brown SA, et al. Outbreaks of Renal of Client-Owned Adult Dogs. J An Phys An Nutr. 2014 (in press).
Failure Associated with Melamine and Cyanuric Acid in Dogs
and Cats in 2004 and 2007. J Vet Diag Invest. 2007;19.5:525-531. 16. Wal J-M. Thermal Processing and Allergenicity of Foods.
Allergy. 2003;58.8:727-729.
6. Arlt SP, Heuwieser W. Diagnostik und Therapie in der Repro-
duktionsmedizin – Was wissen wir wirklich? Tieraerztliche 17. Finot PA. Historical Perspective of the Maillard Reaction in
Umschau. 2012;67:491-495. Food Science. Ann NY Acad Sci. 2005;1043.1:1-8.

7. Nutrient Requirements of Dogs and Cats. National Research 18. Steinmetz, KA, Potter JD. Vegetables, Fruit and Cancer. I.
Council. The National Academies Press, Washington, D.C. 2006. Epidemiology. Cancer Causes & Control. 1991;2.5:325-357.

8. Kienzle E. Carbohydrate Metabolism of the Cat. 2 Digestion 19. Omenn GS, Goodman GE, Hammar S, et al. Effects of a
of Starch. J An Phys An Nutr. 1993;69(1-5):102-114. Combination of Beta-Carotene and Vitamin A on Lung Cancer
and Cardiovascular Disease. N Eng J Med. 1996;334(18):
9. Visscher CF, Winter P, Kamphues J, et al. Effects of Feed- 1150-1155.
Particle Size at Dietary Presence of Added Organic Acids on
Caecal Parameters and the Prevalence of Salmonella in Fattening 20. Treiber KH, Kronfeld DS, Hess TM, et al. Evaluation of
Pigs on Farm and at Slaughter. J An Phys An Nutr. 2009;93: Genetic and Metabolic Redispositions and Nutritional Risk
423-430. Factors for Pasture-Associated Laminitis in Ponies. J Am Vet
Med Assoc. 2006;228(10):1538-1545.
10. Kienzle E, Geiser G, Erhardt W, et al. Eine Zufallsbeobach-
tung zum Einfluss der Fuetterung auf die Wirkung von Probiotika 21. Widdra K. Xenophon - Reitkunst. WuWei Verlag. 2007.
(An Accidental Observation on the Effect of Feeds on Efficiency
of Probiotics). Tieraerztliche Praxis. 1999;27(G):302-305. 22. Steffens B. Ein Beitrag zur Fütterung und Haltung von Mil-
itärpferden im 18. und 19. Jahrhundert. Thesis. Tieraerztliche
11. Holt SH, Brand Miller J. Particle Size, Satiety and the Hochschule Hannover. 1996.
Glycemic Response. Eur J Clin Nutr. 1994;48.7:496-502.

12. Stitt S. An International Perspective on Food and Cooking

Skills in Education. Br Food J. 1996;98.10:27-34.

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Notes

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Notes

92
Toward Optimizing Feline Nutrition: Insights from the
Dietary Nutrient Profile of Feral Cats
Esther A. Hagen-Plantinga, PhD, DVM
Utrecht University
Faculty of Veterinary Medicine
Department of Nutrition
Utrecht, Netherlands
Email: [email protected]

Abstract feeding a high-carbohydrate content is

A recent review of the nutrient profile of
Glossary of Abbreviations thought by some to induce certain health
CP: Crude Protein
feral cats, using the rates of ingestion of disorders, such as obesity and diabetes
DM: Dry Matter
various prey items, expectedly demonstrated mellitus, though data supporting a cause-
EE: Ethereal Extract
the carnivorous nature of cats, with a high GFR: Glomerular Filtration Rate and-effect relationship is lacking.
daily energy intake from protein and fat and ME: Metabolizable Energy The concept of “natural” foods that
a low intake of carbohydrate. The abbreviated NFE: N-Free Extract may better match the physiological and
nutrient profile can be considered a profile PUFA: Polyunsaturated Fatty Acid metabolic makeup of cats is comparable
to which the cat’s metabolic system has to the paradigm that the Palaeolithic
adapted. The question remains to what extent can this nutrient hunter-gatherer diet would better fit modern man than current
profile be considered optimal for today’s domestic cat and to human nutrition. The discordance hypothesis originally described
what extent can the characteristics of the natural diet be used by Eaton and Konner 3,4 states that the human genome evolved
to further optimize commercial feline foods. to adapt to conditions that no longer exist. The change from
Palaeolithic to current nutrition may have occurred too rapidly
Introduction for adequate genetic adaptation, and the resulting mismatch
The domestic cat (F. silvestris catus) can be considered as one helps to cause some common diseases of civilization, such as
of the most popular pet animals worldwide. The cat relatively diabetes mellitus, obesity and dental disease.
recently derived from the wildcat of the Near East (F. silvestris To what extent the discordance hypothesis may also apply
lybica)1 in a process that caused only minor alterations to the for cats and to what extent the nutrient profile of the feral cat’s
animal’s morphology and behavioral repertoire. diet is optimal for domestic cats are subjects for debate. It needs
As for nutrition, the domestic cat’s wild ancestor is known to be noted, however, that the natural nutrient profile originates
to be an obligatory carnivore, consuming prey high in protein from feral cats living under severe physiological and climatic
and moderate in fat and carbohydrate. This consumption pattern conditions and in which nutrition is a precondition for species
has led to unique metabolic idiosyncrasies that are generally survival and procreation. In general, our domestic cats have a
accepted as the direct result of an evolutionary adaptation to a much more sedentary lifestyle, regular meals and a longer life
diet strictly composed of animal tissue. Of these nutritional span, which may have significant effects on nutrient require-
idiosyncrasies, the cat’s limited ability to decrease the activity ments and handling.
of amino-acid catabolizing enzymes most markedly shows the
cat’s carnivorous nature. Other nutritional idiosyncrasies include Natural Nutrient Profile Versus Nutrient Requirements
requirements for arginine, taurine, niacin, arachidonic acid, and Knowledge about the feeding strategies and features of the
vitamins A and D.2 natural diet of a species may provide valuable insights for the
The carnivorous nature of the domestic cat has led to a popular formulation and selection of appropriate diets to maintain and
trend in feline nutrition, in which a feeding strategy is adopted support health. For that reason, the nutrient profile of feral cats
that more closely resembles the cat’s “natural” food intake, was recently reviewed using the rates of ingestion of various
namely feeding a diet high (>45% metabolizable energy [ME]) prey items in the literature.5 The main items consumed by feral
in animal protein and low (5-25% ME) in carbohydrate. The cats were mammals (78%), followed by birds (16%), reptiles and
rationale behind this strategy is the fact that the cat’s metabolism amphibians (3.7%), and invertebrates (1.2%). Consumption of
has evolved on an animal-based, high-protein diet and, as such, plant material was reported but was considered a minor component
is physiologically and metabolically adapted to it. Besides that, of the diet and likely to occur incidentally while foraging for

93
invertebrates. There existed a large variation in types of prey The average nutrient composition of commercial high-quality
items that were consumed by feral cats in different regions and dry extruded (n=252) feline foods9 also are displayed in Table 1.
climates, with a higher consumption of reptiles, amphibians The average dietary NFE content of cats fed dry commercial foods
and invertebrates in warmer climates. These differences clearly is substantially higher (17.2 g/MJ ME), and the CP and phosphorus
show that cats are opportunistic predators, thriving on a wide content is substantially lower (20.0 g/MJ and 0.53 g/MJ ME,
range of prey. respectively) than the dietary NFE, CP and phosphorus content
The nutrient profile that was derived from the ingested prey of the feral cat diet (1.6, 35.5 and 1.0 g/MJ ME, respectively).
items expectedly showed that cats are true carnivores, with 52%
of the daily energy intake being derived from protein, 46% from Dietary NFE
fat and only 2% from N-free extract (NFE). The feral cat’s natural The NFE content in feline commercial foods mainly originates
dietary nutrient profile differs in several aspects from the nutrient from starch of cereal grains. These starches are cooked during
guidelines and characteristics of commercial feline foods. processing and are, therefore, generally well-digested by cats,
Table 1 provides the average dietary nutrient profile for feral with apparent digestibility reaching values of above 90% for
cats (units/MJ ME), based on 27 dietary prey profiles of feral starches in dry extruded diets.10 For feral cats, NFE intake is
cats,5 compared to the minimum and recommended nutrient considered to be low, and it is not likely that they are exposed to
requirement of cats during growth and maintenance as provided a daily glycemic load that pet cats fed commercial foods may
by the National Research Council.6 experience. The question remains to what extent a long-term
The physiological nutrient requirements have been accurately high-carbohydrate intake could potentially lead to unwanted
determined for several nutrients and can be considered to represent health effects throughout the cat’s life.
the limit of the adaptation capacity of domestic cats in relation Recently, Kirk11 wrote an excellent overview regarding current
to dietary nutrient concentrations. Contents of crude protein literature status on carbohydrate intake and metabolism in cats.
(CP), Ca, P, Zn, Fe, Cu, and Mg in the average feral cat diet are It was concluded that although the cat’s metabolic adaptations
well above the minimal nutrient requirement for these nutrients, suggest poor carbohydrate utilization, cats do seem able to readily
though the bioavailability of these nutrients in the natural diet is digest, absorb and utilize carbohydrate up to a level of at least
unknown. Recent studies on apparent macronutrient and energy 6.7 g/kg BW/day, depending on the source of carbohydrate and
digestibility of raw meat diets in felids have shown that CP type of processing. Cats do, however, seem to have a rate-limiting
digestibility ranges from 91 to 96.7% according to the species capacity to digest and utilize large amounts of simple sugars.
studied and meat sources applied.7,8 Data concerning the Dietary carbohydrate intake and the relationship to disease were
bioavailability of micronutrients and trace elements in felids also thoroughly discussed. It was concluded that although an
consuming whole prey items are lacking. However, it may be increased carbohydrate intake may lead to altered metabolic
that absorption of minerals such as Ca and P are much lower in responses, the magnitude of these alterations generally falls well
prey items compared with the forms used to supplement com- within the normal limits of adaptation. Although diabetic cats
mercial feline diets because of the complexity of bone matrix. may benefit from feeding a high-protein and low-carbohydrate

Table 1. Approximated dietary nutrient profiles reported in literature of feral cats,5 minimal and recommended
allowances for feline growth and maintenance,6 and average nutrient profile of commercial feline dry diets.

Item Unit Feral Cat5 National Research Council6 Commercial9

Growth Maintenance Dry
Minimum RA Minimum RA
ME kJ/100g DM 1770 1790
CP g/MJ ME 35.4 10.8 13.5 9.6 12.0 20.0
EE g/MJ ME 12.9 5.4 5.4 9.1
NFE g/MJ ME 1.6 17.2
Ca g/MJ ME 1.5 0.31 0.48 0.10 0.17 0.60
P g/MJ ME 1.0 0.29 0.43 0.08 0.15 0.53
Na g/MJ ME 0.28 0.07 0.08 0.04 0.04 0.36
K g/MJ ME 0.53 0.16 0.24 0.31 NA
Cu mg/MJ ME 0.90 0.26 0.50 0.29 NA
Zn mg/MJ ME 5.5 3.0 4.4 4.4 NA
Fe mg/MJ ME 16.7 4.1 4.8 4.8 NA
Mg mg/MJ ME 73.4 9.6 23.9 12.0 23.9 NA
RA, recommended allowance; ME, metabolizable energy; DM, dry matter; CP, crude protein, EE, ethereal extract; NFE, N-free extract.

94
diet, a cause-and-effect relationship between chronic high- Dietary Lipids and Lipid Profile
carbohydrate intake and development of obesity and diabetes The average content of fat (assayed as ethereal extract [EE])
mellitus is lacking. of the feral cats’ diet is slightly higher than the average content
normally observed in commercial feline foods (Table 1). The
Dietary Protein and Phosphorus origin of lipids in both diets, however, can be expected to be
The natural nutrient profile contains an excess of dietary different, resulting in consumption of a different fatty acid profile.
protein and phosphorus compared to the physiological minimum Feline foods may contain lipids from vegetable oil (e.g., soybean,
requirement for the domestic cat and to the CP and phosphorus sunflower, corn) and/or animal origin (e.g., pork fat, beef tallow,

higher in ω-6 polyunsaturated fatty acids (PUFAs) than ω-3

content of feline dry foods (Table 1). An excess in protein and poultry fat, fish oil). Lipids from vegetable origin are typically
phosphorus may pose a risk for the elderly cat as a significant
decline in renal function is a common finding. It is estimated PUFAs. The PUFA profile of lipids derived from animals is

rearing. The ω-6:ω-3 ratios in fat tissue and muscle lipids of

that one in three cats older than 12 years of age has some form significantly influenced by nutritional fatty acid intake during
of renal insufficiency.12 A prospective longitudinal study by
Jepson et al.13 demonstrated that 30.5% of apparently healthy captive and feedlot animals ranges between 6:1 to 19:1, whereas
and biochemically normal geriatric cats (>9 years) developed a diet based on wild animal species contains a ratio of approxi-
biochemical evidence of azotemia within 12 months. mately 2:1.5

commercial foods consequently result in a higher ω-6:ω-3

Although there is no direct scientific evidence that a chronic The vegetable and animal lipid sources commonly used in
high intake of protein and phosphorus will induce glomerular

For instance, the typical ω-6:ω-3 ratio of commercial dog foods

injury in cats, it can be debated that a high-protein and phosphorus ratio than that of lipids ingested when wild prey are consumed.
intake may have some negative effects on an already impaired
kidney. Ross et al.14 in a model of induced kidney failure in cats (n=12) showed an average of 8:1, ranging from 5:1 to 17:1.19

range. Considering the involvement of ω-3 PUFAs in numerous

demonstrated that a high dietary phosphorus intake (1.56% dry It is expected that feline commercial foods fall within the same
matter [DM]) for up to 11 months was associated with renal
mineralization, fibrosis and mononuclear cell infiltration. In physiological processes, including the mediation of inflammatory
comparison, a low-phosphorus intake (0.42% DM) was not and immune responses, renal functioning, cardiovascular health,
associated with these abnormalities. Adams et al.15 showed and neurologic development,20-23 the fatty acid profiles of our
that in cats with surgically reduced renal mass feeding a high- feline foods deserve careful (re)consideration.
caloric, animal-based, high-protein diet (51.7% protein as is and
38% ME from protein) for up to one year resulted in significant Non-Nutritive Properties of the Natural Diet
renal morphologic injury, which was largely prevented by dietary Although the suitability of the natural nutrient profile may to
protein and calorie restriction. However, Finco et al.16 failed to some respect be open for debate, the non-nutritive characteristics
demonstrate a protein or calorie effect in a one-year study on of the natural diet may provide valuable insights in optimizing
the progression of surgically induced renal failure in cats. today’s feline diets. Feed consistency and texture have been shown
The discrepancy between these two studies was ascribed to to be important characteristics in maintaining a balanced microbial
differences in the absolute potassium, protein and fat intake and population in the gastrointestinal tract of different animal
the sources of protein. Adams et al.15 mainly used animal-based species.24,25 Depauw et al.26 recently researched the effect of
protein sources, whereas in the study of Finco et al.16 a larger food texture on fermentation in captive cheetahs. Both whole
part of the protein was derived from plant-based raw materials. rabbit carcasses and beef chunks were fed to captive cheetahs
Animal protein is thought to alter renal hemodynamics more for four weeks. It was demonstrated that the fermentation rate of
markedly compared to vegetable protein, which may, in part, whole rabbit carcass was much lower compared to the raw beef
explain the found differences.17 Another explanation may be the chunks. This was ascribed to the higher amount of indigestible
fact that in the Adams study some of the cats on the high-protein and hardly fermentable materials, such as hair, in the hindgut.
diet developed hypokalemia. Dow et al.18 demonstrated that As a result, the formation of harmful products, such as indole
hypokalemia was associated with a transient reduction in and phenol, were lower, and the fecal bacterial protein content
glomerular filtration rate (GFR) in clinically normal cats. was increased when rabbit carcasses were fed.
Whether hypokalemia may also cause or enhance renal damage Undigested dietary fractions provide substrate for the micro-
is not yet established. biota in the gut, and the type of substrate can be expected to differ
As a large part of the feline population may suffer from an between consumed prey items and commercial feline foods. Whole
impairment in renal function as age is progressing, one could prey provide low digestible or indigestible substances like carti-
argue there is a lack of suitability of a natural dietary nutrient lage, collagens and glycosaminoglycans, with specific fermen-
profile with high dietary protein (>45% ME) and phosphorus tative characteristics27 other than fibers of vegetable origin and
intake (>0.75 g/MJ) in support of health and longevity. indigestible proteins in processed foods. Given the involvement

95
of the intestinal microbial community in host physiology and 7. Vester BM, Beloshapka AN, Middelbos IS, et al. Evaluation
immune function and behavior,28 the effect of these specific of Nutrient Digestibility and Fecal Characteristics of Exotic
substances on the microbial composition in the feline gut and Felids Fed Horse- or Beef-Based Diets: Use of the Domestic
activity and on (intestinal) health warrants further investigation. Cat as a Model for Exotic Felids. Zoo Biol. 2010;29:432-448.

Conclusion 8. Kerr KR, Vester BM, Boler CL, et al. Apparent Total Tract
Although the natural diet may contain a nutrient profile to which Energy and Macronutrient Digestibility and Fecal Fermentative
the cat’s metabolism is adapted, the question is to what extent End-Product Concentrations of Domestic Cats Fed Extruded,
does the natural nutrient profile optimally support health and Raw Beef-Based and Cooked Beef-Based diets. J An Sci.
longevity of domestic cats with a more sedentary lifestyle in a 2012;90:515-522.
different environment. After all, the natural nutrient profile
originates from feral cats living under severe physiological and 9. Dijcker JC, Hagen-Plantinga EA, Everts H, et al. Factors
climatic conditions and in which nutrition is a precondition for Contributing to the Variation in Feline Urinary Oxalate Excretion
species’ survival and procreation rather than long life. Rate. J An Sci. 2014;epub (Ahead of print).
On one hand, the nutritive characteristics of commercial
foods, which differ markedly from the natural nutrient profile 10. de-Oliveira LD, Carciofi AC, Oliveira MC, et al. Effects of
(a high-carbohydrate content being the most prominent), may Six Carbohydrate Sources on Diet Digestibility and Postprandial
pose physiological and metabolic challenges that cats need to Glucose and Insulin Responses in Cats. J An Sci. 2008;86:2237-
cope with. On the other hand, the natural nutrient profile, with 2246.
a significant excess in protein and phosphorus compared to
minimal and recommended requirements, may pose a challenge 11. Kirk C. Feline Nutrition: What Is Excess Carbohydrate?
for the elderly cat with impaired renal function. Proceedings Nestlé Purina Companion Animal Nutrition Summit.
Nevertheless, valuable insights may be gained by studying 2013. Atlanta, GA.
the natural diet of the domestic cat. Fatty-acid composition data
and non-nutritive characteristics of the natural diet, for instance, 12. Lulich JP, Osborne CA, O’Brien TD, et al. Feline Renal
may provide novel concepts for enhancing feline commercial Failure: Questions, Answers, Questions. Comp Cont Educ
diets in its purpose to further support health and longevity. Pract Vet. 1992;14:127-152.
Laboratory, clinical and epidemiological studies would be
required to challenge these concepts in today’s domestic cat. 13. Jepson RE, Brodbelt D, Vallance C, et al. Evaluation of
Predictors of the Development of Azotemia in Cats. J Vet Int
References Med. 2009;23:806-813.
1. Driscoll CA, Menotti-Raymond M, Roca AL, et al. The Near
Eastern Origin of Cat Domestication. Science. 2007;317:519-523. 14. Ross LA, Finco DR, Crowell WA, et al. Effect of Dietary
Phosphorus Restriction on the Kidneys of Cats with Reduced
2. Morris JG. Idiosyncratic Nutrient Requirements of Cats Appear Renal Mass. Am J Vet Res. 1982;43:1023-1026.
to be Diet-Induced Evolutionary Adaptations. Nutr Res Rev.
2002;15:153-168. 15. Adams LG, Polzin DJ, Osborne CA, et al. Effects of Dietary
Protein and Calorie Restriction in Clinically Normal Cats and
3. Eaton SB, Konner M. Paleolithic Nutrition: A Consideration in Cats with Surgically Induced Chronic Renal Failure. Am J
of its Nature and Current Implications. N Engl J Med. 1985;312: Vet Res. 1993;54:1653-1662.
283-289.
16. Finco DR, Brown SA, Brown CA, et al. Protein and Calorie
4. Eaton SB, Konner M, Shostak M. Stone Agers in the Fast Lane: Effects on Progression of Induced Chronic Renal Failure in
Chronic Degenerative Diseases in Evolutionary Perspective. Cats. Am J Vet Res. 1998;59:575-582.
Am J Med. 1988;84:739-749.
17. Kontessis P, Jones S, Dodds R, et al. Renal, Metabolic and
5. Plantinga EA, Bosch G, Hendriks WH. Estimation of the Hormonal Responses to Ingestion of Animal and Vegetable
Dietary Nutrient Profile of Free-Roaming Feral Cats: Possible Proteins. Kidney Int. 1990;38:136-144.
Implications for Nutrition of Domestic Cats. Br J Nutr. 2011;
106(Suppl 1):S35-S48. 18. Dow SW, Fettman MJ, Smith KR, et al. Effects of Dietary
Acidification and Potassium Depletion on Acid-Base Balance,
6. Nutrient Requirements of Dogs and Cats. National Research Mineral Metabolism and Renal Function in Adult Cats. J Nutr.
Council. The National Academies Press, Washington, D.C. 2006. 1990;120:569-578.

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19. Ahlstrøm Ø, Krogdahl A, Vhile SG et al. Fatty-Acid Compo- 25. Mikkelsen LL, Naughton PJ, Hedemann MS, et al. Effects of
sition in Commercial Dog Foods. J Nutr. 2004;134:S2145-S2147. Physical Properties of Feed on Microbial Ecology and Survival
of Salmonella Enterica Serovar Typhimurium in the Pig Gastro-
20. Simopoulos AP. The Importance of the Ratio of Omega-6/ intestinal Tract. Appl Environ Microbiol. 2004;70:3485-3492.
Omega-3 Essential Fatty Acids. Biomed Pharmacother. 2002;56:
365-379. 26. Depauw S, Hesta M, Vanhaecke L, et al. Impact of Diet
Type on Fermentation Rate of Cheetahs in Captivity. Proceed-
21. Bauer JE. Facilitative and Functional Fats in Diets of Cats ings of the Sixth European Zoo Nutrition Conference. 2010.
and Dogs. J Am Vet Med Assoc. 2006;229:680-684. Barcelona, Spain.

22. Bauer JE. Responses of Dogs to Dietary Omega-3 Fatty 27. Depauw S, Bosch G, Hesta M, et al. Fermentation of Animal
Acids. J Am Vet Med Assoc. 2007;231:1657-1661. Components in Strict Carnivores: A Comparative Study with
Cheetah Fecal Inoculum. J An Sci. 2012;90:2540-2548.
23. Bosch G, Beerda B, Hendriks WH, et al. Impact of Nutrition
on Canine Behavior: Current Status and Possible Mechanisms. 28. Sekirov I, Russell SL, Caetano M Antunes L, et al. Gut Micro-
Nutr Res Rev. 2007;20:180-194. biota in Health and Disease. Physiol Rev. 2010;90:859-904.

24. Huang DS, Li DF, Xing JJ, et al. Effects of Feed Particle Size
and Feed Form on Survival of Salmonella Typhimurium in the
Alimentary Tract and Fecal S. Typhimurium Reduction in Growing
Broilers. Poultry Sci. 2006;85:831-836.

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Notes

98
Raw Meat-Based Diets: Current Evidence Regarding
Benefits and Risks
Beth A. Hamper, DVM, PhD, DACVN
University of Tennessee
Veterinary Medical Center
Knoxville, TN
Email: [email protected]

Introduction Some of the home-prepared RMBDs are

Glossary of Abbreviations
Dogs and cats evolved eating prey-based diets based on a rotation of ingredients with the
AAFCO: Association of American
as their primary (dogs) or sole source (cats) Feed Control Officials belief that this rotation will provide over a
of food. It is only within the past 100 to 150 BARF: Biologically Appropriate period of time necessary amino acids,
years that commercial pet food products have Raw Food fatty acids, vitamins, and minerals.
been made and marketed for dogs and cats.1 DT: Definitive Type
In a survey conducted in 2011,2 10.8% of FDA: Food and Drug Administration Risks
791 pet owners from 44 U.S. states and RMBD: Raw Meat-Based Diet Three primary risk factors have been
six countries fed a commercial or home- reported with the consumption of raw diets
prepared raw meat-based diet (RMBD) as a major component of by pets. These include overall nutritional adequacy, health con-
their pet’s diet and 32.9% fed a home-prepared or commercial cerns such as consumption of raw bones leading to dental frac-
RMBD as some component of their pet’s diet. Those that support tures or gastrointestinal trauma, and consumption of pathogenic
RMBD are very passionate about their benefits, claiming improved bacteria, viruses and protozoa not killed in the normal cooking
pet health that includes improved immune function and decreased process. The most frequently cited concern of these in the veteri-
incidence of many chronic diseases, such as obesity, diabetes nary published literature has been food safety.
mellitus, allergies, feline urological syndrome, arthritis, and
cancer.3–5 Yet, no topic in veterinary nutrition has been more Safety - Pets
emotionally charged over the past 10 to 20 years, mainly due The primary safety concern related to RMBDs is the risk of
to the limited data from high-quality studies evaluating these contamination with pathogens.6 Raw meat, whether sold for
diets. The purpose of this manuscript is to discuss the current human consumption or included in dry extruded or moist canned
evidence regarding the risks and benefits of these diets. pet foods, can be contaminated with a variety of pathogens
including Salmonella spp., Escherichia coli and Campylobacter
Definition of RMBDs spp. While care is used during processing, meat from food animals
Raw meat-based diets are those that include portions of can acquire bacterial contamination from the hide, feathers or
uncooked domesticated or wild-caught food animal species and viscera during slaughter, evisceration, or processing and pack-
that are fed to pet dogs and cats in the home environment. These ing.7–10 Because freezing does not destroy all these pathogens,
uncooked portions include skeletal muscle, bone and internal both home-prepared and commercial RMBDs are at risk for
organs from mammals, fish and poultry. Raw-meat diets can be being contaminated.
divided into two main categories: commercial or home-prepared. Several reports7–9 have been published on the presence of
The commercial RMBDs are fresh, frozen or freeze-dried Salmonella spp. and other pathogens in commercial and home-
diets intended to be nutritionally complete and balanced. These prepared RMBDs. Prevalence rates for contamination with
diets are created from recipes developed by companies marketing Salmonella spp. in commercial RMBDs ranged from 20 to
their specific brand of pet food. In addition to the fresh, frozen 48%.7,9,10 Recently, a Salmonella spp. prevalence rate of 21%
and freeze-dried commercial diets is a premix that includes vita- for 16 commercial RMBD samples was reported.10
mins and minerals intended to have a raw-meat protein source Exotic cats fed raw meat diets have a high prevalence of shedding
added by the pet owner to become a complete diet. fecal Salmonella spp. For example, Salmonella spp. was isolated
Home-prepared RMBDs include a variety of highly publicized in 94% of fecal samples from a zoo and private big cat collection.11
feeding regimens, such as BARF3 (biologically appropriate raw All exotic cats were clinically healthy and were being fed a raw
food), the Volhard4 and the Ultimate Diet.5 Additional RMBDs horsemeat and chicken diet. Prevalence of fecal isolation of
have been developed by veterinarians, breeders and owners. Salmonella spp. in apparent clinically healthy domestic cats

99
ranges from 0 to 18%.12–15 As these values are based on one mercially available pet foods with Salmonella spp. in 2011 and
fecal culture, they probably underestimate prevalence due to 2012, 17 were for dry extruded pet foods, one was for a RMBD,
the difficulty in isolating and culturing Salmonella spp. and due and 11 were for raw or insufficiently processed treats, especially
to its intermittent shedding in the host. Suspected clinical cases raw pig ears.34 Both pathogenic and chemical contamination in
of salmonellosis require three negative cultures before ruling commercial processed pet foods has led to significant morbidity
out the disease.12 Susceptibility and severity of infection depend and mortality in pets with the most notorious being the 2007
on multiple factors, including virulence of the pathogen strain, recall secondary to melamin/cyanuric acid.36 In North America,
infectious dose and host resistance.14 Host resistance factors up to 39,000 dogs and cats may have developed kidney failure
include age, immunocompetence, stress, administration of gluco- as a result of eating these contaminated commercial pet foods.
corticoids, and presence of chronic disease. Although cats may Other problems associated with commercial pet food recalls
carry Salmonella spp. in their digestive tract without associated include vitamin D excess,37,38 thiamine deficiency secondary to
morbidity, there have been reports of morbidity and mortality in irridation39,40 and mycotoxins.41,42 There have also been warnings
cats14,16,17 and dogs18–21 secondary to consumption of RMBDs. concerning a Fanconi-like renal syndrome in dogs after ingestion
Home-prepared RMBDs were evaluated in one study8 in of chicken jerky treats manufactured in China.43 In response to the
which eight of 10 home-prepared raw chicken-based diets fed melamine/cyanuric acid tragedy, the Food and Drug Administra-
to pet dogs had positive results when cultured for Salmonella tion (FDA) Amendments Act of 2007 was passed to strengthen
spp. In addition, there are numerous reports14,22-24 of racing the food recall process. It requires manufacturers to submit a
Greyhounds, sled dogs, guard dogs, and cats with Salmonella report to the FDA no later than 24 hours after determining there
infections attributable to consumption of contaminated raw meat, is a reasonable probability that the use of or exposure to the
including reports of dogs and cats that died from Salmonella- food will cause serious adverse health consequences or the
related sepsis. It is not surprising to find high rates of contami- death of animals (or humans).44,45
nation with Salmonella spp. in home-prepared diets because high Proponents of RMBDs argue that the gastrointestinal tracts of
rates of contamination with Salmonella spp. can be found in raw healthy pets can survive any raw meat product due to an abun-
meats sold for human consumption. Rates of contamination differ dance of gastrointestinal flora46 and shorter intestinal length.5
among studies25-29 but range from 21 to 44% of chicken samples Although the gastrointestinal tracts of dogs and cats are shorter
purchased from retail locations throughout North America. in comparison with that of humans, there is no evidence that a
Contamination of RMBDs with other bacteria and pathogens shorter gastrointestinal tract prevents infection with pathogens.
has also been examined. Escherichia coli are part of the normal Parasite contamination is another safety concern when feed-
commensal gastrointestinal microbiome of mammals, yet certain ing RMBDs to dogs and cats. Cats are the definitive host for
strains of E. coli are known pathogens to both humans and animals. Toxoplasma gondii. Toxoplasma bradyzoites encyst in tissue,
Verocytotoxic strains, including E. coli 0:157:H7, are considered particularly muscle. Cats ingesting tissue cysts can go on to
the most virulent causing hemorrhagic diarrhea. The overall develop systemic infections. Kittens are particularly sensitive
prevalence of pathogenic bacterial contamination in raw meat with transplacental exposure or ingestion through lactation result-
and poultry sold for human consumption varies greatly, depending ing in significant morbidity and mortality.47 In one study,48
on the contaminant, the species of animal used to produce the overall seroprevalence of antibodies to Toxoplasma gondii were
raw ingredient, the amount of processing of the raw ingredient, 53% in cats fed raw meat diets compared to 23% in cats fed
i.e., the number of times the ingredient has been handled and commercial heat-processed diets. Feeding a raw meat is a known
the facility in which it is processed. Overall prevalence of risk factor for Neospora caninum in dogs.49 Affected dogs are
Campylobacter jejuni in poultry ranges from 29 to 74%.25,26,29 generally less than 6 months old and predominantly have signs
In human-grade raw beef products, the prevalence of pathogenic of ascending hind limb paralysis.
E. coli O157:H7 ranges from 0 to 28%.30,31 Cattle are known to
harbor large numbers of E. coli through fecal contamination, Safety – Owners
with as many as one in four animals at slaughter shedding E. coli The potential impact on human health when feeding RMBDs
O157:H7 in their feces.32 The same fecal strains of E. coli have to pets is another risk factor. As stated previously, raw meats are
been recovered throughout the production-processing continuum frequently contaminated with microorganisms including E. coli,
and in the raw beef products.33 Salmonella spp., Campylobacter spp., and Listeria spp.25–29,41,50–53
Pathogen contamination is not unique to unprocessed pet Raw meats can also carry parasites such as Toxoplasma gondii,
foods. Commercial pet foods have been subject to numerous and Trichinella spp.54,54,55 In addition to the diet itself being a
recalls for Salmonella spp.34 As an example, a pet food recall source of pathogens for humans, other sources of contamination
from a single manufacturing plant was linked to 29 human patients include food utensils, feeding bowls and areas of possible fecal
identified with Salmonella enterica serovar Schwaarzengrund contamination. The same pathogens isolated from raw diets have
infections between 2006 and 2008.35 Of 28 recalls and safety been found in dog’s feces8 and, subsequently, in owners/family
alerts because of confirmed or potential contamination of com- members who have become ill.56,57 The populations at greatest

100
risk for contracting illness in households feeding raw diets are small intestine, or colon. Bone foreign bodies were present in
the very young (infants and children), the elderly, pregnant 30 to 80% of dogs and cats with esophageal foreign bodies.70–72
women, and those who are immunocompromised. Those who promote the feeding of raw bones claim that there
Most human cases of salmonellosis are due to exposure to are fewer problems with raw bones than with cooked bones73;
contaminated foodstuffs, but cases of human salmonellosis due however, to current knowledge, the frequency of obstruction or
to direct or indirect contact with animals have been reported.56–58 perforation with raw versus cooked bones has not been evaluated.
As stated previously, Salmonella organisms can frequently live Research is needed to better understand the frequency of these
as a transient member of the intestinal microflora without caus- complications.
ing illness; thus, a human or pet can be a carrier. Direct contact Another potential adverse health effect associated with RMBDs
with infected or carrier animals or their feces is a risk factor for was identified in a recent report.74 Authors of that report74 iden-
salmonellosis in humans.6,53,56,57,59 Several studies8,60–62 have found tified and described 12 dogs with elevations in serum thyroxine
that dogs eating RMBDs are at risk for shedding Salmonella concentration (six of which had clinical signs of hyperthyroidism)
organisms in their feces. Results of these studies8,60–62 indicate caused by eating an RMBD. All dogs had thyroxine concentrations
that between 3 to 50% of dogs fed RMBDs shed Salmonella in within the reference range after the diet was changed.
their feces. In one study,62 when a single meal of a contaminated
commercial RMBD was fed, seven of 16 dogs shed Salmonella Nutritional Adequacy
spp. in their feces for up to seven days. A U.S. study75 in 2001 revealed that all the home-prepared
Fecal shedding of Salmonella spp. in cats can last from three to and commercial RMBDs tested (three home-prepared and two
six weeks, and in some cases up to 14 weeks, after clinical ill- commercial RMBDs) had multiple nutritional imbalances, some
ness.12,63 In cats with salmonellosis, large numbers of bacteria of which could have important adverse effects on the health of
are present in the mouth and their coat can be highly contaminated the animals. Examples included a calcium-to-phosphorus ratio
secondary to their grooming habits.64 Most domestic cats spend of 0.20, vitamin A and E concentrations below the minimum
a large amount of time in close proximity to their owners with detectable value, and a vitamin D concentration nearly twice
ample potential for direct or indirect exposure to zoonotic organ- the Association of American Feed Control Officials (AAFCO)
isms. Of particular concern is the increasing incidence of an maximum amount.75 Authors of a case report76 of a growing dog
antibiotic-resistant strain, Salmonella serovar Typhimurium fed an RMBD (a commercial premix plus raw ground beef
definitive type (DT)104. This strain has become an important prepared in accordance with instructions on the package label)
food safety concern because of its increased incidence in both reported that the nutritionally unbalanced diet resulted in
humans and animals and its ability to cause serious disease vitamin D-dependent rickets type I and nutritional secondary
with resistance to ampicillin, chloramphenicol, streptomycin, hyperparathyroidism.
sulphonamides, and tetracycline. Several studies58,63,65,66 have In a recent study77 in Europe, investigators calculated amounts
identified domestic cats as carriers of multiresistant Salmonella of 12 nutrients (e.g., calcium, phosphorus and vitamin A) for
Typhimurium DT 104 along with farm animals, dogs and birds. 95 homemade RMBDs being fed to dogs, as reported by the
Other pathogens also are of concern for humans exposed to owners. In that study,77 57 diets (60%) had major nutritional
pets shedding bacteria. E. coli O157:H7 transmission from an imbalances. Therefore, there is concern that both commercial
asymptomatic dog to humans has been documented.67 Toxoplasma and homemade RMBDs may have important nutrient deficiencies
gondii infection is another concern to humans, particularly and excesses. Investigators in three studies78–80 evaluated the
pregnant women. Although most cases of human toxoplasmosis nutritional balance of commonly available home-prepared diet
are secondary to consuming undercooked meat or food that has recipes. In the two studies78,79 on animals with medical conditions,
been cross-contaminated from raw meat, toxoplasmosis can be 94 recipes were evaluated, and none had adequate concentrations
passed from cats to humans through exposure to oocysts in the of all essential nutrients. In one of these studies,80 investigators
cats’ feces. Cats with a newly acquired infection will shed the evaluated 200 recipes for healthy dogs and found that 190 (95%)
oocysts for about three weeks following infection. Thus, cleaning recipes had at least one essential nutrient below AAFCO mini-
litter boxes during this timeframe can result in cross-contamina- mums and 167 (84%) recipes had multiple deficiencies.
tion. If infection occurs to the fetus during pregnancy, abortion,
premature birth or permanent neurological impairments can Benefits
occur.68,69 As stated previously, numerous benefits have been ascribed
to feeding pets RMBDs compared to feeding heat-processed
Other Health Concerns foods. Reported benefits include improved skin and coat quality,
In addition to the previously mentioned health problems, improved digestibility and decreased incidence of many medical
RMBDs that contain bones (i.e., the BARF diet) can potentially conditions.3–5,81 To the author’s knowledge, these claims have
result in fractured teeth and gastrointestinal injury. Bones can been based on anecdotal evidence rather than scientific study.
cause obstruction or perforation of the esophagus, stomach, A founding premise regarding RMBDs is that these are the

101
optimal diets for health and wellness based on the theory that compared a raw meat diet with a dry kibble diet in sand cats
dogs and cats evolved over millions of years on a natural raw and found the raw meat diet to have 10% higher digestibility in
diet and logically this is their ideal food source. Advocates claim dry matter and energy and 15% higher digestibility in crude
that processed foods are not what dogs and cats were programmed protein compared to the kibble extruded diet. A more recent
to eat during the long process of evolution and that foods similar study92 looked at feeding the domestic cat’s wild ancestor, Felis
to those eaten by the dog’s/cat’s wild ancestors are more biolog- lybica, a commercial raw meat versus an extruded high-protein
ically appropriate.3 Cats are obligate carnivores with a strong kibble diet. Crude protein digestibility in the raw diet was 8%
predatory instinct.82 Their natural diet in the wild includes a higher compared to the extruded diet. In research done by the
range of small prey species, such as mammals, reptiles, birds, author,94 significantly higher digestibility of dry matter (7 to
and insects. Conversely, dogs have adapted to eating an omniv- 10%), organic matter (5 to 8%), protein (6 to10%), and energy
orous diet and can consume a variety of plant and animal prod- (3 to 6%) was seen in RMBDs compared to a canned heat-
ucts to meet their essential nutrient requirements. processed diet in both kittens and adult cats.
Compared to cats, dogs have undergone an incredible variety Proteins and amino acids undergo substantial physical changes
of selection pressures resulting in large phenotypic differences during processing associated with the manufacture of pet foods.
from their ancestors. A recent study83 found that there were 36 Processing conditions, which primarily involve application of
regions of the genome that differ between dogs and wolves, 10 heat but can also include pressure and water content, can have
of which play a critical role in starch digestion and fat metabo- variable effects on protein digestibility and amino-acid bioavail-
lism. The authors of that study83 concluded that these genetic ability. The effects depend on the ingredients, temperature and
differences in the genome between dogs and wolves have con- type of processing (i.e., canning, extrusion used in the production
tributed to the ability of dogs to digest starch and fat and consti- of most commercial dry pet foods, and freezing or freeze-drying
tuted a crucial step in the early domestication of the dog. Although that would be performed with commercial RMBDs). In addition,
carbohydrate digestibility in cats is nearly 100% for simple food proteins can react with other food components, such as
sugars and starches,84 cats have limited ability to handle high sugars, fats, oxidizing agents, acids, alkalies, polyphenols, and
concentrations of carbohydrate in their diet compared with food additives. Heat processing during the manufacture of dry
other species secondary to having lower levels of pancreatic and extruded or moist pet foods typically results in the denaturing
intestinal amylase compared to dogs85 and minimal glucokinase of proteins and loss of secondary and tertiary protein structure.
activity, an important glycolytic enzyme during high-carbohy- Processing can increase bioavailability of proteins through col-
drate loads.86 Due to these metabolic adaptations, feeding high- lagen breakdown and increased exposure to digestive enzymes,
carbohydrate commercial diets has been theorized to cause a but it also can negatively affect amino acids through proteolysis,
variety of disorders in cats including obesity and diabetes.87 protein crosslinking, amino-acid racemization, protein-polyphenol
A frequently cited benefit to feeding raw food diets is that reactions, oxidative reactions, and browning or Maillard reactions.95
active digestive enzymes remain intact and thereby improve The Maillard reaction accounts for the most important losses of
digestibility and bioavailability of foodstuffs.3,5 Arguments amino-acid bioavailability.96
against these claims are that protein enzymes are denatured and Although conventional heat processing can have negative
inactivated in the stomach secondary to hydrochloric acid and effects on animal tissue proteins, heat processing improves the
pepsin secretion,88 and all the enzymes dogs and cats need for bioavailability of some plant proteins secondary to denaturing
digestion are already produced in the gastrointestinal tract un- of antinutritional factors. For example, legumes contain trypsin
less they have underlying exocrine pancreatic insufficiency.88,89 and chymotrypsin inhibitors that impair protein digestion and
The extent of enzyme degradation in the stomach is not com- reduce protein bioavailability.97 Heat processing denatures
pletely quantified, but treatment for exocrine pancreatic insuffi- these inhibitors and, therefore, increases protein bioavailability.
ciency with raw pancreas is a common practice. In a study90 Improved digestibility results in less digesta in the colon with
comparing raw porcine pancreas to a commercial pancreatic less fecal matter. Decreased fecal output has been found in a
enzyme supplement, the raw porcine pancreas had the highest study92 of feral cats and in experiments conducted by this author.94
level (39.1%) of supplemental lipase recovery in jejunally can- Decreased fecal output is perceived as a benefit by some owners.
nulated dogs compared to the commercial pancreatic supplement Although nondigestible carbohydrates in the form of fiber are
(26.2%). Dietary amylase and protease activity levels were still beneficial to the host,98 undigested dietary protein results in
present in the jejunum from the raw pancreas extract and increased amounts of colonic compounds, such as ammonia,
higher than enzyme levels in a dog with subclinical exocrine phenols, indoles, and amines, which can play a role in diseases
pancreatic insufficiency. like colorectal, stomach and pancreatic cancers.99–101 The author
Several scientific studies91–93 have documented improved is not aware of any reported studies on the potential harmful
digestibility in RMBDs compared to heat-processed diets. effects of undigested dietary protein on colonic health in dogs
Digestibility of RMBDs versus dry extruded diets has been or cats.
examined in both exotic and domesticated cats.91-93 One study91 Heterocyclic amines are compounds formed when muscle

102
meat is cooked to a high temperature. Exposure to high concen- did have lower albumin and higher globulin levels compared to
trations (e.g., milligram/gram of food) of these compounds has the control group, but this was not clinically significant as albumin
been associated with cancer in research animals.102 Concentrations levels were still within normal reference ranges.
found in both pet and human foods are much lower (nanograms/
gram of food), but these concentrations may still have mutagenic Conclusion
activity.103 The cumulative effects of these compounds on genomic It is difficult to make overall recommendations regarding feed-
instability and increased sensitivity to tumor promotion in pets ing raw diets to pets due to the current lack of good data and
and humans require investigation. scientific studies. The infectious disease potential to both the
Another frequently cited benefit when feeding RMBDs is an pet and owners has been well-documented. Owners who elect to
improvement in immune function. In experiments conducted by feed a commercial or home-prepared RMBD should be counseled
this author,94 domestic cats fed an RMBD for 10 weeks had a on the risks to themselves and their pets. Since most home-
significant increase in lymphocyte and immunoglobulin produc- prepared diets are deficient in one or more essential nutrients,
tion, though there were no significant changes over the same a board-certified veterinary nutritionist should review these
study period for cats fed a cooked commercial moist diet. In diets to ensure that they are balanced.
those experiments,94 it was also found that cats fed the RMBD The use of intensive farming practices for meat production has
were fecal shedders of Salmonella spp. Exposure to higher increased dramatically over the past 50 to 100 years.105 Raising
microbial loads, including pathogens and microbial degradation livestock in confinement at high stocking density increases the
products, changes in intestinal microflora, or nutritional differ- risk of pathogen contamination in domestic animals intended for
ences in the diets may have stimulated the immune response slaughter.30,33 Raw meat obtained from these sources is quite
detected for cats fed the RMBD. In the same study,94 there were different compared to intact prey fed upon by nondomesticated
no significant differences found in herpes-specific titers after canids and felids. Further scientific studies examining the effects of
vaccination or parameters of innate immune response (oxida- long-term feeding RMBDs on microbiome, immogenicity, immune
tive burst or phagocytosis) between RMBD feeders or those fed function, gastrointestinal health, and disease are warranted.
the commercial canned heat-processed diet. Although this study
evaluated serum immunoglobulin and innate immune response, References
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Notes

108
How I Feed: The Underweight Senior Cat with
Multiple Problems
Catherine E. Lenox, DVM, CVA, DACVN
Gulf Coast Veterinary Specialists
Lenox Veterinary Nutrition Consulting, PLLC
Houston, TX
Email: [email protected]

Abstract At the time of presentation, the cat

Considerations affecting feeding an
Glossary of Abbreviations was receiving a canned recovery diet a
AAFCO: Association of American Feed
underweight senior cat include appetite mixed with water with approximately
Control Officials
level and concurrent diseases. The nutri- 60 mL given through the tube four times
BW: Body Weight
tional approach is dependent on the HE: Hepatic Encephalopathy daily providing 288 kcal/day. The owner,
patient’s problem list and prioritization MER: Maintenance Energy Requirement in addition to the primary complaints,
of problems if multiple diseases are NRC: National Research Council was having difficulty feeding the cat
present. Goals for general nutritional RER: Resting Energy Requirement four times daily and requested a reduc-
management of underweight senior cats tion in feeding frequency, if possible.
include estimating energy requirements, managing health condi- The cat was not consuming a significant amount of food orally
tions and finding a palatable diet to help improve body condition. at the time of presentation.
The problem list of the cat described in this report included lym- The cat weighed 4.45 kg (9.8 pounds) at the time of presen-
phoma with hepatic involvement, hyporexia, and an underweight tation, and her body condition score was 3-4/9. She had a mild
body condition with weight loss and loss of muscle condition decrease in muscle condition. Physical examination did not
despite a feeding tube. reveal additional abnormalities. The cat’s problem list included
lymphoma with hepatic involvement, hyporexia, and an under-
Case Presentation: History, Diet History, Physical weight body condition with weight loss and loss of muscle
Examination, and Problem List condition despite a feeding tube.
A 9-year-old spayed domestic shorthair female cat was referred
by the oncology service for hyporexia, failure to gain weight Case Presentation: Feeding Recommendations
despite placement of an esophagostomy tube, and granular and Guidelines for Feeding Management
lymphoma affecting the liver and mesenteric lymph nodes. She The patient’s ideal weight was estimated to be approximately
had previously had hypoalbuminemia and icterus, but these prob- 5.45 kg (12 pounds) based on discussion with the owner and the
lems had resolved. The patient had stable anemia. She did not cat’s historical weight. In order to achieve ideal body condition,
have signs of hepatic encephalopathy (HE). She was receiving a two-part diet change was recommended for the patient. First, a
prednisolone and lomustine by mouth, and an esophagostomy new feeding tube blend was recommended along with a seven-day
tube had been placed by the primary veterinarian due to continued transition schedule to the new blend (Table 1). Second, guidelines
hyporexia and weight loss. The owner reported that the cat had for oral feeding were revised and given to the owner to encourage
become less active than usual. the cat to consume food orally.

Table 1. Recommended Feeding Schedule

Day Total Volume Per Day Total Kcal Per Day Volume Per Feeding Feeding Frequency
1-2 (25% new*) Old: 180 ml 290 kcal/day 45 old + 13 new QID (q 6 hours)
New: 52 ml = 58 ml
3-4 (50% new) Old: 133 ml 319 kcal/day 44 old + 37 new TID (q 8 hours)
New: 111 ml = 81 ml
5-6 (75% new) Old: 66 ml 321 kcal/day 22 old + 56 new TID (q 8 hours)
New: 167 ml = 78 ml
7+ (100% new) New: 222 ml 320 kcal/day New only: 74 ml TID (q 8 hours)

*Old = Diet A; New = Diet B/C blend as described

109
 The new feeding tube blend consisted of a canned recovery ideal body condition (≥5/9).3 Recommendations for treatment
dietb and a canned liquid diet.c The diet was mixed in a ratio of of patients with cachexia depend on the underlying cause, the
one 6-ounce can of the recovery diet (159 mL) to one 237 mL disease process, and the severity of cachexia. Some general
can of the liquid diet, and it was recommended that the client recommendations for nutritional management of cachectic
blend the diets in a kitchen blender. The custom feeding tube patients include treating the underlying cause as best as possible,
blend contained 1.44 kcal/mL, representing a 20% increase in addressing issues that can decrease food intake, feeding appro-
calories per mL. The transition to the new diet involved increas- priate levels of nutrients in the form of a complete and balanced
ing the new blend by approximately 25% of total kcal every diet, addressing anorexia or hyporexia, and increasing activity
two days and decreasing the previous blend by approximately level if possible.2
25% simultaneously, with a full transition to the new blend on
the seventh day. In addition to changing the diet, the cat’s caloric Feeding Cats with Liver Disease
intake was increased by 11% during this transition. Feeding Nutritional management of liver disease involves treating
frequency was decreased to three times daily. the clinical signs versus treating the liver disease itself. Liver
In addition to the new feeding tube blend, it was recommended disease can manifest in different ways, depending on the under-
that the client offer food for oral intake prior to tube feeding to lying cause, the severity of the disease, and other factors. Signs
encourage the patient to consume food on her own. Options for of liver disease that require nutritional management include, but
oral intake included the feeding tube blend itself (Diet B/C = are not limited to, hepatic encephalopathy, hypoglycemia or
1.44 kcal/mL), the canned recovery diet used in the new feeding hyperglycemia, and anorexia or hyporexia.
tube blend (Diet B = 2.1 kcal/mL), the previous canned recovery The presence or absence of HE is a major issue in management
diet (Diet A = 1.2 kcal/mL), and an energy-dense dry food d of feline liver disease. The presence of HE indicates that a relative
(Diet D = 592 kcal/237 mL or 8 fluid ounce cup). restriction in dietary protein is necessary due to the production
of ammonia and false neurotransmitters as a result of protein
Management Issues and Diet Selection Rationale metabolism. The absence of HE indicates that protein restriction
Issues involved in management of this patient include cachexia, is not necessary unless there are other diseases present, for example,
feeding cats with liver disease, refeeding patients and preventing renal disease, which necessitate protein restriction. Dietary pro-
refeeding syndrome, cancer diets in cats, and prioritizing the tein restriction can result in the loss of lean body mass and other
patient’s problem list. health concerns. If the patient does not have signs of HE associated
with liver disease, protein requirements set by the NRC and/or
Cachexia the Association of American Feed Control Officials (AAFCO)
At the time of presentation, the cat was consuming resting should be met or exceeded.1,4
energy requirements (RER) x 1.35, assuming RER is calculated In addition to controlling levels of dietary protein for small
using the formula RER = 70 x (BW)0.75 which is above what the animal patients with liver disease, other macronutrient levels are
author typically uses for inactive and altered cats (RER x 1.0-1.2). of concern as well. The presence of persistent hypoglycemia or
The cat was also consuming slightly above the National Research hyperglycemia in a patient with liver disease indicates a need to
Council (NRC) recommendations for maintenance energy control dietary soluble carbohydrates. The patient described
requirements (MER) for lean cats (MER = 100 x BW0.67)1 had lymphoma with liver involvement but did not have HE or
at 106 x BW,0.67 but continued to lose weight at this intake hypoglycemia. The presence of stable blood glucose levels on
despite inactivity. repeated serum chemistry profiles influenced diet selection as
The combination of increased energy requirements (or loss did the presence of severe hyporexia and weight loss that required
of body weight at average or above-average energy intake) and placement of a feeding tube.
loss of muscle mass while consuming a high-protein and high-
fat recovery diet indicates that this patient likely had cachexia. Refeeding Patients and Preventing Refeeding Syndrome
Cachexia is the loss of lean body mass that occurs in patients with Nutritional support should be implemented sooner rather
neoplastic disease or other chronic diseases.2 Cancer cachexia than later to avoid issues with refeeding. This patient had an
is common in cats. In one report, 91% of feline patients with esophagostomy tube at the time of presentation to the nutrition
cancer had loss of muscle condition at multiple sites.3 The service but had continued to lose weight and would not consume
mechanism of cachexia is complex and involves increased food orally. Issues with refeeding, and refeeding syndrome, can
energy requirements, decreased nutrient absorption, decreased occur when a patient receives nutritional support too quickly
energy intake, and metabolic alterations.2 after initiating feeding. Preventing refeeding syndrome involves
Treating patients with cachexia with appropriate nutrition is providing nutrition slowly and addressing the metabolic shifts
key, as it can affect morbidity and mortality. Feline cancer patients that can occur during the refeeding process.
with a body condition score below ideal (<5/9) have a lower The patient described was receiving above-standard mainte-
median survival time compared to cats with ideal or above nance energy requirements at the time of presentation to the

110
nutrition service. Therefore, refeeding was not an immediate was created to meet these goals as well as to reduce feeding
concern. However, in a diseased animal with anorexia or severe frequency for the owner. In addition, to encourage oral intake,
hyporexia, the body shifts to using lipid and protein for energy multiple diet options including canned and dry food that met
compared to carbohydrate, which can affect diet selection despite the same nutritional goals were offered for oral consumption.
the number of calories fed.5,6 Hyperglycemia can occur in patients Fish oil omega-3 fatty acids have been found to be useful in
with anorexia or severe hyporexia that receive nutritional support some patients with cachexia, mainly dogs with congestive heart
via enteral or parenteral routes. Other metabolic derangements failure,8 and might have been useful in this patient as well. Supple-
include alterations in potassium, phosphorus and magnesium. mentation of EPA and DHA was not included in this patient’s
This patient was at high risk for refeeding issues at the time of nutritional plan initially because of potential palatability issues
tube placement due to cancer cachexia in addition to hyporexia. associated with fish oil supplements and the primary goal was
Metabolic shifts also occur in patients with cachexia.2 getting the patient to consume enough calories to achieve ideal
body condition. However, the esophagostomy tube could have
Cancer Diets in Cats been used for administering a fish oil product.
There currently are no data that indicate that a specific diet
or macronutrient profile is ideal for cats with neoplastic disease. Case Outcome
There is minimal research in dogs as well, with most data avail- The cat did very well with the new feeding plan. The feeding
able for dogs with lymphoma. The data that are available indi- schedule, shown in Table 1, was designed to gradually increase
cate that a diet with low dietary carbohydrate, high fat and high calories to the estimated daily energy requirements for weight
protein as well as increased omega-3 fatty acids from fish oil gain (current intake + 10%) and also to reduce the feeding
and arginine may be beneficial for dogs with lymphoma.7 How- frequency for owner convenience. The cat had historically
ever, there is a lack of evidence for a similar diet profile in cats preferred dry food and almost immediately started eating the
with lymphoma or other types of cancer. The author recommends dry food offered (Diet D). The owner began to use the feeding
treating other nutritional problems prior to making decisions tube less. Within two months, the cat had gained weight to 5.3 kg
based on the presence of neoplastic disease. Therefore, the diet (11.65 pounds) and was consuming ½ cup of Diet D per day
profile described for dogs with lymphoma was not a considera- (296 kcal/day). At this weight, the patient had a body condition
tion when making a diet selection for this patient. score of 5/9 with mild loss of muscle condition. The cat was
more active and began to play more, and the feeding tube was
Prioritizing the Patient’s Problem List and Diet removed. It was not replaced due to good oral intake, and intake
Selection Rationale was decreased to seven tablespoons per day (259 kcal/day) due
Senior cats present challenges when developing a nutritional to rapid weight gain and the fact that the cat was approaching
plan due to the presence of one or more health problems that affect estimated ideal body weight. This represented decreased caloric
nutritional management. When treating patients with multiple intake from the initial presentation to the nutrition service and
problems, the problems often need to be prioritized in terms of was presumed to be due to metabolic shifts and decreased energy
severity and the effects on the patient’s quality of life. These requirements, potentially due to chemotherapy treatment. Six
factors must always be balanced with the patient’s appetite level months after initial presentation, the cat continued to have issues
as well. The problem list of the cat described in this report included with maintaining ideal weight without the feeding tube but was
lymphoma with hepatic involvement, hyporexia and an under- maintaining between 4.77 and 5.0 kg (10.5-11 pounds). The
weight body condition with loss of weight and muscle condition owner reported issues with the cat consuming its housemate’s
despite a feeding tube. Had signs of HE been present, diet selec- food, which is less energy-dense than Diet D, and reported that
tion might have been limited to protein-restricted diets. With the cat continued to have a good appetite.
no signs of HE, we were able to select a diet with higher levels
of protein. General Nutritional Recommendations for
The primary goal for all patients is to provide an adequate Underweight Senior Cats
number of calories in the form of a complete and balanced diet. A significant portion of cats over the age of 12 years are under
In hyporexic patients with no need for protein or fat restriction, ideal body condition.9 Underweight senior cats, regardless of the
calories are best provided in the form of a complete and balanced presence of medical problems, have different nutritional needs
energy-dense diet. These diets, which can include recovery diets compared to younger or middle-aged cats. A complete physical
as well as other types of therapeutic or over-the-counter diets, are examination and nutritional assessment including body condition,
often higher in protein and fat than maintenance diets. For this muscle condition and dietary history should be performed to
patient, issues with refeeding, loss of weight and muscle condition, rule out underlying causes for weight loss. A thorough dietary
and cachexia made an energy-dense, high-protein, high-fat diet an history will help determine if the cat is consuming an appropriate
ideal selection. A customized energy-dense feeding tube blend number of calories for weight maintenance or if intake has

111
decreased. If intake is appropriate for the cat’s body weight and References
activity level, it is possible that the energy requirements have 1. Nutrient Requirements of Dogs and Cats. National Research
changed with time. Although the effects of aging on daily energy Council. The National Acadamies Press, Washington, D.C. 2006.
requirements in senior cats are controversial, some studies suggest
that daily energy requirements are increased in senior cats.10 2. Freeman LM. Cachexia and Sarcopenia: Emerging Syndromes
Protein requirements may be altered in older cats as well. In of Importance in Dogs and Cats. J Vet Intern Med. 2012;26:3-17.
the absence of disease, lean body mass may decline with aging.
This condition, called sarcopenia, must be differentiated from 3. Baez JL, Michel KE, Sorenmo K, Shofer FS. A Prospective
cachexia, which occurs in the presence of disease.2 In order to Investigation of the Prevalence and Prognostic Significance of
prevent sarcopenia and the morbidities associated with loss of Weight Loss and Changes in Body Condition in Feline Cancer
lean body mass (which include compromised immune function), Patients. J Feline Med Surg. 2007;9:411-417.
an increase in dietary protein may be necessary for apparently
healthy senior cats.11 4. Association of American Feed Control Officials. Official
The NRC does not set specific nutrient requirements for Publication. 2013.
older cats.1 However, the requirements for specific nutrients are
modified by the diseases that affect the senior cat. The require- 5. Chan DL, Freeman LM. Nutrition in Critical Illness. Vet Clin
ments for vitamins such as cobalamin, minerals including N Am Sm An Pract. 2006;36:1225-1241.
phosphorus and potassium, and other nutrients can vary among
senior cats. For example, a cat that has clinical or subclinical 6. Saker KE, Remillard RL. Critical Care Nutrition and Enteral-
gastrointestinal disease may require cobalamin supplementation, Assisted Feeding. In Small Animal Clinical Nutrition. Hand MS,
though a cat with renal disease requires dietary phosphorus restric- Thatcher CD, Remillard RL, Roudebush P, Novotny BJ (eds).
tion. For underweight senior cats, it is important to consider all Mark Morris Institute, Topeka, KS. 2010:439-476.
nutrients of concern and prioritize the need for supplementation
and restriction of specific nutrients. In addition, steps to enhance 7. Ogilvie GK, Fettman MJ, Mallinckrodt CH, et al. Effect of Fish
palatability of food (for example, offering different types of food Oil, Arginine, and Doxorubicin Chemotherapy on Remission and
or warming the food) should be taken to enhance intake in hypo- Survival Time for Dogs with Lymphoma: A Double-Blind, Ran-
rexic senior cats. domized Placebo-Controlled Study. Cancer. 2000;88:1916-1928.

Conclusions 8. Freeman LM, Rush JE, Kehayias JJ, et al. Nutritional Alter-
This case outlines using a customized nutritional plan to approach ations and the Effect of Fish Oil Supplementation in Dogs with
ideal body weight in a senior cat with lymphoma with liver involve- Heart Failure. J Vet Intern Med. 1998;12:440-448.
ment, hyporexia and a feeding tube. Many senior cats have multiple
health problems that make diet selection difficult. Management 9. Armstrong PJ, Lund EM. Changes in Body Composition and
of these cases includes the primary goals of the cat consuming Energy Balance with Aging. Vet Clin Nutr. 1996;3:83-87.
food regularly and the cat achieving or maintaining ideal body
condition. Feeding adequate levels of nutrients, keeping refeeding 10. Laflamme DP. Nutrition for Aging Cats and Dogs and the
issues in mind with hyporexic animals, and feeding appropriate Importance of Body Condition. Vet Clin N Am Sm An Pract.
levels of nutrients to manage diseases also are important factors 2005;35:713-742.
in management of these patients.
11. Laflamme DP, Hannah SS. Discrepancy Between Use of Lean
Footnotes Body Mass or Nitrogen Balance to Determine Protein Require-
A. Hill’s® Prescription Diet® a/d® ments for Adult Cats. J Feline Med Surg. 2013;15:691-697.
B. Maximum-CalorieTM Plus, Iams Veterinary FormulaTM
C. Clinicare® Canine-Feline Liquid Diet, Abbott Animal Health
D. Purina Veterinary Diets® Dietetic Management® DM

112
Notes

113
Notes

114
Canine Renal Disease: When Is the Right Time to Strike
with Nutritional Therapy?
Julie Churchill, DVM, PhD, DACVN
University of Minnesota
College of Veterinary Medicine
Veterinary Clinical Science Department
St. Paul, MN
[email protected]

Abstract it difficult to assess the effect of nutrient

How do I feed canine patients showing Glossary of Abbreviations intake.1-5 In the quest to develop best prac-
ACVN: American College of Vet- tices for the diagnosis and treatment of
early markers of renal disease without any
erinary Nutrition
clinical signs? Clinical trials have evalu- renal disease in small animals, the Inter-
BCS: Body Condition Score
ated therapeutic dietary management for national Renal Interest Society (IRIS)
CKD: Chronic Kidney Disease
dogs with renal disease Iris stage >2.5. IRIS: International Renal Interest established a set of guidelines for staging
What nutritional factors should we con- Society (stages 1 to 4) and treating CKD in dogs
6
sider for patients before they reach this MCS: Muscle Condition Score and cats. These guidelines recommend
stage? In the absence of evidence, the patient implementing nutritional treatment for
must eat. Assessing each patient individually can help guide the stage 3 CKD, dogs with a creatinine of >2.0 mg/dl (>180 µm/l).
feeding and treatment plan to meet their nutritional needs. Whenever possible, veterinary care should incorporate evidence
from controlled clinical studies. However, there are no nutritional
Introduction clinical trials in dogs with CKD earlier than stage 3.7
For many years, nutritional management has been accepted
as a primary therapeutic modality for dogs and cats with chronic Acting [Feeding] in the Absence of Evidence
kidney disease (CKD). In fact, therapeutic renal foods have been When a dog has laboratory values suggesting an early stage of
1,2
used to treat veterinary patients for decades. Debate remains CKD (<3), the veterinarian is left with formulating a management
regarding the optimal nutrient profile, but compared to canine plan in the absence of evidence. Should we feed the dog, the
pet foods formulated for adult maintenance, the typical modifi- kidneys or both? Recommendations of any specific therapy
cations of therapeutic renal diets are calorically dense foods should be assessed not only on the basis of the grade of evidence
reduced in protein, phosphorus and sodium, and enriched in but also on clinical experience and the pet’s and owner’s prefer-
dietary buffering capacity, omega-3 fatty acids, soluble fiber, ences, tolerances and abilities.1 Performing a thorough medical
water-soluble vitamins, and antioxidants.3 Nutritional therapy is and nutritional assessment can help guide the recommendations
designed to minimize clinical signs and ideally reduce the rate to meet the individual pet’s needs.
of progression of disease. Although current nutritional treatment
using therapeutic renal diets is generally accepted as effective Approach the Patient with an Individualized
therapy, the time to implement nutritional modifications may Care Plan
not have general agreement particularly in the early stages of Performing a Nutritional Assessment
disease. Renal diets may not provide benefit nor may they always The American College of Veterinary Nutrition (ACVN)
meet the patient’s nutritional needs, especially in the early stages developed a Circle of Nutrition as a useful tool and guideline
of renal disease. for performing a nutritional assessment. This should form the
basis of your nutritional plan for every patient every time.7 The
Evidence-Based Therapy circle describes all the factors to consider in making a nutritional
The challenge of applying evidence-based medicine when assessment and recommendation. The interrelationship of all
managing CKD is interpreting results; some are from populations three components (patient, diet and feeding factors) is represented
of experimentally induced disease,4 and others from spontaneously as well as the need for continual reassessment. Health and nutri-
occurring CKD.5 Some studies evaluated single nutrients, and tional status are not static but rather a dynamic process worthy
others evaluated a “diet effect” of combined nutrient modifica- of continued re-evaluation, especially in diseases known to be
tions. Food intake is not always measured or reported, making progressive such as CKD.

115
 Use the Circle of Nutrition (pictured below) to guide the diet Making Your Recommendation
history, which is integral to nutritional management of any patient. There is no published evidence for preventive benefits of
An accurate diet history is invaluable when making an assessment implementing renal diets in canine patients prior to stage 3.
of the health of the patient and will be vital to formulating an Consider the following nutrients of concern when selecting a
individualized diet plan. food for canine patients with early stages of CKD.
Water: In early stages of CKD, a dog’s urine concentrating
Using the Circle of Nutrition in Dogs with Early CKD ability is impaired and there is increased risk of dehydration.
Patient Factors. Assure a plentiful water source and consider adding water or
Once CKD is suspected, the veterinarian should verify selecting a food with higher moisture content.
that the condition is stable in order to apply the IRIS Protein: In a study evaluating unine-phrectomized
staging system.6 In azotemic patients, pre- and geriatric dogs, there was no benefit to renal func-
postrenal causes should be ruled out. Once that tion or structure from long-term feeding of
is done and primary renal disease is confirmed, modest restrictions of protein, phosphorus or
then the kidney disease should be classified as sodium and some concern about meeting mini-
acute or chronic. Evaluate and treat for under- mum protein requirements for senior dogs.14
lying and potentially reversible causes, such as This research population could represent the
systemic infectious/inflammatory conditions, equivalent of IRIS stage 2, patients with a 50%
urolithiasis and urinary tract infection. Identify any reduction of renal mass without azotemia or clinical
underlying factors that could contribute to progression of signs of disease. Consider providing 2.55 gms protein/kg
disease (nephrotoxic medication, breed predispositions for renal body weight (BW) or ~1 gm protein/pound BW as a general
disease9). In CKD, two factors have been associated with faster guide for the “minimum” adult canine daily requirement,15-18 or
rates of progression and a negative prognosis: proteinuria and a level to minimize the risk of creating signs of protein deficiency.
hypertension.10,11 All patients confirmed with CKD should be Senior dogs may need up to 50% more than this.15 Based on the
evaluated for hypertension and proteinuria. The physical exam- diet history, assure the patient is meeting its daily protein needs.
ination should identify other comorbid conditions that may need If consuming levels in excess of their needs, then consider a
to be addressed and should also include the patient’s body weight, decremental reduction in protein consumption. Meet protein
body condition score (BCS)12 and muscle condition score needs and avoid excess.
(MCS)8 as indirect measures of health and nutritional status.13 Phosphorus: There are only experimental models evaluating
phosphate restriction in dogs with induced CKD. Several studies
Dietary Factors. have evaluated the role of phosphorus restriction, however, this
A thorough diet history is critical. Ideally, you would like was evaluated in more severe CKD and phosphorus restriction
enough information that you can reproduce the animal’s exact was often paired with protein restriction.18-21 In light of this, the
diet and know the daily intake. This information taken together IRIS recommendation for stage 2 CKD is restriction of dietary
with the patient assessment provides information about the patient’s phosphorus in the form of renal diets. Without evidence for this
daily caloric requirements and specific nutrient intake. recommendation, this author suggests the patient avoid excess
Treats: The diet history should also identify all snacks or phosphorus intake rather than implement a therapeutic renal diet
treats. When collecting the drug history, investigate whether the unless serum phosphorus is elevated (>1/5 mmol/l or >4.6 mg/dl).
owner is using a food to administer the medication. Meats and Educate owners about treats and foods that provide sources of
dairy products are of special concern since they are palatable phosphorus that should be limited or avoided.
treats and common ways to administer medication. Meat and Omega-3 Fatty Acids: Several positive effects are attributed
dairy products can contribute a significant amount of phosphorus, to omega-3 fatty acids, such as suppressing inflammation and
protein and sodium. platelet aggregation, lowering blood pressure, and modifying
renal hemodynamics.22,23 However, no clinical trials evaluate
Feeding Management/Environment the effects of omega-3 fatty acids in early CKD. Renal therapeutic
A Diet History Is a Valuable Tool. diets incorporate omega-3 fatty acids for the combined “diet
Learning about the pet’s environment and the feeding fac- effects.” There is no evidence for benefit or harm of omega-3
tors, such as access to other animal’s food, acceptance to feed, supplementation of patients with CKD less than IRIS stage 3, and
and whether the pet is fed commercial or home-prepared foods, the therapeutic dose and/or ratio of omega-3:omega-6 fatty acids
will inform the veterinary team about many factors, including is not well-established. If electing to add supplementation to
the human-animal bond and the potential success or problems a patient’s diet, assure that all sources are accounted for (diet
with adherence to the nutritional recommendation. and supplement) to calculate total daily intake and avoid exces-
sive amounts.

116
 Caloric Intake: Food intake should be monitored and adjusted 4. Brown S. Renal Pathophysiology: Lessons Learned from the
to maintain healthy body weight and condition. This can vary Canine Remnant Kidney Model. J Vet Emerg Crit Care. 2013;00:1-7.
by individual, and thus, nutrient intake (gms/100kcals) should
be assessed in the context of food and calorie intake to assure 5. Jacob F, Polzin D, Osborne C, et al. Clinical Evaluation of
the recommended dietary modifications are being achieved. For Dietary Modification for Treatment of Spontaneous Chronic
example, a pet with a reduced appetite consuming a restricted Renal Failure in Dogs. J Am Vet Med Assoc. 2002;220:1163-1170.
nutrient diet may not meet its requirements; on the other hand,
a pet consuming more food than their expected food dose may 6. International Renal Interest Society. (modified 2013) Accessed
not be restricting the desired nutrient. February 2014 at: http://www. iris-kidney.com/_downloads/N378.008
%20IRIS%20Website%20Staging%20of%20CKD %20PDF.PDF
Reasses
A vigilant monitoring plan is an important part of managing 7. International Renal Interest Society. Treatment Recommen-
early stages of CKD in order to detect any signs of progressive dations for Dogs with CKD. Accessed February 2014 at: http://
changes, such as proteinuria and hypertension increasing renal www.iriskidney.com/_downloads/003%20N378.008%20IRIS%
values (creatinine and serum urea nitrogen). Check the patient’s 20Website%20Treatment%20Recommendation%20PDFs%20D
food intake, body weight, BCS, and MCS to monitor nutritional OGS_041113.pdf
status. If dietary changes are implemented to avoid excess
amounts of phosphorus and protein, then monitor renal values 8. Baldwin K, Bartges J, Buffington T, et al. AAHA Nutritional
one month after changing foods. If renal function is stable, Assessment Guidelines for Dogs and Cats. J Am An Hosp Assoc.
reevaluate in three months and tailor the monitoring plan to 2010(July/August);46(4):285-296. Accessed February 2014 at:
the patient’s status. http://www.aahanet.org/Public Documents/NutritionalAssessment
Guidelines.pdf
Summary
Without evidence that early implementation of therapeutic 9. Lees GE. Juvenile and Familial Nephropathies. In: BSAVA
renal diets prevents progression of disease, assess each patient Manual of Canine and Feline Nephrology and Urology. Elliot
individually before using these products. The composite nutrient J, Grauer F (eds). 2007;2:79-86.
modifications may not meet all the patient’s nutritional needs.
For example, a young dog with mildly impaired renal function 10. Jacob F, Polzin DJ, Osborne CA, et al. Association Between
due to renal dysplasia is unlikely to meet its nutritional needs with Initial Systolic Blood Pressure and Risk of Developing a Uremic
a therapeutic renal product. The same could be true for an obese Crisis or of Dying in Dogs with Chronic Renal Failure. J Am
geriatric dog with comorbid conditions exacerbated by obesity. Vet Med Assoc. 2003;222:322-329.
Assure the patient with early CKD is meeting its dietary needs
with a complete and balanced food and a feeding plan that 11. Jacob F, Polzin DJ, Osborne CA, et al. Evaluation of the
avoids dietary excesses. Assure the food meets the protein and Association Between Initial Proteinuria and Morbidity Rate or
calorie needs to maintain health and monitor to assure stable Death in Dogs with Naturally Occurring Chronic Renal Failure.
renal function. Partner with clients to help ensure success and J Am Vet Med Assoc. 2005;226:393-400.
to maintain adherence to your feeding and monitoring goals.
12. Laflamme D. Development and Validation of a Body Con-
References dition Score System for Dogs. Canine Pract. 1997;22:10-15.
1. Roudebush P, Polzin D, Adams L, et al. An Evidence-Based
Review of Therapies for Canine Chronic Kidney Disease. J Sm 13. Parker V, Freeman L. Association Between Body Condition
An Pract. 2010;51:244-252. and Survival in Dogs with Acquired Chronic Kidney Disease.
J Vet Int Med. 2011;25:1306-1311.
2. Brown SA. Management of Chronic Kidney Disease. In:
BSAVA Manual of Canine and Feline Nephrology and Urology. 14. Churchill J. The Influence of Dietary Protein, Lipid, Phos-
Elliot JA, Grauer GF (eds). Brit Sm An Vet Assoc, Gloucester, phorus and Sodium on Renal Structure and Function in Geriatric
UK. 2007;2:223-230. Dogs. PhD thesis. Department of Veterinary Clinical Sciences,
College of Veterinary Medicine, University of Minnesota, St. Paul,
3. Forrester S, Adams L, Allen T. Chronic Kidney Disease. MN. 2001.
In Small Animal Clinical Nutrition. Hand MS, Thatcher CD,
Remillard RL, et al. (eds). Mark Morris Institute, Topeka, KS. 15. Wannemacher RW, McCoy JR. Determination of Optimal
2010;5:765-810. Dietary Protein Requirements of Young and Old Dogs. J Nutr.
1966; 88:66-74.

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16. Laflamme D. Nutrition for Aging Cats and Dogs and the 20. Finco DR, Brown SA, Crowell WA, et al. Effects of Dietary
Importance of Body Condition. Vet Clin N Am Sm An Prac. Phosphorus and Protein in Dogs with Chronic Renal Failure.
2005;35:713-742. Am J Vet Res. 1992(a);53:2264-2271.

17. Hutchinson D, Freeman L, Schreiner K, et al. Survey of 21. Finco DR, Brown SA, Crowell WA, et al. Effects of Phos-
Opinions about Nutritional Requirements of Senior Dogs and phorus/Calcium-Restricted and Phosphorus/Calcium-Replete
Analysis of Nutrient Profiles of Commercially Available Diets 32% Protein Diets in Dogs with Chronic Renal Failure. Am J
for Senior Dogs. Intern J Appl Res Vet Med. 2011;9(1):68-70. Vet Res. 1992(b);53:157-163.

18. Nutrient Requirements of Dogs and Cats. National Research 22. Polzin DJ, Osborne CA, Ross S. Chronic Kidney Disease. In:
Council. The National Academies Press, Washington, D.C. Textbook of Veterinary Internal Medicine. Ettinger SJ, Feldman
2006;119. EC (eds). W.B. Saunders, Philadelphia, PA. 2005;6:1756-1785.

19. Brown S, Crowell W, Barsanti JA, et al. Beneficial Effects 23. Brown SA, Brown CA, Crowell W, et al. Beneficial Effects
of Dietary Mineral Restriction in Dogs with Marked Reduction of Chronic Administration of Dietary Omega-3 Polyunsaturated
of Functional Renal Mass. J Am Soc Nutr.1991;1:1169-1179. Fatty Acids in Dogs with Renal Insufficiency. J Lab Clinic Med.
1998;5:447-455.

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Notes

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Notes

120
How I Feed: The Diabetic Dog
Lisa P. Weeth, DVM, DACVN
Weeth Nutrition Services
Edinburgh, Scotland, UK
Email: [email protected]

Abstract are to change meal times to overlap with

Glossary of Abbreviations insulin administration and to feed a
Dietary and medical management of
DM: Diabetes Mellitus
diabetes mellitus have the same thera- high-fiber diet.8,9 Specific diet changes
MER: Maintenance Energy Requirement
peutic goals: minimize clinical signs are often attempted at the time of diag-
related to hyperglycemia, avoid life-threatening hypoglycemia, nosis, but administering twice-daily injections while changing
help the patient maintain an optimal body weight and condition, the daily diet and treat regime can be daunting for many care-
and improve quality of life parameters for the patient and care- givers. Because owners often focus solely on ensuring their dog
giver. Due to their inadequate insulin production, each canine eats so they can give the required insulin injections, if a veterinarian
diabetic requires twice-daily parenteral insulin. The feeding recommends a new diet early in the disease course that the dog
regime and nutrient content of the diet can both help and hinder doesn’t find palatable, there is a risk that the owner will panic
medical therapy. Dietary modifications for patients with diabetes and give inappropriate foods, such as hotdogs, chicken and cat
include feeding a consistent amount of a consistent diet at con- food, to get the dog to eat. With newer insulin types, improved
sistent times each day to coincide with insulin administration; monitoring and better client education, diabetic dogs now have
feeding higher fiber foods; modification of carbohydrate type; the same expected survival times as non-diabetic dogs.10
and reduction in total carbohydrate content of the foods consumed.
Recommendations should be tailored to the individual patient Changes to Feeding Strategy
based on the diet and medical history as well as concurrent medical Parenteral insulin injections are required from the time of
conditions to ensure patient acceptance and owner compliance. diagnosis in canine diabetes. Initial treatment recommendations
for otherwise healthy diabetic dogs should concentrate on owners
Introduction becoming comfortable and competent with insulin therapy and
Diabetes mellitus (DM) is a disorder of glucose metabolism making adjustments to the daily feeding schedule as opposed to
that involves either insufficient insulin production or a peripheral making any specific diet changes. The current recommendation
insulin resistance. In dogs, DM is most often due to inadequate is to offer a consistent amount of a consistent food once every
insulin production and, thus, requires lifelong twice-daily par- 12 hours to coincide with twice-daily insulin administration8,9
enteral insulin injections. This relative insulin deficiency is due but does not allow for additional food items outside these win-
to a loss of beta-cell activity most often resulting from immune- dows. Although most dogs will readily consume half their daily
mediated destruction of Islet cells or pancreatitis.1,2 DM can requirement in one meal, small-breed or finicky dogs may not
occur in both mixed-breed and purebred dogs but appears to eat the required meal volume. Additionally, this seemly simple
have a genetic component as certain breeds are overrepresented, 3 treatment requirement can result in a dramatic lifestyle change
and it is exacerbated by other concurrent diseases, such as hyper- for both dogs and caregivers as it may not have been the meal
adrenocorticism,4 hypothyroidism5 and obesity.6 In contrast, feline pattern prior to diagnosis. In the author’s experience, feeding
diabetes often occurs due to a peripheral insulin resistance in schedules for otherwise healthy dogs vary day to day based on
1
overweight or obese individuals. The difference in disease family schedules (work, school, etc.) and twice-daily meals are
pathogenesis between dogs and cats can make the initial dietary often not the only foods offered.
recommendations dramatically different between the two species. Providing a consistent feeding schedule and a consistent diet
Some diabetic cats are able to maintain glycemic regulation at each meal are recommended to help prevent life-threatening
without the need for additional medical treatment when fed a hypoglycemia.11 For finicky dogs and caregivers who have dif-
reduced-carbohydrate diet.7 Diabetic dogs, in contrast, have an ficulty with a twice-daily feeding schedule, some flexibility in
absolute requirement for daily insulin injections. Diet modifica- feeding regime may be possible. Postprandial blood glucose
tions are not a replacement for medical therapy in these patients elevations occur within the first two hours of meal ingestion in
but can be used to enhance efficacy of parenteral insulin injections healthy dogs,12 and the commonly used intermediate acting insulin
and improve glycemic regulation. types have peak effects occurring within the first 4-6 hours after
The most common diet recommendations for canine diabetics administration.13 If needed, foods can be divided between a

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“main meal” that provides approximately 40% of the daily intake assuming that the control diet was equivalent to a typical over-
and is given with insulin, and a smaller “treat” that provides an the-counter commercial dog food. Since these studies included
additional 10% of the daily intake and is offered two to three small numbers of test subjects and did not report profiles of the
hours after each insulin injection. These additional food items diets fed or feeding practices prior to the testing period, it is
become part of the dietary plan, and if the caregiver is unable possible that the changes (or lack thereof) in diabetic parameters
to accommodate any of the additional treat times, that food were related to a relative modification in fiber or total digestible
item should be added to the corresponding meal to ensure a carbohydrate intake, or both, as well as improved owner com-
consistent nutrient intake for the given insulin dosage. pliance when participating in a nutritional study.
Transitioning to a veterinary therapeutic diet with a higher fiber
Ensuring Adequate Energy Intake content than the original diet may be beneficial for uncomplicated
For diabetic dogs already at an optimal body weight, the canine diabetics that are difficult to regulate on insulin alone.
goal of therapy is weight maintenance. Diabetes mellitus can These types of therapeutic diets often have higher levels of total
increase daily energy requirements though the extent will vary dietary fiber (both soluble and insoluble) compared to over-the-
with each patient depending on the severity of disease. Initially counter diets, but the specific diet selected should be based on
feed 10-15% above prediabetes requirements and recheck weight the patient’s current fiber intake when possible. Diets with high
regularly. This starting amount can be based on the calculated insoluble fiber levels often have lower calorie densities and lower
maintenance energy requirement (MER) of 70BWkg3/4 x1.6 overall digestibility, and an increase in meal volume is often re-
(neutered adult dog factor), but as individual dogs can vary up quired to prevent unintended calorie restriction and weight loss.
to 50% above or below this amount even without concurrent This may be advantageous in overweight or obese diabetic dogs
disease, evaluating current and previous dietary intake may pro- that require weight loss but is an undesirable side effect in under-
vide a more accurate starting estimate. Weight and body condition weight patients or those with volume limitations. Additionally,
should be measured and recorded at each recheck examination it is also important to inform owners that increasing fiber intake
with an adjustment in energy intake as needed. can increase stool volume and frequency of defecation. In dogs
Even in overweight or obese dogs, the initial recommendation without ready access to proper elimination areas, such as those
should be for weight maintenance until glycemic control is estab- living in apartments, increasing stool volume may pose a husbandry
lished. This will allow the veterinarian and caregiver to evaluate challenge for caregivers.
the efficacy of insulin therapy independent of intentional calorie For owners who decline higher fiber therapeutic diets or for
restriction. A modest reduction in energy intake can then be made animals that refuse to eat a higher fiber therapeutic diet, compar-
to help achieve a rate of no more than 1% of body weight lost ing labels of over-the-counter foods are challenging. Pet food
per week. Loss of adiposity may help minimize peripheral insulin labels in the United States require “Crude Fiber” reporting. Crude
resistance and improve exogenous insulin efficacy. Frequent re- fiber is a laboratory analysis of the insoluble, nonfermentable
evaluations of weight and clinical signs of disease are required plant portion of the diet (primarily cellulose, hemicellulose and
to monitor for any needed change in insulin dosage or changes lignin) and does not reflect the Total Dietary Fiber or Digestible
in energy intake. Hypoglycemia can occur if the overweight or Carbohydrate content of the food. Crude fiber is also reported
obese diabetic dog loses weight quickly without a corresponding as a percentage (i.e., grams per 100 grams as fed) and cannot be
decrease in insulin dosage. readily compared against diets with differing energy densities or
different moisture contents. If needed, a powdered fiber supple-
Nutrient Modifications ment (e.g., psyllium husk or oat bran) or a high-fiber cereal (e.g.,
Dietary Fiber: Research on diet modifications for diabetic Fiber One Original or Grape-Nuts Original) can be mixed with the
dogs has largely focused on changes to fiber type and amount.14-21 original diet at each meal to help increase the individual patient’s
Fiber is a broad nutrient classification and includes types that fiber intake. Caution should be used when selecting fiber sup-
dissolve in water (soluble) and those that do not (insoluble); fiber plements or cereals as many include added fructose, maltose or
is also classified according to whether it is utilized by intestinal sucrose to enhance palatability.
bacteria (fermentable) or not (nonfermentable). For dogs that were Glycemic Index: Every plant-based ingredient used in the
otherwise healthy prior to the diagnosis of diabetes, studies have production of either commercial or home-prepared pet diets will
differed on whether improved glycemic control is seen with have inherently different combinations of protein, fat, carbohy-
higher intake of total dietary fiber (both soluble and insoluble drate, and fiber. The effect that these basic nutrient combinations
types)14-18 or higher intake of insoluble fiber alone,19,20 or whether have on the degree of postprandial hyperglycemia is referred to
fiber should be ignored altogether and diabetic dogs should instead as the “Glycemic Index” of that ingredient. Foods that have high
be fed a lower digestible carbohydrate diet.21 simple sugar or starch contents, such as white rice or white potato,
An important consideration when reconciling these seemingly will have a higher glycemic index, though those that contain
conflicting results is that these researchers used the terms “high” protein, fat and/or fiber in addition to starch, such as barley or
and “low” in reference to the fiber content of the control diets, oats, will have a lower glycemic index. In addition, ingredient

122
and nutrient interactions can
occur during cooking (in both
pet food and human food
manufacturing) that can both
increase and decrease the
glycemic index depending on
the ingredient and ingredient
combination. Information on
glycemic index of specific
human foods can be found
online (glycemicindex.com)
and provided to caregivers.
Simple Sugars: Whenever
possible, simple starches and
sugars should be eliminated
from the diet of diabetic patients.
Many over-the-counter and
prescription chewable supple-
ments, as well as semi-moist
commercial foods and treats
and edible enrichment chews,
may contain simple sugars
(often listed in the ingredients
list as starch, molasses or Figure 1. Factors affecting diet selection for a diabetic dog.
sugar). Owners should be
educated to review ingredient
lists of all selected foods and treats before feeding and to monitor signs of DM. Protein reduction is not warranted early in treatment
for changes in water intake or urination after introduction of any of canine diabetes without evidence of proteinuria. Many diabetic
new foods or treats. dogs can have loss of lean body mass either as a result of inad-
equate energy intake or alteration in muscle catabolism; protein
Clinical Complications reduction would be contraindicated in these patients.
Inadequate insulin levels also can cause a concurrent dysreg-
ulation of fat metabolism leading to hyperlipidemias.22 A reduc- Summary of Recommendations
tion in dietary fat intake may be required if the hyperlipidemia The most important thing to remember when developing a dietary
does not resolve with insulin therapy and improved glycemic plan is that there is not one perfect approach for all diabetic dogs.
regulation. Additionally, patients with a history of pancreatitis or There are commercial diets designed to enhance glycemic reg-
a primary disorder of lipid metabolism (e.g., Miniature Schnauzers) ulation when used in combination with twice-daily insulin, but
may develop life-threatening complications from hypertriglyc- these require owner and patient compliance to be maximally
eridemia and would benefit from early dietary intervention. Fat effective. Recommendations should instead be tailored to the
reduction should always be made relative to the current intake, individual’s medical history, food preferences and concurrent
and in the author’s experience, fat restriction below the adult disease states. A summary of these considerations are listed
dog daily requirement is rarely necessary in diabetic dogs. below and shown in Figure 1. For dietary management of canine
One of the most common complications of long-term manage- diabetes, I have a few simple recommendations.
ment of DM in people is the development of diabetic nephropathy
leading to renal failure and death.23 Although hypertension and 1) Obtain a diet and treat history from the owner. This should
proteinuria have been identified as sequelae of long-term DM in be done at the time of initial diagnosis and rechecked at each
dogs,24,25 progression to overt renal failure and effects on long- office visit to review owner compliance and identify any gaps
term survival are not known. Changes aimed at ameliorating or inconsistencies in management that could lead to current
hypertension and proteinuria, namely dietary sodium and protein or future problems.
reduction, have not been specifically evaluated in canine diabetes. 2) Encourage adherence to a consistent feeding schedule
Avoiding high-sodium diets (i.e., dietary sodium >2.0 grams per that balances patient needs with owner constraints and
1000 kcal of diet) would be prudent as increases in water intake allows the owner to become comfortable with giving twice-
and urination due to dietary sodium content can mimic clinical daily injections.

123
3) Have the owner omit any foods or treats that include simple 6. Verkest KR, Fleeman LM, Rand JS, Morton JM. Evaluation of
sugars or higher sodium contents. Higher sodium foods Beta-Cell Sensitivity to Glucose and First-Phase Insulin Secretion
are not contraindicated with DM but can exacerbate clinical in Obese Dogs. Am J Vet Res. 2011;72:357-366.
signs of polyuria and polydipsia that can be confused with
poor regulation. 7. Bennett N, Greco DS, Peterson ME, et al. Comparison of a
4) Avoid making abrupt diet changes unless additional nutrient Low Carbohydrate-Low Fiber Diet and a Moderate Carbohydrate-
restriction is required (e.g., fat reduction for pancreatitis or High Fiber Diet in the Management of Feline Diabetes Mellitus.
marked hypertriglyceridemia), the patient has other medical J Feline Med Surg. 2006;8:73-84.
conditions that would benefit from a diet modification, or the
owner is feeding a diet that poses a risk to the patient or other 8. Rucinsky R, Cook A, Haley S, et al. AAHA Diabetes Man-
members of the household, such as an unbalanced home- agement Guidelines for Dogs and Cats. J Am An Hosp Adm.
prepared diet or raw meat. 2010;46:215-224.
5) Adjust food intake as needed. For patients that are at an ideal
body condition, or even overweight or obese, I recommend 9. Fleeman LM, Rand JS. Management of Canine Diabetes.
feeding for weight maintenance for the first month. Overweight Vet Clin N Am Sm An Pract. 2001;31:855-880.
and obese patients would benefit from weight loss and gradual
calorie reduction can be done after insulin effectiveness has 10. Guptill L, Glickman L, Glickman N. Time Trends and Risk
been established. Patients that are underweight at the time of Factors for Diabetes Mellitus in Dogs: Analysis of Veterinary
diagnosis may require even higher energy intake to help them Medical Data Base Records (1970-1999). Vet J. 2003;165:240-247.
reach and then maintain a more optimal body condition.
6) If the diabetic patient is difficult to regulate after the first 11. Whitley NT, Drobatz KJ, Panciera DL. Insulin Overdose in
three to four weeks of initiating insulin therapy despite good Dogs and Cats: 28 Cases (1986-1993). J Am Vet Med Assoc.
owner compliance, increasing fiber intake either by transition- 1997;211:326-330.
ing to a higher fiber therapeutic diet or additional supplemental
fiber may improve glycemic control. 12. Nguyen P, Dumon H, Biourge V, Pouteau E. Measurement
7) Don’t focus only on the bloodwork to determine glycemic of Postprandial Incremental Glucose and Insulin Changes in
control. Blood glucose fluctuates day to day and an individual Healthy Dogs: Influence of Food Adaptation and Length of Time
animal’s needs may also change throughout the course of of Blood Sampling. J Nutr. 1998;128(12 Suppl):2659S-2662S.
disease. Monitoring body weight and clinical signs of DM at
each visit are good indicators of overall glycemic regulation.26 13. Hess RS, Ward CR. Effect of Insulin Dosage on Glycemic
Response in Dogs with Diabetes Mellitus: 221 Cases (1993-1998).
References J Am Vet Med Assoc. 2000;216:217-221.
1. Rand JS, Fleeman LM, Farrow HA, et al. Canine and Feline
Diabetes: Nature or Nurture? J Nutr. 2004;134(8S):2072S-2080S. 14. Graham PA, Maskell E, Rawlings L. Influence of a High-
Fiber Diet on Glycemic Control and Quality of Life in Dogs
2. Hoenig M, Dawe DL. A Qualitative Assay for Beta-Cell An- with Diabetes Mellitus. J Sm An Pract. 2002;43:67-73.
tibodies: Preliminary Results in Dogs with Diabetes Mellitus.
Vet Imm Immunopath. 1992;32:195-203. 15. Blaxter AC, Cripps PJ, Gruffydd-Jones TJ. Dietary Fiber
and Postprandial Hyperglycemia in Normal and Diabetic Dogs.
3. Hess RS, Kass PH, Ward CR. Breed Distribution of Diabetes J Sm An Pract. 1990;31:229-233.
Mellitus in Dogs Admitted to a Tertiary Care Facility. J Am Vet
Med Assoc. 2000;216:1414-1417. 16. Nelson RW, Ihle SL, Lewis LD, et al. Effects of Dietary
Fiber Supplementation on Glycemic Control in Dogs with
4. Hess RS, Saunders HM, Van Winkle TJ, Ward CR. Concurrent Alloxan-Induced Diabetes Mellitus. Am J Vet Res. 1991;52:
Disorders in Dogs with Diabetes Mellitus: 221 Cases (1993-1998). 2060-2066.
J Am Vet Med Assoc. 2000;217:1166-1173.
17. Graham PA, Maskell IE, Nash AS. Canned High-Fiber Diet
5. Hofer-Inteeworn N, Panciera DL, Monroe WE, et al. Effect and Postprandial Glycemia in Dogs with Naturally Occurring
of Hypothyroidism on Insulin Sensitivity and Glucose Tolerance Diabetes Mellitus. J Nutr. 1994;124:2712S-2715S.
in Dogs. Am J Vet Res. 2012;73:529-538.

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18. Holste LC, Nelson RW, Feldman EC, Bottoms GD. Effect 23. Gross JL, de Azevedo MJ, Silveiro SP, et al. Diabetic
of Dry, Soft Moist and Canned Dog Foods on Postprandial Blood Nephropathy: Diagnosis, Prevention and Treatment. Diab
Glucose and Insulin Concentrations in Healthy Dogs. Am J Vet Care. 2005;28:164-176.
Res. 1989;50:984-989.
24. Struble AL, Feldman EC, Nelson RW, Kass PH. Systemic
19. Nelson RW, Scott-Montcrieff C, DeVries S, et al. Effect of Hypertension and Proteinuria in Dogs with Diabetes Mellitus.
Dietary Insoluble Fiber on Control of Glycemia in Dogs with J Am Vet Med Assoc.1998;213:822-825.
Naturally Acquired Diabetes Mellitus. J Am Vet Med Assoc.
1998;212:380-386. 25. Herring IP, Panciera DL, Werre SR. Longitudinal Prevalence
of Hypertension, Proteinuria, and Retinopathy in Dogs with
20. Kimmel SE, Michel K.E, Hess RS, Ward CR. Effects of Spontaneous Diabetes Mellitus. J Vet Int Med. 2014 (Epub ahead
Insoluble and Soluble Dietary Fiber on Glycemic Control in of date).
Dogs with Naturally Occurring Insulin-Dependent Diabetes
Mellitus. J Am Vet Med Assoc. 2000;216:1076-1081. 26. Briggs CE, Nelson RW, Feldman EC, et al. Reliability of
History and Physical Examination Findings for Assessing Control
21. Fleeman LM, Rand JS, Markwell PJ. Lack of Advantage of of Glycemia in Dogs with Diabetes Mellitus: 53 Cases (1995-
High-Fiber, Moderate-Carbohydrate Diets in Dogs with Stabilized 1998). J Am Vet Med Assoc. 2000;217:48-53.
Diabetes. J Sm An Prac. 2009;50:604-614.

22. Ling GV, Lowenstine LJ, Pulley LT, Keniko JJ. Diabetes
Mellitus in Dogs: A Review of Initial Evaluation, Immediate
and Long-Term Management, and Outcome. J Am Vet Med
Assoc. 1977;170:521-530.

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Notes

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Management of Overweight Dogs and Cats with Cancer
Glenna E. Mauldin, DVM, MS, DACVIM, DACVN
Western Veterinary Cancer Centre
Western Veterinary Specialist and Emergency Centre
Calgary, Alberta, Canada
Email: [email protected]

Introduction strong and complex association between

Glossary of Abbreviations obesity and malignant disease. Obese
Obesity is the most common form of
BCS: Body Condition Score
malnutrition diagnosed in dogs and cats people are documented to have signifi-
CEA: Carcinoembryonic Antigen
in North America. Estimates of the pro- cantly increased risk of developing neo-
IGF-1: Insulin-Like Growth Factor 1
portion of affected animals vary, but it is IMRT: Intensity Modulated Radiation plasms of the esophagus, pancreas, colon,
generally accepted that between 20 and Therapy endometrium, breast, and kidney, and
45% of dogs and cats are overweight.1 PSA: Prostate Specific Antigen they are also more likely to develop mul-
At the same time, necropsy surveys suggest SRT: Stereotactic Radiotherapy tiple myeloma, non-Hodgkin’s lymphoma
that as many as 45% of dogs older than and some types of leukemia.6 A number
2
10 years will die of cancer. Given this background, it is not of different mechanisms have been proposed to explain the observed
surprising that many dogs and cats are overweight at the time increase in cancer incidence in this population. Increased secretion
they are diagnosed with cancer. Management of these patients of insulin-like growth factor 1 (IGF-1) induced by the insulin
can be challenging not only because of their complex clinical resistance associated with obesity may promote induction and
presentation but also because of widespread misconceptions progression of malignant disease by stimulating cell prolifera-
regarding optimal nutritional management of animals with neo- tion, inhibiting apoptosis and enhancing angiogenesis.7 Higher
plastic disease in general. This paper will first examine what is levels of sex hormones, especially the estrogen synthesized by
known about the relationship between obesity and cancer in excess adipose tissue, are hypothesized to increase cancer risk
both people and animals. A practical step-wise approach that by disrupting normal cellular growth and differentiation and in-
can be used to manage individual animals with cancer and con- hibiting apoptosis.8 Increased synthesis of the polypeptide hor-
current obesity will then be presented. mone leptin by the increased mass of adipose tissue in obese
individuals could also promote tumor development because it
Relationship Between Obesity and Cancer in People stimulates cell proliferation and inhibits apoptosis.9 Finally,
The type of malnutrition historically considered most typical obesity itself is a chronic inflammatory disease and, as such, is
of the tumor-bearing state is not obesity but rather the form of recognized to have wide-ranging effects on the production and
protein-energy malnutrition termed “cancer cachexia.” Cancer function of various cytokines and other mediators of inflamma-
cachexia in people and animals is characterized clinically by tion. These may have a permissive effect on tumor development.8
weight loss, fatigue, anemia, and loss of both lean body mass In addition to the role that it plays in the pathogenesis of
3
and adipose stores, and can be classified as either primary or cancer on the cellular level, once a tumor is present, obesity can
4
secondary. Primary cancer cachexia is an incompletely under- have a number of significantly negative consequences with respect
stood paraneoplastic syndrome in which the intermediary metab- to both the diagnosis and treatment of neoplastic disease in
olism of fat, protein and carbohydrate is altered by an aberrant people.10 Obese people are less likely to participate in cancer-
systemic inflammatory response to the underlying tumor, ultimately screening programs, so a definitive diagnosis of cancer may be
leading to inefficient energy utilization and weight loss. Secondary delayed or missed altogether. It also has been suggested that
cancer cachexia is caused by functional abnormalities that are not obesity can decrease levels of tumor biomarkers, such as prostate
necessarily specific to neoplastic disease, such as treatment-related specific antigen (PSA) and carcinoembryonic antigen (CEA),
nausea and vomiting or compromised gastrointestinal function through increased plasma volume and hemodilution, leading to
caused by the physical presence of neoplastic cells, which can false negative or equivocal screening test results.11,12 The quality
cause weight loss as well. Regardless of whether it is primary or and accuracy of ultrasound, CT and MRI images can be com-
secondary, the negative impact of cancer cachexia on quality of promised by the presence of excessive adipose tissue, making it
life and survival is well-documented and accepted in people and difficult to define the location and extent of neoplastic disease.10
is becoming increasingly well understood in dogs and cats.3,5 With respect to cancer treatment, dosing of the appropriate
Despite the classic association of cachexia with malignant cytotoxic chemotherapy drugs can be challenging in obese indi-
disease, however, it is increasingly evident that there also is a viduals. Many drugs are dosed on a body surface area basis,
127
and some studies examining frequency of chemotherapy dose concentrations are increased in obese dogs and cats, as they are
reductions as well as incidence and severity of treatment-related in people.18,19 Canine adipocytes also possess the genes needed
side effects, such as myelosuppression, suggest that obese people to synthesize the proinflammatory cytokine interleukin-6, and
receiving chemotherapy for treatment of their cancers may be obese dogs have been shown to have increased serum concen-
undertreated.13,14 Obesity is likely to have a negative effect on trations of tumor necrosis factor-α and IGF-1.20,21 However, a
the pharmacokinetics of some chemotherapy agents as well, link between these specific changes and increased cancer risk
altering important factors such as the volume of drug distribution has yet to be established.
and hepatic drug metabolism.10 Problems are often encountered Several authors have investigated the potential role of body
in the delivery of radiotherapy in obese people. In particular, the condition over time in the pathogenesis of cancer in the dog.
precise and repeatable positioning that is essential for safe and Dogs with mammary gland tumors have been most frequently
effective delivery of intensity modulated radiation therapy (IMRT) studied. One case control study investigated the effect of body
and stereotactic radiotherapy (SRT) can be challenging in obese condition and diet on the risk of mammary cancer in dogs and
individuals because of increased skin mobility, increased motion found that risk was decreased in both spayed and unspayed dogs
of intra-abdominal organs within abdominal adipose tissue, and that had been thin at 9 to 12 months of age.22 A similar study
obscured bony landmarks.10 Finally, although major complications found that obesity at 12 months of age was associated with an
and short-term mortality do not appear to be increased, minor increased risk of mammary cancer. This study also implicated
complications are reported to be more likely after cancer surgery regular consumption of human foods in tumor development
in obese people.15 Based on all these considerations, it should not because dogs with breast cancer were more likely to have high
be surprising that there is evidence that people with established intake of red meat.23 The authors of a third study were unable to
obesity have shorter survival times and higher all-cause, cancer- find an association between survival and obesity in dogs with
specific and cardiovascular death rates after they are diagnosed malignant mammary tumors, though they did not specifically
with a variety of types of cancer.16,17 They also tend to have evaluate the impact of historical obesity on tumor development
compromised health-related quality of life.10 later in life.24 Overall, these studies suggest a possible role for
The authors of a recent review identified four major challenges fat intake and obesity in the pathogenesis of canine mammary
associated with the clinical management of obese people with tumors, as is the case in women.
cancer: obesity-related comorbidities, such as hypertension, Published surveys, so far, confirm that concurrent obesity is
cardiovascular disease and type 2 diabetes mellitus; polypharmacy relatively common among dogs with cancer but have been unable
often directed at obesity-related comorbidities along with its to definitively prove that there is a cause-and-effect relationship
associated drug interactions; development of sarcopenic obesity; between overweight and cancer incidence. In one study, 29% of
and further weight gain after cancer diagnosis and treatment.10 dogs treated at a referral oncology practice were obese based on
Of these four challenges, sarcopenic obesity was felt to be of body condition score. Weight loss was documented in 68% of
particular clinical significance. This is a condition described in dogs, but it represented less than 5% of the precancer body weight
some overweight people with neoplastic disease. Sarcopenic in 31% of cases.25 The distribution of body condition scores
obesity is characterized by severe excess of body fat with a among dogs with a variety of types of cancer was also investi-
concurrent decrease in muscle mass and is believed to be initiated gated and compared to dogs without cancer in a much larger
by the chronic inflammation associated with obesity. Sarcopenic study.26 The overall prevalence of overweight (BCS>6/9) and
obesity is important because it has a negative impact on outcome obese (BCS>7/9) dogs in the total population in this study was
and survival. Affected individuals have significant loss of muscle 21.6% and 14.8%, respectively. However, the authors were unable
and muscle function, reduced performance scores, and increased to find an association between obese body condition and tumor
risk of cancer treatment-related toxicity compared to obese people development. In fact, there was a slight but significantly lower
with normal muscle mass. Early diagnosis and appropriate prevalence of overweight (BCS>6/9) and obese (BCS>7/9) dogs
treatment is important for prognosis, and high-protein diets in the group with malignant disease as compared to dogs without
combined with physical exercise were proposed as effective cancer. Age, breed, neuter status, tumor type, and a history of
potential interventions.10 corticosteroid administration were identified as important con-
founding factors affecting nutritional status in this study.
Relationship Between Obesity and Cancer in Although fewer studies have been published that evaluate
Dogs and Cats nutritional status in cats with cancer, work to date suggests that
Although the relationship between obesity and cancer in dogs obesity may be less common in cats with cancer than it is in dogs.
and cats could be similar in many respects to that seen in people, In one study looking at body condition and weight loss in cats
this has not been thoroughly investigated or proved. Early work with cancer, almost half the cats evaluated were underweight or
shows that some of the endocrine changes believed to be involved very thin and over 90% of them had clinically detectable evidence
in the pathogenesis of malignant disease in people are also of muscle wasting. Body condition score was strongly correlated
present in obese dogs and cats. For instance, circulating leptin with survival time and prognosis in this study, with cats that had

128
low body condition scores having markedly shorter survival stressful and difficult for a devoted owner to implement. The
times.27 Preliminary data suggest that sick cats are more likely to expected survival time for an overweight pet with neoplastic
experience a decline in nutritional status than sick dogs, regard- disease must be long enough to justify the time and effort necessary
less of whether they have cancer (Mauldin GE, unpublished data). to achieve optimal body condition. Finally, it is also important
Further work is needed to determine if the lower body condition to recognize and accept that if the owner has made an informed
scores and relatively decreased incidence of obesity reported to decision to pursue palliative treatment alone for their pet’s malig-
date in the cats with cancer is specifically related to the presence nant disease, a stringent weight-loss program is unlikely to improve
of underlying neoplastic disease or whether weight loss is sim- quality or quantity of life for anyone. Obviously, the animal’s quality
ply a more generic feline response to illness. of life is of paramount concern, but the owner’s quality of life as he or
she struggles to implement a weight-loss program for his or her pet
Practical Management of Obesity in Dogs and with potentially incurable malignancy should also be considered.
Cats with Cancer Once a decision to implement a weight-loss program has been
The clinical approach to achieving successful weight loss in made, a clinical baseline including all diagnostics indicated for
a dog or cat with uncomplicated obesity involves six relatively management of the animal’s obesity as well as tumor staging
standard steps as outlined below. However, underlying neoplastic should be carefully established. A minimum database should
disease presents some unique and specific challenges that must always include screening reference laboratory bloodwork (complete
also be taken into account in these animals. blood count, serum biochemical profile and urinalysis) and will
often include endocrine testing, imaging (radiographs, ultra-
1. Conduct a thorough patient assessment. sonography and/or cross-sectional imaging), and fine-needle
The biggest initial challenge associated with the management aspiration cytologies.
of overweight dogs and cats with cancer is deciding whether a
weight-loss program is actually indicated. Is it reasonable to 2. Calculate appropriate energy intake for safe weight loss.
expect that weight loss will provide objective clinical benefit The weight-reduction protocols that are routinely applied in
for the animal? Simply stated, will weight loss either prolong otherwise healthy animals1 are not necessarily suitable for
survival time or improve quality of life? If the answer to these overweight dogs and cats with cancer. A very conservative
questions is “no” or “likely not,” then the time, effort and expense reduction in caloric intake below the calculated maintenance
necessary for successful weight loss will not be worthwhile for energy requirement at estimated ideal body weight is probably
the animal or its owner. There is no doubt that the health risks most appropriate to start for animals that are clinically stable
of obesity in otherwise normal small animals are well-established and self-supportive, especially if cancer therapy and weight loss
and include musculoskeletal disease, glucose intolerance, diabetes are planned to occur simultaneously. The goal is to gradually
mellitus, immunosuppression, and respiratory compromise.1 and safely achieve a more optimal body condition score and
Dogs that are maintained in optimal body condition have been nutritional status, even if that process takes longer than would
shown to live longer than dogs that are overweight.28 Although normally be expected in a case of uncomplicated obesity. Aggres-
not specifically proven, it seems likely that obesity poses the sive weight-loss programs are contraindicated during cancer-
same health risks in dogs and cats that also have cancer. Further- related critical illness, even in dogs and cats that are very obese.
more, it is intuitive that the negative impact of obesity on outcome, Severe caloric restriction in a sick animal could contribute to
as suggested for people with cancer, exists in small animals as clinically significant protein-calorie malnutrition with loss of
well. This includes inaccurate diagnostic test results, altered lean body mass, including skeletal muscle atrophy, hypopro-
physiology and drug pharmacokinetics, suboptimal chemotherapy teinemia, delayed wound healing, immunosuppression, and
dosing and radiotherapy delivery, and the necessity of managing compromised organ function. This situation would be similar to
conflicting comorbidities (i.e., the need to administer corticos- “sarcopenic obesity,” as described in detail above.
teroids to an obese cat with lymphoma that is also diabetic).
Based on these considerations, it would then seem that weight 3. Choose a weight-loss ration.
loss would be indicated in many or even most overweight dogs The most consistent features of available prescription diets
and cats with cancer. However, this is not necessarily the case. intended for weight loss in dogs and cats are decreased caloric
Some animals may have what is termed “metabolically healthy density and an optimized essential nutrient profile that takes into
obesity.” In people this condition is not associated with deleterious account the decreased calories that will be consumed during the
comorbidities, and it is not clear that weight loss in these indi- course of weight loss. Decreased caloric density is achieved by
viduals can provide significant clinical benefit.10 Arguably, even decreasing the fat content of the diet and in some cases through
more important than the hypothetical advantages that could be the addition of various types of fiber that are intended to increase
gained from achieving more optimal body condition is the expected gut fill and satiety. Most weight-loss rations are also relatively
survival time associated with the animal’s underlying cancer. high in protein in order to spare lean body mass while adipose
Effective weight-loss programs are labor-intense and can be tissue is lost.

129
 Unfortunately, the characteristics of a typical prescription improved survival among some dogs with lymphoma was also
weight-loss ration may not necessarily be considered ideal for a heavily enriched with omega-3 fatty acids. Changing the dietary
dog or cat with cancer, even when that animal is significantly ratio of omega-6 to omega-3 fatty acids alters the fatty acid
overweight. Whether true or not, it is a commonly held belief composition of cell membranes throughout the body, and this,
of owners and veterinarians alike that dogs and cats with malig- in turn, impacts cell membrane eicosanoid production, cytokine
nant disease should consume high levels of protein and fat. The synthesis and the inflammatory cascade. Although supplementation
rations typically recommended deliver 35 to 50% of calories as with omega-3 fatty acids is often proposed as an adjunct for the
protein, contain as few carbohydrate calories as possible, and management of cancer cachexia, it seems possible that it may
are high in fat. The purpose of this recommendation is twofold. paradoxically provide benefit for obese animals with cancer as
First, it seeks to provide all the protein and amino acids that well. Both cancer cachexia and obesity are considered to be
might possibly be needed to protect and expand lean body mass, chronic inflammatory conditions. If they were added to a
including synthesis of various enzymes, clotting factors, immuno- weight-loss ration, care would obviously have to be taken to
globulins, and support of tissue healing. Second, it also attempts ensure that omega-3 fatty acids did not increase caloric intake
to provide ample energy for an animal generally assumed to be above that required for weight loss or significantly dilute the
at risk for weight loss and in a form that is less likely to be usable concentration of any essential nutrients. Another option may be
by cells that have undergone malignant transformation. Since to choose a complete and balanced commercial prescription
neoplastic cells oxidize fat inefficiently, a high-fat, low-carbo- product based primarily on its enrichment with omega-3 fatty
hydrate diet could preferentially supply energy to host tissues acids. For instance, some rations intended for chronic manage-
while avoiding inadvertent “feeding” of the tumor. In one study, ment of dogs with degenerative joint disease contain high levels
a high-fat ration was successful in normalizing some aspects of of omega-3 fatty acids and are also designed to help maintain
carbohydrate metabolism and appeared to prolong survival in a optimal body condition.
subset of dogs with lymphoma.29 However, it is important to rec-
ognize that a convincing clinical association among documented 4. Institute an individualized weight-loss program.
metabolic abnormalities, actual weight loss and poor prognosis Although the ration chosen and the initially recommended
has yet to be demonstrated in dogs or cats with any type of cancer. level of caloric intake may differ between obese dogs and cats
More work is needed to prove that high-fat diets can provide an that have cancer and those that do not, the fourth step in the
objective benefit for dogs and cats with neoplastic disease. process of weight loss is essentially the same in both groups.
It can be extremely difficult to reconcile the competing dietary Here, the owner is given explicit written instructions regarding
recommendations for weight loss and malignant disease in dogs exactly how much of what type of food to feed, including all
and cats. This will be especially true when the pet owner is con- treats and supplements. Specific instructions for physical activity
vinced that feeding a high-fat diet will result in a survival benefit are also provided, taking care to begin slowly in previously
for his or her animal, regardless of its current body condition. sedentary animals. Ten minutes of supervised activity each day
In the end, the most appropriate diet is recommended based on is a reasonable starting point in such cases, with an increase of
an objective as possible assessment of the risk to benefit ratio five to 10 minutes per day each week if tolerated. Extrapolation
of weight loss. When obesity is significant (i.e., body condition from studies performed in people with malignant disease suggests
score 7/9 or greater) and the expected survival time after cancer that physical activity will help to maintain lean body mass and
therapy is relatively prolonged (i.e., a year or more), it seems avoid sarcopenic obesity in overweight dogs and cats with cancer
logical that a prescription weight-loss ration would be the safest and may improve quality of life as well as cancer-specific and
and most-efficient way to achieve optimal body condition along overall survival. Encouraging pet owners to keep a diary to
with its associated health benefits. Open, rational and nonjudg- record body weight, type and amount of food consumed, all
mental discussion of the compromised survival documented in treats and supplements, exercise and other observations, includ-
obese people with cancer will be helpful in convincing skeptical ing clinical signs and side effects of cancer therapy, will make
owners of the benefits of weight loss. They may also be reassured monitoring simpler. It will also facilitate troubleshooting in
to find that most weight-loss products contain ample protein, just cases where problems are encountered.
like “cancer diets.” In cases where overweight is less severe or
cancer survival times are anticipated to be shorter, incrementally 5. Carefully monitor response to energy restriction.
decreased intake of a high-quality complete and balanced com- Obese dogs and cats with cancer that are undergoing weight
mercial ration with a somewhat higher fat content may be an loss should be thoroughly re-evaluated on a regular basis. Two
acceptable compromise. to four initial biweekly rechecks, followed by monthly visits
One final consideration in the choice of a weight-loss ration for the duration of the weight-loss program, are a reasonable
for use in a dog or cat with cancer may be its level of enrich- schedule in most cases. Frequent re-evaluation allows the animal’s
ment with omega-3 fatty acids. It is interesting to note that the response to anti-cancer therapy to be assessed and permits
high-fat ration used in the study cited above that demonstrated treatment-related toxicities to be identified and addressed. Reg-

130
ularly scheduled rechecks also facilitate the serial measurements 3. Vaughan VC, Martin P, Lewandowski PA. Cancer Cachexia:
of body weight and body condition score that are essential in Impact, Mechanisms and Emerging Treatments. J Cachexia
confirming successful weight loss. Repeat bloodwork is recom- Sarcopenia Muscle. 2013;4:95-109.
mended to ensure that weight loss is well-tolerated, though the
potential side effects of caloric restriction will have to be dis- 4. Strasser F, Bruera ED. Update on Anorexia and Cachexia.
tinguished from changes secondary to cancer therapy in some Hematol Oncol Clin N Am. 2002;16:589-617.
cases. Obese cats should be monitored for biochemical evidence
of hepatic lipidosis; subtle changes, such as normocytic, normo- 5. Freeman LM. Cachexia and Sarcopenia: Emerging Syndromes
chromic anemia and lymphopenia, in both dogs and cats can also of Importance in Dogs and Cats. J Vet Intern Med. 2012;26:3-17.
reflect development of protein-calorie malnutrition.
Although weight loss will be slower if a relatively conservative 6. Renehan AG, Tyson M, Egger M, et al. Body-Mass Index
decrease in caloric intake has been recommended as described and Incidence of Cancer: A Systematic Review and Meta-Analysis
above, there should still be a clear and consistent downward trend of Prospective Observational Studies. Lancet. 2008;371:569-578.
in both body weight and body condition score. As much as
possible, muscle mass should be carefully assessed to make 7. Samani AA, Yakar S, LeRoith D, et al. The Role of the IGF
sure there is no evidence of atrophy as adipose tissue is lost. System in Cancer Growth and Metastasis: Overview and Recent
Caloric intake should be increased if weight loss is too rapid Insights. Endocr Rev. 2007;28:20-47.
or if evidence of muscle atrophy or protein-calorie malnutrition
develops; intake should obviously be decreased if weight loss 8. Calle EE, Kaaks R. Overweight, Obesity and Cancer: Epidemi-
does not occur as planned. ological Evidence and Proposed Mechanisms. Nat Rev Cancer.
2004;4:579-591.
6. Transition to maintenance ration or maintenance energy
intake. 9. Garofalo C, Surmacz E. Leptin and Cancer. J Cell Physiol.
Once the target weight has been reached in a previously obese 2006;207:12-22.
dog or cat with concurrent cancer, food intake must be adjusted
to maintain the target weight and stop additional weight loss. In 10. Tao W, Lagergren J. Clinical Management of Obese Patients
some cases, the target weight will correspond to an optimal body with Cancer. J Nat Rev Clin Oncol. 2013;10:519-533.
condition score of 5/9, but in others, the decision will reasonably
be made based on underlying cancer diagnosis or other factors 11. Pater LE, Hart KW, Blonigen BJ, et al. Relationship Between
to stop weight loss at a slightly overweight body condition (i.e., Prostate-Specific Antigen, Age, and Body Mass Index in a Prostate
body condition score of 6/9). If a prescription weight-loss product Cancer Screening Population. Am J Clin Oncol. 2012;35:490-492.
was used to allow weight loss, transition to a maintenance
product may have to be made. Rations containing ample protein 12. Park JS, Choi GS, Jang YS, et al. Influence of Obesity on
are likely to be preferred in order to maintain lean body mass most the Serum Carcinoembryonic Antigen Value in Patients with
effectively; however, use of a “cancer diet” with high-protein and Colorectal Cancer. Cancer Epidemiol Biomarkers Prev. 2010;19:
-fat content may simply promote regain of all weight that was lost. 2461-2468.
Alternatively, if weight loss was accomplished through decreased
intake of a complete and balanced commercial ration not specifi- 13. Griggs JJ, Sorbero ME, Lyman GH. Undertreatment of
cally designed for weight loss, then all that is required to maintain Obese Women Receiving Breast Cancer Chemotherapy. Arch
stable weight may be a slight increase in intake of the same diet. Intern Med. 2005;165:1267-1273.
Regardless, more frequent rechecks (i.e., biweekly) during this
transition phase will help to ensure that a healthy weight and 14. Poikonen P, Blomqvist C, Joensuu H. Effect of Obesity on
body condition score are maintained and that all new dietary the Leukocyte Nadir in Women Treated with Adjuvant Cyclo-
recommendations are well-accepted. phosphamide, Methotrexate and Fluorouracil Dosed According
to Body Surface Area. Acta Oncol. 2001;40:67-71.
References
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(eds). John Wiley and Sons Inc., Chichester, UK. 2012:109-124. Association or Need for Alternative Measurements of Obesity?
Ann Surg Oncol. 2010;2264-2273.
2. Bronson RT. Variation in Age at Death of Dogs of Different
Sexes and Breeds. Am J Vet Res. 1982;43:2057-2059.

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Obesity and Mortality from Cancer in a Prospectively Studied Habitual Diet and Danine Mammary Tumor in a Case-Control
Cohort of U.S. Adults. N Engl J Med. 2003;348:1625-1638. Study. J Vet Intern Med. 1998;12:132-139.

17. Campbell PT, Newton CC, Dehal AN, et al. Impact of Body 24. Philibert JC, Snyder PW, Glickman N, et al. Influence of
Mass Index on Survival after Colorectal Cancer Diagnosis: The Host Factors on Survival in Dogs with Malignant Mammary
Cancer Prevention Study-II Nutrition Cohort. J Clin Oncol. 2012; Gland Tumors. J Vet Intern Med. 2003;17:102-106.
30:42-52.
25. Michel KE, Sorenmo K, Shofer FS. Evaluation of Body
18. Ishioka K, Hosoya K, Kitagawa H, et al. Plasma Leptin Condition and Weight Loss in Dogs Presented to a Veterinary
Concentration in Dogs: Effects of Body Condition Score, Age, Oncology Service. J Vet Intern Med. 2004;18:692-695.
Gender and Breeds. Res Vet Sci. 2007;82:11-15.
26. Weeth LP, Fascetti AJ, Kass PH, et al. Prevalence of Obese
19. Appleton DJ, Rand JS, Sunvold GD. Plasma Leptin Concen- Dogs in a Population of Dogs with Cancer. Am J Vet Res. 2007;
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Relationship with Adiposity as Measured by Dual Energy X-Ray
Absorptiometry. J Feline Med Surg. 2000;2:191-199. 27. Baez JL, Michel KE, Sorenmo K, et al. A Prospective Inves-
tigation of the Prevalence and Prognostic Significance of Weight
20. Badman MK, Flier JS. The Adipocyte as an Active Participant Loss and Changes in Body Condition in Feline Cancer Patients.
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28. Lawler DF, Evans RH, Larson BT, et al. Influence of Life-
21. Gayet C, Baihache E, Dumon H, et al. Insulin Resistance time Food Restriction on Causes, Time and Predictors of Death
and Changes in Plasma Concentrations of TNFα, IGF1 and in Dogs. J Am Vet Med Assoc. 2005;226:225-231.
NEFA in Dogs During Weight Gain and Obesity. J An Physiol
An Nutr. 2004;88:157-165. 29. Ogilvie GK, Fettman MJ, Mallinckrodt CH, et al. Effect of
Fish Oil, Arginine and Doxorubicin Chemotherapy on Remission
22. Sonnenschein EG, Glickman LT, Goldschmidt MH, et al. and Survival Time for Dogs with Lymphoma: A Double-Blind,
Body Conformation, Diet and Risk of Breast Cancer in Pet Dogs: Randomized Placebo-Controlled Study. Cancer. 2000;88:1916-1928.
A Case-Control Study. Am J Epidemiol. 1991;133:694-703.

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Notes

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Notes

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Appendix | 2014 CAN Summit: Nutrition for Life Speakers
Epigenetics and Perinatal Nutrition: A Key Factor the next four years in private emergency veterinary practice,
of the Life Course Model of Public Health initially in the Twin Cities and then in Washington, D.C., at
Friendship Hospital for Animals. She joined the faculty at the
Robert H. Lane, MD, MS, Medical College of Wisconsin
University of Georgia in 2003 as an emergency medicine clinician,
Dr. Robert H. Lane earned his medical degree from Northwestern where she subsequently completed her residency in small animal
University School of Medicine in 1989, and then served an intern- internal medicine and her master’s degree in infectious diseases.
ship and residency in pediatrics there from 1989 to 1992. He Dr. Creevy is an associate professor in small animal internal med-
earned a research fellowship in the Pediatric Scientist Training icine at the University of Georgia, and her research interests include
Program at the University of Chicago, and he completed his infectious diseases, causes of mortality in dogs and pedagogy.
clinical fellowship in neonatal-perinatal medicine at Children’s
Memorial Hospital. Dr. Lane received a master’s degree in health- The Challenge of Providing Feeding
care management in 2011 from the University of Texas at Dallas Recommendations for Puppies after Neutering
and the UT Southwestern. He moved through the ranks at
Northwestern, the University of Pittsburgh, UCLA, and the Laura A. Eirmann, DVM, DACVN, Nestlé Purina PetCare
University of Utah. In 2013, the Medical College of Wisconsin Dr. Laura A. Eirmann received her veterinary degree from Cornell
and Children’s Hospital of Wisconsin named Dr. Lane as the University. She completed an internship at The Animal Medical
Barri L. and David J. Drury Chair of Pediatrics and Pediatrician Center in New York City, and then returned to Cornell University
in Chief. Dr. Lane has received several national grants throughout as an instructor. In 1997, Dr. Eirmann joined the staff of the
his career, including awards from the National Institute of Child Oradell Animal Hospital in Paramus, N.J., and in 1998, she
Health and Development (NICHD), National Heart, Lung and joined Nestlé Purina PetCare as a veterinary communications
Blood Institute (NHLBI), and the National Institute of Diabetes manager. In 2010, she completed a residency in small animal
and Digestive and Kidney Diseases (NIDDK). He participated clinical nutrition and became a Diplomate of the American
in vision meetings for NICHD and NHLBI, and he previously College of Veterinary Nutrition. Dr. Eirmann continues to work
served as president of the international Perinatal Research Society. at Nestlé Purina as a veterinary communications manager and
Dr. Lane’s research focuses on how epigenetics inform the at Oradell Animal Hospital as a clinical nutritionist.
Developmental Origins of Disease hypothesis. This hypothesis
states that early life events predict later diseases, such as obesity Feeding Management of the Neutered Cat
and diabetes.
Jennifer A. Larsen, DVM, PhD, DACVN,
University of California-Davis
Programming Food and Flavor Preferences:
Impact of Early Experience Dr. Jennifer A. Larsen earned a master’s degree in animal science
and her veterinary degree from the University of California-Davis.
Sandra Lyn, PhD, Nestlé Purina Research After some time in private practice, she returned to Davis to com-
Dr. Sandra Lyn is an animal behaviorist with Nestlé Purina plete a clinical nutrition residency and to qualify to become a
Research. Dr. Lyn received her doctorate degree in behavioral Diplomate of the American College of Veterinary Nutrition.
psychology from the University of Florida. For more than 20 Dr. Larsen also completed a doctorate in nutritional biology at the
years, she has conducted research on the ingestive behavior of University of California-Davis. She currently serves as an assis-
humans and animals. She has been an active member of the tant professor of clinical nutrition at the University of California-
Nestlé Purina research team for more than a decade, studying Davis and does clinical nutrition consulting through the Veterinary
the feeding behavior of cats and dogs. Currently, she leads the Medical Teaching Hospital Nutrition Support Service.
Nestlé Purina Global R&D Feeding Behavior research program.
Aging & Stroke: The Human Condition
The Long-Term Health Effects of Spay and James W. Simpkins, PhD, West Virginia University
Castration for Dogs
Dr. James W. Simpkins received his bachelor’s and master’s
Kate E. Creevy, DVM, MS, DACVIM-SAIM, degrees from the University of Toledo, and in 1977 received a
University of Georgia doctorate degree in physiology from Michigan State University.
Dr. Kate E. Creevy attended Georgetown University for her under- He joined the faculty at the University of Florida College of
graduate education, and then earned her veterinary degree from Pharmacy in 1997 and rose through the ranks to professor of
the University of Tennessee in 1998 and completed a rotating pharmacodynamics. He has served as Chair of the Departments of
small animal internship at the University of Minnesota. She spent Pharmacodynamics and Pharmaceutics, Associate Dean for

135
Research and Graduate Studies, and Director of the Center for Antioxidants for Eye Health
the Neurobiology of Aging at the University of Florida. In 1996,
Wei Wang, PhD, Nestlé Research Center
Dr. Simpkins was appointed as the Frank Duckworth Professor of
Drug Discovery at the University of Florida. He has more than Dr. Wei “Wendy” Wang received a degree in biochemical engineer-
295 peer-reviewed publications, a dozen patents for his discov- ing from Beijing Technology and Business University through
eries and has edited two texts on Alzheimer’s disease therapy. a program designed to train engineers for food fermentation
He also served as the Director of the University of Florida Drug and the wine industry. Instead of going into the food industry,
Discovery Group for Alzheimer’s Disease, which has received she pursued her research interests and studied abroad to receive
funding from the National Institute on Aging to support research a master’s degree in animal and food sciences from the University
in the pharmacotherapy for Alzheimer’s disease. In 1999, he was of Vermont. Following this, she continued advanced studies in
appointed to the Medical and Scientific Advisory Council of human nutrition and received a doctorate in nutrition from the
the National Alzheimer’s Association. In 2000, he became the University of California at Berkeley. She then went to Oregon
Chair of the Department of Pharmacology and Neuroscience Health & Science University School of Medicine, where she
and Director of the Institute for Aging and Alzheimer’s Disease completed postdoctoral training and served as a research assistant
Research at the University of North Texas Health Science Center professor. Her primary research interests during her doctorate and
at Fort Worth. Dr. Simpkins is currently on the faculty at West subsequent postdoctoral posts were in lipids and carotenoids.
Virginia’s Center for Neuroscience, where he and his group study Dr. Wang joined Nestlé Purina in 2007, and currently serves as a
the causes and potential treatments for Alzheimer’s disease and research nutritionist at the Nestlé Research Center in St. Louis.
stroke in animal models and in human subjects.
Adapting to a New Diet During Dog
Enhancing Cognitive Function Through Diet in Cats Domestication: Implications for the
Yuanlong Pan, PhD, Nestlé Research Center Domestication Process and Dog Health
Dr. Yuanlong “Gary” Pan received a bachelor’s degree in vet- Erik Axelsson, PhD, Uppsala University
erinary medicine in 1984 and a master’s degree in comparative Dr. Erik Axelsson is an assistant professor in the Department of
anatomy in 1987 from The Gansu University of Agriculture, P.R., Medical Biochemistry and Microbiology at Uppsala University
China. Dr. Pan earned a doctorate degree in animal nutrition at in Sweden. He completed a master’s degree in biology, followed
Virginia Tech as a Pratt Fellow. He then switched to human by a doctorate degree in evolutionary genetics under Hans Ellegren.
nutrition and earned a doctorate in nutrition science from the He then completed several postdoctoral appointments at Uppsala
University of North Carolina at Greensboro. In 1996, Dr. Pan University, Copenhagen University and the University of California-
accepted a position as a research associate at Wake Forest Uni- Berkeley. Among his several publications, his groundbreaking
versity School of Medicine, where he investigated the effects of research on the genomic signature of dog domestication was
soy isoflavones on brain aging and cognitive functions in post- published in Nature.
menopausal animal models (rats and monkeys). In 2000, Dr. Pan
accepted a position as a research scientist at the Nestlé Research Evolutionary Versus Evidence-Based Diets
Center in St. Louis, where he is responsible for developing and
Ellen Kienzle, Dr.med.vet.habil., ECVCN,
implementing a number of research projects in the areas of
Ludwig-Maximilians-Universität
healthy aging and weight management.
Dr. Ellen Kienzle holds the Chair of Animal Nutrition and
Systemic Illness: The Role of Oxidative Stress and Dietetics in the Department of Veterinary Sciences of the
Antioxidant Supplementation Veterinary Faculty at the Ludwig-Maximilians-University in
Munich. Dr. Kienzle is a veterinarian and a Diplomate of the
Katrina R. Viviano, DVM, PhD, DACVIM, DACVCP, European College of Veterinary and Comparative Nutrition.
University of Wisconsin She is co-editor of the Journal of Animal Physiology and
Dr. Katrina R. Viviano completed a doctorate in organic chemistry Animal Nutrition. She has also been a member and president of
at the University of Massachusetts before earning her veterinary various international organizations with respect to veterinary
degree from the University of Wisconsin. She then completed and comparative nutrition.
an internship at the University of Minnesota and returned to
Wisconsin to complete a residency in small animal internal Toward Optimizing Feline Nutrition: Insights from
medicine. Dr. Viviano is a Diplomate of the American Colleges the Dietary Nutrient Profile of Feral Cats
of Veterinary Internal Medicine and Veterinary Clinical Pharma-
Esther Hagen-Plantinga, PhD, DVM, Utrecht University
cology. She currently serves as an assistant clinical professor at
the University of Wisconsin School of Veterinary Medicine. Dr. Esther Hagen-Plantinga received her veterinary degree from
Utrecht University in the Netherlands, where she also obtained her

136
doctorate degree in animal nutrition. Since 2007, she has served Dr. Churchill serves on the Non-Branded Tools Committee of
as an assistant professor in animal nutrition at Utrecht University. the Pet Nutrition Alliance and the American Animal Hospital
Her research interests include the influence of nutrition on Association committee on nutrition communications.
diseases of the urinary system in companion animals and the
nutrition of dogs and cats during the Palaeolithic Period. She How I Feed: The Diabetic Dog
currently is completing a residency in animal nutrition to become
Lisa P. Weeth, DVM, DACVN, Weeth Nutrition Services
a board-certified veterinary nutritionist of the European College
of Veterinary and Comparative Nutrition. Dr. Lisa P. Weeth received her veterinary degree from the Uni-
versity of California-Davis in 2002. After several years in prac-
Raw Meat-Based Diets: Current Evidence tice, she went back to Davis to complete a residency in clinical
nutrition. She then became a Diplomate of the American College
Regarding Benefits and Risks
of Veterinary Nutrition in 2007. Dr. Weeth began working as a
Beth A. Hamper, DVM, PhD, DACVN, University of Tennessee clinical nutritionist at the Red Bank Veterinary Hospital in the
Dr. Beth A. Hamper received her veterinary degree from the University fall of 2007, providing consultation to clinicians and pet owners.
of Minnesota. After several years in private practice, she completed While there, she addressed nutritional issues that include the
a residency in nutrition at the University of Tennessee and qualified dietary management of specific disease states; feeding healthy
as a Diplomate of the American College of Veterinary Nutrition. dogs and cats; formulation of home-prepared diets (for wellness
She recently completed her doctorate degree and dissertation on or disease management); development of weight-loss plans; and
the nutritional adequacy and performance of raw food diets in feeding hospitalized dogs and cats, which involves development
kittens, examining growth parameters, digestibility, levels of oxida- of assisted feeding tube plans and the formulation of parenteral
tive stress, and immune function in kittens fed raw diets versus nutritional solutions. Dr. Weeth recently moved to Edinburgh,
canned heat-processed diets. Her research interests include immuno- Scotland, and began her own nutrition consultation service,
nutrition and the impact of diet on the gastrointestinal microbiome. Weeth Nutrition Services.

How I Feed: The Underweight Senior Cat Management of Overweight Dogs and
with Multiple Problems Cats with Cancer
Catherine E. Lenox, DVM, CVA, DACVN, Gulf Coast Glenna E. Mauldin, DVM, MS, DACVIM, DACVN,
Veterinary Specialists and Lenox Veterinary Nutrition Western Veterinary Cancer Centre and Western Veterinary
Consulting, PLLC, Houston, TX Specialist and Emergency Centre
Dr. Catherine E. Lenox is a practicing clinical nutritionist at Gulf Dr. Glenna E. Mauldin graduated from the Western College of
Coast Veterinary Specialties in Houston, Texas, and she also runs Veterinary Medicine in Saskatoon, Saskatchewan, Canada, in
a private consulting nutrition firm. Dr. Lenox received her veteri- 1985. After completing her internship in 1986 and veterinary
nary degree from the University of Missouri, and then completed oncology residency in 1988 at The Animal Medical Center in
an internship at Colorado State University. After a couple of years New York City, Dr. Mauldin attended Cornell University and
working at an emergency veterinary clinic in St. Louis, Mo., was awarded a master’s degree in nutrition. She became a
she completed a residency in clinical nutrition at the Virginia- Diplomate of the American College of Veterinary Internal
Maryland Regional College of Veterinary Medicine, qualifying Medicine, in the specialty of oncology, in 1991, and the American
for Diplomate status with the American College of Veterinary College of Veterinary Nutrition in 2004. Dr. Mauldin served as
Nutrition. Dr. Lenox is also a certified veterinary acupuncturist. a staff veterinarian in oncology and nutrition at The Animal
Medical Center from 1990 to 1997 and as an associate professor
Canine Renal Disease: When Is the Right Time to of veterinary oncology at Louisiana State University from 1998
Strike with Nutritional Therapy to 2007. She joined the staff of Western Veterinary Specialist
and Emergency Centre in Calgary, Canada, in the fall of 2007.
Julie Churchill, DVM, PhD, DACVN, University of Minnesota She was president of the American College of Veterinary Internal
Dr. Julie Churchill is an assistant clinical professor at the Univer- Medicine, Specialty of Oncology, from 2004 to 2007, and was a
sity of Minnesota. Dr. Churchill received her veterinary degree member at large for the American College of Veterinary Nutrition
at Michigan State University, followed by an internship at the from 2007 to 2010. Dr. Mauldin has written more than 75 scien-
University of Georgia and an internal medicine residency at the tific articles, book chapters and abstracts and lectures frequently
University of Minnesota. She then completed a residency in at national and international meetings. Together, with her husband,
clinical nutrition and a doctorate degree in comparative medi- Dr. Neal Mauldin, she has successfully trained 15 residents who
cine (emphasis in nutrition and renal aging) at the University of are now board-certified in medical oncology. Her areas of interest
Minnesota. Dr. Churchill is a Diplomate of the American College include nutritional management of dogs and cats with cancer,
of Veterinary Nutrition. She has received many teaching awards, canine and feline lymphoma, and hematology.
including the Merck Award and multiple outstanding faculty awards.

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Notes

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