Prolonging Healthy Aging: Longevity Vitamins and Proteins: Perspective
Prolonging Healthy Aging: Longevity Vitamins and Proteins: Perspective
Prolonging Healthy Aging: Longevity Vitamins and Proteins: Perspective
PERSPECTIVE
Prolonging healthy aging: Longevity vitamins
and proteins
Bruce N. Amesa,1
Edited by Cynthia Kenyon, Calico Labs, San Francisco, CA, and approved September 13, 2018 (received for review May 30, 2018)
It is proposed that proteins/enzymes be classified into two classes according to their essentiality for
immediate survival/reproduction and their function in long-term health: that is, survival proteins versus
longevity proteins. As proposed by the triage theory, a modest deficiency of one of the nutrients/cofactors
triggers a built-in rationing mechanism that favors the proteins needed for immediate survival and
reproduction (survival proteins) while sacrificing those needed to protect against future damage (longevity
proteins). Impairment of the function of longevity proteins results in an insidious acceleration of the risk of
diseases associated with aging. I also propose that nutrients required for the function of longevity proteins
constitute a class of vitamins that are here named “longevity vitamins.” I suggest that many such nutrients
play a dual role for both survival and longevity. The evidence for classifying taurine as a conditional vitamin,
and the following 10 compounds as putative longevity vitamins, is reviewed: the fungal antioxidant ergo-
thioneine; the bacterial metabolites pyrroloquinoline quinone (PQQ) and queuine; and the plant antioxidant
carotenoids lutein, zeaxanthin, lycopene, α- and β-carotene, β-cryptoxanthin, and the marine carotenoid
astaxanthin. Because nutrient deficiencies are highly prevalent in the United States (and elsewhere), appro-
priate supplementation and/or an improved diet could reduce much of the consequent risk of chronic
disease and premature aging.
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vitamins essential minerals aging nutrition
I propose that an optimal level of many of the known adverse health effects. They include vitamins A, B1, B2,
30 vitamins and essential minerals/elements (V/M), B6, B12, biotin, C, choline, D, E, folic acid, K, niacin,
plus that of 11 new putative vitamins described herein, pantothenate; and minerals/elements calcium, chloride,
is necessary for promoting healthy aging. The “triage chromium, cobalt, copper, iodine, iron, manganese,
theory” (1) had previously introduced the concept that magnesium, molybdenum, phosphorus, potassium,
proteins/enzymes that are sacrificed on a V/M short- selenium, sodium, sulfur, and zinc. Some additional im-
age are necessary for supporting long-term health. portant nutrients, the marine omega-3 fatty acids doco-
This insight is being broadened here to classify also sahexaenoic acid (DHA) and eicosapentanoic acid (EPA),
many V/M as necessary for supporting long-term are discussed here, although they are not known as vi-
health. I present evidence that the deficiency of many tamins. Nine essential dietary amino acids are also im-
V/M specifically increases the risk of future disease portant for the synthesis of proteins and hormones (2) but
and shortens the lifespan. Thus, I propose that such will not be discussed. The abbreviated term V/M is used
V/M be named “longevity vitamins,” and that proteins throughout this presentation because it refers to a co-
associated with them be named “longevity proteins.” herent category of nutrients, although only a few min-
Prolongation of healthy aging has not been generally erals/elements are discussed.
understood as being related to V/M levels. Most of the world’s population—even in developed
countries—consume many of the V/M at levels below
Deficiencies in Vitamins and Minerals those recommended (3, 4). Using as reference the
Approximately 30 V/M are cofactors necessary for me- estimated average requirement (EAR) values [the in-
tabolism to function properly and were discovered be- take level for a nutrient at which the needs of half
cause severe dietary deficiencies were linked to serious of the healthy population is adequate and half is
a
Nutrition and Metabolism Center, Children’s Hospital Oakland Research Institute (CHORI), Oakland, CA 94609-1809
Author contributions: B.N.A. wrote the paper.
The author declares no conflict of interest.
This article is a PNAS Direct Submission.
Published under the PNAS license.
1
Email: [email protected].
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1809045115/-/DCSupplemental.
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UV light to a precursor of vitamin D steroid hormone. Then the now considered an essential fatty acid, but it is still unclear
final steroid hormone binds to a protein, the vitamin D receptor whether it is just needed as a precursor of DHA/EPA, which are
protein; the latter interacts with a 12-base regulatory sequence in inefficiently made from it.
vitamin D receptor-dependent genes and regulates them either in
a positive or negative fashion (12, 13). About 2,700 such binding Magnesium. Mg is present in the center of the chlorophyll mol-
sites have been found in the human genome as interacting with ecule, with plants being a major dietary source, together with
the vitamin D receptor protein (14). Extensive evidence shows that whole grains, nuts, and seeds (41). Mg deficiency affects about
vitamin D deficiency causes—or has been associated with—a 45% of the United States population and has been associated with
large number of diseases that affect healthy aging, such as all- increased all-cause mortality, poor DNA repair capacity, increased
cause mortality, cancer, cardiovascular disease (CVD), diabetes, risk of lung cancer and various other kinds of cancer, heart dis-
brain function, and so forth. Considering this high level of de- ease, telomere shortening, and risk of stroke (SI Appendix, SI-3
ficiency and the important implications of vitamin D interactions, it Survival V/M That Are also Longevity V/M).
is particularly important to tune up metabolism (15) with respect to A recent review on the subclinical effects of Mg deficiency
vitamin D. See SI Appendix, SI-3 Survival V/M That Are also makes the case that this deficiency is a principal driver of CVD, a
Longevity V/M for the large literature on vitamin D clinical trials worldwide underrecognized problem, and thus that it is a major
and Mendelian randomization studies. public health crisis (42). Mg is required to convert vitamin D to its
Supplementation with vitamin D, which would prevent and active steroid hormone form (43).
relieve some of these problems, has been discouraged for two In conclusion, these three examples of V/M deficiencies, to-
reasons: fear of toxicity (in older studies) and numerous in- gether with the vitamin K and selenium studies, provide consid-
adequate clinical trials. Newer evidence on the effect of vitamin D erable evidence that these compounds fit the definition of
on all-cause mortality supersedes these toxicity studies, concluding longevity V/M, as well as being essential for survival, and that
that there was no increased risk even when blood levels of optimizing their intake offers a way to lengthen healthy longevity.
25(OH)D were as high as 100 ng/mL (16–18).
The use of randomized clinical trials (RCTs) for studying the Conditional Vitamins
effect of nutrients, as opposed to drug trials, can be subject to A conditional vitamin is synthesized by the body, but not at a level
misinterpretation unless the level of the nutrient is measured both that is sufficient to optimize metabolism.
before supplementation starts and at its end. This precaution is
necessary because many of the subjects may not be deficient in Choline. Choline was the first example of a conditional vitamin
the nutrient being tested and the amount supplemented may be (44): only 11% of women achieve the recommended intake and
insufficient to raise levels adequately. The absence of such mea- the average intakes for the population are half to two-thirds of this
surements can lead to erroneous negative results, as shown for recommendation (45); severe choline deficiency results in DNA
various RCTs for vitamin D (19) and as pointed out repeatedly in strand breaks in rodents, alterations to epigenetic markers and
the nutrition literature (20–28). Many conclusions, both in medical histones, and affects brain development (46–48).
journals (e.g., refs. 29 and 30) and in books (e.g., ref. 31), that
supplemental vitamins are ineffective in performing some func- Taurine (2-Aminoethanesulfonic Acid). Taurine is another ex-
tion generally ascribed to them, should be taken skeptically if the ample of a conditional vitamin because it is synthesized by ani-
RCT did not include measurements of the vitamin. mals (including humans), but not in sufficient amounts. It has been
Thus, it is clear that vitamin D performs more than just its ini- shown to be important in preventing numerous health problems,
tially assigned function of maintaining bone health. It is important such as CVD, brain function, diabetes, and mitochondrial dis-
for a healthy long life, and thus it is a longevity vitamin. eases, as summarized below. Because of taurine’s extensive in-
volvement in health problems that lead to long-term damage, it is
Marine Omega-3 Fatty Acids, DHA and EPA. The intake of proposed here that it is also a longevity vitamin.
these compounds is inadequate in most of the United States The synthesis of taurine involves cysteine decarboxylation and
population (8). Low EPA and DHA levels in red blood cells were sulfhydryl oxidation. The rate of its biosynthesis is species-
found to be associated with increased all-cause mortality in a dependent, with a low level in humans, compared with rodents
study of 6,501 elderly women followed for 14.9 y (32). A meta- (which led to the suggestion that supplementation might be ben-
analysis reported that each 1% increase in plasma DHA/EPA was eficial) (49). It is located in the cytosol and in mitochondria and it is
linked with a 20% decreased risk in all-cause mortality (33). present in virtually all human tissues at millimolar concentrations; it
DHA/EPA are present in high levels in the central nervous sys- is especially high in electrically excitable and secretory tissues and
tem and are important for brain and retinal structure and function in platelets. A 70-kg human contains about 70 g of taurine (50). An
(34). In an RCT on first-episode schizophrenia patients, omega- excellent review of all of the earlier work on taurine is available in
3 fatty acids supplementation prevented cortical loss of gray mat- Huxtable (50). Most of taurine is acquired from the diet, mainly from
ter thickness and promises a possible treatment for schizophrenia fish and other seafood, seaweed, eggs, and dark-meat poultry (51).
(35). The role of DHA in aging, Alzheimer, Parkinson, schizophrenia, Taurine is particularly important in the mitochondria, where it is
bipolar, and depression have been recently reviewed (34). present as 5-taurinomethyl-uridine in tRNA-leu and tRNA-trp, and
Low blood levels of DHA/EPA were shown in a 5-y study to be as 5-taurinomethyl-2-thiouridine in tRNA-glu, tRNA-gln, and
associated with a faster rate of telomere shortening, a marker of tRNA-lys. In all five tRNAs, it is located in the wobble position,
cell aging (36). Supplemental fish oil (2.5 g/d) slowed telomere where it functions to read accurately alternate codons in the mi-
shortening and lowered biomarkers of oxidation in older adults tochondrial genome (52). A taurine modification defect in mito-
(37). Daily supplemental DHA (2 g/d) increased the rate of clear- chondrial tRNA is associated with the mitochondrial diseases
ance of amyloid plaques in people with mild cognitive impairment MELAS (mitochondrial encephalopathy, encephalopathy, lactic
(38). DHA/EPA are important for vitamin D steroid hormone ef- acidosis, and stroke-like episodes) and MERRF (myoclonus epi-
fectiveness (13). Evidence of their role in reducing the risk of heart lepsy with ragged-red fibers) (52), suggesting causality, and also
disease has been obtained (39, 40). Linolenic acid (omega-3) is that a taurine deficiency could result in the same diseases.
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Pyrroloquinoline Quinone. PQQ is made by many species of controlling executive function, and its relevance to autism, at-
bacteria, but not by animals or plants. It is a cofactor for several tention deficit/hyperactivity disorder, bipolar, and schizophrenia
bacterial dehydrogenases, such as glucose and methanol de- (12, 13, 109–111). Queuine-deficient mice become tyrosine-
hydrogenases (92, 93). It is synthesized by soil bacteria, enters deficient, dying within 18 d of its withdrawal (112), despite the
plants from the soil (94), and thus enters human diets; it was de- fact that tyrosine is a nonessential amino acid, presumably be-
tected in every sample of fruits and vegetables tested at levels 5– cause it results in BH4 deficiency.
10 times higher than in human tissues and fluids. PQQ is an im- A recent key paper (113) shows that queuine and a synthetic
portant plant growth factor imported from rhizobacteria (95). It is a analog have been proven effective in a mouse model of multiple
powerful antioxidant and is much more stable than ascorbic acid; in sclerosis in eliciting full remission from the disease. Animals de-
redox cycling, PQQ has 20,000 potential catalytic cycles, compared ficient in the tRNA guanine transglycosylase, and thereby in-
with 4 for ascorbic acid (92). capable of modifying tRNA, fail to respond to therapy, implying
The health benefits of PQQ in humans have been reviewed that modulation of protein translation is the principal means
recently, including for diabetes, antioxidant activity, neuro- through which the therapeutic effect is elicited.
protection, cognition (96), and lowering the level of C-reactive The finding that queuine is located in the wobble position of
protein (i.e., inflammation). In addition, PQQ supplementation tRNA (an ancient molecule), that a number of dedicated enzymes
improved antioxidant potential and decreased the levels of for queuine utilization have been strongly conserved in eukary-
mitochondrial-related intermediates and metabolites in urine, otes, the existence of a dedicated transporter, the effect on
providing support for previous studies that demonstrated that BH4 synthesis, together with its broad distribution, all suggest
PQQ improved mitochondrial efficiency (97). that queuine should be classified as a putative longevity vitamin. It
PQQ has been repeatedly suggested to be a vitamin, although will be desirable to obtain evidence of human pathologies, and
arguments have been raised against it (92). The case for its being thus of unhealthy aging, consequent to a lack of queuine.
classified as a vitamin has become stronger due to a recent
breakthrough study (98) of five mouse proteins that bind PQQ. Carotenoids. There are ∼600 carotenoids synthesized by plants,
This work confirmed that the activity of at least one mammalian but not by animals. They act as antioxidant pigments in all plants
enzyme, rabbit lactic dehydrogenase-A, depends on PQQ to and usually contain 11 conjugated double bonds, which accounts
catalyze the key conversion of lactate to pyruvate at physiological for their yellow/orange/red colors. All photosynthetic plants syn-
PQQ levels (98). This activity enables mitochondria, when limited thesize carotenoids to quench singlet oxygen, a highly energetic
in activity by reductive stress (i.e., high NADH/NAD ratio), to and toxic form of oxygen created in cells by strong light. The
synthesize more ATP as an alternative to exporting lactate. PQQ toxicity of singlet oxygen is due to its ability to oxidize proteins,
has also been shown to induce mitochondrial biogenesis at low lipids, and nucleic acids, which can lead to cell death (114). The
physiological levels (∼250 μg/kg in rat) through the proliferator- extra singlet oxygen energy is dissipated as heat via the long
activated receptor-γ coactivator-1 α (PGC-1α) in peroxisomes (99, chain of conjugated double bonds in these compounds. They
100). Experiments in cats and rodents on PQQ are numerous and mimic enzymes in that one molecule of carotenoid can destroy
confirmatory (SI Appendix, SI-5 Putative Longevity Vitamins). hundreds of molecules of singlet oxygen. It should be noted that
PQQ is promising as a longevity vitamin in humans. It is nec- because the carotenoid family is very large, carotenoids related to
essary for mitochondrial health (although most of the evidence for each other may replace each other to perform the same functions,
the latter comes from rodent studies). depending on the individual diet.
The following six carotenoids account for 95% of the caroten-
Queuine. Queuine is an evolutionarily ancient compound (101). It oids found in American blood and brain: lutein, zeaxanthin, lyco-
is a 7-deazaguanine derivative present in bacteria, which are pene, α- and β-carotene, and β-cryptoxanthin. The importance for
unique in their ability to synthesize it and pass it on to plants and health of a seventh carotenoid, the powerful marine carotenoid
animals (102). Detectable amounts of queuine have been identi- astaxanthin, which contains 13 conjugated double bonds, is also
fied in tomatoes, wheat, coconut water, and milk from humans, discussed (SI Appendix, SI-5 Putative Longevity Vitamins). These
cows, and goats (102). Humans and mice recover queuine from are increasingly being accepted as vitamin-like nutrients (115).
either ingested food or the gut flora. All eukaryotic organisms, There is good evidence that these carotenoids help optimize a
including humans, convert queuine to queuosine by placing it in healthy lifespan: low intake of these carotenoids has been associ-
the wobble position (anticodon) of several tRNAs: aspartic acid, ated with all-cause mortality, macular degeneration and associated
asparagine, histidine, and tyrosine (101, 103, 104). For details, see blindness, cognitive decline, CVD, various types of cancer, meta-
SI Appendix, SI-5 Putative Longevity Vitamins. bolic syndrome, oxidative damage to DNA, high blood pressure,
Queuine deficiency, uptake, and function have been reviewed hearing loss, decreased visual acuity, inflammation, immune decay,
(102). It is notable that eukaryotes have retained a number of and cognitive decay. It is well known that α- and β-carotene, and
dedicated proteins for queuine utilization, which include a con- β-cryptoxanthin are precursors of vitamin A; thus, some of the
served mitochondrial tRNA transglycosylase, thus indicating its health effects upon their deficiency may be due to insufficient vi-
essentiality (105). The cellular uptake of queuine appears to occur tamin A. A description of their chemical nature and properties,
through a dedicated transporter (102). Queuine deficiency in together with a summary of the analysis of their link to diseases of
human cells in vitro and in animals results in a reduced level of the aging, appears in SI Appendix, SI-5 Putative Longevity Vitamins.
cofactor tetrahydrobiopterin, BH4 (106). BH4 is a necessary co- Carotenoids are included among putative longevity vitamins
factor for the conversion of phenylalanine to tyrosine, of trypto- because of the evidence that they protect long-term health. The
phan to serotonin, of tyrosine to DOPA (which gets converted into strength of the evidence varies, but they deserve more attention
epinephrine and norepinephrine), of arginine to NO, and for the for their role for achieving a healthy longevity.
oxidation of alkyl glycerol lipids (107, 108). The essentiality of
BH4 for the hydroxylation of tryptophan to produce serotonin Discussion
could be of relevance to numerous neurological conditions, Prolonging good health while aging is an important issue in
especially considering serotonin’s role as a social hormone a world with large increases in life expectancy. Mechanistic,
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