Hallmark of Aging 2023 Update

Please cite this article in press as: López-Otı́n et al., Hallmarks of aging: An expanding universe, Cell (2023), https://doi.org/10.
1016/
j.cell.2022.11.001
ll
Leading Edge
Review
Hallmarks of aging: An expanding universe
Carlos López-Otı́n,1,2,3,* Maria A. Blasco,4 Linda Partridge,5,6 Manuel Serrano,7,8,9 and Guido Kroemer10,11,12,*
1Departamento de Bioquı́mica y Biologı́a Molecular, Instituto Universitario de Oncologı́a (IUOPA), Universidad de Oviedo, Oviedo, Spain
2Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
3Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain
4Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre (CNIO), Madrid, Spain
5Department of Genetics, Evolution and Environment, Institute of Healthy Ageing, University College London, London, UK
6Max Planck Institute for Biology of Ageing, Cologne, Germany
7Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
8Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
9Altos Labs, Cambridge, UK
10Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM
U1138, Institut Universitaire de France, Paris, France

11Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France
12Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France
*Correspondence: [email protected] (C.L.-O.), [email protected] (G.K.)

https://doi.org/10.1016/j.cell.2022.11.001
SUMMARY
Aging is driven by hallmarks fulfilling the following three premises: (1) their age-associated manifestation, (2)
the acceleration of aging by experimentally accentuating them, and (3) the opportunity to decelerate, stop, or
reverse aging by therapeutic interventions on them. We propose the following twelve hallmarks of aging:
genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautoph-
agy, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion,
altered intercellular communication, chronic inflammation, and dysbiosis. These hallmarks are intercon-
nected among each other, as well as to the recently proposed hallmarks of health, which include organiza-
tional features of spatial compartmentalization, maintenance of homeostasis, and adequate responses to
stress.
INTRODUCTION biological and chronological age can reflect the efficacy of

age-accelerating or -decelerating manipulations that evaluate
Aging research explores the decline in function of organisms the contribution of a given hallmark to the aging process. For
during adulthood. Since 2013, when the first edition of the hall- this reason, standardized physiological measurements (e.g.,
marks of aging was published in Cell,1 close to 300,000 articles respirometry to measure basal and maximal energy expendi-
dealing with this subject have been published, which is as many ture), functional tests (e.g., at the sensory, psychomotor, and
as during the preceding century. Hence, time has become ripe cognitive levels), and ever more sophisticated ‘‘omics’’ technol-
for a new edition of the hallmarks of aging incorporating the ogies (e.g., genomics, epigenomics, transcriptomics, prote-
main knowledge obtained a decade on. omics, and metabolomics), often applied at the single-cell level,
The distinction among ‘‘hallmarks’’ is intrinsically diffuse, since are instrumental for evaluating the spatiotemporal patterns of
they interact and are not independent of each other. Therefore, health degradation and the (in)efficacy of anti-aging strategies.
their classification is inevitably arbitrary, but we proposed three In 2013, we suggested nine molecular, cellular, and systemic
criteria that must apply for each hallmark of aging: (1) the time- hallmarks of aging: DNA instability, telomere attrition, epigenetic
dependent manifestation of alterations accompanying the aging alterations, loss of proteostasis, deregulated nutrient-sensing,
process, (2) the possibility to accelerate aging by experimentally mitochondrial dysfunction, cellular senescence, stem cell
accentuating the hallmark, and—most decisively—(3) the oppor- exhaustion, and altered intercellular communication.1 Recent
tunity to decelerate, halt, or reverse aging by therapeutic inter- research has confirmed and extended the importance of all
ventions on the hallmark. Rather than elaborating a compendium these hallmarks. They have withstood scrutiny by tens of
of age-associated alterations, we shall focus on the molecular, thousands of aging researchers, but they require an update to
cellular, and systemic processes mechanistically accounting deal with the discoveries of the last decade. For example, in
for their manifestation. That said, both in laboratory animals 2013, much of the evidence on anti-aging interventions was
and in human medicine, objective quantification of morpholog- limited to non-mammalian model organisms including yeast,
ical and functional decline affecting the aging organism is essen- nematodes, and fruit flies. Fortunately, experiments involving
tial to measure biological aging. Indeed, disparity between mice (and in some cases, non-human primates) have now
Cell 186, January 19, 2023 ª 2022 Elsevier Inc. 1

Please cite this article in press as: López-Otı́n et al., Hallmarks of aging: An expanding universe, Cell (2023), https://doi.org/10.1016/
j.cell.2022.11.001
ll
Review
Figure 1. The hallmarks of aging
The scheme compiles the 12 hallmarks of aging
proposed in this work: genomic instability, telo-
mere attrition, epigenetic alterations, loss of
proteostasis, disabled macroautophagy, deregu-
lated nutrient-sensing, mitochondrial dysfunction,
cellular senescence, stem cell exhaustion, altered
intercellular communication, chronic inflamma-
tion, and dysbiosis. These hallmarks are grouped
into three categories: primary, antagonistic, and
integrative.
GENOMIC INSTABILITY
Genome integrity and stability are perva-

sively threatened by exogenous chemi-
cal, physical, and biological agents,
as well as by endogenous challenges
such as DNA replication errors, chromo-
some segregation defects, oxidative pro-
cesses, and spontaneous hydrolytic reac-
tions. The wide range of genetic lesions
caused by these extrinsic or intrinsic sour-
ces of damage include point mutations,
deletions, translocations, telomere short-
ening, single- and double-strand breaks,
chromosomal rearrangements, defects
in nuclear architecture, and gene disrup-
tion caused by the integration of viruses
or transposons. All these molecular alter-
ations and the resulting genomic mosai-
cism may contribute to both normal and
pathological aging.3 Accordingly, organ-
corroborated the validity of most of these hallmarks in mammals. isms have evolved a complex array of DNA repair and mainte-
Of note, human age-related diseases have statistically higher nance mechanisms to deal with the damage inflicted to nuclear
chances to co-occur and to share genomic characteristics and mitochondrial DNA (mtDNA) and to ensure the appropriate
when they are causally linked to the same hallmark rather than chromosomal architecture and stability. These DNA repair net-
to different hallmarks,2 clinically validating the approach that works lose efficiency with age, which accentuates the accumula-
we have chosen. tion of genomic damage and the ectopic accumulation of DNA in
Besides the necessary update of the previous hallmarks, the cytosol4 (Figure 2A).
we have also introduced some reorganizations and included
the following three additional hallmarks of aging: disabled mac- Nuclear DNA
roautophagy, chronic inflammation, and dysbiosis. Disabled Cells from aged humans and model organisms accumulate so-
macroautophagy was initially treated as a special case of loss matic mutations at nuclear DNA.5 Other forms of damage,
of proteostasis. However, macroautophagy does not only affect such as chromosomal aneuploidy and copy-number variations,
proteins but can target entire organelles and non-proteinaceous are also associated with aging. All these DNA alterations may
macromolecules, justifying its discussion as a separate entity. affect essential genes and transcriptional pathways, resulting
Moreover, we considered that the final hallmark that we listed in dysfunctional cells that may finally compromise tissue and
in 2013, altered intercellular communication, was too vast, organismal homeostasis. This is especially relevant when DNA
requiring a separate discussion of chronic inflammation and damage impacts on stem cells, hampering their role in tissue
age-associated dysbiosis (Figure 1). renewal or leading to their exhaustion, which in turn promotes
The interdependence of aging hallmarks means that the aging and increases susceptibility to age-related pathologies.6,7
experimental accentuation or attenuation of one specific hallmark The mutational burden in histologically normal human tissues is
usually affects other hallmarks as well. This underscores the fact remarkable. For example, normal esophageal epithelium cells
that aging is a complex process that has to be conceived as a from young individuals already display hundreds of mutations
whole. Accordingly, each of the hallmarks should be considered and may carry more than 2,000 mutations per cell by middle
as a point-of-entry for future exploration of the aging process, as age.8 The accumulation of DNA mutations throughout life is
well as for the development of new anti-aging medicines. likely tolerated because of the excessive energetic cost of the
2 Cell 186, January 19, 2023

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Review
accelerate aging because they require a permissive microenvi-

ronment created by non-mutagenic promoting factors to
become penetrant.10
Comparative analysis of the mutational landscape across
mammalian species has shown that species-specific somatic
mutation rate is inversely correlated with lifespan.11 To date,
there is no clear evidence that the normal rate of mutation fixa-
tion is responsible for aging, but numerous studies have shown
that DNA repair deficiencies have the potential to cause aging.
Thus, alterations in DNA repair mechanisms accelerate
aging in mice and underlie several human progeroid syn-
dromes.12 Conversely, transgenic mice overexpressing the
mitotic checkpoint kinase BubR1 exhibit an extended healthy
lifespan13 (Table 1). Moreover, studies in humans and other
long-lived species have shown that enhanced DNA repair mech-
anisms coevolve with increased longevity.14 Sirtuin-6 (SIRT6)
may play a major role in this differential reparative efficiency
across species. Overexpression of SIRT6 in mice reduces
genomic instability, improves double-strand break repair, and
extends lifespan15 (Table 1), although other explanations, such
as improved glucose metabolism and restoration of energy
homeostasis, have been proposed to explain the prolongevity
effects of SIRT6.16 Notably, recent work has shown that
small-molecule activation of 8-oxoguanine DNA glycosylase 1
increases oxidative DNA damage repair and may have therapeu-
tic applications in the context of aging and other processes
linked to excessive oxidative damage.17 These findings suggest
that interventions aimed at reducing the mutational load of nu-
clear DNA or at enhancing or rerouting its repair mechanisms
may delay aging and the onset of age-related diseases, but
further causal evidence in this regard is still missing.
Mitochondrial DNA
Genomic instability affecting mtDNA may contribute to aging and
age-related pathologies.96 mtDNA is strongly impacted by ag-
ing-associated mutations and deletions due to its high replicative
index, the limited efficiency of its repair mechanisms, its oxidative
microenvironment, and the lack of protective histones embracing
this small DNA molecule. Somatic mtDNA alterations increase
across human tissues during aging, but it remains unclear whether
Figure 2. Loss of cellular integrity caused by genomic instability, this increase truly impacts the aging process at the functional level.
telomere attrition, and epigenetic alterations The causal implication of mtDNA mutations in driving aging has
(A) Endogenous or exogenous agents cause a variety of DNA lesions that been difficult to assess because of ‘‘heteroplasmy,’’ which implies
contribute to both normal and pathological aging. Such lesions can by repaired the co-existence of mutated and wild-type genomes within the
by a variety of mechanisms that lose efficiency with age. Excessive DNA
damage, insufficient DNA repair, alterations in nuclear architecture, and same cell. However, deep-sequencing of aged cells revealed
telomere attrition favor the aging process. BER, base excision repair; HR, that their mtDNA mutational load may substantially increase
homologous recombination; NER, nucleotide excision repair; NHEJ, non-ho- through clonal expansion events.97 The accelerated expansion
mologous end joining; MMR, mismatch repair; SAC, spindle assembly
checkpoint; TERT, telomerase reverse transcriptase; TLS, trans-lesion syn-
of mitochondrial mutations with age has also been observed in
thesis. both primate oocytes and somatic tissues,98 as well as in lympho-
(B) Changes in the acetylation and methylation of DNA or histones, as well as in blasts from patients with neurodegenerative diseases.99 Of note,
levels or activity of chromatin-associated proteins or of non-coding RNAs ultra-sensitive sequencing indicates that most mtDNA mutations
(ncRNAs) induce epigenetic changes that contribute to the aging process. The
red portions of the hourglasses indicate age-associated alterations and the in aged cells arise from replication errors caused by mtDNA poly-
blue portions strategies for avoiding them. merase g rather than from oxidative stress.96
Preliminary evidence that mtDNA mutations might be directly
complete repair of all genomic damages caused by exogenous involved in aging and age-related pathologies was provided by hu-
and endogenous challenges. Consequently, cells favor survival man disorders that are caused by mtDNA damage and partially
over genomic integrity.9 These data also suggest that similar to phenocopy aging.100 Further causative evidence has arisen from
carcinogenesis, driver mutations alone may not be sufficient to studies on mice deficient in DNA polymerase g that exhibit
Cell 186, January 19, 2023 3

4 Cell 186, January 19, 2023
Table 1. Examples of anti-aging effects of hallmark-targeted interventions in mammals
j.cell.2022.11.001
Hallmark Species/model Intervention Outcome Ref
Genomic mouse BubR1 overexpression increased longevity North et al.13
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instability mouse SIRT6 overexpression increased longevity Tian et al.15
HGPS mouse farnesyl transferase inhibitors healthspan and lifespan extension Gordon et al.18
HGPS human
Telomere mouse telomere lengthening lifespan extension Tomás-Loba et al.19
attrition telomerase- telomerase reactivation lifespan extension Jaskelioff et al.20
null mouse
mouse pharmacological or genetic delayed aging Bernardes de
activation of telomerase Jesus et al.21
mouse hyperlong telomeres increased lifespan; metabolic health Muñoz-Lorente et al.22
improvement
mouse telomere maintenance in preservation of neuron survival and Shim et al.23
adult neurons cognitive function
mouse telomerase activation by improvement in models of Povedano et al.24
gene therapy strategy pulmonary fibrosis and aplastic and Bär et al.25
anemia
Epigenetic human a-ketoglutarate delayed epigenetic clock Demidenko et al.26
alterations human thymus regeneration by delayed epigenetic clock Fahy et al.27
GH +DHEA+ metformin
mouse Kat7 inactivation lifespan extension Wang et al.28
human stem KAT7 inactivation decreased H3 acetylation, reduced Wang et al.28
cells cell senescence
mouse Sirt1 overexpression improved genomic stability and Bhatt and Tiwari29
metabolism
mouse Sirt3 overexpression reversed regenerative capacity Bhatt and Tiwari29
of HSC
mouse miR-188 depletion alleviated age-related vascular He et al.30
problems
mouse miR-455-3p overexpression improved mitochondrial and Kumar et al.31
cognitive function; extended
lifespan
aged or Sirt6/ nucleoside reverse-transcriptase improved healthspan and lifespan Simon et al.32
mouse inhibitors
Loss of mouse transgenic expression of LAMP2a improved hepatocyte viability in Dong et al.33
proteostasis in hepatocytes or HSC aged mice. Improved function and
metabolic properties of HSC
mouse pharmacological induction of CMA improved Alzheimer’s pathology Madrigal-Matute
Review
and arteriosclerosis in disease et al.34
models
(Continued on next page)
Review
Table 1. Continued
j.cell.2022.11.001
mouse intranasal administration of enhanced lifespan (m), improved Bobkova et al.35
recombinant human HSP70 cognitive functions, and
proteasome activity; reduced brain
lipofuscin
mouse 4-phenylbutyrate administered reduced ER stress in cortex and Hafycz et al.36

to aged mice hippocampus and improved
cognition
human guanabenz in patients with ALS reduced progression to bulbar stage Dalla Bella et al.37
(FDA approved)
Disabled mouse transgenic overexpression of Atg5 improved longevity, metabolic Pyo et al.38
macroautophagy health and motor function
mouse mutation of beclin 1 extended longevity of C57BL/6 mice Fernández et al.39
(Becn1F121A/F121A) to reduce its and progeroid klotho-ko mice. and Wang et al.40
inhibition by Bcl-2 Prolonged neurogenesis
mouse spermidine in drinking water extended longevity, reduced Eisenberg et al.41
cardiac aging and oxidative stress,
sinusoidal dilation in liver
mouse salicylates (salicylate, EP300 inhibition; autophagy- Castoldi et al.42
acetylsalicylate) dependent hepatoprotection;
improved cancer
immunosurveillance
mouse nordihydroguairaretic acid longevity extension (m) with EP300 Tezil et al.43
inhibition
human oral NMN in prediabetic women increased insulin sensitivity of Yoshino et al.44
(phase III trial) skeleton muscle
human oral NR in Parkinson disease clinical improvement, reduced Brakedal et al.45
patients (phase 1 trial) inflammatory cytokines in serum
and cerebrospinal fluid
human NAM in patients with 2 non- reduced rates of new non- Chen et al.46
melanoma skin cancers in the melanoma skin cancers and
preceding 5 years (phase 3 trial) keratosis
human urolithin A to middle-aged adults improved aerobic endurance and Singh et al.47
(randomized phase 2) physical performance; reduced
Cell 186, January 19, 2023 5
plasma CRP
Deregulated mouse inducible GH receptor knockout longevity and enhanced insulin Duran-Ortiz et al.48
nutrient-sensing at 6 months sensitivity; less neoplasms (m)
mouse caloric restriction by 30% of male lifespan extension of 10%–30% Acosta-Rodrı́guez
C57BL/6J mice et al.49
human caloric restriction by 14% for 2 years improved thymopoiesis and anti- Spadaro et al.50
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(phase 2) inflammatory effects on adipose
tissues. Reduced PLA2G7
6 Cell 186, January 19, 2023
Table 1. Continued
j.cell.2022.11.001
expression (gene knockout in mice
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ameliorates metabolic health)
mouse ß-hydroxybutyrate in drinking water higher energy expenditure, Fan et al.51
improved motor fitness and memory
Mitochondrial mouse TPP-thiazole (inhibitor of respiratory improved mitochondrial Tavallaie et al.52
dysfunction chain complex IV) metabolism, reduced visceral fat
and higher glucose tolerance in
old mice
mouse CRMP that preferentially acts to administration to obese old mice Goedeke et al.53
uncouple hepatocyte mitochondria reduces hepatosteatosis and liver
insulin resistance
mouse elamipretide to inhibit mitochondrial improved mitochondrial function Zhang et al.54
permeability transition and avoidance of diastolic heart
dysfunction, especially if combined
with NMN
primates spontaneous or diet-induced enhanced hepatic mitochondrial fat Goedeke et al.55
obesity in cynomolgus and rhesus oxidation, improved insulin
macaques, treated with CRMP tolerance, reduced hepatic and
plasma triglycerides, reduced
cholesterol
human clinical trial evaluating elamipretide improved walking test, muscle and Reid Thompson et al.56
on Barth syndrome (randomized cardiac parameters, overall
phase 2/3 trial) improvement
human clinical trial with L-carnitine increased muscle carnitine content Chee et al.57
supplementation to older man and fatty acid oxidation during
(phase 2 trial) exercise
Cellular mouse genetic ablation of p16- increased health- and lifespan. Baker et al.58
senescence expressing cells Treatment starting at 1 year age
mouse senolytic treatment with dasatinib + increased health- and lifespan. Xu et al.59
quercetin Treatment starting at 2 years age
mouse senolytic treatment with fisetin increased health- and lifespan. Yousefzadeh et al.60
Treatment starting at 1.6 years age
human senolytic treatment with dasatinib + improved physical performance; Justice et al.61
quercetin of patients with pulmonary reduction in pro-inflammatory and
fibrosis (phase 1 trial) pro-fibrotic factors in serum;
elevation of aKlotho in urine
human senolytic treatment with dasatinib + reduction of senescent cells and Hickson et al.62
quercetin of patients with diabetic macrophages in adipose tissue, and
kidney disease (phase 1 trial) of pro-inflammatory factors in serum
Review
Review
Table 1. Continued
j.cell.2022.11.001
Stem cell mouse transgenic expression of OSKM longevity extension of HGPS Wang et al.,28
exhaustion progeroid mice. Preservation of Ocampo et al.,63
hippocampal neurogenesis and Browder et al.,64
function in normal mice. Improved Chen et al.,65
tissue repair immediately after injury Hishida et al.,66
or in a subsequent injury Rodrı́guez-Matellán
et al.,67 Gao et al.,68
and Doeser et al.69
mouse AAV2-driven expression of OSK restoration of visual acuity to old Lu et al.70
in the eye mice and to mice with glaucoma.
Improved repair of crushed
optical nerve
Altered intercellular mouse dilution of blood from old mice rejuvenation in multiple tissues Mehdipour et al.71
communication with saline/albumin
mouse blood transfusion improved muscle repair; reduced Rebo et al.72
liver steatosis and fibrosis
mouse human umbilical cord plasma improved hippocampal Castellano et al.73
neurogenesis
mouse heterochronic parabiosis rejuvenation in multiple tissues Ma et al.74 and Pálovics et al.75
mouse CCL3/MIP1a administration HSC rejuvenation Ma et al.74
mouse TIMP2 i.v. administration hippocampus rejuvenation Castellano et al.73
mouse IL-37 injection into old mice improved metabolism and Ballak et al.76
endurance exercise
mouse GDF11 i.v. administration rejuvenation of brain, muscle and Frohlich and Vinciguerra77
pancreas, but pro-fibrotic effects
mouse transgenic overexpression of VEGF improved health- and lifespan, Grunewald et al.78
enhanced liver and muscle repair
mouse human cells YAP expression rejuvenation of old cells, prevention Sladitschek-Martens et al.79
of emergence of aging features
human cells ECM from young fibroblasts rejuvenation of aged senescent cells Choi et al.80
mouse chondroitin 6-sulfo-transferase improved memory in old mice Yang et al.81
overexpression
Chronic mouse blockade of TNF-a with etanercept prevention of sarcopenia and Desdin-Mico et al.82; Sciorati et al.83
Cell 186, January 19, 2023 7
inflammation from 16 to 18 months of age in increased lifespan (f)

C57BL/6 mice
rat blockade of TNF-a with etanercept prevention of cognitive deficits, Gocmez et al.84
from 24 to 26 months of age in male endothelial dysfunction, peripheral
Wistar albino rats and neuro-inflammation
mouse knockout of prostaglandin E2 improved cognition and reduced Minhas et al.85
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receptor EP2 in myeloid cells or age-associated inflammation
treatment of C57BL/6 mice with
EP300 inhibitors
8 Cell 186, January 19, 2023
j.cell.2022.11.001
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Table 1. Continued
mouse knockout of NLRP3 in C57BL/6 mice improved glucose tolerance, Marı́n-Aguilar et al.86
cognition, motor performance and
female fertility due to reduced
ovarian aging
human treatment of patients with a history reduced incidence of hypertension Ridker et al.87
of myocardial infarction and high and diabetes; reduced frequency of
hsCRP with canakinumab (phase recurrent myocardial infarction and
3 trial) non-small cell lung cancer
Dysbiosis HGPS mouse fecal microbiota transplantation enhanced healthspan and lifespan Bárcena et al.88
from WT mice; Akkermansia
muciniphila administration
SAMP8 mouse Lactobacillus plantarum GKM3 longevity promotion and alleviation Lin et al.89
of age-related cognitive impairment
mouse microbiota transplantation from improved maintenance of brain Boehme et al.90
young mice to aged host health and immunity
mouse fecal microbiota transplantation improved ovarian function in Xu et al.91
aged mice
mouse fecal microbiota transplantation improved germinal centre reactions Stebegg et al.92
in lymph nodes
mouse indole metabolites reduction of inflammation Krishnan et al.93
during aging
mouse short-chain fatty acids restored microglial function in Cryan et al.94
aged mice
human oral administration of Akkermansia improved metabolic parameters in Depommier et al.95
muciniphila (randomized phase obese or diabetic patients
1/2 trial)
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accelerated aging and reduced lifespan associated with deletions genomic instability which unambiguously favors oncogenesis,
rather than point mutations in mtDNA101 (Table 1). Overall, these telomere attrition may antagonize malignancy. For this reason,
data suggest that the avoidance, attenuation, or correction of we consider telomere attrition as a hallmark of aging that is
mtDNA mutations might contribute to extend healthspan and life- separable from genomic instability.110
span. Nevertheless, as in the case of nuclear DNA mutations, Telomerase deficiency in humans is associated with prema-
experimental evidence demonstrating deceleration of aging ture development of diseases such as pulmonary fibrosis, aplas-
by gain of function in mtDNA repair mechanisms is still largely tic anemia, and dyskeratosis congenita, all of which hamper the
missing. regenerative capacity of the affected tissues.111 Telomere short-
ening is also observed during normal aging in many different
Nuclear architecture species, including humans and mice.112 The telomeric attrition
Defects in the nuclear lamina, which constitutes a scaffold rate is influenced by age, genetic variants, lifestyle, and social
for tethering chromatin and protein complexes, can generate factors; depends on the proliferative activity of the affected cells;
genome instability.102 Accelerated aging syndromes such as the and predicts lifespan in a wide variety of species.112 Telomere
Hutchinson-Gilford and the Néstor-Guillermo progeria syndromes uncapping can also result from deficiencies in shelterins, a group
(HGPS and NGPS, respectively) are caused by mutations in genes of proteins that block the DNA damage response at chromo-
LMNA and BANF1 encoding protein components of nuclear lam- some ends and modulate telomere length. Several loss-of-func-
ina. Alterations of the nuclear lamina and production of an aberrant tion models for shelterin components indicate a decline of tissue
prelamin A isoform called progerin are also characteristics of regenerative capacity and accelerated aging, even in the pres-
normal human aging, and lamin B1 levels decline during cellular ence of telomeres with a normal length.113
senescence.18 Animal and cellular models have facilitated the Genetically modified animal models have revealed causal links
identification of the response mechanisms and stress pathways between telomere attrition, cellular senescence, and organismal
elicited by nuclear lamina aberrations caused by aging and proge- aging. Mice with shortened or lengthened telomeres exhibit
ria, including activation of tumor suppressor protein p53 (TP53), decreased or increased lifespan, respectively.19 Notably, the
deregulation of the somatotrophic axis, and attrition of adult premature aging of telomerase-deficient mice can be reverted
stem cells.18 when telomerase is genetically reactivated20 (Table 1). More-
The causal implication of nuclear lamina abnormalities in pre- over, normal aging can be delayed in mice by pharmacological
mature aging has been corroborated by the observation that activation or systemic viral transduction of telomerase,21
decreasing prelamin A or progerin levels delays the onset of pro- whereas mice with hyperlong telomeres show increased lifespan
geroid features and extends lifespan in mouse models of HGPS. and metabolic health improvement22 (Table 1). Likewise, mice
This can be achieved by systemic injection of antisense oligonu- engineered to maintain physiological levels of telomerase in
cleotides, farnesyltransferase inhibitors, a combination of statins adult neurons preserve the survival of these cells and maintain
and aminobisphosphonates, restoration of the somatotrophic cognitive function in Alzheimer’s disease models23 (Table 1).
axis, or blockade of NF-kB signaling.103 Some of these interven- Thus, aging can be modulated by telomerase activation.
tions have been already approved for use in progeria patients.104
Moreover, gene editing strategies have been recently developed Telomerase activation to decelerate aging and treat
to correct LMNA mutations in cells from HGPS patients and in telomere diseases
animal models of this disease.105,106 Hopefully, these ap- In humans, many studies have provided evidence for causal
proaches will be clinically implemented for the future treatment associations between short telomere length and age-related
of progeria, but to date, no evidence is available showing that diseases.114 In particular, generation of mouse models with short
reducing progerin would delay normal aging. telomeres has demonstrated that telomeric attrition is at the
origin of telomere syndromes115 and prevalent age-associated
TELOMERE ATTRITION diseases, such as pulmonary and kidney fibrosis.24,116 These
links between telomere dynamics and organismal aging
DNA damage at the end of chromosomes (telomeres) contrib- have resulted in the design of new interventions to delay
utes to aging and age-linked diseases.107 Replicative DNA poly- aging and age-related diseases. As an example, telomerase
merases are unable to complete the copy of telomere regions of activation using a gene therapy strategy has shown therapeutic
eukaryotic DNA. Accordingly, after several rounds of cell divi- effects on mouse models of pulmonary fibrosis and aplastic
sion, telomeres undergo a substantial shortening that induces anemia.24,25
genomic instability and finally leads to either apoptosis or cell
senescence. These deleterious effects can be prevented EPIGENETIC ALTERATIONS
by the reverse-transcriptase activity of telomerase, an active
ribonucleoprotein that elongates telomeres to maintain their The large variety of epigenetic changes that contribute to aging
adequate length.108,109 However, most mammalian somatic include alterations in DNA methylation patterns, abnormal post-
cells do not express telomerase, which leads to the progressive translational modification of histones, aberrant chromatin
and cumulative erosion of telomere sequences from chromo- remodeling, and deregulated function of non-coding RNAs
some ends throughout life. There are several examples in which (ncRNAs) (Figure 2B). These regulatory and often reversible
telomere attrition attenuates carcinogenesis through limiting the changes impact on gene expression and other cellular pro-
replicative lifespan of malignant cells. Hence, in contrast to cesses, resulting in the development and progression of several
Cell 186, January 19, 2023 9

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age-related human pathologies, such as cancer, neurodegener- fying enzymes such as members of the SIRT family of protein
ation, metabolic syndrome, and bone diseases. A vast array of deacetylases and ADP-ribosyltransferases also contribute to
enzymatic systems is involved in the generation and mainte- healthy aging.29 Transgenic overexpression of SIRT1 improves
nance of epigenetic patterns. These enzymes include DNA genomic stability and metabolic efficiency during aging in mice,
methyltransferases, histone acetylases, deacetylases, methyl- although without increasing longevity.29 Overexpression of
ases, and demethylases, as well as protein complexes mitochondrial SIRT3 reverses the regenerative capacity lost in
implicated in chromatin remodeling or in ncRNA synthesis and aged hematopoietic stem cells (HSCs) and can mediate the
maturation. beneficial effects of dietary restriction in longevity.123 Similarly,
Sirt6 ablation in mice results in accelerated aging,124 whereas
DNA methylation Sirt6 overexpression extends lifespan.16 The underlying mech-
The human DNA methylation landscape accumulates multiple anisms derive from the fact that Sirt6 is a multitask protein with
changes with the passage of time.117 Early studies described ability to interconnect chromatin dynamics with metabolism
an age-associated global hypomethylation, but further ana- and DNA repair.125 Finally, Sirt7 deficiency induces global
lyses revealed that specific loci, including those of several genomic instability, metabolic dysfunctions, and premature ag-
tumor suppressor genes and Polycomb target genes, are hy- ing.29 Together, these findings are consistent with the idea that
permethylated with age. Cells from patients and mice with pro- a decrease in deacetylase activity would result in chromatin
geroid syndromes also exhibit DNA methylation changes that relaxation, increased exposure to DNA damaging agents, and
partially recapitulate those found in normal aging.118 The func- enhanced genomic instability.126 Conversely, genetic inactiva-
tional consequences of most of these age-related epimutations tion of the histone acetyltransferase KAT7 in human stem cells
are uncertain, as the majority of changes affect introns and in- decreases histone H3K14 acetylation and alleviates cell senes-
tergenic regions.119 cence features.28 Moreover, intravenous injection of lentiviral
Epigenetic clocks based on DNA methylation status at vectors encoding Cas9/sg-Kat7 ameliorates hepatocyte
selected sites have been introduced to predict chronological senescence and liver aging and extends lifespan in both normal
age and mortality risk as well as to evaluate interventions and progeroid mice.28 Inhibitors of histone acetyltransferases
that may extend human lifespan.119 This has been demon- also ameliorate the premature aging phenotype and extend life-
strated with protocols aimed at thymus regeneration, which span of progeroid mice, whereas histone deacetylase activa-
resulted in improved risk indices for many age-related dis- tors promote longevity in part via upregulation of SIRT1 activ-
eases and a mean epigenetic age approximately 1.5 years ity.127 Together, these findings suggest that histone-modifiers
less than baseline after 1 year of treatment. Moreover, predic- should be further explored as part of therapeutic strategies
tions of human morbidity and mortality showed a 2-year against age-associated cognitive decline, although it is still un-
decrease in epigenetic versus chronological age, which per- clear whether these interventions influence aging and longevity
sisted 6 months after discontinuing treatment.27 Likewise, through purely epigenetic mechanisms, by impinging on DNA
a-ketoglutarate supplementation for 7 months turned back repair and genome stability or via transcriptional alterations
the epigenetic clock by 8 years.26 In summary, DNA methyl- affecting metabolic or signaling pathways.
ation changes are associated with aging, but there is no defin-
itive evidence that they actually cause aging. Further studies
will be necessary to demonstrate that defective maintenance Chromatin remodeling
of DNA methylation produces accelerated aging and that Besides DNA- and histone-modifiers, several chromosomal
improved fidelity in maintenance of DNA methylation patterns proteins and chromatin remodeling factors, such as the hetero-
extends longevity. It will be also necessary to identify the mo- chromatin protein 1a (HP1a) and Polycomb group proteins
lecular drivers responsible for the modulation of changes which are implicated in genomic stability DNA repair, may modu-
occurring in the aged human methylome. late aging.128 Alterations in these epigenetic factors result in
profound changes in chromatin architecture, including global
Histone modifications heterochromatin loss and redistribution, which are common
Global loss of histones and tissue-dependent changes in their events in aged cells.
post-translational modifications are also closely linked to aging. The causal relevance of these chromatin alterations in aging
Increased histone expression extends lifespan in Drosophila,120 has been largely studied in invertebrates in which loss-of-func-
whereas increased histone H4K16 acetylation or H3K4 trime- tion mutations in HP1a decrease longevity, whereas its overex-
thylation and decreased levels of H3K9 or H3K27 trimethylation pression expands healthspan and lifespan129 (Table 1). Similar
are found in fibroblasts from aged individuals and progeroid studies in mammals are still limited, but most studies indicate
patients. These histone modifications can lead to transcrip- that heterochromatin relaxation contributes to aging and
tional changes, loss of cellular homeostasis, and age-associ- aging-related pathologies, whereas maintenance of heterochro-
ated metabolic decline.121 Of note, loss of heterochromatic matin promotes longevity. For example, loss of PIN1—a
marks at telomeres has been shown to lead to telomere prolyl isomerase essential to preserve heterochromatin is asso-
lengthening.122 ciated with premature aging and neurodegeneration in different
Histone demethylases modulate lifespan by targeting com- species from Drosophila to mammals130 (Table 1). Nevertheless,
ponents of key longevity routes such as the insulin/insulin experiments aimed at extending vertebrate longevity by gain of
growth factor-1 (IGF-1) signaling pathway. Other histone-modi- function of chromatin remodeling factors are still missing.
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Non-coding RNAs stronger suppressor of LINE1 retrotransposons, enhances

The large and growing universe of ncRNAs, including lncRNAs genome stability, and can more robustly kill cancer cells than
(such as telomeric RNAs or TERRA), microRNAs (miRNAs), and wild-type SIRT6.137 Collectively, these findings suggest that ret-
circular RNAs, has emerged as epigenetic factors with ability rotransposons causally contribute to the aging process and
to influence aging. ncRNAs modulate healthspan and lifespan that interventions that oppose retrotransposon activity might
by post-transcriptional targeting of components of longevity improve healthy longevity. Further clinical studies in aged popu-
networks or by regulating stem cell behavior.131 A circular RNA lations with drugs targeting the different functions of retrotrans-
mediates the effect of the insulin/IGF-1 signaling pathway on posons may delineate novel intervention strategies on aging and
Drosophila lifespan,132 but most studies have focused on aging-related pathologies.
miRNAs, and there is still debate on the extent to which other
ncRNAs may derive from transcriptional noise, with their regula- Gene expression changes
tory roles in human physiology and pathology only circum- The mechanisms underlying the effects of all the above epigenetic
scribed to few specific cases.133 factors converge at the modulation of gene expression levels. Ag-
Gain- and loss-of-function studies first confirmed the capacity ing causes an increase of the transcriptional noise and an aberrant
of several miRNAs to modulate longevity in invertebrates. Sub- production and maturation of many mRNAs.138,139 Microarray-
sequent studies in mice have provided causal evidence on the based comparisons of young and old tissues from human and
functional relevance of miRNAs in aging (Table 1). For example, other species have identified age-related transcriptional signa-
miRNA-188-3p expression is upregulated in skeletal endothe- tures that result from epigenetic changes occurring during aging.
lium during aging and contributes to vascular problems associ- Environmental exposures also cause alterations in gene regulation
ated with the passage of time. Depletion of miR-188 in mice al- via DNA methylation alterations and histone modifications and
leviates the age-related decline in beneficial bone capillary promote aging-related epigenetic changes including the acceler-
subtypes, whereas endothelial-specific overexpression of this ation of epigenetic clocks.140
miRNA decreases bone mass and delays bone regeneration.30 Single-cell transcriptomic and plasma proteomics of multiple
Conversely, depletion of miR-455-3p in mice exhibits deleterious cell types and organs at several ages across the entire mouse life-
effects on mitochondrial dynamics, cognitive behavior, and span have unveiled remarkable gene expression shifts during
lifespan, whereas its overexpression preserves these functions aging.138 These changes specially affect certain biological pro-
and extends lifespan.31 Overall, these findings suggest that cesses, such as inflammation, protein folding, extracellular matrix
miRNAs may causally contribute to aging and aging-related pa- (ECM) regulation, and mitochondrial function, which are widely
thologies and represent potential therapeutic targets for delaying deregulated in aging.141 The common expression patterns
or ameliorating these conditions. observed during aging in different tissues may help to guide future
interventions aimed at improving healthspan and lifespan (Ta-
Derepression of retrotransposons ble 1). Likewise, the observed decline in transcriptional and
Recent studies have unveiled the role of retrotransposons in ag- post-transcriptional efficiency and fidelity in the course of aging,
ing of complex metazoans, including humans.134 These retro- and its negative consequences on the proteome health may
transposable elements are mobile genetic units that can move also open new opportunities for prolongevity strategies.139
from one genomic location to another, using a molecular mech-
anism that involves an RNA intermediate. Retrotransposons LOSS OF PROTEOSTASIS
consist of long interspersed nuclear elements (LINEs), which
encode the required proteins for retrotransposition, and SINEs, Aging and several age-related morbidities, such as amyotrophic
which are short, non-coding RNAs that hijack the LINE protein lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease,
machinery. Retrotransposons are reactivated in senescent cells and cataract, are associated with impaired protein homeostasis
and during lifetime and generate deleterious effects through ge- or proteostasis, leading to the accumulation of misfolded,
netic and epigenetic changes or by activation of immune path- oxidized, glycated, or ubiquitinylated proteins that often form ag-
ways triggered after identification of retrotransposon nucleic gregates as intracellular inclusion bodies or extracellular amyloid
acids as foreign DNA.134 Mechanistically, epigenetic derepres- plaques.142
sion of LINE-1 RNA inhibits the epigenetic reader Suv39H1,2
resulting in global reduction of H3K9me3 and heterochoma- Proteostasis collapse
tin,135 whereas reverse transcription of LINE-1 RNA results in Intracellular proteostasis can be disrupted due to the enhanced
double-stranded cDNA that activates the cGAS/STING/inter- production of erroneously translated, misfolded or incomplete
feron pathway.136 proteins (Figure 3). Genetic manipulation of the ribosomal protein
Treatments with nucleoside reverse-transcriptase inhibitors RPS23 to improve the accuracy of RNA-to-protein translation
(NRTIs), which suppress or attenuate retrotransposition, extend extends lifespan in Schizosaccharomyces pombe, Caenorhabdi-
lifespan of Sirt6-null mice and improve healthspan, ameliorating tis elegans, and Drosophila melanogaster,143 whereas a mutation
bone and muscle phenotypes (Table 1). Likewise, treatment of in RPS9 that favors error-prone translation causes premature
aged wild-type mice with NRTIs reduces the levels of DNA damaging in mice.144 Another mechanism driving the collapse of
age markers.32 Moreover, in vivo targeting of retrotransposons the proteostasis network resides in slowed translation elonga-
with antisense oligonucleotides increases the lifespan of proge- tion and cumulative oxidative damage of proteins, increasingly
roid mice.135 Notably, a rare SIRT6 variant in centenarians is a distracting the chaperones from folding healthy proteins
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Figure 3. Loss of protein and organellar
turnover
Loss of proteostasis and disabled macro-
autophagy are characterized by a deviation from
the young equilibrium state in which an accumu-
lation of waste products results from a variety of
age-associated alterations and simultaneously
waste removal is compromised through a variety
of mechanisms. The functional consequences of
these alterations are listed. Some strategies for
reestablishing proteostasis and autophagy are
exemplified on the left and on the right.
agy upon their inclusion in two-membrane

vesicles, the autophagosomes, for their
later fusion with lysosomes.152 Since auto-
phagosomes can envelop non-proteina-
ceous structures, this process will be dis-
cussed separately from proteostasis in
the next hallmark section (disabled macro-
autophagy). Nonetheless, stimulation of
autophagy constitutes a valid strategy for
the elimination of intracellular protein ag-
gregates.153
Proteostasis, aging, and longevity

Perturbation of general proteostasis ac-
celerates aging. For example, feeding
D. melanogaster with advanced glyca-
tion end products (AGEs) or lipofuscin
(an aggregate of covalently cross-linked
proteins, sugars, and lipids) causes the
required for cellular fitness.145 In addition, numerous age-related accumulation of AGE-modified and carbonylated proteins
neurodegenerative diseases including ALS and Alzheimer can with a reduction of healthspan and lifespan that is further
be caused by mutations in proteins that render them intrinsically accentuated upon knockdown of the lysosomal protease
prone to misfolding and aggregation, hence saturating the cathepsin D.154 Loss of the protease ZMPSTE24 abolishes
mechanisms of protein repair, removal, and turnover that are the normal proteolytic maturation of prelamin A and causes a
required for maintenance of the healthy state.146 progeroid syndrome in mice, phenocopying that observed in
The proteostasis network also collapses when mechanisms as- humans with loss-of-function mutations of ZMPSTE24.18 In
suring quality control fail, for instance, due to reduced function of mice, knockout of LAMP2A (essential for CMA) in neurons pro-
the unfolded protein response (UPR) in the endoplasmic reticulum foundly affects the proteome, yielding similar changes as found
(ER),147 when stabilization of correctly folded proteins is compro- in Alzheimer patients. Indeed, inhibition of CMA in mice exacer-
mised or when mechanisms for the degradation of proteins by bates experimental Alzheimer’s disease, whereas its stimula-
the proteasome or the lysosome become insufficient (Figure 3). tion by a pharmacological CMA activator attenuates the pa-
Reduction of proteasome activity has been observed in aged or- thology.155
gans including the brain of the short-lived fish Nothobranchius Experimental amelioration of proteostasis can retard the
furzeri.148 Moreover, some mono-ubiquitinylated proteins accu- aging process (Table 1). Intranasal application of recombinant
mulate in aging tissues from flies, mice, monkeys, and humans, human HSP70 protein to mice enhances proteasome activity, re-
as documented for histone 2A.149 duces brain lipofuscin levels, enhances cognitive functions, and
The degradation of proteins by the lysosome can be achieved in extends lifespan.35 Similarly, administration of the chemical
a specific fashion, through chaperone-mediated autophagy chaperone 4-phenylbutyrate to aged mice reduces ER stress
(CMA), wherein proteins exposing a pentapeptide motif resem- in the brain and improves cognition.36 In nematodes and flies,
bling KFERQ first bind to heat shock protein HSC70 and then to transfection-enforced overexpression of isolated proteasome
lysosome-associated membrane protein type 2A (LAMP2A), subunits improves proteostasis and increases lifespan.156
which facilitates the translocation of the client protein into the In mice, stimulation of CMA by transgenic expression of
lumen of the lysosome.150 Hepatic LAMP2A expression declines LAMP2a HSCs improve the survival of the targeted cell popula-
with age in mice, and its transgenic re-expression reduces liver ag- tions,33 in line with the observation that pharmacological
ing.151 Protein aggregates can also be removed by macroautoph- enhancement of CMA attenuates Alzheimer’s pathology and
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arteriosclerosis.155,34 Hence, activation of CMA may constitute a described for some organs, pleading in favor of the idea that auto-
valid strategy for delaying the aging process. phagic flux is compromised with age. Reduction of autophagic flux
A phase 3 clinical trial has revealed that in patients with recent may participate in the accumulation of protein aggregates and
ALS diagnosis, administration of the antihypertensive guana- dysfunctional organelles, reduced elimination of pathogens, and
benz inhibits progression to the life-threatening bulbar stage.37 enhanced inflammation because autophagy eliminates proteins
Guanabenz may act to stimulate the phosphorylation (or to involved in inflammasome and their upstream triggers.169
inhibit the dephosphorylation) of eukaryotic translation initiation Genetic inhibition of autophagy accelerates the aging process
factor 2a (eIF2a), which occurs in the context of the ‘‘integrated in model organisms. This process is partially reversible, as illus-
stress response (ISR)’’ as part of the UPR,157 although it remains trated in mice in which Atg5 is downregulated by a doxycycline-
under debate to what extent the actions of guanabenz are inducible shRNA. Atg5 knockdown causes the premature
mediated by the stimulation of the ISR.158 Importantly, eIF2a degeneration and senescence of multiple organ systems leading
phosphorylation causes a switch from 50 cap-dependent to 50 to premature death.170 Upon withdrawal of doxycycline, auto-
cap-independent RNA translation, knowing that the latter is phagy restoration is accompanied by attenuated systemic
enhanced by several longevity-extending manipulations.159 inflammation and segmental reduction of aging. Of note, in this
Moreover, eIF2a phosphorylation is essential for the induction model, the transient inhibition of autophagy is followed by a ma-
of stress granules, which are required for longevity extension jor increase in the incidence of malignancies. Hence, autophagy
by dietary restriction in worms.160 Finally, eIF2a phosphorylation apparently acts as a tumor-suppressive mechanism, which may
is indispensable for the induction of autophagy,161 which is a ma- involve cell-autonomous processes and cancer immunosurveil-
jor anti-aging mechanism (see below), suggesting a crosstalk lance.153 In patients, loss-of-function mutations of genes that
between UPR and autophagy in prolongevity pathways. Future regulate or execute autophagy have been causally linked to a
studies must determine whether the capacity of guanabenz to broad spectrum of cardiovascular, infectious, neurodegenera-
attenuate neurodegeneration is mediated via ISR stimulation or tive, metabolic, musculoskeletal, ocular, and pulmonary disor-
alternative mechanisms. Indeed, it has been proposed that ders, many of which resemble to premature aging at the histo-
inhibitors of ISR might be also used for the treatment of neurode- pathological and functional levels.152,153
generative diseases.162
Autophagy stimulation for decelerated aging
DISABLED MACROAUTOPHAGY There is ample evidence that stimulation of autophagic flux in-
creases healthspan and lifespan in model organisms (Table 1).
Macroautophagy (that we will refer to as ‘‘autophagy’’) involves For example, increasing autophagy solely in the enterocytes of
the sequestration of cytoplasmic material in two-membrane ves- the intestine increases Drosophila lifespan.120 In mice, trans-
icles, the autophagosomes, which later fuse with lysosomes for genic overexpression of Atg5 under the control of a ubiquitously
the digestion of luminal content.152 Thus, autophagy is not only expressed promoter is sufficient to extend lifespan and to
involved in proteostasis but also affects non-proteinaceous improve metabolic health and motor function.38 Moreover,
macromolecules (such as ectopic cytosolic DNA, lipid vesicles, knockin mutation of beclin 1 (Becn1F121A/F121A) to reduce its inhi-
and glycogen) and entire organelles (including dysfunctional bition by Bcl-2 causes an increase in autophagic flux, as well as
mitochondria targeted by ‘‘mitophagy,’’ and other organelles an extension of lifespan. This effect is coupled to a reduction of
leading to ‘‘lysophagy,’’ ‘‘reticulophagy,’’ or ‘‘pexophagy’’), as age-associated pathologies and spontaneous tumorigenesis,39
well as invading pathogens (‘‘xenophagy’’).152 An age-related as well as to increased neurogenesis.40
decline in autophagy constitutes one of the most important Oral supplementation of spermidine to mice induces auto-
mechanisms of reduced organelle turnover, justifying its discus- phagy in multiple organs and extends longevity by up to 25%,
sion as a new hallmark of aging. As a note of caution, genes accompanied by reduced cardiac aging. This latter effect is
and proteins that participate in the autophagic process are lost upon cardiomyocyte-specific knockout of Atg7, suggesting
also involved in alternative degradation processes such as that it relies on autophagy.41 Mechanistically, the pro-autopha-
LC3-associated phagocytosis of extracellular material,163 and gic effects of spermidine have been linked to an inhibition of
the extrusion of intracellular waste (e.g., dysfunctional mitochon- the acetyl transferase EP300 (resulting in reduced acetylation
dria) in the form of exospheres for their subsequent removal by of several core autophagy proteins)171 or to the hypusination of
macrophages.164 That said, there is strong evidence that the eIF5A, which is essential for the synthesis of the autophagy tran-
core process of autophagy is relevant to aging (Figure 3). scription factor TFEB.167 Among these factors, EP300 is the
target of the longevity-enhancing drugs nordihydroguairaretic
Accelerated aging due to autophagy inhibition acid43 and salicylate.42 Pharmacological inhibition of EP300
In humans, the expression of autophagy-related genes, such as with C646 mimics the stimulatory effects of spermidine on auto-
ATG5, ATG7, and BECN1, declines with age.165 CD4+ T lympho- phagy and cancer immunosurveillance.172 When circulating B
cytes isolated from the offspring of parents with exceptional lymphocytes or CD8+ T cells from aged human donors are
longevity show enhanced autophagic activity compared with cultured in the presence of spermidine, the cells recover
age-matched controls.166 Decreased autophagy in circulating B juvenile levels of TFEB and eIF5A, coupled to a normalization
and T lymphocytes from aging donors is accompanied by a reduc- of autophagic flux.167,168 Moreover, in Drosophila, hypusination
tion of the pro-autophagic metabolite spermidine.167,168 Similarly, deficiency due to a heterozygous mutation or knockdown of
in rodents, a progressive deterioration of autophagy has been deoxyhypusine synthase abolished lifespan extension by
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spermidine supplementation.173 Deoxyhypusine synthase defi- pathway enhance lifespan and retard facets of age-associated
ciency in murine T cells triggers severe intestinal inflammation deterioration (Table 1). Innate defects in the somatotrophic axis
coupled to epigenetic remodeling and rewiring of the tricarbox- cause dwarfism, but inhibition of this axis from early adulthood
ylic acid cycle,174 whereas spermidine treatment of wild-type has beneficial effects on organismal health (Figure 4).
mice protects against colitis and colon carcinogenesis.175 Another signaling pathway involved in nutrient-sensing
Hence, both EP300 inhibition and eIF5A hypusination appear relies on the receptor tyrosine kinase ALK (Figure 4), which, in
plausible targets to explain the in vivo effects of spermidine. mice, is induced in the hypothalamus by feeding183 and re-
Pharmacological agents that induce mitophagy and have a sponds to the ligands augmentor a and b (Auga and Augb).184
positive impact on murine healthspan include NAD+ precursors In Drosophila, knockdown of ALK decreases triglyceride levels
(such as nicotinamide, nicotinamide mononucleotide, and nico- and the expression of several insulin-like peptides, whereas ge-
tinamide riboside)176 and urolithin A.177 Clinical trials have netic or pharmacological inhibition of ALK extends healthspan
demonstrated the efficacy of NAD+ precursors in the chemopre- and lifespan, mostly in females.183 In mice, body-wide or hypo-
vention of non-melanoma skin cancer,46 in reversing insulin thalamus-specific deletion of ALK, as well as double knockout of
resistance in prediabetic women,44 and in reducing neuroinflam- Auga and Augb, promotes resistance against diet-induced
mation in patients with Parkinson’s disease.45 Moreover, a obesity, and in humans, a loss-of-function mutation of ALK is
phase 3 trial has revealed the capacity of urolithin A to improve associated with leanness.183,184 Hence, this pathway may offer
muscle strength and to reduce C-reactive protein (CRP).47 additional targets for interventions on metabolic aging.
Drugs targeting diseases such as cancer and metabolic dis-
DEREGULATED NUTRIENT-SENSING ease often engage the nutrient-sensing network, thus such
drugs are candidates for repurposing as geroprotectors. Rapa-
The nutrient-sensing network is highly conserved in evolution. It mycin and rapalogs, which disrupt the MTORC1 complex,
includes extracellular ligands, such as insulins and IGFs, the have proved to extend lifespan in model organisms even with
receptor tyrosine kinases with which they interact, as well as treatment starting late in adulthood.185 In mice, rapamycin can
intracellular signaling cascades. These cascades involve the increase diverse aspects of health, although it exacerbates
PI3K-AKT and the Ras-MEK-ERK pathways, as well as tran- some age-related traits such as cataract, and it is protective in
scription factors, including FOXOs and E26 factors, which models of neurodegenerative and other age-related diseases.
transactivate genes involved in diverse cellular processes. The Elderly humans are susceptible to viral respiratory infections.
mechanistic target of rapamycin (MTOR) complex-1 (MTORC1) Pre-treatment with MTORC1 inhibitors increased the immune
responds to nutrients, including glucose and amino acids, and response of elderly volunteers to immunization against influ-
to stressors such as hypoxia and low energy to modulate the enza186 and reduced viral respiratory infections in the ensuing
activity of numerous proteins including transcription factors winter,187 thus pointing to a potential strategy for reverting
such as SREBP and TFEB. This network is a central regulator age-related immunosenescence.
of cellular activity, including autophagy, mRNA and ribosome
biogenesis, protein synthesis, glucose, nucleotide and lipid Mechanisms
metabolism, mitochondrial biogenesis, and proteasomal activ- In humans, IGF1 peaks during the second decade of life but
ity. Network activity responds to nutrition and stress status by declines with aging. Inhibition of the GH/IGF1 pathway in adult
activating anabolism if nutrients are present and stress is low or late life extends lifespan in model organisms, including
or by inducing cellular defense pathways in response to stress mice.48 Inhibition of cardiac IGF1R by expression of a dominant
and nutrient-shortage. There is extensive intracellular crosstalk negative p110a isoform of PI3K increases maximum lifespan of
and feedback within the network, and between it and other intra- male mice and improves heart function in aged mice.188 More-
cellular signaling pathways. Genetically reduced activity of com- over, enzymatic inhibition of IGF1R with tyrosine kinase
ponents of the nutrient-sensing network can increase lifespan inhibitors improves anticancer immunosurveillance requiring
and healthspan in diverse animal models178,179 (Table 1). More- autophagy induction in malignant cells.189 Long-term administra-
over, genetic association studies in humans have implicated the tion of an anti-IGF1R antibody enhances the longevity of female
FOXO3 transcription factor180 and genetic variants encoding (but not male) mice, although reducing inflammation and tumor
components of the network in human longevity.178 Epigenetic development. These findings suggest that the IGF1/IGF1R
age is also associated with nutrient-sensing in human cells.181 signaling axis may constitute a target for anti-aging interventions.
In youth, activity of this signaling network thus functions to In favor for this conjecture, in elderly women (R95 years), as well
promote beneficial anabolic processes, but during adulthood, as in a mixed population of older adults (mean age 76 years), low
it acquires pro-aging properties (Figure 4). IGF1 levels correlate with a low probability of cognitive impairment
The somatotrophic axis—the first one historically implicated in and death.190 Moreover, in a large cohort from the UK Biobank,
the control of aging—is a growth-stimulatory cascade that, at its significant positive correlations were noted between the hazard
apex, involves growth hormone (GH) produced by the hypophy- associated with high IGF-1 and age for dementia, diabetes,
sis. GH acts on the GH receptor of hepatocytes to stimulate the vascular disease, osteoporosis, and overall mortality.191 In cente-
secretion of IGFs, in particular IGF1, which promotes growth and narians, the concentrations of IGF1BP2 and IGFBP6 are
development via the IGF1R to stimulate trophic signals through elevated.192 Future will tell whether yet-to-be-developed anti-
activation of PI3K-AKT and the MTORC1 network.182 In multiple bodies or small molecules that selectively inhibit IGF1R signaling
model organisms, spontaneous or engineered mutations of this without affecting other receptor tyrosine kinases (and in particular
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Figure 4. Metabolic alterations

A simplified version of intertwined trophic pathways is shown for deregulated nutrient-sensing with their possible countermeasures to restore nutrient-sensing. Of
note, the reduced activity of the nutrient-sensing network influences numerous processes beyond metabolism modulation during aging, including resistance to
diverse stressors, activation of repair mechanisms, autophagy stimulation, or inflammation control. Similarly, for mitochondrial dysfunction, a series of age-
associated alterations with their possible antidotes are listed. The functional consequences of age-associated metabolic alterations, some of which are relevant
to other hallmarks of aging, are exemplified in the lower part of the graph.
the insulin receptor) might be used for the pulsatile inhibition of the possible via reduction of overall caloric intake, manipulation of
somatotropic axis to achieve health benefits with acceptable side the dietary composition,194,195 or time-restricted feeding.196 Di-
effects. etary restriction regimens are particularly successful in extend-
ing lifespan in male C57BL/6J mice, if the animals are completely
Effects of nutrition deprived from nutrients during daytime.49 However, dietary re-
Diet is one of the most practical targets for interventions into hu- striction regimens do not extend lifespan in all mouse strains,
man aging. Mechanistically, overnutrition: (1) triggers intracel- supporting the contention that they must be adapted to the
lular nutrient sensors, such as MTORC1 (activated by leucine genetic makeup of each individual.197 In humans, clinical assays
and other amino acids), and the acetyltransferase EP300 (acti- based on dietary restriction are complicated by poor compli-
vated by acetyl coenzyme A); (2) inhibits sensors that detect ance, yet suggest positive effects on immunity and inflam-
nutrient scarcity, such as AMP-activated kinase (AMPK) and mation.50
the deacetylases SIRT1 and SIRT3 (which respond to NAD+); Intermittent fasting (e.g., 1 day without nutrients, followed by
and (3) abolishes catabolic reactions (glycogenolysis, proteoly- 1 day of ad libitum feeding) can avoid long-term weight loss
sis for gluconeogenesis, and lipolysis coupled to ketogenesis) induced by caloric restriction, yet increases lifespan in mice195
with consequent suppression of adaptive cellular stress re- and improves biomarkers of health in clinical trials.198,199 Life
sponses, including autophagy, antioxidant defense, and DNA time extension of a similar intermittent fasting regimen in flies
repair. Conversely, fasting and dietary restriction inhibit has been attributed to the nighttime-specific upregulation of
MTORC1 and EP300; activate AMPK, SIRT1, and SIRT3; and autophagy-stimulatory genes,200 but this has not yet been inves-
stimulate adaptive cellular stress responses as they suppress tigated in mammals. Rapamycin-induced longevity extension
the somatotrophic axis and extend longevity in multiple model (which in flies partially depends on autophagy induction) can
organisms including primates.193 be obtained by constant-long term exposure, as well as by inter-
Nutrient sensors constitute targets for potential longevity mittent regimens,201 suggesting that pulsatile inhibition of this
drugs (Figure 4), but health benefits and extended lifespan might axis is sufficient to obtain the benefits of lifespan extension.
also be achieved by dietary restrictions. Mechanistically, this is The optimal interval for such intermittent treatments has not
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yet been determined for clinical use, although partial caloric re- improving glucose tolerance, mitochondrial quality, and oxida-
striction for 4–7 days every 3–4 weeks may be sufficient to tive metabolism.52 Partial uncoupling of hepatic mitochondria
improve metabolic syndrome and anticancer immunosur- by means of a controlled release mitochondrial protonophore
veillance.202 (CRMP) also reverses age-related metabolic syndrome in mice
Another potentially beneficial regimen is ketogenic diet, which with high-fat diet-induced obesity.53 In non-human primate
is a low-carbohydrate, high-fat, and adequate protein diet. Both models including spontaneously obese rhesus macaques and
fasting and ketogenic diet increase the production of ketone high-fat, high-fructose-fed cynomolgus macaques, CRMP re-
bodies (in particular 3-hydroxybutyrate), which are synthesized verses signs of metabolic syndrome and improves fatty acid
from acetyl coenzyme A in the liver in an autophagy-dependent oxidation.55 These effects are coupled to a reduction of hepatic
fashion, can reach millimolar concentrations in the plasma and acetyl-coenzyme A levels, a phenomenon known to stimulate
replace glucose as an essential fuel, for instance, for the mainte- autophagy.208 Protonophores induce mitophagy,209 which might
nance of brain function.203 Permanent but not cyclic administra- explain their positive effects on metabolism as well. Metformin,
tion of 3-hydroxybutyrate in the drinking water increases lifespan an antidiabetic considered as a weak complex I inhibitor, has
and healthspan in mice.51 This strongly suggests that this ketone been discussed as a possible anti-aging drug.210 However,
body mediates some of the beneficial effects of ketogenic diet. thus far, there is no evidence that challenging mitochondria
Mechanistically, 3-hydroxybutyrate induces vasodilatation and can increase healthspan or lifespan in humans.
activates immune responses acting on GTP protein coupled re- Increased mitochondrial membrane permeability (MMP)
ceptor 109A,203 whereas it directly inhibits the NLRP3 inflamma- due to the absence of serum/glucocorticoid regulated kinase-1
some,204 indicating a potential pleiotropic mode of action. decreases lifespan, which is further compromised when
autophagy is enhanced but normalized when autophagy is in-
MITOCHONDRIAL DYSFUNCTION hibited by knockdown of essential autophagy-relevant genes in
C. elegans.211 Hence, MMP may constitute a life-threatening con-
Mitochondria are not only the powerhouses of the cell but also dition that is aggravated by autophagy. A modified tetrapeptide,
constitute latent triggers of inflammation (when reactive oxygen elamipretide, has been developed to target cardiolipin in the inner
species [ROS] or mtDNA leak out of the organelle causing activa- mitochondrial membrane (IMM) and then turned out to bind to the
tion of inflammasomes or cytosolic DNA sensors, respectively) IMM protein adenine-nucleotide translocator-1 to inhibit the
and cell death (when activators of caspases, nucleases, or other mitochondria permeability transition, which is one particular
lethal enzymes are released from the intermembrane space).146 mechanism leading to MMP.54 Elamipretide has positive effects
With aging, mitochondrial function deteriorates due to multiple in- on multiple aging-related phenotypes in mice and has yielded
tertwined mechanisms including the accumulation of mtDNA mu- positive results in a clinical trial on patients with Barth syndrome56
tations, deficient proteostasis leading to the destabilization of res- (Table 1). It will be important to understand whether elamipretide
piratory chain complexes, reduced turnover of the organelle, and can be advantageously combined with other lifespan-enhancing
changes in mitochondrial dynamics. This situation compromises drugs including autophagy enhancers. In addition to these works,
the contribution of mitochondria to cellular bioenergetics, en- there are also several preclinical and clinical studies evaluating the
hances the production of ROS, and may trigger accidental perme- potential beneficial effects of the antioxidant lipophilic cations Mi-
abilization of mitochondrial membranes causing inflammation and toQ and SkQ1.212 Further research will define the utility of all these
cell death.182 Logically, the function of mitochondria is primordial compounds in the context of other interventions aimed at amelio-
for the maintenance of health, and its progressive deterioration rating age-associated mitochondrial dysfunctions.
contributes to the aging phenotype (Figure 4).
Mitochondrial microproteins and aging
Mitochondrial function and longevity Plasma levels of the microprotein humanin, which is encoded by
Healthspan-extending interventions can stimulate the function of mtDNA, decline with age. However, centenarians and their
mitochondria. For instance, placebo-controlled trials have re- offspring exhibit high levels of humanin.213 Notably, humanin
vealed positive effects of L-carnitine supplementation on both levels negatively correlate with IGF1 in humans and treatment
pre-frail subjects and elderly men57 (Table 1). The effect is of patients with GH-insufficiency, with GH or IGF1, reduces
possibly mediated by counteracting age-related declining circulating humanin.214 Transgenic expression of humanin in
L-carnitine levels which may limit fatty acid oxidation by mito- C. elegans extends longevity through autophagy induction, and
chondria.205 Paradoxically, in model organisms, lifespan can treatment of middle-aged mice with the humanin analog HNG
be improved by compromising mitochondrial function, which in- improves metabolic healthspan and reduces systemic inflamma-
duces a hormetic response (‘‘mitohormesis’’), provided that this tion.213 Another mtDNA-encoded microprotein, MOTS-c,
inhibition is partial and occurs early during development. In declines with age but can be induced by exercise.215 MOTS-c fa-
C. elegans, partial inhibition of mitochondrial protein synthesis vors the production of the metabolite 5-aminoimidazole-4-
or import enhances lifespan through a mechanism involving carboxamide-1-beta-4-ribofuranoside (AICAR), which acts as
the mitochondrial UPR (UPRmt).206 In Drosophila, muscle-spe- an endogenous AMPK agonist, thereby preventing age-depen-
cific knockdown of complex I subunit NDUFS1/ND75 extends dent and high-fat-diet-induced insulin resistance, as well as
longevity in an UPRmt-dependent fashion.207 Mild inhibition of diet-induced obesity.215 Hence, mitochondrial microproteins
mitochondrial ATP synthesis with TPP-thiazole can improve emerge as potential anti-aging factors that link organellar func-
metabolic health in aging mice, reducing visceral fat and tion to organismal homeostasis.
16 Cell 186, January 19, 2023

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CELLULAR SENESCENCE of senescent cells: (1) the transcriptional derepression of endog-

enous retroviruses, most notably LINE-1, which causes cytosolic
Cellular senescence is a response elicited by acute or chronic leakage of double-stranded DNA and activates the cGAS/STING
damage.216 In humans, senescent cells accumulate in multiple tis- and TLR pathways;136 (2) the mitochondrial overproduction of
sues at different rates, from 2- to 20-fold when comparing young ROS; and (3) the perturbation of the autophagy-lysosomal sys-
(<35 years) to old (>65 years) healthy donors,217 mainly affecting fi- tem leading to an expansion of lysosomal content that facilitates
broblasts, endothelial cells, and immune cells, although all cell the histochemical detection of lysosomal senescence-associ-
types can undergo senescence during aging,218 a process that is ated beta-galactosidase (SABG).227
triggered at least in part by telomere shortening with aging.109 In SASP is highly heterogeneous, depending on the cell type-spe-
fact, even post-mitotic or slowly proliferating tissues, such as the cific activation of innate immunity signaling pathways (cGAS/
brain or the heart, may harbor senescent cells.219 In addition, focal STING, TLRs, and NLRPs), mTORC1, and transcription factors
or tissue-specific accumulation of senescent cells occurs in many (NF-kB, CBPs, GATA4, and others). SASP usually has simulta-
diseases.220 The most compelling evidence for the causal role of neous and partially conflicting consequences on the microenviron-
cellular senescence in aging is that continued genetic or pharma- ment: (1) to recruit and activate immune cells through the secretion
cological elimination of senescent cells extends the healthspan of chemokines (CCL2, CXCL2, and CXCL3) and cytokines (IL-1b,
and longevity of naturally aged mice.59 Also, genetic or pharmaco- IL-2, IL-6, and IL-8); (2) to suppress the immune system through
logical elimination of senescent cells is therapeutic in many dis- the secretion of TGF-b; (3) to trigger fibroblast activation and
eases modeled in mice,221 and at least 3 clinical trials have been collagen deposition through pro-fibrotic factors (TGF-b, IL-11,
completed and 15 clinical trials are ongoing or planned to target and PAI1); (4) to remodel the ECM through the secretion of matrix
senescence for a variety of indications.222 metalloproteases; (5) to trigger the activation and proliferation of
The types of damage that trigger primary senescence include progenitor cells through the secretion of growth factors (EGF and
oncogenic signaling, genotoxic damage, critically short telo- PDGF); and (6) to trigger paracrine senescence in neighboring cells
meres, mitochondrial damage, viral or bacterial infection, oxida- (TGF-b, TNF-a, and IL-8). In many diseases, the net effect of SASP
tive damage, nutrient imbalance, and mechanical stress.216 In is chronic inflammation and progressive fibrosis.228
addition, secondary or paracrine senescence can be triggered Although there is not a single unequivocal marker of cellular
by extracellular mediators of inflammation and fibrosis including senescence, this process can be identified by the co-existence
CCL2, IL-1b, IL-6, IL-8, and TGF-b.223 There is evidence suggest- of a combination of features that, together, are specific and pro-
ing that primary and secondary senescence differ in relevant bio- vide a molecular definition to the phenomenon:216 (1) lysosomal
logical aspects, but the molecular basis of this distinction remains expansion, detectable by SABG; (2) upregulation of CDK inhibi-
elusive. Historically, the most salient feature of cellular senes- tors, particularly p16 and/or p21; (3) loss of LMNB1 from the
cence is a stable proliferative arrest mediated by the activation nuclear envelope; (4) loss of the chromatin component
of the tumor suppressors TP53 and CDKN2A/p16, and their HMGB1 from the nucleus and its extracellular release as an alar-
downstream effectors CDKN1A/p21 and retinoblastoma-1 (RB1) min; (5) heterochromatic foci, visualized as HP1g nuclear foci or
family proteins, respectively. Together, these proteins inhibit cy- SAHFs; (6) high levels of ROS; (7) exacerbated DNA damage,
clin-dependent kinases (CDKs) and transcriptional activators visualized as gH2AX nuclear foci; and (8) high levels of SASP fac-
(E2F family) that drive the cell cycle.216 Another important event tors, notably IL-6, TGF-b, PAI1, and others.
during senescence is the depletion of lamin B1 from the nuclear Given the association between cellular senescence and multi-
envelope. This results in the loss of lamin-associated heterochro- ple pathologies, the question arises about the biological purpose
matin and de novo formation of heterochromatin rich in H3K9me3, of such a cellular response. Cellular senescence is a potent tu-
a process that can be visualized as HP1a foci or senescence- mor suppressor mechanism, but mounting evidence has linked
associated heterochromatin foci (SAHFs).224 The net result is a cellular senescence to tissue repair processes in which senes-
long-term and viable proliferative arrest with a low rate of sponta- cent cells promote localized fibrosis and the recruitment of im-
neous escape. Depending on their molecular makeup, cancer mune cells that then remove damaged and senescent cells. In
cells exposed to genotoxic therapy may undergo a canonical this regard, tissue repair can be considered a two-step process:
senescence response with a highly stable cell cycle arrest or cellular senescence followed by immune recruitment and im-
can undergo a senescence-like response with a highly reversible mune clearance of senescence (Figure 5A). In this scenario,
arrest or can even completely bypass senescence.225 Of note, senescence is a temporally restricted response that programs
senescence also plays a role during embryogenesis in the pro- its self-elimination with a beneficial outcome.229 The patholog-
grammed elimination of specific cells and structures.226 ical consequences of senescence only become visible when
the second step of immune clearance is not achieved, and the
Senescence and human diseases accumulation of senescent cells and the SASP effects on the tis-
Cellular senescence is implicated in multiple non-proliferative sue microenvironment eventually result in fibrosis.
diseases, including lung fibrosis, kidney diseases, liver steatosis,
obesity-associated metabolic syndrome, type I and II diabetes, Senolytics
atherosclerosis, as well as Alzheimer’s and Parkinson’s dis- The strong association between cellular senescence and multiple
eases.220 The pathogenic role of cellular senescence in these pathologies has spurred the search for small chemical compounds
diseases can be explained by the senescence-associated that selectively kill senescent cells and that are referred to as ‘‘se-
secretory phenotype (SASP). SASP results from three features nolytics.230’’ Of note, senolysis (elimination of senescent cells) is
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Figure 5. Cellular senescence and stem cell
exhaustion
(A) Cellular senescence usually promotes tissue
repair after injury and protects the organism from
oncogenic damage. This is achieved in two steps:
(1) establishment of senescence and (2) recruit-
ment of immune cells that will eliminate the se-
nescent cells, thereby promoting tissue repair. If
any of these steps fails, the organism is prone to
develop diseases.
(B) Stem cell exhaustion results from the loss of
cellular plasticity required for tissue repair. Tissue
repair requires a modified microenvironment
through the secretion of cytokines (in part due to
the senescence-associated secretory response),
growth factors and modulators of the extracellular
matrix (ECM) that favors the de-differentiation and
plasticity of cells from different tissue compart-
ments. These injury-induced plastic cells may
acquire multipotent progenitor function. Transient
expression of OSKM factors represses the tran-
scription of cell identity programs causing global
de-differentiation (OSKMon) and the acquisition of
plasticity. For rejuvenation, the process must be
interrupted at this point (OSKMoff) to allow cells to
re-differentiate and to restore their original cell
identities.
quercetin and fisetin are natural flavonoids

with multiple targets. D/Q has been tested
in clinical trials with promising results in
the case of lung and kidney fibrosis.62,61
Cardiac glycosides inhibit the plasma
membrane Na+/K+-ATPase present in all
cells causing a cationic imbalance and
lowering the intracellular pH.233 The
mechanism of senolysis by cardiac glyco-
sides is likely connected to the vulnera-
bility of senescent cells to low intracellular
very different from the cancellation of the senescence response, pH. Thus, chemical inhibition of glutaminase deprives cells of a
which can result, for example, from mutation of p16 or p21. Senol- mechanism to counteract low pH and results in senolysis.234 All
ysis does not prevent the execution of senescence but rather reca- the above-discussed senolytic compounds exert therapeutic ac-
pitulates the natural immune clearance of senescent cells tivity in a wide range of murine disease models associated with
(Figure 5A). In support of this, mice subjected to long-term ge- senescence. Senolysis can also be achieved by immunological
netic-induced or pharmacologically induced senolysis present approaches that target proteins appearing on the surface of se-
extended longevity without increased cancer incidence or signs nescent cells. In particular, antibodies directed against the glyco-
of defective tissue repair.59,58 protein NMB (GPNMB)235 and CAR T cells directed against the
The number of senolytic therapies is still limited, but some have receptor uPAR236 attenuate senescence-associated disease
been extensively used in preclinical models of disease, as exem- models in mice.
plified by navitoclax, dual treatment with dasatinib and quercetin In summary, cellular senescence is an important response to
(D/Q), fisetin, cardiac glycosides, and others.221 The survival and stress and damage that, in normal physiology, is followed by im-
apoptotic resistance of senescent cells strongly depends on the mune clearance, but that upon aging or chronic damage fails to
BCL2 family of proteins, specially BCLXL, but also BCL2 and be eliminated by immune mechanisms and hence is pathogenic
BCLW. This renders senescent cells highly vulnerable to navito- due to the abundant secretion of pro-inflammatory and pro-
clax, which targets these three proteins.231 Navitoclax has been fibrotic factors. Therapeutic strategies aimed at killing senescent
evaluated in clinical trials for antitumor activity and it is expected cells have been extensively explored in animal models and are
that this drug (or derivatives lacking toxicity on platelets) will enter now in clinical trials (Table 1).
clinical trials for senescence-associated diseases.232 Other po-
tential senolytic treatments such as D/Q230 and fisetin60 are STEM CELL EXHAUSTION
approved for human use and are being tested in various clinical tri-
als for multiple indications. The mechanistic basis for their action Aging is associated with reduced tissue renewal at steady state,
remains unclear. Dasatinib is a promiscuous kinase inhibitor, and as well as with impaired tissue repair upon injury, with each
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organ having its own strategy for renewal and repair.237 For epigenetic and transcriptional programs, and this may also erase
example, in skeletal muscle, one single-cell type, the satellite aging-associated alternations. Upon interruption of partial re-
cell, is placed at the apex of a unipotent and unidirectional hier- programming, cells re-stablish their original epigenetic and tran-
archy, both for renewal and repair. In skin epidermis, which is scriptional status in a process of re-differentiation that, interest-
characterized by high renewal and exposure to injury, there are ingly, does not re-stablish the erased aging-associated changes
multiple stem cell niches, particularly in association to the hair and therefore resets the epigenome and transcriptome to a
follicles, each one generating its progeny and territory. However, younger state.
upon injury, multiple cells can acquire stem cell properties and Transient reprogramming in mice confers repair capacity to
subvert territorial boundaries. Other organs like liver, lung, or old tissues so that a subsequent damage is repaired as efficiently
pancreas exhibit rather low renewal rates under normal condi- as in young individuals. This increased repair capacity has been
tions, contrasting with the acquisition of stem cell properties shown for models of tissue damage in the endocrine pancreas,63
including proliferation and multipotency by different cell types skeletal muscle,63 nerve fibers,70 eye,70 skin,64 heart,65 and liver.66
(Figure 5B). Indeed, tissue repair is believed to rely to a large Also, tissue dysfunctions characteristic of natural aging, such as
extent on injury-induced cellular de-differentiation and plasticity. reduced visual acuity70 and the loss of adult neurogenesis in the
For example, in the intestine, brain, and lung, injury induces de- hippocampus and long-term memory,67 can be partially reversed
differentiation of non-stem cells, which reactivates normally si- by transient reprogramming. There are a few instances in which
lent embryonic and stemness transcription programs, thus transient reprogramming is beneficial also during the process of
acquiring the plasticity needed for tissue repair.238–240 Injury- tissue repair (and not only prior to the injury). This is the case for
induced plasticity (and its progressive loss with aging) may be traumatic brain injury68 and skin wound healing.69 Finally, it should
more relevant for aging than the plasticity of resident stem be mentioned that the lifespan of progeroid mice can be extended
cells under normal homeostatic conditions. Stem and progenitor by transient reprogramming,63 although extension of longevity by
cells are all subject to the same hallmarks of aging as are OSKM has not yet been reported for wild-type mice.
cells without stem potential, and for this reason, we do not Partial reprogramming recapitulates features of natural tissue
discuss here the abundant literature about the impact of each repair (Figure 5B). In both cases, cells undergo a transient pro-
hallmark of aging on stem cell function. Instead, we will focus cess of de-differentiation, acquisition of embryonic and progen-
on a general strategy to counter the decline of stem cell function itor features, and subsequent re-differentiation. Thus, de- and
with aging based on the concept of ‘‘cellular reprogramming.’’ re-differentiation could explain tissue rejuvenation, in line with
This process is thought to act in a cell-autonomous manner on the observation that transient de-differentiation of myocytes,
multiple cell types; however, its impact on stem and progenitor followed by their re-differentiation, induces rejuvenation of
cells is considered of higher relevance because of its long-term the transcriptome.248 The natural process of tissue repair may
impact. imply some degree of cellular rejuvenation, in accord with the
finding that the epigenetic methylation clock accelerates soon
Rejuvenation of tissue repair by reprogramming after tissue injury and partially reverses during tissue repair.249
Cellular reprogramming toward pluripotency consists in the con- Moreover, tissue damage reportedly creates a tissue microenvi-
version of adult somatic cells into embryonic pluripotent cells ronment that is highly permissive for IL-6-driven reprogram-
(known as induced pluripotent stem cells or iPSCs) by the ming.250 Finally, cyclic expression of the transcription
concomitant action of four externally transduced transcription factor FOXM1 extends the longevity of progeroid mice and
factors, namely, OCT4, SOX2, KLF4, and MYC (OSKM).241 The wild-type mice.251 Although the detailed mechanism is still
process of reprogramming usually requires several weeks during unexplored, FOXM1 is induced in the kidney upon injury and
which cells first lose their differentiated phenotype by transcrip- participates in triggering de-differentiation and proliferation
tional repression of cell identity genes and subsequently trans- of tubular epithelial cells during the repair process.252
activate pluripotency genes.242 Full reprogramming not only im- Thus, several features of natural tissue repair and artificial
plies a change of cellular identity but also cellular rejuvenation, reprogramming may converge, perhaps allowing refinement
characterized by a number of aging features that are reset to of strategies for restoring repair capacity in aging tissues.
the embryonic state, as indicated by p16 reduction,243 extension
of telomeres,244 and resetting of the DNA methylation clock.245 ALTERED INTERCELLULAR COMMUNICATION
Interestingly, rejuvenation occurs in a progressive fashion start-
ing shortly after the initiation of de-differentiation.246 Indeed, it is Aging is coupled to progressive alterations in intercellular
possible to initiate reprogramming with OSKM, interrupt the pro- communication that increase the noise in the system and
cess at an intermediate state, and allow cells to return to their compromise homeostatic and hormetic regulation. Thus, aging
original identity. This transient cellular perturbation, variously involves deficiencies in neural, neuroendocrine, and hormonal
known as ‘‘partial,’’ ‘‘transient,’’ or ‘‘intermediate’’ reprogram- signaling pathways, including the adrenergic, dopaminergic,
ming, is able to rejuvenate cellular markers of aging such as and insulin/IGF1-based and renin-angiotensin systems, as well
the DNA methylation clock, DNA damage, epigenetic patterns, as sex hormones commensurate with the loss of reproductive
and aging-associated changes in the transcriptome, both functions.182,253 Although the primary causes of such alterations
in vitro and in vivo.63,64,70,246,247 Therefore, it can be proposed are cell intrinsic, as this is particularly well documented for the
that the processes of de-differentiation and rejuvenation are SASP, these derangements in intercellular communication
coupled. Specifically, de-differentiation implies the erasure of ultimately sum up to a hallmark on its own that bridges the
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cell-intrinsic hallmarks to meta-cellular hallmarks including the involves the interaction among short-lived extracellular mole-
chronification of inflammatory reactions coupled to the decline cules (such as ROS, nitric oxide, nucleic acids, prostaglandins,
of immunosurveillance against pathogens and premalignant and other lipophilic molecules), soluble factors that are released
cells, as well as the alterations in the bidirectional communica- from various tissues including white adipose tissue (adipokines),
tion between human genome and microbiome, which finally re- brown adipose tissue (baptokines), heart (cardiokines), liver
sults in dysbiosis. A number of studies in this regard have (hepatokines) and skeletal muscles (myokines, including exer-
focused on the search for blood-borne systemic factors with kines produced in response to exercise), cell-bound ligands,
pro-aging or prolongevity properties, the role of diverse commu- and receptors on other cells (as exemplified by IL-1a that can
nication systems between cells, and the evaluation of the remain cell-bound), as well as direct cell-to-cell interactions
functional relevance of ECM disruption during aging. mediated by tight junctions or gap junctions. All these communi-
cation systems may be altered during aging and hence are being
Pro-aging blood-borne factors scrutinized for their potential pro- and anti-aging properties.258
A single transfusion of old blood induces features of aging in
young mice within a few days,72 and the simple dilution of the Extracellular matrix
blood of old mice with saline buffer containing 5% albumin in- Aging causes numerous damages in the long-lived protein com-
duces rejuvenation in multiple tissues,71 indicating ponents of the ECM, including AGEs, carbonylation and carba-
the existence of circulating factors that favor the aging process. mylation, elastin fragmentation, and collagen crosslinking,261
Among the pro-aging blood-borne factors, the chemokine thus leading to tissue fibrosis (fibroaging).262 This deleterious
CCL11/eotaxin and the inflammation related protein b2-micro- process is in part due to the excessive release of TGF-b and
globulin reduce neurogenesis,254,255 IL-6 and TGF-b impair he- other growth factors, and the nuclear translocation of TAZ and
matopoiesis,256 and the complement factor C1q compromises YAP transcription factors, which act as mechanotransducers
muscle repair.257 Theoretically, the neutralization of these fac- and trigger the expression of pro-fibrotic genes such as
tors might have potent anti-aging effects. Indeed, several among transglutaminase-2, lysyl oxidase (LOX), and LOX-like en-
the aforementioned factors are secreted in the context of SASP zymes.262 ECM stiffness also affects the function of senescent
and may be co-responsible for the phenomenon of ‘‘contagious’’ cells, which in turn secrete matrix metalloproteases that amplify
aging, which also involves extracellular vesicles.258 Thus, so- the damage of the ECM,263 and proteolytically generate dam-
called ‘‘senomorphics’’ might be used to repress SASP and age-associated molecular patterns to activate pro-senescent,
slow down aging. pro-fibrotic, and pro-inflammatory pathways.262 The increasing
stiffness of the aging matrix may also favor WNT signaling to
Anti-aging blood-borne factors induce fibroblast activation and expression of pro-fibrotic
Soluble factors present in the blood of young mice effectively genes.264 This pathway exhibits extensive crosstalk with other
restore renewal and repair capacity in old mice259 (Table 1). Het- pro-fibrotic pathways, such as NOTCH, RAS, TGF-b/SMAD,
erochronic parabiosis experiments followed by extensive single- and hedgehog/GLI, thereby demonstrating the complexity and
cell transcriptomics have confirmed the capacity of young blood interconnections of mechanisms underlying the development
to rejuvenate multiple tissues74 and to restore age-associated of age-linked fibrosis.262 Of note, mechanical change caused
reduction in general gene expression, in particular that of mito- by matrix stiffness is sufficient to cause age-related loss of func-
chondrial genes involved in the electron transport chain.75 The tion of oligodendrocyte progenitor cells in a process mediated by
chemokine CCL3/MIP-1a acts as a rejuvenating factor for he- the mechanoresponsive ion channel PIEZO1.265
matopoietic stem and progenitor cells;74 the metalloproteinase Several studies have provided causal evidence for the
inhibitor TIMP2 has been implicated in rejuvenating the hippo- contribution of ECM stiffness to aging and have also suggested
campus;73 the anti-inflammatory interleukin IL-37 (which de- approaches for improving healthy aging (Table 1). In vivo inhibi-
clines in monocytes from aged humans) improves increased tion of Piezo1 using AAV vectors results in rejuvenation of the
endurance exercise and ameliorates whole-body metabolism oligodendrocyte progenitors in the brain of old mice.265 Genetic
in old mice;76 the cytokine GDF11 rejuvenates some tissues, inactivation of YAP/TAZ in stromal cells causes accelerated
such as muscle, brain, and endocrine pancreas, although it im- aging, although sustaining YAP function rejuvenates old
pairs the function and repair of other tissues due to its pro- cells and prevents the emergence of aging features by control-
fibrotic side effects;77 and finally, mice with transgene-enforced ling cGAS-STING signaling.79 Moreover, mice engineered to
VEGF overexpression exhibit enhanced liver and muscle repair, produce collagenase-resistant type I collagen (Col1a1r/r)
improved general health and an extension in average longevity exhibit vascular cell senescence, accelerated aging, and short-
by 40%.78 ened lifespan.266 The importance of collagen for human
longevity has been reinforced by the discovery of rare variants
Long-range and short-range communication systems in COL25A1—encoding a brain-specific collagen—that may
The central nervous system controls multiple facets of aging have a protective role against Alzheimer’s disease.267 Moreover,
affecting peripheral organs, explaining how brain-specific gene ECM prepared from young human fibroblasts induces a youthful
manipulations like overexpression of SIRT1, UCP1, or knockout state in aged senescent cells.80 ECM compounds such as chon-
of IKBKB and TRPV1 can enhance mouse longevity (Table 1). droitin sulfate and hyaluronic acid restore the age-related
The precise mechanisms of these long-range activities are yet decline of collagen and increase lifespan in nematodes.268
to be determined.260 Of note, intercellular communication also Conversely, ectopic expression of human hyaluronidase
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Figure 6. Derangement of supracellular
functions
Altered intercellular communication bridges the
cell-intrinsic hallmarks to meta-cellular hallmarks
including the chronic inflammation, and the alter-
ations in the crosstalk between human genome
and microbiome, which finally result in dysbiosis.
(A) Chronic inflammation during aging occurs as a
consequence of multiple derangements that stem
from all the other hallmarks. Several representa-
tive examples of anti-inflammatory interventions
with positive effects on healthspan and lifespan
are shown in the right part of the figure.
(B) Dysbiosis contributes to multiple pathological
conditions associated with aging. The human gut
microbiota significantly changes during aging,
finally leading to a general decrease in ecological
diversity. The main features of the mechanisms
underlying these microbiota changes and some
examples of interventions on the gut microbiota
composition which can promote healthy aging are
shown in the lower part of the right panel. CVDs,
cardiovascular diseases; SCFAs, short-chain
fatty acids.
CHRONIC INFLAMMATION
Inflammation increases during aging (‘‘in-

flammaging’’) with systemic manifesta-
tions, as well as with pathological local
phenotypes including arteriosclerosis,
neuroinflammation, osteoarthritis, and
intervertebral discal degeneration.
Accordingly, the circulating concentra-
tions of inflammatory cytokines and bio-
markers (such as CRP) increase with ag-
ing. Elevated IL-6 levels in plasma
constitute a predictive biomarker of all-
cause mortality in aging human popula-
tions.271 In association with enhanced
inflammation, immune function declines,
a phenomenon that can be captured by
high-dimensional monitoring of myeloid
and lymphoid cells in the blood from pa-
tients and from mouse tissues.272 For
example, a population of age-associated
T cells—termed Taa cells—is composed
of exhausted memory cells that mediate
pro-inflammatory effects via granzyme
K. Shifts in T cell populations entail the
hyperfunction of pro-inflammatory TH1
TMEM2 promotes resistance to ER stress and extends lifespan and TH17 cells, defective immunosurveillance (with a negative
in C. elegans through changes in p38/ERK MAPK signaling.269 impact on the elimination of virus-infected, malignant or senes-
In mice, deletion of chondroitin 6-sulfotransferase results in an cent cells), loss of self-tolerance (with a consequent age-associ-
abnormal ECM in the brain, early memory loss, and accelerated ated increase in autoimmune diseases), and reduced mainte-
brain aging, whereas overexpression of this enzyme improved nance and repair of biological barriers, altogether favoring
memory in old mice.81 Retrospective analyses indicate that systemic inflammation273 (Figure 6A).
oral intake of glucosamine/chondroitin sulfate leads to a reduc-
tion in all-cause mortality in humans.270 However, there is no Links between inflammation and other aging hallmarks
prospective proof thus far that such a prolongevity effect would Inflammaging occurs as a result of multiple derangements that
be mediated through an amelioration of the ECM. stem from all the other hallmarks. For example, inflammation is
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triggered by the translocation of nuclear and mtDNA, into the There are multiple examples of broad healthspan and lifespan-
cytosol where it stimulates pro-inflammatory DNA sensors, expanding effects of anti-inflammatory treatments (Figure 6A;
especially when autophagy is ineffective and hence unable to Table 1). Thus, blockade of TNF-a prevents sarcopenia in mice
intercept ectopic DNA.4 Genomic instability favors clonal and improves cognition in aging rats.83,84 Blockade of the com-
hematopoiesis of indeterminate potential (CHIP), with the mon type 1 interferon receptor (IFNAR1) reverses the accumula-
expansion of myeloid cells that often bear a pro-inflammatory tion of monocytes in the aging mouse lung.279 Knockout of the
phenotype, driving for instance cardiovascular aging.274 Intrigu- prostaglandin E2 receptor EP2 in myeloid cells or treatment of
ingly, the most frequent CHIP-associated mutations affect aged mice with pharmacological EP2 inhibitors ameliorates
the epigenetic modifiers DNMT3 (which methylates cytosine cognition.85 Knockout of the inflammasome protein NLRP3
residues in DNA) and TET2 (which catalyzes the oxidation of improves metabolic biomarkers, glucose tolerance, cognition,
methylcytosine to 5-hydroxymethylcytosine). Mechanistically, and motor performance and extends mouse longevity.86 Phar-
CHIP affecting TET2 enhances IL-1b and IL-6 production by macological inhibitors of NLRP3 or of its downstream enzyme
myeloid cells and stimulates cardiovascular disease (CVD), caspase-1 have encouraging preclinical effects on normal and
which is attenuated among individuals bearing a loss-of-function accelerated aging models.280 Most importantly, inhibition of
mutation in the IL-6 receptor or treated with an IL-1b neutralizing the caspase-1 product IL-1b with canakinumab exemplifies an
antibody.275 anti-aging treatment applicable to patients. The phase 3 clinical
Overexpression of pro-inflammatory proteins can be second- trial CANTOS evaluated the capacity of canakinumab to prevent
ary to epigenetic dysregulation, deficient proteostasis, or recurrent CVD in patients with a history of myocardial infarction
disabled autophagy. Excessive trophic signals resulting in and signs of pronounced inflammation. Beyond meeting the pri-
activation of the GH/IGF1/PI3K/AKT/mTORC1 axis trigger mary endpoint of the trial, canakinumab reduced the incidence
inflammation. In addition, inflammation is favored by the SASP of diabetes and hypertension, as well as the incidence of, and
secondary to the accrual of senescent cells, as well as by the mortality from, lung cancer.87 Finally, although long-term use
accumulation of extracellular debris and infectious pathogens, of non-steroidal anti-inflammatory agents such as aspirin may
which are not cleared due to senescence, and by exhaustion have positive effects on human health—in particular with respect
of myeloid and lymphoid cells. This latter phenomenon involves to the prevention of CVD and gastrointestinal cancers—a large
age-associated thymic involution, abrogating thymopoiesis with phase 3 clinical trial in which aspirin was administered to over
the consequent rarefaction of the T cell repertoire and the 70-year-old subjects yielded negative results.281 Hence, further
inability to mount efficient immune responses against novel anti- studies will be necessary to explore the value of prophylactic
gens.276 Of note, thymopoiesis is improved by CR in humans, treatments with aspirin at a younger age to combine aspirin
and a CR-downregulated gene coding for platelet activation fac- with other medications or to replace aspirin by less toxic anti-in-
tor acetyl hydrolase A2 group VII (PLA2G7) can be knocked out in flammatory drugs.
mice to combat thymic atrophy.50 Finally, inflammaging is also
exacerbated by perturbations of circadian rhythms and by DYSBIOSIS
intestinal barrier dysfunction.277
Over recent years, the gut microbiome has emerged as a key
Anti-inflammatory, anti-aging interventions factor in multiple physiological processes such as nutrient diges-
Although systemic inflammation is mechanistically linked to all tion and absorption, protection against pathogens, and produc-
the aforementioned age-associated alterations, inflammation tion of essential metabolites including vitamins, amino acid de-
constitutes a hallmark on its own. Indeed, specific manipulations rivatives, secondary bile acids, and short-chain fatty acids
of the inflammatory and immune system can accelerate or decel- (SCFAs). The intestinal microbiota also signals to the peripheral
erate the aging process across different organ systems. For and central nervous systems and other distant organs and
example, a T cell-specific defect in the mitochondrial transcrip- strongly impacts on the overall maintenance of host health.146
tion factor A (TFAM) is sufficient to drive cardiovascular, cogni- Disruption of this bacteria-host bidirectional communication re-
tive, metabolic, and physical aging coupled to an increase in sults in dysbiosis and contributes to a variety of pathological
circulating cytokines. The TNF-a inhibitor etanercept partially conditions, such as obesity, type 2 diabetes, ulcerative colitis,
reversed this phenotype.82 Heterozygous deletion of the DNA neurological disorders, CVDs, and cancer.282 The progress in
repair protein ERCC1 in hematopoietic cells from mice is suffi- this field has generated an enormous interest in exploring gut mi-
cient to induce immunosenescence and aging of non-lymphoid crobiota alterations in aging (Figure 6B).
organs, as well as numerous signs of organ damage coupled
to reduced lifespan. This phenotype was alleviated by the seno- Microbiota alterations in aging
lytic fisetin.278 These results support the idea that aging of the The microbial community within the intestinal tract is highly var-
immune system may drive organismal aging. Of note, adoptive iable among individuals as a consequence of host genetic vari-
transfer of TFAM-null T cells, young ERCC-deficient spleno- ants (ethnicity), dietary factors, and lifestyle habits (culture), as
cytes, or aged wild-type splenocytes into young mice induced well as environmental conditions (geography), which makes diffi-
senescence, whereas the transfer of young immune cells into cult to unveil the relationships between microbiota and pleio-
ERCC-deficient mice attenuated senescence, pointing to the ca- tropic age-associated disease manifestations. Nonetheless,
pacity of immune cells to modulate organismal aging in both some meta-analyses have revealed microbiota-disease associ-
positive and negative terms.82,278 ations that have been validated across distinct pathologies283
22 Cell 186, January 19, 2023

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and countries.284,285 Studies in both humans and animal models of inflammatory responses through binding of the arylhydrocar-
have provided valuable information on clinical, epidemiological, bon receptor.93
sociological, and molecular aspects that underlie the complex Further metabolomics and functional analysis of the gut micro-
effects of an aged microbiome on human health and disease.286 biome of centenarians have shown its enrichment in some
Once bacterial diversity is established during childhood, it re- particular bacteria, such as Alistipes putredinis and Odoribacter
mains relatively stable during adulthood. However, the architec- splanchnicus. Some of these bacterial species are capable of
ture and activity of this bacterial community undergoes gradual generating unique secondary bile acids, including isoallo-litho-
changes during aging, finally leading to a general decrease in cholic, which exerts potent antimicrobial effects against gram-
ecological diversity. Thus, several studies conducted on cente- positive multidrug-resistant pathogens such as Clostridioides
narian populations showed a reduction in core abundant taxa, difficile and Enterococcus faecium.291 Thus, specific bile
such as Bacteroides and Roseburia, but also an increase in acid metabolism may be involved in reducing the risk of patho-
several genera such as Bifidobacterium and Akkermansia, which biont infection and contribute to intestinal homeostasis,
appear to have prolongevity effects.287 thereby decreasing the susceptibility to age-associated chronic
These studies have been extended by recent analysis of the diseases.
gut microbiome and phenotypic data from over 9,000 individuals
of three independent cohorts spanning 18–101 years of age.288 Fecal microbiota transplantation and aging
Of note, individual gut microbiomes become increasingly more Multiomics studies in pathological aging have revealed that two
unique to each individual with age, and this uniqueness is asso- different mouse models of progeria exhibit intestinal dysbiosis
ciated with well-known microbial metabolites involved in im- mainly characterized by an increase in the abundance of Proteo-
mune regulation, inflammation, and aging. In older age, healthy bacteria and Cyanobacteria and a decrease in levels of Verruco-
participants show continued drift toward a unique microbial microbia. Consistent with these findings, human progeria
composition, whereas this drift is reduced or absent in individ- patients with HGPS or NGPS also show intestinal dysbiosis,
uals in worse health. The identified microbiome pattern of whereas long-lived humans exhibit a substantial reduction in
healthy aging is characterized by a depletion of core taxa, Proteobacteria and a significant increase in Verrucomicrobia.88
such as Bacteroides, present across most humans. Moreover, The causal implications of these changes were demonstrated
in individuals approaching extreme age, retention of high Bacter- in vivo by fecal microbiota transplantation (FMT). FMT from
oides levels and a low gut microbiome uniqueness measure are wild type to progeroid mice recipients enhanced healthspan
significantly associated with decreased survival. However, find- and lifespan in both accelerated-aging models, whereas admin-
ings in microbiota from centenarians and supercentenarians are istration of the verrucomicrobium Akkermansia muciniphila was
not always concordant with those derived from elderly popula- also sufficient to obtain such effects. Conversely, FMT from
tions. The ELDERMET study reported an increased dominance progeroid donors to wild-type recipients induced detrimental
of the core genera Bacteroides, Alistipes, and Parabacteroides metabolic alterations. Restoration of secondary bile acids and
in old individuals compared with younger controls. This study other metabolites depleted in progeroid mice phenocopied the
also identified age-related shifts in gut microbiota composition beneficial effects of reestablishing a healthy microbiome88
linked to frailty, cognition, depression, and inflammation.289 (Table 1).
Another study revealed age-related trajectories of the microbiota FMT also revealed the causative role of gut dysbiosis in the
shared across populations of different ethnicities, as well chronic systemic inflammation and the decline in adaptive
as a common age-related decrease in sex-dependent differ- immunity associated with aging and age-related diseases.
ences in gut microbiota. Of note, older adults exhibit higher Transfer of the gut microbiota from old mice to young germ-
abundances of several health-promoting bacterial species, free mice triggered inflammatory responses characterized by
including Akkermansia.290 These results suggest that age- enhanced CD4+ T cell differentiation in spleen, upregulation of
related physiological changes, beyond dietary changes and life- inflammatory cytokines, and increased circulation of inflamma-
style of older adults, may have profound effects on the human tory factors of bacterial origin.292 FMT also provided evidence
gut microbiota. for the implication or the gut microbiota in the maintenance of
The heterogeneity of findings in all these studies indicates that brain health and immunity during aging.90 Microbiota from young
there may be multiple gut microbiome trajectories of aging. How- mice donors reversed aging-associated differences in hippo-
ever, there is an interesting convergence in plasma concentra- campal metabolites and brain immunity and ameliorated age-
tions of microbiota-produced amino acid derivatives. These me- associated impairments in cognitive behavior when transplanted
tabolites include indoles derived from gut bacterial degradation into an aged host. These works open the possibility of manipu-
of tryptophan, and several fermentation products of phenylala- lating the gut microbiota with pre-, pro-, and post-biotics to reju-
nine/tyrosine, such as p-cresolsulfate, phenylacetylglutamine, venate the immune system and the aging brain. Heterochronic
and p-cresol glucuronide. This finding is consistent with data fecal transfers confirmed the causal link between age-depen-
from the ELDERMET cohort showing that fecal concentrations dent changes in microbial composition and a decline in the func-
of p-cresol correlate with increased frailty and may contribute tion of the host immune system.92 Indeed, the defective germinal
to age-associated decline in this population. Conversely, plasma center reaction in Peyer’s patches of aged mice can be rescued
concentrations of certain indole metabolites correlate with by FMT from younger animals without affecting germinal center
improved fitness in older adults. Indole metabolites increase reactions in peripheral lymph nodes. Finally, FMT from young
healthspan and lifespan in mice, at least in part, by attenuation donor mice improves ovarian function and fertility in aged
Cell 186, January 19, 2023 23

j.cell.2022.11.001
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mice. These beneficial effects are associated with an improve- ations (via histone deacetylation), loss of proteostasis (via the
ment in the immune microenvironment of aged ovaries, with removal of protein aggregates), disabled macroautophagy (via
decreased macrophages and macrophage-derived multinucle- autophagy enhancement), deregulated nutrient-sensing (via
ated giant cells, reduced levels of pro-inflammatory IFNg, and activation of nutrient scarcity sensors), and mitochondrial
increased abundance of the anti-inflammatory cytokine IL-4.91 dysfunction (via an increase in mitophagy-dependent quality
control).176 Spermidine complexes to DNA (hence counteracting
Other prolongevity interventions on gut microbiota genomic instability), affects translation (avoiding loss of proteo-
The probiotic Lactobacillus plantarum GKM3 promotes longevity stasis), stimulates macroautophagy, reverses lymphocyte
and alleviates age-related cognitive impairment in the SAMP8 senescence, prevents the exhaustion of muscle stem cells,
mouse model of accelerated aging.89 Interventions on gut maintains circadian rhythms, suppresses inflammation, stimu-
microbiota composition also restored the age-linked decline in lates cancer immunosurveillance, and is produced by intestinal
microglial maturation and function which causes altered brain bacteria.294 Metformin has a pleiotropic mode of action including
plasticity and promotes neurodegeneration. Recolonization ex- induction of autophagy, activation of the nutrient scarcity sensor
periments or administration of gut microbiota metabolites, AMPK, inhibition of mitochondrial respiration, alleviation of
such as SCFAs, prevented the age-associated decline of bene- adipocyte senescence, suppression of inflammation, and
ficial Bifidobacterium, increased Akkermansia abundance, and favorable shifts in the gut microbiota.210 Similarly, maintenance
restored microglial function in middle-aged mice.94 Moreover, of eubiosis by oral supplementation of A. muciniphila stimulates
caloric restriction diets induce structural changes of the gut mi- intestinal autophagy, reduces metabolic syndrome, dampens
crobiome increasing the abundance of Lactobacillus and other inflammation, and enhances anticancer immune responses.295
species that influence healthy aging. The gut microbiota- Indeed, a notable feature of effective anti-aging interventions,
induced inflammaging and the consequent increase in insulin such as lowered insulin/IGF-1 signaling296 and disruption of
resistance can also be reversed by restoring abundance of bene- the TORC1 complex,296,297 is the diversity of mechanisms by
ficial SCFA-producing bacteria, such as A. muciniphila, in aged which they target different aging hallmarks in different tissues
mice and macaques.293 Similarly, a randomized, double-blind, to maintain healthspan of the whole organism.
placebo-controlled pilot study in overweight/obese insulin-resis- Although each of the 12 hallmarks of aging can be targeted
tant volunteers showed that oral administration of pasteurized one by one, yielding tangible benefits for healthspan and lifespan
A. muciniphila improved insulin sensitivity reduced insulinemia (Table 1), there is some kind of hierarchy among them (Figure 1).
and plasma total cholesterol levels.95 Collectively, these results Thus, as we initially proposed,1 the primary hallmarks, which
underscore the causal links between aging and dysbiosis and reflect damages affecting the genome, telomeres, epigenome,
suggest that interventions aimed at restoring a youthful micro- proteome, and organelles, progressively accumulate with time
biome may extend healthspan and lifespan. and unambiguously contribute to the aging process.298 The
antagonistic hallmarks, which reflect responses to damage,
INTEGRATION OF HALLMARKS play a more nuanced role in the aging process. For example,
trophic signaling and anabolic reactions activated by nutrient-
All the 12 hallmarks of aging are strongly related among each sensing have beneficial actions in youth but are largely pro-age-
other. For example, genomic instability (including that caused ing later on. Thus, in an archetypal case of antagonistic
by telomere shortening) crosstalks to epigenetic alterations pleiotropy, the nutrient-sensing network contributes to organ
(e.g., through the loss-of-function mutation of epigenetic modi- development until young adulthood but plays a detrimental role
fiers such as TET2), loss of proteostasis (e.g., due to the produc- beyond this stage. Additionally, reversible and low-dose mito-
tion of mutated, misfolded proteins), disabled macroautophagy chondrial dysfunction can stimulate beneficial counterreactions
(e.g., through the capacity of autophagy to remove supernumer- (via mitohormesis), whereas limited and spatially confined
ary centrosomes, extranuclear chromatin, and cytosolic DNA), levels of cellular senescence contribute to the suppression of
deregulated nutrient-sensing (e.g., because SIRT6 is an NAD+ oncogenesis and improve wound healing. Finally, the integrative
sensor involved in DNA repair but also responding to nutrient hallmarks arise when the accumulated damage inflicted
scarcity), mitochondrial dysfunction (e.g., due to the mutation by the primary and antagonistic hallmarks cannot be compen-
of mtDNA), cellular senescence (e.g., because DNA damage trig- sated any more, resulting in stem cell exhaustion, intercellular
gers senescence), altered intercellular communication (e.g., by communication alterations including ECM damage, chronic
hampering activation of communication pathways), chronic inflammation, and dysbiosis, which together dictate the pace
inflammation (e.g., because CHIP and leakage of DNA into the of aging.
cytosol induce inflammation), and dysbiosis (e.g., because Recently, we postulated the existence of eight hallmarks of
mutations in intestinal cells favors dysbiosis, whereas specific health,146 which include organizational features of spatial
microbial proteins and metabolites act as mutagens). Similar compartmentalization (integrity of barriers and containment of
functional relationships can be listed for most if not all hallmarks local perturbations), maintenance of homeostasis over time
of aging, illustrating their formidable interconnectivity. (recycling and turnover, integration of circuitries, and rhythmic
This entanglement is also visible at the level of experimental oscillations), and an array of adequate responses to perturbation
anti-aging interventions that often simultaneously target several (homeostatic resilience, hormetic regulation, and repair and
hallmarks. Thus, SIRT activators including NAD+ precursors regeneration). Undoubtedly, aging is linked to progressive dete-
attenuate genomic instability (via DNA repair), epigenetic alter- rioration of these eight hallmarks of health, implying a ramping
24 Cell 186, January 19, 2023

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Figure 7. Integration of hallmarks

All the 12 hallmarks of aging proposed in this work are functionally related among each other. These determinants of aging are also interconnected to the eight
hallmarks of health, which include organizational features of spatial compartmentalization, maintenance of homeostasis over time, and an array of responses to
perturbation.146 Finally, the hallmarks of aging are interconnected to the eight proposed strata of organismal organization146 and create a multidimensional space
of interactions that may contribute to explain some important features of the aging process.
incapacity to maintain spatial compartmentalization (with the the capacity of the young system to rejuvenate an older one
consequent loss of integrity of internal and external barriers, as or, vice versa, the ability of pro-aging factors to precipitate the
well as the incapacity to contain perturbations of such barriers senescence of young cells.74,75 This type of experiment
in space and time), to assure long-term homeostasis (with demonstrates that aging relies on the integration of cell-autono-
reduced capacity of recycling and turnover, inefficient coordina- mous and non-cell-autonomous mechanisms that also have
tion among different systems via integrated circuitries, and de- been revealed in Drosophila (in which stimulation of autophagy
synchronization of ultradian, circadian, or infradian rhythms), in the intestine is sufficient to extend lifespan of the entire
and to adequately respond to stress by complete repair and organism)120 and mice (in which injection of a few thousands of
regeneration, homeostatic resilience, and hormetic regulation senescent fibroblasts is sufficient to trigger invalidating osteoar-
(Figure 7). This decline affects all eight strata of organismal orga- thritis).299 Hence, pro-aging and anti-aging mechanisms can be
nization, across different classes of molecules (such as communicated among distinct cell types, perhaps explaining
DNA, RNA, proteins, and metabolites), organelles (such as that ‘‘normal’’ aging usually affects multiple organs in a close-
nuclei, mitochondria, and lysosomes), cell types (such as paren- to-synchronous fashion, at difference with ‘‘pathological’’ aging
chymatous, auxiliary/stromal, and inflammatory/immune cells), in which time-dependent diseases precociously manifest in spe-
supracellular units constituting the minimal functional entities cific locations, in the form of initially isolated cardiovascular,
of organs, entire organs within their anatomical boundaries, oncological, or neurodegenerative disorders. However, the
organ systems (such as the gastrointestinal, respiratory, and distinction between normal and pathological aging is debat-
urinary tracts), systemic circuitries (with their endocrine, neuro- able,300 and some progeroid syndromes manifest signs of
logical, lymphatic, and vascular connections), as well as the incomplete or segmental aging, as exemplified by the absence
meta-organism (that includes the microbiota). As a result, the of a central nervous phenotype in HGPS.
12 hallmarks of aging are interconnected to the eight hallmarks In view of the spectacular progress of developing longevity
of failing health and the eight strata of organismal organization strategies in mammalian model organisms and initial clinical tri-
(Figure 7), creating a multidimensional space of interactions als (Table 1), it will be important to develop rational strategies for
that may explain some features of the aging process. intervening into human aging. The question arises to which
Heterochronic parabiosis experiments, in which the vascular extent strategies for extending human healthspan should be
systems of young and old mice are connected, may illustrate based on the avoidance of age-accelerating environmental fac-
best the importance of systemic regulatory factors (such as tors (such as pollution, stress, inadequate physical activity, and
hormones and circulating cells) on the aging process. This unhealthy diets, often unavoidable in a context of poverty, pre-
phenomenon has been extensively characterized at the level of cariousness, and wartime), the adoption of health-promoting
single-cell transcriptomics, yielding a spatiotemporal map of lifestyle factors (such as diet, exercise, regular sleeping patterns,
Cell 186, January 19, 2023 25

j.cell.2022.11.001
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and social activities), the administration of relatively non-spe- Joint Programme on Rare Diseases; the European Union Horizon 2020
cific, pleiotropic drugs (exemplified by NAD+ precursors, metfor- Projects Oncobiome and Crimson; Fondation Carrefour; Institut National du
Cancer; Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-
min, spermidine, or MTORC1 inhibitors), or more specific medi-
IDEX-0001); a Cancer Research ASPIRE Award from the Mark Foundation;
cal interventions. Such specific treatments may involve the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell
pharmacological agents—with the prospective of a broad imple- DNA Repair and Tumor Immune Elimination (SOCRATE); and SIRIC Cancer
mentation, genetic or cell-based therapies—with rather complex Research and Personalized Medicine (CARPEM). This study contributes to
logistics and elevated costs, or bioengineering methods for sur- the IdEx Université de Paris ANR-18-IDEX-0001.
gical tissue replacement, which most likely will mainly remain in
the realm of experimentation. Given the multiplicity of hallmarks DECLARATION OF INTERESTS
offering therapeutic strategies for decelerating, halting, or
M.A.B. is founder and shareholder of Life Length, SL, which commercializes
reversing aging, it will be interesting to evaluate combination reg-
telomere length measurements for biomedical use. M.S. is shareholder and
imens with the scope of maximizing benefits and minimizing side advisor of Rejuveron Senescence Therapeutics, AG, and Altos Labs, Inc.;
effects. The question remains open whether such healthspan and shareholder of Senolytic Therapeutics, Inc., and Life Biosciences, Inc.
and lifespan extending prophylactic treatments will profit from G.K. has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido,
personalization based on individual patient characteristics Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics,
determined by the genetic, epigenetic, metabolomic, or pheno- Sanofi, Sotio, Tollys, Vascage, and Vasculox/Tioma; consulting for Reithera
and is on the Board of Directors of the Bristol Myers Squibb Foundation
typic assessments of aging clocks.
France. G.K. is a scientific co-founder of everImmune, Osasuna Therapeutics,
Aging is not yet a recognized target for drug development or for Samsara Therapeutics, and Therafast Bio. G.K. is the inventor of patents
treatment. For this reason, the first clinical trials evaluating anti- covering therapeutic targeting of aging, cancer, cystic fibrosis, and metabolic
aging interventions must deal with the prevention or mitigation disorders and has been holding research contracts with Daiichi Sankyo, Eleor,
of age-associated pathologies rather than aging itself. Although Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Thera-
such trials have been designed to target high-risk populations peutics, Sanofi, Tollys, and Vascage; has been consulting for Reithera; is on
(such as patients with myocardial infarction and laboratory signs the Board of Directors of the Bristol Myers Squibb Foundation France, and
is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara
of inflammation in the CANTOS trial or patients with frailty or car-
Therapeutics, and Therafast Bio. G.K.’s wife, Laurence Zitvogel has held
diovascular events to be enrolled in future metformin-related trials) research contracts with 9 Meters Biopharma, Daiichi Sankyo, Pilege, was on
and to measure the manifestation of a second cardiovascular the on the Board of Directors of Transgene, is a co-founder of everImmune,
event or aggravation of frailty, there is a risk that they are pro- and holds patents covering the treatment of cancer and the therapeutic manip-
grammed too late, which is of significant concern. Indeed, at ulation of the microbiota. G.K.’s brother, Romano Kroemer, was an employee
this point, academic geroscience may raise or fall as the function of Sanofi and has consulted for Boehringer-Ingelheim. None of the funders had
any role in study design, data collection and analysis, decision to publish, or
of the outcome of the first randomized, double-blinded phase 3 tri-
preparation of the manuscript.
als. The new directions of the hallmarks of aging may provide an
improved framework for the development of effective interven-
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INTRODUCTION biological and chronological age can reflect the efficacy of

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Genome integrity and stability are perva-

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accelerate aging because they require a permissive microenvi-

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Table 1. Examples of anti-aging effects of hallmark-targeted interventions in mammals

mouse 4-phenylbutyrate administered reduced ER stress in cortex and Hafycz et al.36

inflammation from 16 to 18 months of age in increased lifespan (f)

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Non-coding RNAs stronger suppressor of LINE1 retrotransposons, enhances

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agy upon their inclusion in two-membrane

Proteostasis, aging, and longevity

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Figure 4. Metabolic alterations

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CELLULAR SENESCENCE of senescent cells: (1) the transcriptional derepression of endog-

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quercetin and fisetin are natural flavonoids

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Inflammation increases during aging (‘‘in-

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Figure 7. Integration of hallmarks

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