The Hallmarks of Aging

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Cell. 2013 June 6; 153(6): 11941217. doi:10.1016/j.cell.2013.05.039.
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The Hallmarks of Aging

Carlos Lpez-Otn1, Maria A. Blasco5, Linda Partridge3,4, Manuel Serrano2,*, and Guido
Kroemer6,7,8,9,10
1Departamento de Bioqumica y Biologa Molecular, Instituto Universitario de Oncologa (IUOPA),
Universidad de Oviedo, Oviedo, Spain
2Tumor
Suppression Group, Molecular Oncology Program, Spanish National Cancer Research

Centre (CNIO), Madrid, Spain
3Max
Planck Institute for Biology of Ageing, Cologne, Germany
4Institute
of Healthy Ageing, Department of Genetics, Evolution and Environment, University

College London, London, UK
5Telomeres
and Telomerase Group, Molecular Oncology Program, Spanish National Cancer

Research Centre (CNIO), Madrid, Spain
6INSERM,
U848, Villejuif, France
7Metabolomics
8Centre
9Ple
Platform, Institut Gustave Roussy, Villejuif, France
de Recherche des Cordeliers, Paris, France
de Biologie, Hpital Europen Georges Pompidou, AP-HP, Paris, France
10Universit
Paris Descartes, Sorbonne Paris Cit, Paris, France
Abstract
Aging is characterized by a progressive loss of physiological integrity, leading to impaired
function and increased vulnerability to death. This deterioration is the primary risk factor for
major human pathologies including cancer, diabetes, cardiovascular disorders, and
neurodegenerative diseases. Aging research has experienced an unprecedented advance over
recent years, particularly with the discovery that the rate of aging is controlled, at least to some
extent, by genetic pathways and biochemical processes conserved in evolution. This review
enumerates nine tentative hallmarks that represent common denominators of aging in different
organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability,
telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing,
mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular
communication. A major challenge is to dissect the interconnectedness between the candidate
hallmarks and their relative contribution to aging, with the final goal of identifying pharmaceutical
targets to improve human health during aging with minimal side-effects.
Keywords
aging; cancer; DNA damage; epigenetic; healthspan; lifespan; longevity; metabolism;
mitochondria; nutrient-signaling pathways; senescence; stem cells; telomeres
Correspondence to: Manuel Serrano [email protected].
Lpez-Otn et al.
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Introduction
Aging, which we broadly define as the time-dependent functional decline that affects most
living organisms, has attracted curiosity and excited imagination throughout the history of
humankind. However, it is only 30 years since a new era in aging research was inaugurated
after the isolation of the first long-lived strains in Caenorhabditis elegans (Klass, 1983).
Nowadays, aging is subjected to scientific scrutiny based on the ever-expanding knowledge
of the molecular and cellular bases of life and disease. The current situation of aging
research exhibits many parallels with that of cancer research in previous decades. The
cancer field gained major momentum in 2000 with the publication of a landmark paper that
enumerated six hallmarks of cancer (Hanahan and Weinberg, 2000), and that has been
recently expanded to ten hallmarks (Hanahan and Weinberg, 2011). This categorization has
helped to conceptualize the essence of cancer and its underlying mechanisms.
At first sight, cancer and aging may seem opposite processes: cancer is the consequence of
an aberrant gain of cellular fitness, while aging is characterized by a loss of fitness. At a
deeper level, however, cancer and aging may share common origins. The time-dependent
accumulation of cellular damage is widely considered the general cause of aging (Gems and
Partridge, 2013; Kirkwood, 2005; Vijg and Campisi, 2008). Concomitantly, cellular damage
may occasionally provide aberrant advantages to certain cells, which can eventually produce
cancer. Therefore, cancer and aging can be regarded as two different manifestations of the
same underlying process, namely, the accumulation of cellular damage. In addition, several
of the pathologies associated with aging, such as atherosclerosis and inflammation, involve
uncontrolled cellular overgrowth or hyperactivity (Blagosklonny, 2008). Based on this
conceptual framework, a series of critical questions have arisen in the field of aging
regarding the physiological sources of aging-causing damage, the compensatory responses
that try to re-establish homeostasis, the interconnection between the different types of
damage and compensatory responses, and the possibilities to intervene exogenously to delay
aging.
Here, we have attempted to identify and categorize the cellular and molecular hallmarks of
aging. We propose nine candidate hallmarks that are generally considered to contribute to
the aging process and together determine the aging phenotype (Figure 1). Given the
complexity of the issue, we have emphasized current understanding of mammalian aging,
while recognizing pioneer insights from simpler model organisms (Gems and Partridge,
2013; Kenyon, 2010). Each hallmark should ideally fulfil the following criteria: (i) it
should manifest during normal aging; (ii) its experimental aggravation should accelerate
aging; and (iii) its experimental amelioration should retard the normal aging process and,
hence, increase healthy lifespan. This set of ideal requisites is met to varying degrees by the
proposed hallmarks, an aspect that will be discussed in detail for each of them. The last
criterion is the most difficult to achieve, even if restricted to just one aspect of aging. For
this reason, not all the hallmarks are fully supported yet by interventions that succeed in
ameliorating aging. This caveat is tempered by the extensive interconnectedness between the
aging hallmarks, implying that experimental amelioration of one particular hallmark may
impinge on others.
Genomic Instability
One common denominator of aging is the accumulation of genetic damage throughout life
(Moskalev et al., 2012) (Figure 2A). Moreover, numerous premature aging diseases, such as
Werner syndrome and Bloom syndrome, are the consequence of increased DNA damage
accumulation (Burtner and Kennedy, 2010), although the relevance of these and other
progeroid syndromes to normal aging remains unresolved due in part to the fact that they
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recapitulate only some aspects of aging. The integrity and stability of DNA is continuously
challenged by exogenous physical, chemical and biological agents, as well as by
endogenous threats including DNA replication errors, spontaneous hydrolytic reactions, and
reactive oxygen species (ROS) (Hoeijmakers, 2009). The genetic lesions arising from
extrinsic or intrinsic damage are highly diverse and include point mutations, translocations,
chromosomal gains and losses, telomere shortening, and gene disruption caused by the
integration of viruses or transposons. To minimize these lesions, organisms have evolved a
complex network of DNA repair mechanisms that are collectively capable of dealing with
most of the damage inflicted to nuclear DNA (Lord and Ashworth, 2012). The genomic
stability systems also include specific mechanisms for maintaining the appropriate length
and functionality of telomeres (which are the topic of a separate hallmark, see below), and
for ensuring the integrity of mitochondrial DNA (mtDNA) (Blackburn et al., 2006; Kazak et
al., 2012). In addition to these direct lesions in the DNA, defects in the nuclear architecture,
known as laminopathies, can cause genome instability and result in premature aging
syndromes (Worman, 2012).
Nuclear DNA
Somatic mutations accumulate within cells from aged humans and model organisms
(Moskalev et al., 2012). Other forms of DNA damage, such as chromosomal aneuploidies
and copy-number variations have also been found associated with aging (Faggioli et al.,
2012; Forsberg et al., 2012). Increased clonal mosaicism for large chromosomal anomalies
has been also reported (Jacobs et al., 2012; Laurie et al., 2012). All these forms of DNA
alterations may affect essential genes and transcriptional pathways, resulting in
dysfunctional cells that, if not eliminated by apoptosis or senescence, may jeopardize tissue
and organismal homeostasis. This is especially relevant when DNA damage impacts on the
functional competence of stem cells, thus compromising their role in tissue renewal (Jones
and Rando, 2011; Rossi et al., 2008) (see also the section Stem Cell Exhaustion).
Causal evidence for the proposed links between lifelong increase in genomic damage and
aging has arisen from studies in mice and humans, showing that deficiencies in DNA repair
mechanisms cause accelerated aging in mice and underlie several human progeroid
syndromes such as Werner syndrome, Bloom syndrome, xeroderma pigmentosum,
trichothiodystrophy, Cockayne syndrome, or Seckel syndrome (Gregg et al., 2012;
Hoeijmakers, 2009; Murga et al., 2009). Moreover, transgenic mice overexpressing BubR1,
a mitotic checkpoint component that ensures accurate segregation of chromosomes, exhibit
an increased protection against aneuploidy and cancer, and extended healthy lifespan (Baker
et al., 2012). These findings provide experimental evidence that artificial reinforcement of
nuclear DNA repair mechanisms may delay aging.
Mitochondrial DNA
Mutations and deletions in aged mtDNA may also contribute to aging (Park and Larsson,
2011). mtDNA has been considered a major target for aging-associated somatic mutations
due to the oxidative microenvironment of the mitochondria, the lack of protective histones
in the mtDNA, and the limited efficiency of the mtDNA repair mechanisms compared to
those of nuclear DNA (Linnane et al., 1989). The causal implication of mtDNA mutations in
aging has been controversial because of the multiplicity of mitochondrial genomes, which
allows for the co-existence of mutant and wild-type genomes within the same cell, a
phenomenon that is referred to as heteroplasmy. However, single-cell analyses have
revealed that, despite the low overall level of mtDNA mutations, the mutational load of
individual aging cells becomes significant and may attain a state of homoplasmy in which a
mutant genome dominates the normal one (Khrapko et al., 1999). Interestingly, contrary to
previous expectations, most mtDNA mutations in adult or aged cells appear to be caused by
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replication errors early in life, rather than by oxidative damage. These mutations may
undergo polyclonal expansion and cause respiratory chain dysfunction in different tissues
(Ameur et al., 2011). Studies of accelerated aging in HIV-infected patients treated with antiretroviral drugs, which interfere with mtDNA replication, have supported the concept of
clonal expansion of mtDNA mutations originated early in life (Payne et al., 2011).
The first evidence that mtDNA damage might be important for aging and age-related
diseases derived from the identification of human multisystem disorders caused by mtDNA
mutations that partially phenocopy aging (Wallace, 2005). Further causative evidence comes
from studies on mice deficient in mitochondrial DNA polymerase . These mutant mice
exhibit aspects of premature aging and reduced lifespan in association with the accumulation
of random point mutations and deletions in mtDNA (Kujoth et al., 2005; Trifunovic et al.,
2004; Vermulst et al., 2008). Cells from these mice show impaired mitochondrial function
but, unexpectedly, this is not accompanied by increased ROS production (Edgar et al., 2009;
Hiona et al., 2010). Moreover, stem cells from these progeroid mice are particularly
sensitive to the accumulation of mtDNA mutations (Ahlqvist et al., 2012) (see also the
section on Stem Cell Exhaustion). Future studies are necessary to determine whether genetic
manipulations that decrease the load of mtDNA mutations are able to extend lifespan.
Nuclear architecture
In addition to genomic damage affecting nuclear or mtDNA, defects in the nuclear lamina
can also cause genome instability (Dechat et al., 2008). Nuclear lamins constitute the major
components of the nuclear lamina, and participate in genome maintenance by providing a
scaffold for tethering chromatin and protein complexes that regulate genomic stability
(Gonzalez-Suarez et al., 2009; Liu et al., 2005). The nuclear lamina attracted the attention of
aging researchers after the discovery that mutations in genes encoding protein components
of this structure, or factors affecting their maturation and dynamics, cause accelerated aging
syndromes such as the Hutchinson-Gilford and the Nstor-Guillermo progeria syndromes
(HGPS and NGPS, respectively) (Cabanillas et al., 2011; De Sandre-Giovannoli et al., 2003;
Eriksson et al., 2003). Alterations of the nuclear lamina and production of an aberrant
prelamin A isoform called progerin have also been detected during normal human aging
(Ragnauth et al., 2010; Scaffidi and Misteli, 2006). Telomere dysfunction also promotes
progerin production in normal human fibroblasts upon prolonged in vitro culture, suggesting
intimate links between telomere maintenance and progerin expression during normal aging
(Cao et al., 2011). In addition to these age-associated changes in A-type lamins, lamin B1
levels decline during cell senescence, pointing to its utility as a biomarker of this process
(Freund et al., 2012; Shimi et al., 2011).
Animal and cellular models have facilitated the identification of the stress pathways elicited
by aberrations in the nuclear lamina characteristic of HGPS. These pathways include the
activation of p53 (Varela et al., 2005), deregulation of the somatotrophic axis (Marino et al.,
2010), and attrition of adult stem cells (Espada et al., 2008; Scaffidi and Misteli, 2008). The
causal relevance of nuclear lamina abnormalities in premature aging has been supported by
the observation that decreasing prelamin A or progerin levels delays the onset of progeroid
features and extends lifespan in mouse models of HGPS. This can be achieved by systemic
injection of antisense oligonucleotides, farnesyltransferase inhibitors or a combination of
statins and aminobisphosphonates (Osorio et al., 2011; Varela et al., 2008; Yang et al.,
2006). Restoration of the somatotrophic axis through hormonal treatments or inhibition of
NF-B signaling also extends lifespan in these progeroid mice (Marino et al., 2010; Osorio
et al., 2012). Moreover, a homologous recombination-based strategy has been developed to
correct the LMNA mutations in induced pluripotent stem cells (iPSCs) derived from HGPS
patients, opening an avenue towards future cell therapies (Liu et al., 2011b). Further studies
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are necessary to validate the idea that reinforcement of the nuclear architecture can delay
normal aging.
Overview
There is extensive evidence that genomic damage accompanies aging and that its artificial
induction can provoke aspects of accelerated aging. In the case of the machinery that ensures
faithful chromosomal segregation, there is genetic evidence that its enhancement can extend
longevity in mammals (Baker et al., 2012). Also, in the particular case of progerias
associated with nuclear architecture defects, there is proof of principle for treatments that
can delay premature aging. Similar avenues should be explored to find interventions that
reinforce other aspects of nuclear and mitochondrial genome stability, such as DNA repair,
and their impact on normal aging (telomeres constitute a particular case and are discussed
separately).
Telomere Attrition
Accumulation of DNA damage with age appears to affect the genome near-to-randomly, but
there are some chromosomal regions, such as telomeres, that are particularly susceptible to
age-related deterioration (Blackburn et al., 2006) (Figure 2A). Replicative DNA
polymerases lack the capacity to replicate completely the terminal ends of linear DNA
molecules, a function that is proprietary of a specialized DNA polymerase known as
telomerase. However, most mammalian somatic cells do not express telomerase and this
leads to the progressive and cumulative loss of telomere-protective sequences from
chromosome ends. Telomere exhaustion explains the limited proliferative capacity of some
types of in vitro cultured cells, the so-called replicative senescence or Hayflick limit
(Hayflick and Moorhead, 1961; Olovnikov, 1996). Indeed, ectopic expression of telomerase
is sufficient to confer immortality to otherwise mortal cells, without causing oncogenic
transformation (Bodnar et al., 1998). Importantly, telomere shortening is also observed
during normal aging both in human and mice (Blasco, 2007).
Telomeres can be regarded as DNA breaks that are made invisible to the DNA repair
machinery through the formation of specialized nucleoprotein complex known as shelterin
(Palm and de Lange, 2008). This adds another peculiarity to telomeres, not only telomeres
are progressively shortened in the absence of telomerase but, also, even in the presence of
telomerase, the infliction of exogenous DNA damage to telomeres becomes invisible to the
DNA repair machineries due to the presence of shelterins. Therefore, DNA damage at
telomeres causes a persistent type of DNA damage that leads to deleterious cellular effects
including senescence and/or apoptosis (Fumagalli et al., 2012; Hewitt et al., 2012).
Telomerase deficiency in humans is associated with premature development of diseases,
such as pulmonary fibrosis, dyskeratosis congenita and aplastic anemia, which involve the
loss of the regenerative capacity of different tissues (Armanios and Blackburn, 2012).
Severe telomere uncapping can also result from deficiencies in shelterin components (Palm
and de Lange, 2008). Shelterin mutations have been found in some cases of aplastic anemia
and dyskeratosis congenita (Savage et al., 2008; Walne et al., 2008; Zhong et al., 2011).
Various loss-of-function models for shelterin components are characterized by rapid decline
of the regenerative capacity of tissues and accelerated aging, a phenomenon that occurs even
in the presence of telomeres with a normal length (Martinez and Blasco, 2010).
Genetically-modified animal models have established causal links between telomere loss,
cellular senescence and organismal aging. Thus, mice with shortened or lengthened
telomeres exhibit decreased or increased lifespan, respectively (Armanios et al., 2009;
Rudolph et al., 1999; Tomas-Loba et al., 2008). Recent evidence also indicates that aging
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can be reverted by telomerase activation. In particular, the premature aging of telomerasedeficient mice can be reverted when telomerase is genetically reactivated in these aged mice
(Jaskelioff et al., 2011). Moreover, normal physiological aging can be delayed without
increasing the incidence of cancer in adult wild-type mice by pharmacological activation or
systemic viral transduction of telomerase (Bernardes de Jesus et al., 2012; de Jesus et al.,
2011). In humans, recent meta-analyses have indicated a strong relation between short
telomeres and mortality risk, particularly at younger ages (Boonekamp et al., 2013).
Overview
Normal aging is accompanied by telomere attrition in mammals. Moreover, pathological
telomere dysfunction accelerates aging in mice and humans, while experimental stimulation
of telomerase can delay aging in mice, thus fulfilling all of the criteria for a hallmark of
aging.
Epigenetic Alterations
A variety of epigenetic alterations affects all cells and tissues throughout life (Talens et al.,
2012) (Figure 2B). Epigenetic changes involve alterations in DNA methylation patterns,
post-translational modification of histones, and chromatin remodeling. Increased histone
H4K16 acetylation, H4K20 trimethylation or H3K4 trimethylation, as well as decreased
H3K9 methylation or H3K27 trimethylation, constitute age-associated epigenetic marks
(Fraga and Esteller, 2007; Han and Brunet, 2012). The multiple enzymatic systems assuring
the generation and maintenance of epigenetic patterns include DNA methyltransferases,
histone acetylases, deacetylases, methylases and demethylases, as well as protein complexes
implicated in chromatin remodeling.
Histone modifications
Histone methylation meets the criteria for a hallmark of aging in invertebrates. Deletion of
components of histone methylation complexes extends longevity in nematodes and flies
(Greer et al., 2010; Siebold et al., 2010). Moreover, histone demethylases modulate lifespan
by targeting components of key longevity routes such as the insulin/IGF-1 signaling
pathway (Jin et al., 2011). It is not clear yet whether manipulations of histone-modifying
enzymes can influence aging through purely epigenetic mechanisms, by impinging on DNA
repair and genome stability, or through transcriptional alterations affecting metabolic or
signaling pathways outside of the nucleus.
The sirtuin family of NAD-dependent protein deacetylases and ADP-ribosyltransferases has
been studied extensively as potential anti-aging factors. Interest in this family of proteins in
relation to aging stems from a series of studies in yeast, flies and worms reporting that the
single sirtuin gene of these organisms, named Sir2, had a remarkable longevity activity
(Guarente, 2011). Overexpression of Sir2 was first shown to extend replicative lifespan in
Saccharomyces cerevisiae (Kaeberlein et al., 1999), and subsequent reports indicated that
enhanced expression of the worm (sir-2.1) and fly (dSir2) orthologs could extend lifespan in
both invertebrate model systems (Rogina and Helfand, 2004; Tissenbaum and Guarente,
2001). These findings have recently been called into question, however, with the report that
the lifespan extension originally observed in the worm and fly studies was mostly due to
confounding genetic background differences and not to the overexpression of sir-2.1 or
dSir2, respectively (Burnett et al., 2011). In fact, careful reassessments indicate that
overexpression of sir-2.1 only results in modest lifespan extension in C. elegans
(Viswanathan and Guarente, 2011).
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Regarding mammals, several studies have shown that several of the seven mammalian
sirtuins can delay various parameters of aging in mice (Houtkooper et al., 2012; Sebastian et
al., 2012). In particular, transgenic overexpression of mammalian SIRT1, which is the
closest homologue to invertebrate Sir2, improves aspects of health during aging but does not
increase longevity (Herranz et al., 2010). The mechanisms involved in the beneficial effects
of SIRT1 are complex and interconnected, including a wide range of cellular actions from
improved genomic stability (Oberdoerffer et al., 2008; Wang et al., 2008) to enhanced
metabolic efficiency (Nogueiras et al., 2012) (see also Deregulated Nutrient-sensing). More
compelling evidence for a sirtuin-mediated pro-longevity role in mammals has been
obtained for SIRT6, which regulates genomic stability, NF-B signaling and glucose
homeostasis through histone H3K9 deacetylation (Kanfi et al., 2010; Kawahara et al., 2009;
Zhong et al., 2010). Mutant mice deficient in SIRT6 exhibit accelerated aging
(Mostoslavsky et al., 2006), whereas male transgenic mice overexpressing Sirt6 have a
longer lifespan than control animals, associated with reduced serum IGF-1 and other
indicators of IGF-1 signaling (Kanfi et al., 2012). Interestingly, the mitochondria-located
SIRT3 has been reported to mediate some of the beneficial effects of dietary restriction (DR)
in longevity, although its effects are not due to histone modifications but to the deacetylation
of mitochondrial proteins (Someya et al., 2010). Very recently, overexpression of SIRT3 has
been reported to reverse the regenerative capacity of aged hematopoietic stem cells (Brown
et al., 2013). Therefore, in mammals, at least three members of the sirtuin family, SIRT1,
SIRT3 and SIRT6, contribute to healthy aging.
DNA methylation
The relationship between DNA methylation and aging is complex. Early studies described
an age-associated global hypomethylation, but subsequent analyses revealed that several
loci, including those corresponding to various tumor suppressor genes and Polycomb target
genes, actually become hypermethylated with age (Maegawa et al., 2010). Cells from
patients and mice with progeroid syndromes exhibit DNA methylation patterns and histone
modifications that largely recapitulate those found in normal aging (Osorio et al., 2010;
Shumaker et al., 2006). All of these epigenetic defects or epimutations accumulated
throughout life may specifically affect the behavior and functionality of stem cells (Pollina
and Brunet, 2011) (see section on Stem Cell Exhaustion). Nevertheless, thus far there is no
direct experimental demonstration that organismal lifespan can be extended by altering
patterns of DNA methylation.
Chromatin remodeling
DNA- and histone-modifying enzymes act in concert with key chromosomal proteins, such
as the heterochromatin protein 1 (HP1), and chromatin remodeling factors, such as
Polycomb group proteins or the NuRD complex, whose levels are diminished in both
normally and pathologically aged cells (Pegoraro et al., 2009; Pollina and Brunet, 2011).
Alterations in these epigenetic factors together with the above discussed epigenetic
modifications in histones and DNA-methylation determine changes in chromatin
architecture, such as global heterochromatin loss and redistribution, which constitute
characteristic features of aging (Oberdoerffer and Sinclair, 2007; Tsurumi and Li, 2012).
The causal relevance of these chromatin alterations in aging is supported by the finding that
flies with loss-of-function mutations in HP1 have a shortened lifespan, whereas
overexpression of this heterochromatin protein extends longevity in flies and delays the
muscular deterioration characteristic of old age (Larson et al., 2012).
Supporting the functional relevance of epigenetically-mediated chromatin alterations in
aging, there is a notable connection between heterochromatin formation at repeated DNA
domains and chromosomal stability. In particular, heterochromatin assembly at pericentric
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regions requires trimethylation of histones H3K9 and H4K20, as well as HP1 binding, and
is important for chromosomal stability (Schotta et al., 2004). Mammalian telomeric repeats
are also enriched for these chromatin modifications, indicating that chromosome ends are
assembled into heterochromatin domains (Gonzalo et al., 2006). Subtelomeric regions also
show features of constitutive heterochromatin including H3K9 and H4K20 trimethylation,
HP1 binding, and DNA hypermethylation. Thus, epigenetic alterations can directly
impinge on the regulation of telomere length, one of the hallmarks of aging. Moreover, in
response to DNA damage, SIRT1 and other chromatin-modifying proteins relocalize to
DNA breaks to promote repair and genomic stability (Oberdoerffer et al., 2008). Beyond its
role in chromatin remodeling and DNA repair, SIRT1 also modulates proteostasis,
mitochondrial function, nutrient-sensing pathways and inflammation (see below),
illustrating the interconnectedness between aging hallmarks.
Transcriptional alterations
Aging is associated with an increase in transcriptional noise (Bahar et al., 2006), and an
aberrant production and maturation of many mRNAs (Harries et al., 2011; Nicholas et al.,
2010). Microarray-based comparisons of young and old tissues from several species have
identified age-related transcriptional changes in genes encoding key components of
inflammatory, mitochondrial and lysosomal degradation pathways (de Magalhaes et al.,
2009). These aging-associated transcriptional signatures also affect non-coding RNAs,
including a class of miRNAs (gero-miRs) that is associated with the aging process and
influences lifespan by targeting components of longevity networks or by regulating stem cell
behavior (Boulias and Horvitz, 2012; Toledano et al., 2012; Ugalde et al., 2011). Gain- and
loss-of-function studies have confirmed the capacity of several miRNAs to modulate
longevity in Drosophila melanogaster and C. elegans (Liu et al., 2012; Shen et al., 2012;
Smith-Vikos and Slack, 2012).
Reversion of epigenetic changes
Unlike DNA mutations, epigenetic alterations are at least theoretically reversible, hence
offering opportunities for the design of novel anti-aging treatments (Freije and Lopez-Otin,
2012; Rando and Chang, 2012). Restoration of physiological H4 acetylation through
administration of histone deacetylase inhibitors, avoids the manifestation of age-associated
memory impairment in mice (Peleg et al., 2010), indicating that reversion of epigenetic
changes may have neuroprotective effects. Inhibitors of histone acetyltransferases also
ameliorate the premature aging phenotype and extend longevity of progeroid mice (Krishnan
et al., 2011). Moreover, the recent discovery of transgenerational epigenetic inheritance of
longevity in C. elegans suggests that manipulation of specific chromatin modifications in
parents can induce an epigenetic memory of longevity in their descendants (Greer et al.,
2011). Conceptually similar to histone acetyltransferase inhibitors, histone deacetylase
activators may conceivably promote longevity. Resveratrol has been extensively studied in
relation to aging and among its multiple mechanisms of action is the upregulation of SIRT1
activity, but also other effects associated with energetic deficits (see Mitochondrial
Dysfunction).
Overview
There are multiple lines of evidence suggesting that aging is accompanied by epigenetic
changes, and that epigenetic perturbations can provoke progeroid syndromes in model
organisms. Furthermore, SIRT6 exemplifies an epigenetically relevant enzyme whose lossof-function reduces longevity and whose gain-of-function extends longevity in mice (Kanfi
et al., 2012; Mostoslavsky et al., 2006). Collectively, these works suggest that understanding
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and manipulating the epigenome holds promise for improving age-related pathologies and
extending healthy lifespan.
Loss of Proteostasis
Aging and some aging-related diseases are linked to impaired protein homeostasis or
proteostasis (Powers et al., 2009) (Figure 3). All cells take advantage of an array of quality
control mechanisms to preserve the stability and functionality of their proteomes.
Proteostasis involves mechanisms for the stabilization of correctly folded proteins, most
prominently the heat-shock family of proteins, and mechanisms for the degradation of
proteins by the proteasome or the lysosome (Hartl et al., 2011; Koga et al., 2011; Mizushima
et al., 2008). Moreover, there are regulators of age-related proteotoxicity, such as MOAG-4,
that act through an alternative pathway distinct from molecular chaperones and proteases
(van Ham et al., 2010). All these systems function in a coordinated fashion to restore the
structure of misfolded polypeptides or to remove and degrade them completely, thus
preventing the accumulation of damaged components and assuring the continuous renewal
of intracellular proteins. Accordingly, many studies have demonstrated that proteostasis is
altered with aging (Koga et al., 2011). Additionally, chronic expression of unfolded,
misfolded or aggregated proteins contributes to the development of some age-related
pathologies, such as Alzheimers disease, Parkinsons disease and cataracts (Powers et al.,
2009).
Chaperone-mediated protein folding and stability
The stress-induced synthesis of cytosolic and organelle-specific chaperones is significantly

impaired in aging (Calderwood et al., 2009). A number of animal models support a causative
impact of chaperone decline on longevity. In particular, transgenic worms and flies
overexpressing chaperones are long-lived (Morrow et al., 2004; Walker and Lithgow, 2003).
Also, mutant mice deficient in a co-chaperone of the heat-shock family exhibit acceleratedaging phenotypes, whereas long-lived mouse strains show a marked up-regulation of some
heat-shock proteins (Min et al., 2008; Swindell et al., 2009). Moreover, activation of the
master regulator of the heat-shock response, the transcription factor HSF-1, increases
longevity and thermotolerance in nematodes (Chiang et al., 2012; Hsu et al., 2003), while
amyloid-binding components can maintain proteostasis during aging and extend lifespan
(Alavez et al., 2011). In mammalian cells, deacetylation of HSF-1 by SIRT1 potentiates the
transactivation of heat-shock genes such as Hsp70, whereas down-regulation of SIRT1
attenuates the heat-shock response (Westerheide et al., 2009).
Several approaches for maintaining or enhancing proteostasis aim at activating protein
folding and stability mediated by chaperones. Pharmacological induction of the heat-shock
protein Hsp72 preserves muscle function and delays progression of dystrophic pathology in
mouse models of muscular dystrophy (Gehrig et al., 2012). Small molecules may be also
employed as pharmacological chaperones to assure the refolding of damaged proteins and to
improve age-related phenotypes in model organisms (Calamini et al., 2012).
Proteolytic systems
The activities of the two principal proteolytic systems implicated in protein quality control,
namely, the autophagy-lysosomal system and the ubiquitin-proteasome system, decline with
aging (Rubinsztein et al., 2011; Tomaru et al., 2012), supporting the idea that collapsing
proteostasis constitutes a common feature of old age.
Regarding autophagy, transgenic mice with an extra copy of the chaperone-mediated
autophagy receptor LAMP2a do not experience aging-associated decline in autophagic
activity and preserve improved hepatic function with aging (Zhang and Cuervo, 2008).
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Interventions using chemical inducers of macroautophagy (another type of autophagy

different from chaperone-mediated autophagy) have spurred extraordinary interest after the
discovery that constant or intermittent administration of the mTOR inhibitor rapamycin can
increase the lifespan of middle-aged mice (Blagosklonny, 2011; Harrison et al., 2009).
Notably, rapamycin delays multiple aspects of aging in mice (Wilkinson et al., 2012). The
lifespan-extending effect of rapamycin is strictly dependent on the induction of autophagy in
yeast, nematodes and flies (Bjedov et al., 2010; Rubinsztein et al., 2011). However, similar
evidence does not exist yet for the effects of rapamycin on mammalian aging, and other
mechanisms such as inhibition of the ribosomal S6 protein kinase 1 (S6K1) implicated in
protein synthesis (Selman et al., 2009), could contribute to explain the pro-longevity effects
of rapamycin (see section on Deregulated Nutrient-sensing). Spermidine, another
macroautophagy inducer that, in contrast to rapamycin, has no immunosuppressive sideeffects, also promotes longevity in yeast, flies and worms via the induction of autophagy
(Eisenberg et al., 2009). Similarly, nutrient supplementation with polyamine preparations
containing spermidine or provision of a polyamine-producing gut flora increases longevity
in mice (Matsumoto et al., 2011; Soda et al., 2009). Dietary supplementation with -6
polyunsaturated fatty acids also extends lifespan in nematodes through autophagy activation
(ORourke et al., 2013).
In relation to the proteasome, activation of EGF-signaling extends longevity in nematodes
by increasing the expression of various components of the ubiquitin-proteasome system (Liu
et al., 2011a). Likewise, the enhancement of proteasome activity by deubiquitylase
inhibitors or proteasome activators accelerates the clearance of toxic proteins in human
cultured cells (Lee et al., 2010), and extends replicative lifespan in yeast (Kruegel et al.,
2011). Moreover, increased expression of the proteasome subunit RPN-6 by the FOXO
transcription factor DAF-16 confers proteotoxic stress resistance and extends lifespan in C.
elegans (Vilchez et al., 2012).
Overview
There is evidence that aging is associated with perturbed proteostasis, and experimental
perturbation of proteostasis can precipitate age-associated pathologies. There are also
promising examples of genetic manipulations that improve proteostasis and delay aging in
mammals (Zhang and Cuervo, 2008).
Deregulated Nutrient-sensing
The somatotrophic axis in mammals comprises the growth hormone (GH), produced by the
anterior pituitary, and its secondary mediator, the insulin-like growth factor (IGF-1),
produced in response to GH by many cell types, most notably hepatocytes. The intracellular
signaling pathway of IGF-1 is the same as that elicited by insulin, which informs cells of the
presence of glucose. For this reason, IGF-1 and insulin signaling are known as the insulin
and IGF-1 signaling (IIS) pathway. Remarkably, the IIS pathway is the most conserved
aging-controlling pathway in evolution and among its multiple targets are the FOXO family
of transcription factors and the mTOR complexes, which are also involved in aging and
conserved through evolution (Barzilai et al., 2012; Fontana et al., 2010; Kenyon, 2010).
Genetic polymorphisms or mutations that reduce the functions of GH, IGF-1 receptor,
insulin receptor or downstream intracellular effectors such as AKT, mTOR and FOXO, have
been linked to longevity, both in humans and in model organisms, further illustrating the
major impact of trophic and bioenergetic pathways on longevity (Barzilai et al., 2012;
Fontana et al., 2010; Kenyon, 2010) (Figure 4A).
Consistent with the relevance of deregulated nutrient-sensing as a hallmark of aging, dietary
restriction (DR) increases lifespan or healthspan in all investigated eukaryote species,
Lpez-Otn et al.
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including unicellular and multicellular organisms of several distinct phyla, including nonhuman primates (Colman et al., 2009; Fontana et al., 2010; Mattison et al., 2012).
The insulin and IGF-1 signaling pathway
Multiple genetic manipulations that attenuate signaling intensity at different levels of the IIS
pathway consistently extend the lifespan of worms, flies and mice (Fontana et al., 2010).
Genetic analyses indicate that this pathway mediates part of the beneficial effects of DR on
longevity in worms and flies (Fontana et al., 2010). Among the downstream effectors of the
IIS pathway, the most relevant one for longevity in worms and flies is the transcription
factor FOXO (Kenyon et al., 1993; Slack et al., 2011). In mice, there are four FOXO
members, but the effect of their over-expression on longevity and their role in mediating
increased healthspan through reduced IIS have not yet been determined. Mouse FOXO1 is
required for the tumor suppressive effect of DR (Yamaza et al., 2010), but it is not yet
known whether this factor is involved in DR-mediated lifespan extension. Mice with
increased dosage of the tumor suppressor PTEN exhibit a general down-modulation of the
IIS pathway and an increased energy expenditure that is associated with improved
mitochondrial oxidative metabolism, as well as with an enhanced activity of the brown
adipose tissue (Garcia-Cao et al., 2012; Ortega-Molina et al., 2012). In line with other
mouse models with decreased IIS activity, Pten-overexpressing mice, as well as
hypomorphic PI3K mice show an increased longevity (Foukas et al., 2013; Ortega-Molina et
al., 2012).
Paradoxically, GH and IGF-1 levels decline during normal aging, as well as in mouse
models of premature aging (Schumacher et al., 2008). Thus, a decreased IIS is a common
characteristic of both physiological and accelerated aging, while a constitutively decreased
IIS extends longevity. These apparently contradictory observations could be accommodated
under a unifying model by which IIS down-modulation reflects a defensive response aimed
at minimizing cell growth and metabolism in the context of systemic damage (Garinis et al.,
2008). According to this view, organisms with a constitutively decreased IIS can survive
longer because they have lower rates of cell growth and metabolism, and hence lower rates
of cellular damage. Along the same lines, physiologically or pathologically aged organisms
decrease IIS in an attempt to extend their lifespan. However, and this is a concept that will
recur in the following sections, defensive responses against aging may have the risk of
eventually becoming deleterious and aggravating aging. Thus, extremely low levels of IIS
signaling are incompatible with life, as exemplified by mouse null mutations in the PI3K or
AKT kinases that are embryonic lethal (Renner and Carnero, 2009). Also, there are cases of
progeroid mice with very low levels of IGF-1, in which supplementation of IGF-1 can
ameliorate premature aging (Marino et al., 2010).
Other nutrient-sensing systems: mTOR, AMPK and sirtuins
In addition to the IIS pathway that participates in glucose-sensing, three additional related
and interconnected nutrient-sensing systems are the focus of intense investigation: mTOR,
for the sensing of high amino acid concentrations; AMPK, which senses low energy states
by detecting high AMP levels; and sirtuins, which sense low energy states by detecting high
NAD+ levels (Houtkooper et al., 2010) (Figure 4A).
The mTOR kinase is part of two multiprotein complexes, mTORC1 and mTORC2, that
regulate essentially all aspects of anabolic metabolism (Laplante and Sabatini, 2012).
Genetic down-regulation of mTORC1 activity in yeast, worms and flies extends longevity
and attenuates further longevity benefits from DR, suggesting that mTOR inhibition
phenocopies DR (Johnson et al., 2013). In mice, treatment with rapamycin also extends
longevity in what is considered the most robust chemical intervention to increase lifespan in
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mammals (Harrison et al., 2009). Genetically-modified mice with low levels of mTORC1
activity, but normal levels of mTORC2, have increased lifespan (Lamming et al., 2012), and
mice deficient in S6K1 (a main mTORC1 substrate) are also long-lived (Selman et al.,
2009), thus pointing to the downregulation of mTORC1/S6K1 as the critical mediator of
longevity in relation to mTOR. Moreover, mTOR activity increases during aging in mouse
hypothalamic neurons, contributing to age-related obesity, which is reversed by direct
infusion of rapamycin to the hypothalamus (Yang et al., 2012). These observations, together
with those involving the IIS pathway, indicate that intense trophic and anabolic activity,
signaled through the IIS or the mTORC1 pathways, are major accelerators of aging.
Although inhibition of TOR activity clearly has beneficial effects during aging, it also has
undesirable side-effects, such as impaired wound healing, insulin resistance, cataract and
testicular degeneration in mice (Wilkinson et al., 2012). It will thus be important to
understand the mechanisms involved, in order to determine the extent to which beneficial
and damaging effects of TOR inhibition can be separated from each other.
The other two nutrient sensors, AMPK and sirtuins, act in the opposite direction to IIS and
mTOR, meaning that they signal nutrient scarcity and catabolism instead of nutrient
abundance and anabolism. Accordingly, their up-regulation favors healthy aging. AMPK
activation has multiple effects on metabolism and, remarkably, shuts off mTORC1 (Alers et
al., 2012). There is evidence indicating that AMPK activation may mediate lifespanextension following metformin administration to worms and mice (Anisimov et al., 2011;
Mair et al., 2011; Onken and Driscoll, 2010). The role of sirtuins in lifespan regulation has
been discussed above (see section on Epigenetic Alterations). In addition, SIRT1 can
deacetylate and activate the PPAR co-activator 1 (PGC-1) (Rodgers et al., 2005).
PGC-1 orchestrates a complex metabolic response that includes mitochondriogenesis,
enhanced anti-oxidant defenses, and improved fatty acid oxidation (Fernandez-Marcos and
Auwerx, 2011). Moreover, SIRT1 and AMPK can engage in a positive feedback loop, thus
connecting both sensors of low-energy states into a unified response (Price et al., 2012).
Overview
Collectively, current available evidence strongly supports the idea that anabolic signaling
accelerates aging, and decreased nutrient signaling extends longevity (Fontana et al., 2010).
Even more, a pharmacological manipulation that mimics a state of limited nutrient
availability, such as rapamycin, can extend longevity in mice (Harrison et al., 2009).
Mitochondrial Dysfunction
As cells and organisms age, the efficacy of the respiratory chain tends to diminish, thus
increasing electron leakage and reducing ATP generation (Green et al., 2011) (Figure 4B).
The relation between mitochondrial dysfunction and aging has been long suspected but
dissecting its details remains as a major challenge for aging research.
Reactive oxygen species (ROS)
The mitochondrial free radical theory of aging proposes that the progressive mitochondrial
dysfunction that occurs with aging results in increased production of reactive oxygen species
(ROS), which in turn causes further mitochondrial deterioration and global cellular damage
(Harman, 1965). Multiple data support a role for ROS in aging, but we focus here on the
developments of the last five years which have forced an intense re-evaluation of the
mitochondrial free radical theory of aging (Hekimi et al., 2011). Of particular impact has
been the unexpected observation that increased ROS may prolong lifespan in yeast and C.
elegans (Doonan et al., 2008; Mesquita et al., 2010; Van Raamsdonk and Hekimi, 2009). In
mice, genetic manipulations that increase mitochondrial ROS and oxidative damage do not
Lpez-Otn et al.
Page 13
accelerate aging (Van Remmen et al., 2003; Zhang et al., 2009), manipulations that increase
antioxidant defenses do not extend longevity (Perez et al., 2009), and, finally, genetic
manipulations that impair mitochondrial function but do not increase ROS accelerate aging
(Edgar et al., 2009; Hiona et al., 2010; Kujoth et al., 2005; Trifunovic et al., 2004; Vermulst
et al., 2008). These and similar data have paved the way to a reconsideration of the role of
ROS in aging (Ristow and Schmeisser, 2011). Indeed, parallel and separate to the work on
the damaging effects of ROS, the field of intracellular signaling has been accumulating solid
evidence for the role of ROS in triggering proliferative and survival signals, in response to
physiological signals and stress conditions (Sena and Chandel, 2012). The two lines of
evidence can be harmonized if ROS is regarded as a stress-elicited survival signal aimed at
compensating for the progressive deterioration associated with aging. As chronological age
advances, the levels of ROS increase in an attempt to maintain survival until they betray
their original purpose and eventually aggravate, rather than alleviate, the age-associated
damage (Hekimi et al., 2011). This new conceptual framework may accommodate
apparently conflicting evidence regarding the positive, negative or neutral effects of ROS on
aging.
Mitochondrial integrity and biogenesis
Dysfunctional mitochondria can contribute to aging independently of ROS, as exemplified
by studies with mice deficient in DNA polymerase (Edgar et al., 2009; Hiona et al., 2010)
(see above Genomic Instability). This could happen through a number of mechanisms, for
example, mitochondrial deficiencies may affect apoptotic signaling by increasing the
propensity of mitochondria to permeabilize in response to stress (Kroemer et al., 2007), and
trigger inflammatory reactions by favoring ROS-mediated and/or permeabilizationfacilitated activation of inflammasomes (Green et al., 2011). Also, mitochondrial
dysfunction may directly impact on cellular signaling and interorganellar crosstalk, by
affecting mitochondrion-associated membranes that constitute an interface between the outer
mitochondrial membrane and the endoplasmic reticulum (Raffaello and Rizzuto, 2011).
The reduced efficiency of mitochondrial bioenergetics with aging may result from multiple
converging mechanisms including reduced biogenesis of mitochondria, for instance as a
consequence of telomere attrition in telomerase-deficient mice, with subsequent p53mediated repression of PGC-1 and PGC-1 (Sahin and Depinho, 2012). This mitochondrial
decline also occurs during physiological aging in wild-type mice and can be partially
reversed by telomerase activation (Bernardes de Jesus et al., 2012). SIRT1 modulates
mitochondrial biogenesis through a process involving the transcriptional co-activator
PGC-1 (Rodgers et al., 2005) and the removal of damaged mitochondria by autophagy
(Lee et al., 2008). SIRT3, which is the main mitochondrial deacetylase (Lombard et al.,
2007), targets many enzymes involved in energy metabolism, including components of the
respiratory chain, tricarboxylic acid cycle, ketogenesis and fatty acid -oxidation pathways
(Giralt and Villarroya, 2012). SIRT3 may also directly control the rate of ROS production
by deacetylating manganese superoxide dismutase, a major mitochondrial antioxidant
enzyme (Qiu et al., 2010; Tao et al., 2010). Collectively, these results support the idea that
sirtuins may act as metabolic sensors to control mitochondrial function and play a protective
role against age-associated diseases.
Other mechanisms causing defective bioenergetics include accumulation of mutations and
deletions in mtDNA, oxidation of mitochondrial proteins, destabilization of the
macromolecular organization of respiratory chain (super)complexes, changes in the lipid
composition of mitochondrial membranes, alterations in mitochondrial dynamics resulting
from imbalance of fission and fusion events, and defective quality control by mitophagy, an
organelle-specific form of macroautophagy that targets deficient mitochondria for
proteolytic degradation (Wang and Klionsky, 2011). The combination of increased damage
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Page 14
and reduced turnover in mitochondria, due to lower biogenesis and reduced clearance, may
contribute to the aging process (Figure 4B).
Interestingly, endurance training and alternate-day-fasting may improve healthspan through

their capacity to avoid mitochondrial degeneration (Castello et al., 2011; Safdar et al., 2011).
It is tempting to speculate that these beneficial effects are mediated, at least in part, through
the induction of autophagy, for which both endurance training and fasting constitute potent
triggers (Rubinsztein et al., 2011). However, autophagy induction is probably not the sole
mechanism through which a healthy lifestyle can retard aging since, depending on the
precise DR regime, additional longevity pathways can be activated (Kenyon, 2010).
Mitohormesis
Mitochondrial dysfunctions during aging are also connected with hormesis, a concept on
which a number of aging research lines have recently converged (Calabrese et al., 2011).
According to this concept, mild toxic treatments trigger beneficial compensatory responses
that surpass the repair of the triggering damage, and actually produce an improvement in
cellular fitness when compared to the starting pre-damage conditions. Thus, although severe
mitochondrial dysfunction is pathogenic, mild respiratory deficiencies may increase
lifespan, perhaps due to a hormetic response (Haigis and Yankner, 2010). Such hormetic
reactions may consist in the induction of a mitochondrial stress response either in the same
tissue in which mitochondria are defective, or even in distant tissues, as shown in C. elegans
(Durieux et al., 2011). There is compelling evidence that compounds such as metformin and
resveratrol are mild mitochondrial poisons that induce a low energy state characterized by
increased AMP levels and activation of AMPK (Hawley et al., 2010). Importantly,
metformin extends lifespan in C. elegans through the induction of a compensatory stress
response mediated by AMPK and the master anti-oxidant regulator Nrf2 (Onken and
Driscoll, 2010). Recent studies have also shown that metformin retards aging in worms by
impairing folate and methionine metabolism of their intestinal microbiome (Cabreiro et al.,
2013). Regarding mammals, metformin can increase mouse lifespan when administered
from early life (Anisimov et al., 2011). In the cases of resveratrol and the sirtuin activator
SRT1720, there is convincing evidence that they protect from metabolic damage and
improve mitochondrial respiration in a PGC-1-dependent fashion (Baur et al., 2006; Feige
et al., 2008; Lagouge et al., 2006; Minor et al., 2011), although resveratrol does not extend
mouse lifespan under normal dietary conditions (Pearson et al., 2008; Strong et al., 2012).
Further support for the role of PGC-1 in longevity comes from the observation that
PGC-1 overexpression suffices to extend Drosophila lifespan in association with improved
mitochondrial activity (Rera et al., 2011). Finally, mitochondrial uncoupling, either
genetically through the overexpression of the uncoupling protein UCP1 or by administration
of the chemical uncoupler 2-4-dinitrophenol can increase lifespan in flies and mice (Caldeira
da Silva et al., 2008; Fridell et al., 2009; Gates et al., 2007; Mookerjee et al., 2010).
Overview
Mitochondrial function has a profound impact on the aging process. Mitochondrial
dysfunction can accelerate aging in mammals (Kujoth et al., 2005; Trifunovic et al., 2004;
Vermulst et al., 2008), but it is less clear whether improving mitochondrial function, for
example through mitohormesis, can extend lifespan in mammals, although suggestive
evidence in this sense already exists.
Cellular Senescence
Cellular senescence can be defined as a stable arrest of the cell cycle coupled to stereotyped
phenotypic changes (Campisi and dAdda di Fagagna, 2007; Collado et al., 2007; Kuilman
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Page 15
et al., 2010) (Figure 5A). This phenomenon was originally described by Hayflick in human
fibroblasts serially passaged in culture (Hayflick and Moorhead, 1961). Today, we know
that the senescence observed by Hayflick is caused by telomere shortening (Bodnar et al.,
1998), but there are other aging-associated stimuli that trigger senescence independently of
this telomeric process. Most notably, non-telomeric DNA damage and de-repression of the
INK4/ARF locus, both of which progressively occur with chronological aging, are also
capable of inducing senescence (Collado et al., 2007). The accumulation of senescent cells
in aged tissues has been often inferred using surrogate markers such as DNA damage. Some
studies have directly used senescence-associated -galactosidase (SABG) to identify
senescence in tissues (Dimri et al., 1995). Of note, a detailed and parallel quantification of
SABG and DNA damage in liver produced comparable quantitative data, yielding a total of
~8 % senescent cells in young mice and ~17% in very old mice (Wang et al., 2009). Similar
results were obtained in the skin, lung and spleen, but no changes were observed in heart,
skeletal muscle and kidney (Wang et al., 2009). Based on these data, it is clear that cellular
senescence is not a generalized property of all tissues in aged organisms. In the case of
senescent tumor cells, there is good evidence that they are subjected to strict immune
surveillance and are efficiently removed by phagocytosis (Hoenicke and Zender, 2012;
Kang et al., 2011; Xue et al., 2007). Conceivably, the accumulation of senescent cells with
aging can reflect an increase in the rate of generation of senescent cells and/or a decrease in
their rate of clearance, for example, as a consequence of an attenuated immune response.
Since the amount of senescent cells increases with aging, it has been widely assumed that
senescence contributes to aging. However, this view undervalues what conceivably is the
primary purpose of senescence, which is to prevent the propagation of damaged cells and to
trigger their demise by the immune system. Therefore, it is possible that senescence is a
beneficial compensatory response that contributes to rid tissues from damaged and
potentially oncogenic cells. This cellular checkpoint, however, requires an efficient cell
replacement system that involves clearance of senescent cells and mobilization of
progenitors to re-establish cell numbers. In aged organisms, this turnover system may
become inefficient or may exhaust the regenerative capacity of progenitor cells, eventually
resulting in the accumulation of senescent cells that may aggravate the damage and
contribute to aging (Figure 5A).
In recent years, it has been appreciated that senescent cells manifest dramatic alterations in
their secretome, which is particularly enriched in pro-inflammatory cytokines and matrix
metalloproteinases, and is referred to as the senescence-associated secretory phenotype
(Kuilman et al., 2010; Rodier and Campisi, 2011). This pro-inflammatory secretome may
contribute to aging (see section on Intercellular Communication).
The INK4a/ARF locus and p53
In addition to DNA damage, excessive mitogenic signaling is the other stress most robustly
associated to senescence. A recent account listed more than 50 oncogenic or mitogenic
alterations that are able to induce senescence (Gorgoulis and Halazonetis, 2010). The
number of mechanisms that implement senescence in response to this variety of oncogenic
insults has also grown, but, still, the originally reported p16INK4a/Rb and p19ARF/p53
pathways remain, in general, the most important ones (Serrano et al., 1997). The relevance
of these pathways for aging becomes even more striking when considering that the levels of
p16INK4a (and to a lower extent also p19ARF) correlate with the chronological age of
essentially all tissues analyzed, both in mice and humans (Krishnamurthy et al., 2004;
Ressler et al., 2006). We are not aware of any other gene or protein whose expression is so
robustly correlated with chronological aging, across tissues, across species, and with a range
of variation that, on average, is one order of magnitude between young and old tissues. Both
Lpez-Otn et al.
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p16INK4a and p19ARF are encoded by the same genetic locus, the INK4a/ARF locus. A
recent meta-analysis of more than 300 genome wide association studies (GWAS) identified
the INK4a/ARF locus as the genomic locus that is genetically linked to the highest number
of age-associated pathologies, including several types of cardiovascular diseases, diabetes,
glaucoma, and Alzheimers disease (Jeck et al., 2012).
The critical role of p16INK4a and p53 in the induction of cell senescence has favored the
hypothesis that p16INK4a-induced and p53-induced senescence contribute to physiological
aging. According to this view, the pro-aging activity of p16INK4a and p53 would be a
tolerable toll compared to their benefits in tumor suppression. In support of this, mutant
mice with premature aging due to extensive and persistent damage, present dramatic levels
of senescence and their progeroid phenotypes are ameliorated by elimination of p16Ink4a or
p53. This is the case of mice deficient in BRCA1 (Cao et al., 2003), of a mouse model of
HGPS (Varela et al., 2005), and of mice with defective chromosomal stability due to a
hypomorphic mutation of BubR1 (Baker et al., 2011). However, other evidence suggests a
more complicated picture. In contrast to their anticipated pro-aging role, mice with a mild
and systemic increase in p16Ink4a, p19Arf or p53 tumor suppressors exhibit extended
longevity, which cannot be accounted for by their lower cancer incidence (Matheu et al.,
2009; Matheu et al., 2007). Also, elimination of p53 aggravates the phenotypes of some
progeroid mutant mice (Begus-Nahrmann et al., 2009; Murga et al., 2009; Ruzankina et al.,
2009). Again, as discussed above for senescence, the activation of p53 and INK4a/ARF can
be regarded as a beneficial compensatory response aimed at avoiding the propagation of
damaged cells and its consequences on aging and cancer. However, when damage is
pervasive, the regenerative capacity of tissues can be exhausted or saturated and, under these
extreme conditions, the p53 and INK4a/ARF responses can become deleterious and
accelerate aging.
Overview
We propose that cellular senescence is a beneficial compensatory response to damage that

becomes deleterious and accelerates aging when tissues exhaust their regenerative capacity.
Given these complexities, it is not possible to give a simple answer to the question of
whether cell senescence fulfills the third ideal criteria for the definition of a hallmark. A
moderate enhancement of the senescence-inducing tumor suppressor pathways may extend
longevity (Matheu et al., 2009; Matheu et al., 2007), and, at the same time, elimination of
senescent cells in an experimental progeria model delays age-related pathologies (Baker et
al., 2011). Therefore, two interventions that are conceptually opposite are able to extend
healthspan.
Stem Cell Exhaustion

The decline in the regenerative potential of tissues is one of the most obvious characteristics
of aging (Figure 5B). For example, hematopoiesis declines with age, resulting in a
diminished production of adaptive immune cells, a process termed immunosenescence, and
in an increased incidence of anemia and myeloid malignancies (Shaw et al., 2010). A similar
functional attrition of stem cells has been found in essentially all adult stem cell
compartments, including the mouse forebrain (Molofsky et al., 2006), the bone (Gruber et
al., 2006), or the muscle fibers (Conboy and Rando, 2012). Studies on aged mice have
revealed an overall decrease in cell cycle activity of hematopoietic stem cells (HSCs), with
old HSCs undergoing fewer cell divisions than young HSCs (Rossi et al., 2007). This
correlates with the accumulation of DNA damage (Rossi et al., 2007), and with the
overexpression of cell cycle-inhibitory proteins such as p16INK4a (Janzen et al., 2006). In
fact, old INK4a/ HSCs exhibit better engraftment capacity and increased cell cycle
activity compared with old wild-type HSCs (Janzen et al., 2006). Telomere shortening is
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Page 17
also an important cause of stem cell decline with aging in multiple tissues (Flores and
Blasco, 2010; Sharpless and DePinho, 2007). These are just examples of a much larger
picture where stem cell decline emerges as the integrative consequence of multiple types of
damage.
Although deficient proliferation of stem and progenitor cells is obviously detrimental for the
long-term maintenance of the organism, an excessive proliferation of stem and progenitor
cells can also be deleterious by accelerating the exhaustion of stem cell niches. The
importance of stem cell quiescence for the long-term functionality of stem cells has been
compellingly demonstrated in the case of Drosophila intestinal stem cells, where excessive
proliferation leads to exhaustion and premature aging (Rera et al., 2011). A similar situation
is encountered in p21-null mice, which present premature exhaustion of HSCs and neural
stem cells (Cheng et al., 2000; Kippin et al., 2005). In this regard, the induction of INK4a
during aging (see section on Cellular Senescence) and the decrease of serum IGF-1 (see
section on Deregulated Nutrient-sensing), may both reflect an attempt of the organism to
preserve the quiescence of stem cells. Also, recent studies have shown that an increase in
FGF2 signaling in the aged muscle stem cell niche results in the loss of quiescence, and
eventually in stem cell depletion and diminished regenerative capacity, while suppression of
this signaling pathway rescues these defects (Chakkalakal et al., 2012). This opens the
possibility of designing strategies aimed at inhibiting FGF2 signaling to reduce stem cell
exhaustion during aging.
An important debate regarding the decline in stem-cell function is the relative role of cellintrinsic pathways compared to cell-extrinsic ones (Conboy and Rando, 2012). Recent work
has provided strong support for the latter. In particular, DR increases intestinal and muscle
stem functions through cell-extrinsic mechanisms (Cerletti et al., 2012; Yilmaz et al., 2012).
Likewise, transplantation of muscle-derived stem cells from young mice to progeroid mice
extends lifespan and improves degenerative changes of these animals even in tissues where
donor cells are not detected, suggesting that their therapeutic benefit may derive from
systemic effects caused by secreted factors (Lavasani et al., 2012). Furthermore, parabiosis
experiments have demonstrated that the decline in neural and muscle stem cell function in
old mice can be reversed by systemic factors from young mice (Conboy et al., 2005; Villeda
et al., 2011).
Pharmacological interventions are also being explored to improve stem cell function. In
particular, mTORC1 inhibition with rapamycin, which can postpone aging by improving
proteostasis (see section on Loss of Proteostasis) and by affecting energy sensing (see
section on Deregulated Nutrient-sensing), may also improve stem cell function in the
epidermis, in the hematopoietic system, and in the intestine (Castilho et al., 2009; Chen et
al., 2009; Yilmaz et al., 2012). This illustrates the difficulty of disentangling the mechanistic
basis for the anti-aging activity of rapamycin, and underscores the interconnectedness
between the different hallmarks of aging discussed here. It is also worth mentioning that it is
possible to rejuvenate human senescent cells by pharmacological inhibition of the GTPase
CDC42, whose activity is increased in aged HSCs (Florian et al., 2012).
Overview
Stem cell exhaustion unfolds as the integrative consequence of multiple types of agingassociated damages and likely constitutes one of the ultimate culprits of tissue and
organismal aging. Recent promising studies suggest that stem cell rejuvenation may reverse
the aging phenotype at the organismal level (Rando and Chang, 2012).
Lpez-Otn et al.
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Altered Intercellular Communication
Beyond cell-autonomous alterations, aging also involves changes at the level of intercellular
communication, be it endocrine, neuroendocrine or neuronal (Laplante and Sabatini, 2012;
Rando and Chang, 2012; Russell and Kahn, 2007; Zhang et al., 2013) (Figure 5C). Thus,
neurohormonal signaling (eg, renin-angiotensin, adrenergic, insulin-IGF1 signaling) tends to
be deregulated in aging as inflammatory reactions increase, immunosurveillance against
pathogens and premalignant cells declines, and the composition of the peri- and extracellular
environment changes, thereby affecting the mechanical and functional properties of all
tissues.
Inflammation
A prominent aging-associated alteration in intercellular communication is inflammaging,

i.e. a smoldering pro-inflammatory phenotype that accompanies aging in mammals
(Salminen et al., 2012). Inflammaging may result from multiple causes such as the
accumulation of pro-inflammatory tissue damage, the failure of an ever more dysfunctional
immune system to effectively clear pathogens and dysfunctional host cells, the propensity of
senescent cells to secrete pro-inflammatory cytokines (see section on Cellular Senescence),
the enhanced activation of the NF-B transcription factor, or the occurrence of a defective
autophagy response (Salminen et al., 2012). These alterations result in an enhanced
activation of the NLRP3 inflammasome and other pro-inflammatory pathways, finally
leading to increased production of IL-1, tumor necrosis factor and interferons (Green et al.,
2011; Salminen et al., 2012). Inflammation is also involved in the pathogenesis of obesity
and type 2 diabetes, two conditions that contribute to, and correlate with aging in the human
population (Barzilai et al., 2012). Likewise, defective inflammatory responses play a critical
role in atherosclerosis (Tabas, 2010). The recent finding that age-associated inflammation
inhibits epidermal stem cell function (Doles et al., 2012), further supports the intricate
concatenation of different hallmarks that reinforces the aging process. Paralleling
inflammaging, the function of the adaptive immune system declines (Deeks, 2011). This
immunosenescence may aggravate the aging phenotype at the systemic level, due to the
failure of the immune system to clear infectious agents, infected cells, and cells on the verge
of malignant transformation. Moreover, one of the functions of the immune system is to
recognize and eliminate senescent cells (see section on Stem Cell Exhaustion), as well as
hyperploid cells that accumulate in aging tissues and premalignant lesions (Davoli and de
Lange, 2011; Senovilla et al., 2012).
Global studies on the transcriptional landscape of aged tissues have also emphasized the
relevance of inflammatory pathways in aging (de Magalhaes et al., 2009; Lee et al., 2012).
Over-activation of the NF-B pathway is one of these transcriptional signatures of aging and
conditional expression of an NF-B inhibitor in the aged skin of transgenic mice causes the
phenotypic rejuvenation of this tissue, as well as the restoration of the transcriptional
signature corresponding to young age (Adler et al., 2007). Likewise, genetic and
pharmacological inhibition of NF-B signaling prevents age-associated features in different
mouse models of accelerated aging (Osorio et al., 2012; Tilstra et al., 2012). A novel link
between inflammation and aging derives from the recent finding that inflammatory and
stress responses activate NF-B in the hypothalamus and induce a signaling pathway that
results in reduced production of gonadotropin-releasing hormone (GnRH) by neurons
(Zhang et al., 2013). This GnRH decline can contribute to numerous aging-related changes
such as bone fragility, muscle weakness, skin atrophy and reduced neurogenesis.
Consistently, GnRH treatment prevents aging-impaired neurogenesis and decelerates aging
development in mice (Zhang et al., 2013). These findings suggest that the hypothalamus
may modulate systemic aging by integrating NF-kB-driven inflammatory responses with
GnRH-mediated neuroendocrine effects.
Lpez-Otn et al.
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Further in vivo evidence linking inflammation and aging derives from work on the mRNA
decay factor AUF1, which is implicated in the cessation of the inflammatory response by
mediating cytokine mRNA degradation (Pont et al., 2012). AUF1-deficient mice exhibit a
marked cellular senescence and premature aging phenotype that can be rescued by reexpression of this RNA-binding factor. Interestingly, and in addition to directing
inflammatory cytokine mRNA decay, AUF1 contributes to maintaining telomere length by
activating the expression of the telomerase catalytic subunit TERT (Pont et al., 2012), again
demonstrating that one single factor may have a strong impact on different aging hallmarks.
A similar situation occurs with sirtuins, which may also have an impact on inflammatory
responses associated with aging. Several studies have revealed that, by deacetylating
histones and components of inflammatory signaling pathways such as NF-B, SIRT1 can
down-regulate inflammation-related genes (Xie et al., 2012). Consistent with these findings,
reduction of SIRT1 levels correlates with the development and progression of many
inflammatory diseases, while pharmacologic activation of SIRT1 may prevent inflammatory
responses in mice (Gillum et al., 2011; Yao et al., 2012; Zhang et al., 2010). SIRT2 and
SIRT6 may also down-regulate the inflammatory response through deacetylation of NF-kB
subunits and transcriptional repression of their target genes (Kawahara et al., 2009;
Rothgiesser et al., 2010).
Other types of intercellular communication
Beyond inflammation, accumulating evidence indicates that aging-related changes in one

tissue can lead to aging-specific deterioration of other tissues, explaining the inter-organ
coordination of the aging phenotype. In addition to inflammatory cytokines, there are other
examples of contagious aging or bystander effects in which senescent cells induce
senescence in neighboring cells via gap junction-mediated cell-cell contacts and processes
involving ROS (Nelson et al., 2012). The microenvironment contributes to the age-related
functional defects of CD4 T cells, as assessed by using an adoptive transfer model in mice
(Lefebvre et al., 2012). Likewise, impaired kidney function can increase the risk of heart
disease in humans (Sarnak et al., 2003). Conversely, lifespan-extending manipulations
targeting one single tissue can retard the aging process in other tissues (Durieux et al., 2011;
Lavasani et al., 2012; Tomas-Loba et al., 2008).
Restoring defective intercellular communication
There are several possibilities for restoring defective intercellular communication underlying
aging processes, including genetic, nutritional or pharmacological interventions that may
improve the cell-cell communication properties that are lost with aging (Freije and LopezOtin, 2012; Rando and Chang, 2012). Of special interest in this regard are the DR
approaches to extend healthy lifespan (Piper et al., 2011; Sanchez-Roman et al., 2012), and
the rejuvenation strategies based on the use of blood-borne systemic factors identified in
parabiosis experiments (Conboy et al., 2005; Loffredo et al., 2013; Villeda et al., 2011).
Moreover, the long-term administration of anti-inflammatory agents such as aspirin may
increase longevity in mice and healthy aging in humans (Rothwell et al., 2011; Strong et al.,
2008). Additionally, given that the gut microbiome shapes the function of the host immune
system and exerts systemic metabolic effects, it appears possible to extend lifespan by
manipulating the composition and functionality of the complex and dynamic intestinal
bacterial ecosystem of the human body (Claesson et al., 2012; Ottaviani et al., 2011).
Overview
There is compelling evidence that aging is not an exclusively cell biological phenomenon
and that it is coupled to a general alteration in intercellular communication, offering
opportunities to modulate aging at this level. Excitingly, proof of principle exists for
Lpez-Otn et al.
Page 20
rejuvenation through blood-borne systemic factors (Conboy et al., 2005; Loffredo et al.,
2013; Villeda et al., 2011).
Conclusions and Perspectives

A global view at the nine candidate hallmarks of aging enumerated in this review allows
grouping them into three categories: primary hallmarks, antagonistic hallmarks, and
integrative hallmarks (Figure 6). The common characteristic of the primary hallmarks is the
fact that they are all unequivocally negative. This is the case of DNA damage, including
chromosomal aneuploidies, mitochondrial DNA mutations and telomere loss, epigenetic
drift, and defective proteostasis. In contrast to the primary hallmarks, antagonistic hallmarks
have opposite effects depending on their intensity. At low levels, they mediate beneficial
effects, but at high levels, they become deleterious. This is the case for senescence, which
protects the organism from cancer, but in excess can promote aging; similarly, reactive
oxygen species (ROS) mediate cell signaling and survival, but at chronic high levels can
produce cellular damage; likewise, an optimal nutrient-sensing and anabolism is obviously
important for survival but in excess and during time can become pathological. These
hallmarks can be viewed as designed for protecting the organism from damage or from
nutrient scarcity, but when exacerbated or chronic, subvert their purpose and generate
further damage. A third category comprises the integrative hallmarks, stem cell exhaustion
and altered intercellular communication, which directly affect tissue homeostasis and
function. Notwithstanding the interconnectedness between all hallmarks, we propose some
degree of hierarchical relation between them (Figure 6). The primary hallmarks could be the
initiating triggers whose damaging events progressively accumulate with time. The
antagonistic hallmarks, being in principle beneficial, become progressively negative in a
process that is partly promoted or accelerated by the primary hallmarks. Finally, the
integrative hallmarks arise when the accumulated damage caused by the primary and
antagonistic hallmarks cannot be compensated by tissue homeostatic mechanisms. Because
the hallmarks co-occur during aging and are interconnected, understanding their exact causal
network is an exciting challenge for future work.
The definition of hallmarks of aging may contribute to build a framework for future studies
on the molecular mechanisms of aging as well as for designing interventions to improve
human healthspan (Figure 7). However, there are still numerous challenges ahead in relation
to understanding this complex biological process (Martin, 2011; Miller, 2012). The rapid
development of next-generation sequencing technologies may have a special impact on
aging research by facilitating the evaluation of the genetic and epigenetic changes
specifically accumulated by individual cells in an aging organism (de Magalhaes et al.,
2010; Gundry and Vijg, 2012). These techniques are already being used to determine the
whole-genome sequence of individuals with exceptional longevity, to perform comparative
genomic studies between short-lived and long-lived animal species and strains, and to
analyze age-associated epigenetic changes at maximum resolution (Heyn et al., 2012; Kim
et al., 2011; Sebastiani et al., 2011). Parallel in vivo studies with gain- or loss-of-function
animal models will be necessary for moving beyond correlative analyses and providing
causal evidence in favor of the implication of these proposed hallmarks in the aging process.
Besides the characterization of individual hallmarks, systems biology approaches will be
required to understand the mechanistic links among the processes that accompany and lead
to aging (Gems and Partridge, 2013; Kirkwood, 2008). Additionally, molecular analysis of
the genome-environment interactions that modulate aging will help to identify drug targets
for longevity promotion (de Magalhaes et al., 2012). We surmise that ever more
sophisticated approaches for disentangling the complexities of normal, accelerated and
delayed aging will eventually resolve many of the pending issues. Hopefully, these
combined approaches will allow a detailed understanding of the mechanisms underlying the
Lpez-Otn et al.
Page 21
hallmarks of aging and will facilitate future interventions for improving human healthspan
and longevity.
Acknowledgments
We thank all members of our labs for their helpful comments on the manuscript and apologize for omission of
relevant works due to space constraints. C.L-O. is supported by grants from Ministerio de Economa y
Competitividad (MINECO) and Instituto de Salud Carlos III (RTICC), and is an Investigator of the Botn
Foundation. M.S. is funded by grants from the MINECO, European Union (ERC Advanced Grant), Regional
Government of Madrid, Botn Foundation, Ramn Areces Foundation, and AXA Foundation. L.P. is supported by
the Max Planck Society, the ERC and the Wellcome Trust (UK). M.A.B. is funded by ERC Project TEL STEM
CELL, FP7 Projects MARK-AGE and EuroBATS, MINECO, Regional Government of Madrid, AXA Research
Fund, Botn Foundation and Fundacin Lilly (Spain). G.K. is supported by the Ligue Nationale contre le Cancer
(Equipes labellise), Agence Nationale pour la Recherche, AXA Foundation Chair for Longevity Research,
European Commission (ERC Advanced Grant, ArtForce, ChemoRes), Fondation pour la Recherche Mdicale
(FRM), Institut National du Cancer (INCa), Fondation de France, Cancrople Ile-de-France, Fondation
Bettencourt-Schueller, the LabEx Immuno-Oncology, and the Paris Alliance of Cancer Research Institutes.
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Figure 1. The Hallmarks of Aging
The scheme enumerates the nine hallmarks described in this review: genomic instability,
telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient-sensing,
mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered
intercellular communication.
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Figure 2. Genomic and Epigenomic Alterations
A) Genomic instability and telomere attrition. Endogenous or exogenous agents can

stimulate a variety of DNA lesions that are schematically represented on one single
chromosome. Such lesions can by repaired by a variety of mechanisms. Excessive DNA
damage or insufficient DNA repair favors the aging process. Note that both nuclear DNA
and mitochondrial DNA (not represented here) are subjected to age-associated genomic
alterations. BER, base excision repair; HR, homologous recombination; NER, nucleotide
excision repair; NHEJ, non-homologous end joining; MMR, mismatch repair; ROS, reactive
oxygen species; TLS, translesion synthesis; SAC, spindle assembly checkpoint.
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B) Epigenetic alterations. Alterations in the acetylation and methylation of DNA or

histones, as well as of other chromatin-associated proteins, can induce epigenetic changes
that contribute to the aging process.

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Figure 3. Loss of Proteostasis
Endogenous and exogenous stress causes the unfolding of proteins (or impairs proper
folding during protein synthesis). Unfolded proteins are usually refolded by heat-shock
proteins (HSP) or targeted to destruction by the ubiquitin-proteasome or lysosomal
(autophagic) pathways. The autophagic pathways include recognition of unfolded proteins
by the chaperone Hsc70 and their subsequent import into lysosomes (chaperone-mediated
autophagy) or sequestration of damaged proteins and organelles in autophagosomes that
later fuse with lysosomes (macroautophagy). Failure to refold or degrade unfolded proteins
can lead to their accumulation and aggregation, resulting in proteotoxic effects.
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Figure 4. Metabolic Alterations
A) Deregulated nutrient-sensing. Overview of the somatroph axis involving growth

hormone (GH) and the insulin/insulin growth factor 1 (IGF-1) signaling pathway, and its
relationship to dietary restriction and aging. Molecules that favor aging are shown in orange,
while molecules with anti-aging properties are shown in light green.
B) Mitochondrial dysfunction. Mitochondrial function becomes perturbed by agingassociated mtDNA mutations, reduced mitochondriogenesis, destabilization of the electron
transport chain (ETC) complexes, altered mitochondrial dynamics or defective quality
control by mitophagy. Stress signals and defective mitochondrial function generate ROS
that, below a certain threshold, induce survival signals to restore cellular homeostasis, but at
higher or continued levels can contribute to aging. Similarly, mild mitochondrial damage
can induce a hormetic response (mitohormesis) that triggers adaptive compensatory
processes.
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Figure 5. Cellular Senescence, Stem Cell Exhaustion and Altered Intercellular Communication
A) Cellular senescence. In young organisms, cellular senescence prevents the proliferation

of damaged cells, thus protecting from cancer and contributing to tissue homeostasis. In old
organisms, the pervasive damage and the deficient clearance and replenishment of senescent
cells results in their accumulation, and this has a number of deleterious effects on tissue
homeostasis that contribute to aging.
B) Stem cell exhaustion. Consequences of the exhaustion of hematopoietic stem cells
(HSCs), mesenchymal stem cells (MSCs), satellite cells and intestinal epithelial stem cells
(IESCs) are exemplified.
C) Altered intercellular communication. Examples of altered intercellular communication
associated with aging.
Lpez-Otn et al.
Page 46

Figure 6. Functional Interconnections between the Hallmarks of Aging
The proposed nine hallmarks of aging are grouped into three categories. In the top, those
hallmarks considered to be the primary causes of cellular damage. In the middle, those
considered to be part of compensatory or antagonistic responses to the damage. These
responses initially mitigate the damage, but eventually, if chronic or exacerbated, they
become deleterious themselves. In the bottom, there are integrative hallmarks that are the
end result of the previous two groups of hallmarks and are ultimately responsible for the
functional decline associated with aging.
Lpez-Otn et al.
Page 47

Figure 7. Interventions that Might Extend Human Healthspan
The nine hallmarks of aging are shown together with those therapeutic strategies for which
there are proof of principle in mice.

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