ASSOCIATE EDITOR: MARK P. MATTSON
Genome-Environment Interactions That Modulate
Aging: Powerful Targets for Drug Discovery
Joa ˜o Pedro de Magalha ˜es, Daniel Wuttke, Shona H. Wood, Michael Plank, and Chintan Vora1
Integrative Genomics of Ageing Group, Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
II. Environmental manipulations of aging in animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
III. Diet, health, and aging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
IV. Genome-environment interactions as targets for dietary interventions and drug discovery . . . . . .
V. Functional genomics of aging, target prioritization, and future prospects. . . . . . . . . . . . . . . . . . . . . .
A. Functional genomics of aging and longevity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
B. Prioritizing targets for drug discovery and network approaches . . . . . . . . . . . . . . . . . . . . . . . . . . .
C. Translation to extend human healthspan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
D. Future prospects in epigenetics and aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
VI. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Abstract——Aging is the major biomedical challenge
of this century. The percentage of elderly people, and
consequently the incidence of age-related diseases
such as heart disease, cancer, and neurodegenerative
diseases, is projected to increase considerably in the
coming decades. Findings from model organisms have
revealed that aging is a surprisingly plastic process
that can be manipulated by both genetic and environ-
mental factors. Here we review a broad range of find-
ings in model organisms, from environmental to ge-
netic manipulations of aging, with a focus on those
with underlying gene-environment interactions with
potential for drug discovery and development. One
well-studied dietary manipulation of aging is caloric
restriction, which consists of restricting the food in-
take of organisms without triggering malnutrition
and has been shown to retard aging in model organ-
isms. Caloric restriction is already being used as a
paradigm for developing compounds that mimic its
life-extension effects and might therefore have thera-
peutic value. The potential for further advances in
this field is immense; hundreds of genes in several
pathways have recently emerged as regulators of ag-
ing and caloric restriction in model organisms. Some
of these genes, such as IGF1R and FOXO3, have also
been associated with human longevity in genetic asso-
ciation studies. The parallel emergence of network
approaches offers prospects to develop multitarget
drugs and combinatorial therapies. Understanding
how the environment modulates aging-related genes
may lead to human applications and disease therapies
through diet, lifestyle, or pharmacological interven-
tions. Unlocking the capacity to manipulate human
aging would result in unprecedented health benefits.
Aging, the inevitable and irreversible process of loss of
viability and increase in vulnerability, is shaping mod-
ern society and medicine. In some European countries,
such as Italy, Spain, and the United Kingdom, it is
estimated that by 2050, the proportion of people older
than 60 will rise from roughly 20% to almost 40%
(Weiss, 2002). Because age is a risk factor for most
human diseases, ranging from arthritis to life-threaten-
ing diseases such as type 2 diabetes and most types of
cancer, this “graying” of the population is arguably the
major biological and biomedical challenge of the 21st
century. Age-related diseases such as heart disease, can-
cer, and neurodegenerative diseases are already among
the leading causes of death in industrialized countries,
and their prevalence will inevitably increase (Olshansky
et al., 2006; Butler et al., 2008). By 2050, there may be
four times more patients with Alzheimer’s disease. On
Address correspondence to: Joa ˜o Pedro de Magalha ˜es, University
of Liverpool, Biosciences Building, Room 245, Crown Street, Liver-
pool L69 7ZB, UK. E-mail: firstname.lastname@example.org
1Current affiliation: Xcelris Labs Ltd., Ahmedabad, India.
This article is available online at http://pharmrev.aspetjournals.org.
Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
Pharmacol Rev 64:88–101, 2012
Vol. 64, No. 1
top of an aging population, the obesity epidemic affect-
ing several modern societies, such as the United States
and the United Kingdom, further emphasizes the need
to develop interventions that minimize the effects of the
metabolic syndrome and impact of diseases such as type
2 diabetes (Wang et al., 2007).
With an aging population, there is a great and urgent
need to develop approaches and therapies targeting the
aging process and age-related diseases (Butler et al.,
2008). Delaying the process of aging, even slightly,
would have profound social, medical and economic ben-
efits (Olshansky et al., 2006; Butler et al., 2008). For
example, slowing aging by a mere 7 years would cut
mortality of age-related diseases by half at every age.
Therefore, the potential benefits from research on the
basic biology and genetics of aging are unparalleled in
terms of improving quality of life and health. Although
much debate remains regarding the molecular causes of
aging, findings from model organisms show that aging is
surprisingly plastic and can be manipulated by both
genetic and environmental factors (Finch and Ruvkun,
2001; Kenyon, 2010). In principle, therefore, it is possi-
ble to manipulate human aging. Unlocking this capacity
to manipulate aging in people would result in unprece-
dented human health benefits, and it opens new oppor-
tunities for industry.
The remarkable discoveries of the past 2 decades
showing that single genes can regulate aging in model
organisms demonstrate that aging can be genetically
manipulated (Finch and Ruvkun, 2001; Kenyon, 2010).
Hundreds of genes that modulate longevity have now
been identified in model organisms (de Magalha ˜es et al.,
2009a). In some cases (e.g., in worms), mutations in
single genes can extend lifespan by almost 10-fold (Ayy-
adevara et al., 2008). Nonetheless, aging is a complex
process that derives not from single genes but from the
interactions of multiple genes with each other and with
the environment. Evidence from animal systems shows
a major impact of the environment on aging, yet envi-
ronmental manipulations of aging act through genes
and proteins, usually by triggering signaling pathways
and modulating gene expression. In fact, some genes
have been shown in model organisms to have varying
effects on lifespan depending on diet (Heikkinen et al.,
2009). Genes that can regulate aging in model organ-
isms cannot be directly applied to humans through ge-
netic manipulations for numerous legal, ethical, and
technical reasons. If we could understand how the envi-
ronment modulates these aging-related genes, we might
be able to create antiaging therapies applicable to hu-
mans, potentially through diet, lifestyle, and even phar-
macological interventions. Therefore, understanding ge-
nome-environment interactions in the context of aging
can be a powerful approach to identify attractive targets
for drug design.
In this review, we give an overview of the major envi-
ronmental factors that modulate aging in animals, in
particular those with underlying gene-environment in-
teractions with potential for improving human health
and drug discovery. Moreover, we provide a snapshot of
the relevance of these to human biology and to antiaging
applications in diet, industry, pharmacy, and healthcare.
II. Environmental Manipulations of Aging
There are multiple examples of environmental manip-
ulations of aging in animal systems. A well known ex-
ample of this is temperature; in many poikilotherms,
environmental temperature has been known for decades
to modulate life history, including lifespan. Invertebrate
model organisms such as fruit flies (Drosophila melano-
gaster) and nematode worms (Caenorhabditis elegans)
exhibit longer lifespan (up to a certain threshold) at
lower temperatures (Lamb, 1968; Klass, 1977). Such
effects have been observed in other species such as fish
(for review, see Conti, 2008). Although obviously not
easy to apply to humans, it is interesting to note that
mice genetically engineered to have a lower body tem-
perature are long-lived (Conti et al., 2006; Conti, 2008;
Carrillo and Flouris, 2011).
Organisms adapt to their environment and, particu-
larly during development, can alter their phenotypes in
response to environmental cues, a process known as
phenotypic plasticity. Often, as organisms adapt to their
environment, they adapt their developmental programs
in ways that affect adult lifespan. The classic example
comes from the caste systems found in social insects
such as ants and bees. Queens, who are fed a different
diet, can considerably outlive workers (Finch, 1990;
Rueppell et al., 2007). Another example in alternative
life history strategies is the dauer pathway of C. elegans.
In low-food or crowded conditions, worms enter a form of
developmental arrest called dauer, once believed to fore-
stall aging completely, that considerably extends lifes-
pan (Klass and Hirsh, 1976). Larvae of the sea slug
(Phestilla sibogae), in contrast, require a particular en-
vironmental cue (a food source) in order to metamor-
phose, and, because postlarval lifespan is unaffected by
how long it takes for the larvae to metamorphose, life-
span can be considerably extended by artificially pre-
venting the larvae from coming in contact with its meta-
morphic stimulus (Miller and Hadfield, 1990). These
animals clearly illustrate how environmental conditions
can result in developmental plasticity that has profound
effects on aging and longevity.
More recently, work has focused on another nematode
worm, Strongyloides ratti, that exhibits alternative life
histories. S. ratti is a parasite, the free-living form is
very short-lived (?5 days), yet once inside a host, female
worms can live for more than a year (Gardner et al.,
2006). These remarkable (?50-fold) differences in life-
span from the same genome are, as far as we are aware,
the largest lifespan difference caused by the environ-
AGING GENES AS TARGETS FOR DRUG DISCOVERY
ment. It should be noted, however, that the two forms of
S. ratti are quite different morphologically and physio-
logically, and so identifying the specific mechanisms
involved in life-extension is difficult.
One last example is the Australian redback spider
(Latrodectus hasselti), in which male spiders do not eat
as adults and are thus short-lived. Their development,
reproduction, and aging can be modulated, however, by
the presence of female spiders: male spiders reared in
the absence of female spiders develop slowly and main-
tain a high body condition, whereas male spiders reared
in the presence of female spiders develop rapidly and
have a shorter lifespan. It is possible that the male
spiders sense pheromones from female spiders, which
trigger the male spiders’ development and consequently
degeneration and death (Kasumovic et al., 2009). Envi-
ronmental sensing involving the olfactory system and, at
least in invertebrates, specific sensory neurons has been
shown to be part of the cascade linking the environment
to longevity (Libert and Pletcher, 2007).
Although there are many other examples, these ani-
mals illustrate how environmental conditions can lead
to extreme alterations in aging and longevity. Their
relevance to humans may appear at first glance to be
minimal. For instance, epidemiological evidence sug-
gests that, if anything, single men have on average a
shorter lifespan (Kaplan and Kronick, 2006), so parallels
between the redback spider and humans are unlikely to
exist. Remarkably, however, the recent investigation in
model organisms of some of the genetic and molecular
pathways involved in environmental manipulations of
aging, particularly in the dauer formation in worms,
indicates these may lead to human applications and
therapies. Among the first genes shown to regulate lon-
gevity was daf-2, identified by Kenyon et al. (1993) by
focusing on genes that regulate the dauer pathway (“daf”
comes from abnormal dauer formation). Worms with
daf-2 mutations live more than twice as long as normal.
In recent years, some of the aging-related genes identi-
fied in worms have been shown to have mammalian
homologs that modulate longevity and delay age-related
diseases in mice, in particular as part of the insulin/
insulin-like growth factor (IGF12)/growth hormone (GH)
pathway (Bartke, 2005), and variants in these genes
have even been associated with human longevity, such
as the daf-2 homolog IGF1R (Suh et al., 2008). There-
fore, there is great potential for human homologs of
genes shown to modulate aging in model organisms to
represent pharmaceutical targets with human applica-
III. Diet, Health, and Aging
The previous examples of how diet can modulate aging
(e.g., social insects and the dauer pathway) are extreme
cases not observed in humans. There is evidence, how-
ever, that the environment, and diet in particular, can
influence aging trajectories in humans. Such environ-
mental influences can be observed from an early age
with long-lasting effects. Early nutrition can affect late-
life diseases, such as cardiovascular disease (Barker and
Osmond, 1986) and mortality (Gluckman et al., 2008;
Hanson and Gluckman, 2008). Likewise, infections in
early life can increase inflammatory levels and, together
with diet, contribute to late-life diseases (Finch, 2010).
The specific genes and mechanisms involved are largely
unknown, but these epidemiological studies clearly dem-
onstrate that early life environment can affect aging,
and these effects are most likely mediated by gene-
There is a vast amount of literature showing the di-
etary influences on health, longevity, and aging. In
mammals, and humans in particular, there has been a
great interest in identifying what constitutes a healthy
diet, and numerous studies have focused on the health
and longevity benefits of specific dietary components.
From epidemiological studies to studies in model organ-
isms—including longevity studies (for a review, see
Lebel et al., 2011)—thousands of compounds and diets
have been studied with varying degrees of success. Al-
though it is important to understand how variations in
diet and how specific dietary components affect health
and longevity, it is crucial to point out that understand-
ing how to manipulate the basic process of aging (even
slightly) will bring more health benefits than any di-
etary manipulation or lifestyle studied to date (Olshan-
sky et al., 2006; Butler et al., 2008). As such, herein, we
focus on interventions that may retard the aging process.
By far the most widely studied dietary manipulation
of aging is caloric restriction (CR), also called dietary
restriction. CR consists of restricting the food intake of
organisms normally fed ad libitum without triggering
malnutrition and is the only dietary intervention shown,
to date, to increase longevity and modulate the process
of aging in several model organisms (Bishop and Guar-
ente, 2007; Fontana et al., 2010; Spindler, 2010). Even in
mammals, such as mice and rats, CR can extend longev-
ity by up to 50%, delay physiological aging, and postpone
or diminish the morbidity of most age-related diseases
(Masoro, 2005). Ongoing studies in rhesus monkeys sug-
gest that CR can lower the incidence of aging-related
deaths in primates (Colman et al., 2009).
Although effects vary across species and strains, evi-
dence from rodents suggests that CR can retard the
aging process in mammals and hence delay the appear-
ance and onset of the major age-related pathological
conditions, including immune diseases, neurological dis-
eases, diabetes, stroke, metabolic and cardiovascular
2Abbreviations: 4E-BP, eukaryotic translation initiation factor 4E
binding protein; AMPK, AMP-activated protein kinase; APOE, apo-
lipoprotein E; CETP, cholesteryl ester transfer protein; CR, caloric
restriction; daf, abnormal dauer formation; GH, growth hormone;
GHR, growth hormone receptor; IGF, insulin-like growth factor;
IGF1R, insulin-like growth factor I receptor; SIRT1, sirtuin 1; TOR,
target of rapamycin.
DE MAGALHÃES ET AL.
diseases, as well as cancer (Weindruch and Walford,
1988; Masoro, 2005; Fontana et al., 2010). Studies in
rhesus monkeys suggest that CR can reduce body fat
and inflammation in primates, in addition to delaying
the onset of age-related diseases (Colman et al., 2009). It
is noteworthy that results from flies and mice suggest
that CR exerts its beneficial effects, including reduced
mortality, even when started late in life (Mair et al.,
2003; Spindler, 2005). The optimum level of restriction
for a given species is not known, however, and in mice
seems to depend on genetic background (Liao et al.,
Despite its health and longevity benefits, CR in mam-
mals is associated with negative functional conse-
quences and side-effects such as a reduction in fecun-
dity, muscle mass, and wound healing capacity as well
as increased susceptibility to infections (Dirks and Leeu-
wenburgh, 2006; Fontana et al., 2010). Clearly these
side effects are problematic for establishing such dietary
regimens in our current society as a means to retard the
rate of aging. Therefore, developing CR mimetics, drugs
or foods that reproduce the actions of CR without its side
effects, is of immense scientific, social, and commercial
interest (Ingram et al., 2006).
Although the mechanisms by which CR extends life-
span remain a subject of debate, and CR responses are
complex, neuroendocrine adaptations and ultimately
cellular responses to the environment seem to be crucial.
One emerging hypothesis is that CR exerts its effects
through hormonal changes that affect cells and induce a
survival response (Sinclair, 2005). It is noteworthy that
the mechanisms by which CR modulates aging have
been shown in model organisms to be mediated by genes
and, although not fully understood, signaling pathways
(Fig. 1). The ability of individual genes and pathways to
affect CR is a major area of research with many poten-
tial human applications (Bishop and Guarente, 2007).
Given the heterogeneity of human populations, it is
unlikely that CR will have the marked longevity benefits
in humans that it has in rodents, in particular for those
individuals already on a relatively healthy diet (de Grey,
2005; Phelan and Rose, 2005). In fact, CR in wild-de-
rived mice, which, unlike typical laboratory strains, are
genetically heterogeneous, does not alter average life-
span even if it increases maximum lifespan (Harper et
al., 2006). This suggests variable responses to CR de-
pending on genotype, possibly making CR beneficial to
some individuals but not to others. Nonetheless, the
widespread effects of CR in multiple diseases across
species suggest that some benefits can be expected for
some people (Fontana et al., 2010), in particular given
the modern obesity epidemic and growing incidence of
metabolic diseases such as type 2 diabetes. One prelim-
inary study in humans suggested benefits of CR on
cardiovascular disease (Fontana et al., 2004), and bio-
markers of CR, such as body temperature and insulin
levels, have been associated with human longevity (Roth
et al., 2002). In men and women undergoing CR for an
average of six years, CR has been reported to lower body
temperature (Soare et al., 2011). Moreover, the Oki-
nawan population in Japan, by avoiding high-calorie
sugars, saturated fats, and processed foods and instead
consuming more vegetables and fruits, seems to have
undergone a mild form of CR for decades that could have
contributed to the lower risk of age-related chronic dis-
eases and mortality among older Okinawans compared
with elderly people in the rest of Japan (Willcox et al.,
It seems that organisms from yeast to mammals have
evolved genetic programs to cope with periods of starva-
tion that can also postpone aging and age-related dis-
eases, but how can we take advantage of those mecha-
nisms to improve human health? Because assaying the
longevity effects of CR in humans is practically impos-
sible, studying its molecular mechanisms in lower life
forms could be beneficial to humans through the identi-
fication of candidate genes, pathways and molecular
mechanisms. Although CR will not be suitable for every-
one, targeting its mechanisms and developing CR mi-
metics may lead to drug development for a number of
age-related and metabolic diseases.
IV. Genome-Environment Interactions as Targets
for Dietary Interventions and Drug Discovery
“…[It’s] possible that we could change a human gene
and double our life span.”—Cynthia Kenyon (Duncan,
According to the GenAge database of aging-related
genes (http://genomics.senescence.info/genes/), more than
700 genes have been identified that regulate lifespan in
model organisms (de Magalha ˜es et al., 2009a). Many of
these genes and their associated pathways—such as the
gevity across different model organisms (Kenyon, 2010).
Therefore, at least some mechanisms of aging are evolu-
tionarily conserved and may have potential therapeutic
applications (Baur et al., 2006). For example, evidence
suggests the use of lowered IGF signaling (e.g., by target-
ing IGF receptors) to treat certain age-related diseases
such as cancer (Pollak et al., 2004), Alzheimer’s disease
(Cohen et al., 2009), and autoimmune diseases (Smith,
2010). Moreover, a number of genes and pathways associ-
ated with longevity and CR are part of nutrient-sensing
pathways that also regulate growth and development, in-
cluding the insulin/IGF1/GH pathway (Narasimhan et
al., 2009; Stanfel et al., 2009). Many of these genes
modulate the response to environmental signals, such as
food availability, and act in signaling pathways that if
understood can be targeted (Fig. 1). The genetic regula-
tion of aging is therefore an emerging field with multiple
applications in the human nutrition, cosmetic, and phar-
AGING GENES AS TARGETS FOR DRUG DISCOVERY
In addition to genes associated with aging, research has
focused on identifying genes associated with the life-
extending effects of CR. One method is to identify genes
that decrease or cancel out the life-extending effects of CR
when mutated (Gems et al., 2002; Bishop and Guarente,
2007). More than 100 such genes have been identified in
model organisms (D. Wuttke, C. Vora, J. P. de Magalhães,
unpublished observations). The growth hormone receptor
(GHR) is the only gene so far identified in mammals that
mediates CR lifespan effects (Bonkowski et al., 2006); most
CR-related genes have been identified in lower life forms,
such as yeast, flies, and worms (http://genomics.senescence.
info/diet/). Nonetheless, most of these genes have mam-
malian homologs and represent potential targets for in-
terventions to improve human health and/or optimize a
healthy diet (Fig. 1). Potential pharmacological inter-
ventions may be developed by targeting these genes and
pathways; examples of this approach are discussed
Applied research based on aging-related pathways is
dominated by CR mimetics, and some developments
have already captured widespread attention (Ingram
FIG. 1. Overview of CR-associated signaling and some of its key players. CR acts on the hypothalamus, which controls the secretion of GH from
the pituitary. CR also lowers glucose levels and diminishes secretion of insulin from the pancreas. GH acting on the liver causes the release to the
plasma of IGF1. IGF1 binds to IGF1R or insulin receptor a (IRa?-IRa?) and triggers its autophosphorylation, which in turn serves as an anchor for
recruiting various downstream effectors. Phosphotidylinositol-3-kinase (PI3K) is either activated via direct interaction with, for example, the
insulin-like substrate 1 (IRS1) or RAS. PI3K catalyzes the phosphorylation of phosphatidyl-inositols, such as the conversion of phosphatidyl inositol
4,5-bisphosphate (PIP2) to phosphatidyl inositol 3,4,5-trisphosphate (PIP3). PIP3serves as a binding site for phosphoinositide-dependent protein
kinase (PDK1), which activates the serine/threonine protein kinase AKT. AKT phosphorylates tuberous sclerosis protein 1 and 2 (TSC1/2) as well as
FOXO transcription factors and cAMP response element-binding (CREB). TSC1/2 phosphorylation by AKT inhibits the Ras homolog enriched in brain
(RHEB). RHEB stimulates the phosphorylation of the ribosomal protein S6 kinase (S6K1) and 4E-BP1 through activation of TOR. TOR’s activation
of S6K1 and inhibition of 4E-BP1 enhances translation. FOXO phosphorylation prevents its nuclear translocation and activation of its stress response
target genes. Various cellular forms of stress and AKT activity lead to the depletion of ATP and elevation of AMP. AMPK positively regulates TSC2
and FOXO, negatively regulates CREB, and enforces energy homeostasis. FOXO and AMPK promote autophagy, whereas TOR suppresses it. Under
CR, GH levels decline and therefore, via this pathway, TOR signaling decreases (CR also suppresses TOR signaling through other mechanisms)
whereas AMPK and some FOXO factors are activated, in turn decreasing translation while increasing stress responses and autophagy, which seem
to be some of the mechanisms by which CR retards aging. Human homologs of genes directly linked to CR life-extending effects in model organisms
are highlighted with a blue halo.
DE MAGALHÃES ET AL.
and Roth, 2011). In yeast, the NAD?-dependent class III
of histone deacetylase enzymes called sirtuins have been
reported to mediate the life-extending effects of CR.
Specifically, Sir2 overexpression extended lifespan in
yeast and CR failed to extend the lifespan of Sir2 mu-
tants (Lin et al., 2000). By screening compounds that
activate Sir2, Howitz et al. (2003) identified a number of
molecules, including plant polyphenols such as resvera-
trol. Because resveratrol is usually found in plants and
in particularly high concentrations in red wine, it was
argued that these findings may have implications for
health care and for establishing healthy lifestyles (Guer-
rero et al., 2009). Feeding resveratrol to yeast, flies,
worms, and fishes results in life extension (for review,
see Baur, 2010). In mammals, resveratrol was reported
to activate the closest mammalian homolog of Sir2,
SIRT1, and survivorship of mice on a high-fat diet in-
creased if supplemented with resveratrol (Baur et al.,
2006). CR up-regulated the protein level of SIRT1 in
several rat tissues, also culturing cells in serum of CR
rats up-regulated SIRT1 protein levels; insulin and
IGF1 have been shown to reduce SIRT1 protein levels
(Cohen et al., 2004).
Based on the work described above, a number of lab-
oratories and companies, including Sirtris (http://www.
sirtrispharma.com/), cofounded by David Sinclair, have
since focused on identifying compounds that modulate
the levels or activity of sirtuins. One screen for environ-
mental chemicals that inhibit sirtuins found that
dihydrocoumarin, a flavoring agent found in food and
cosmetics, inhibited SIRT1 and increased apoptosis
(Olaharski et al., 2005). Likewise, one study assayed a
panel of 18 drugs commonly used in clinical practice for
SIRT1 expression and identified three compounds (L-
thyroxin, sodium nitroprusside, and, surprisingly, insu-
lin) to be activators of SIRT1 (Engel and Mahlknecht,
2008). Although the relevance of these results remains
to be established (see below for concerns about resvera-
trol and SIRT1), these approaches demonstrate how
knowledge of aging-related genes can be helpful in terms
of optimizing diet for health and on assessing long-term
use of drugs.
As detailed ahead, testing compounds directly for ef-
fects on human aging is not possible; companies often
focus on age-related diseases for which drug develop-
ment can be assessed and validated for therapeutic ef-
fects. Consequently, Sirtris has taken a leading role in
translating research on sirtuins to multiple therapeutic
areas, particularly in terms of activating SIRT1 as a
therapy for type 2 diabetes (Lavu et al., 2008). Indeed,
more potent small molecule SIRT1 activators than res-
veratrol identified via high-throughput screening have
been reported to improve insulin sensitivity and lower
plasma glucose in obese mice (Milne et al., 2007). At the
time of writing, clinical trials for sirtuin activators are
also being tested for muscular atrophy, cancer, psoriasis,
and sepsis (http://clinicaltrials.gov/ct2/show/NCT01154101;
show/NCT00964340). The work on sirtuins is an example of
how it is possible to move from genes acting on longevity
toward developing pharmacological products targeting age-
It is important to note that resveratrol and even the
health benefits of SIRT1 activation have more recently
come under attack. Resveratrol does not extend the life-
span of mice fed a normal diet (Pearson et al., 2008;
Miller et al., 2011), and the effects of SIRT1 on mamma-
lian aging and CR are controversial. It has been reported
that resveratrol does not directly activate SIRT1 (Pacho-
lec et al., 2010), although more recent results from Sir-
tris argue otherwise (Dai et al., 2010), and even if the
mechanism is indirect, there is evidence that resveratrol
has SIRT1-dependent effects in mammalian cells (Baur,
2010). Crucially, although SIRT1 overexpression in mice
has been reported to have some health benefits, such as
protecting against some types of cancer, it does not ex-
tend longevity (Herranz et al., 2010). Moreover, contrary
to Sirtris’ work, studies in rats suggest that SIRT1 in-
hibition may be a potential therapy for type 2 diabetes
(Erion et al., 2009).
Even if sirtuins and resveratrol do not live up to their
expectations, this research is pioneering in terms of
genome-environment interactions and nutritional ma-
nipulations of aging. These studies also show the path
from basic discovery on the biology of aging to potential
antiaging and pharmacological interventions and can
therefore be applied to other genes and pathways. The
lessons learned from the pitfalls of SIRT1 and resvera-
trol research can also help others to translate basic
research on the biology of aging to the clinic, such as
avoiding the use of short-lived rodent strains (e.g., by
using unhealthy diets), which may lead to findings that
only apply to a subset of individuals.
As mentioned above, a number of genes regulating
longevity also control growth and development. Some of
these, such as the insulin/IGF1/GH pathway, have been
suggested to play a role in the mechanisms of CR (Fig.
1). An emerging critical player is the target of rapamycin
(TOR) signaling pathway, which involves both nutrient
sensing and regulation of growth. Several genes in the
TOR pathway, and the TOR gene itself, regulate longev-
ity in flies (Kapahi et al., 2004) and both longevity and
dauer diapause in worms (Jia et al., 2004). Strikingly,
not only have genetic manipulations of the TOR gene
extended lifespan in yeast and worms (Stanfel et al.,
2009) but also feeding rapamycin (which inhibits TOR
and is also known as sirolimus) to middle-aged mice
significantly (9–14%) increased lifespan (Harrison et al.,
2009). Whether rapamycin is extending lifespan by de-
laying of aging or by affecting a specific disease, such as
cancer, remains unclear. More recent studies show that
starting rapamycin administration earlier in life does
AGING GENES AS TARGETS FOR DRUG DISCOVERY
not result in a significantly greater increase in lifespan
(10–18%) than that obtained in middle-aged mice
(Miller et al., 2011).
Rapamycin has serious side effects, particularly as an
immunosuppressor, and thus it is not suitable as an
antiaging drug. As in sirtuins, however, these studies
highlight the road from basic discovery on the biology of
aging to antiaging interventions. Further studies of the
TOR pathway and of repressors more specific of its
downstream signaling pathway are ongoing. Whether
rapamycin produces a change in another parameter re-
lated to energy uptake or utilization is unknown, and
determining which of its effects modulate lifespan is an
important unsolved question. Like resveratrol, TOR has
attracted considerable attention from the pharmaceuti-
cal industry, particularly in the context of cancer (Meric-
Bernstam and Gonzalez-Angulo, 2009).
Other candidate CR mimetics are also being explored,
including 2-deoxyglucose and the diabetes drug met-
formin, which inhibit glycolysis, and many others are in
the pipeline (Ingram et al., 2006; Ingram and Roth,
2011). Metformin, which activates the nutrient and en-
ergy sensor AMP-activated protein kinase (AMPK) pre-
viously associated with lifespan and CR in worms (Ke-
nyon, 2010) extends lifespan of murine disease models
(Anisimov et al., 2008), yet failed to extend the lifespan
of normal rats (Smith et al., 2010). One study reported
that metformin slightly increased lifespan in female
mice but decreased lifespan in male mice (Anisimov et
al., 2010). Another recent study suggested beneficial ef-
fects of metformin in a mouse model of Alzheimer’s disease
independent of AMPK activation (Kickstein et al., 2010).
For some aging-related pathways, therapies may focus on
specific diseases or even on cosmetic applications.
Knowledge of genetic and molecular pathways related
to aging and its modulation can also be translated into
predictions on health effects of dietary components
(Mu ¨ller and Kersten, 2003). Therefore, in addition to
pharmaceuticals, another marketplace for basic aging
research involves supplements, which avoids the need
for clinical trials. Indeed, companies are now focusing on
nutritional supplements that target genes/pathways in-
volved in aging. One example is Genescient (http://www.
genescient.com/), a biotechnology company; its strategy
involves choosing supplements that affect pathways
that may be important in long-lived flies as assayed from
gene expression analyses (Rose et al., 2010).
V. Functional Genomics of Aging, Target
Prioritization, and Future Prospects
The ability to modulate SIRT1 and the recent findings
from rapamycin offer a glimpse of what can be achieved
by focusing on aging-related genes. A single gene that
regulates aging can have a profound impact on health
and several age-related diseases. Given how CR delays
the onset of multiple age-related diseases, such as type 2
diabetes and cancer, manipulation of CR pathways
might have applications at least in disease prevention
and possibly even in a clinical setting. However, in ad-
dition to sirtuins and TOR, there are already hundreds
of genes associated with aging and CR in model organ-
isms, and this provides an excellent opportunity for tar-
get discovery (Fig. 2). Besides, we have only begun to
study the genetics of aging and thus such genes repre-
sent only the “tip of the iceberg.” Therefore, there is a
huge potential to discover new therapeutic targets
among aging-related genes and those that regulate the
effects of diet on lifespan.
A. Functional Genomics of Aging and Longevity
In addition to genetic manipulation experiments to
identify genes of interest, another approach involves
identifying genes specifically up-regulated or down-reg-
ulated in a particular experimental setting. One study
found longevity effects when genes differentially ex-
pressed in long-lived worms were mutated (Murphy et
al., 2003). Likewise, another study associated the up-
regulation of one gene, the eukaryotic translation initi-
ation factor 4E binding protein (4E-BP), with CR effects
in mitochondrial activity and life-extension in flies (Zid
et al., 2009), although it should be noted that null mu-
tations of 4E-BP decrease lifespan in normal flies (Tett-
weiler et al., 2005). Another study in flies focused on the
temporal transcriptional responses caused by feeding
and identified nutrient-responsive genes, many of which
under the control of the forkhead box transcription fac-
tor dFOXO (Gershman et al., 2007). We have analyzed
aging gene expression data to identify common molecu-
FIG. 2. Overview and overlap of genes related to aging, human lon-
gevity, and CR. Shown are the intersections between human orthologs of
genes identified via genetic manipulation experiments in model organ-
isms (aging-associated), genes that disrupt or cancel life-extending effects
of CR when mutated in model organisms (CR-essential), aging differen-
tially expressed genes in mammals (aging-differential), CR-differentially
expressed genes in mammals (CR-differential) and genes associated with
human longevity in at least one epidemiological study (human longevity-
associated). All data obtained from the GenAge database (http://genomics.
senescence.info/genes/), except for the CR-associated genes, which come
from data sets assembled by the authors from the literature, available on
DE MAGALHÃES ET AL.
lar signatures of mammalian aging. Some of the genes
overexpressed with age seem to be a response to aging,
in that they have been previously found to have protec-
tive functions (de Magalha ˜es et al., 2009b). As such,
these genes may help organisms manage aging and
could be targets for manipulation. Likewise, gene ex-
pression analysis of CR has been conducted to identify
associated genes (Lee et al., 1999, 2000). A number of
molecular signatures have emerged from such studies
that could be useful to identify candidate processes and
pathways that affect aging, biomarkers (see below), and
candidate regulators (Anderson and Weindruch, 2010;
Hong et al., 2010).
Gene expression profiles of aging and CR may serve as
biomarkers for testing drug effects on inducing “youthful
levels” or CR-like gene expression patterns, respectively,
without doing full lifespan experiments (Spindler, 2006).
SIRT1 activators have been evaluated this way by Sir-
tris (Smith et al., 2009). Because some mouse models
respond differently to CR, studies have focused on iden-
tifying differential responses that can be associated with
the mechanisms of CR and/or used as biomarkers
(Bartke et al., 2008). More recent work has also focused
on identifying genes that influence the life-extending
effects of CR by classic genetics using differences in
lifespan in different mouse recombinant inbred strains
(Liao et al., 2010).
In addition to aging- and CR-related genes, another
source of candidate genes and pathways for drug design
are human longevity-associated genes (Barzilai and
Shuldiner, 2001; Browner et al., 2004; Kenyon, 2010).
Dozens of genes have now been associated with human
longevity (de Magalha ˜es et al., 2009a), although only a
handful of genes have been shown to have consistent
effects across populations.
Many longevity-associated genes are related to spe-
cific diseases and have deleterious genotypes for which
incidence decreases with age, resulting in the alterna-
tive allele unrelated to disease to become more prevalent
in older individuals. However, some evidence suggests
that a few longevity-conferring genes, such as the cho-
lesteryl ester transfer protein (CETP), have alleles with
protective effects against diseases (Bergman et al.,
2007). Therefore, extreme longevity is not due simply to
a lack of disease-associated alleles, but some alleles
seem to protect against multiple age-related diseases.
CETP is a promising target for drug discovery because
its alleles have been associated not only with longevity
but also with a lower risk of specific age-related dis-
eases, such as cardiovascular diseases, cognitive decline,
and dementia (including Alzheimer’s disease) (Barzilai
et al., 2003; Sanders et al., 2010). In fact, CETP inhibi-
tors (such as torcetrapib) that can raise HDL cholesterol
have already been developed, and it is hoped these can
be used as preventive therapy for heart disease (Kon-
tush et al., 2008). The identification of drugs that mimic
the effects of longevity genes, and of alleles associated
with exceptional human longevity in particular (e.g.,
centenarians), is thus an appealing area of research.
One current difficulty is that for many of these longevity
genes, we do not know the biochemistry behind the
longevity effects or the functional consequences of the
different alleles; therefore, we do not know whether
we should aim to activate or inhibit these genes. Some
promising candidates have emerged, however.
One of the first genes associated with human longev-
ity was apolipoprotein E (APOE), which is involved in
lipid metabolism and cholesterol transport. Variants of
APOE have been associated with age-related diseases
al., 1994). APOE has gathered considerable interest be-
cause its polymorphisms are associated with response to
therapy in patients with Alzheimer’s disease (Evans and
McLeod, 2003). Besides, one recent study showed that
APOE isoforms differentially regulate clearance of am-
yloid-? from the brain (Castellano et al., 2011). Conse-
quently, some human longevity genes are already under
the spotlight of academia and industry, and this number
is bound to increase in the near future as high-through-
put sequencing becomes widespread, facilitating ge-
nome-wide association studies of longevity (de Magal-
ha ˜es et al., 2010). Moreover, human longevity genes can
give clues as to which pathways are associated with
healthy human aging, which in turn can be targeted by
B. Prioritizing Targets for Drug Discovery and
Genome analyses from CR, aging, and human longev-
ity genes provide biological targets for drug discovery.
Screening natural products, existing drugs, and chemi-
cal libraries for molecules that affect “druggable” targets
associated with aging may lead to compounds of thera-
peutic value. Given the hundreds of genes associated
with aging and CR, however, it is important to identify
the most promising targets. Integrating information
from different datasets can help prioritize candidates
(Fig. 2). It is interesting to note the two genes shown in
model organisms to be related with aging, associated
with human longevity, and essential to CR effects:
IGF1R and FOXO3 (Fig. 2). IGFR1 is part of the insulin/
IGF1/GH pathway, the down-regulation of which has
been associated with life-extension in several model sys-
tems and, as mentioned above, is already a target of
pharmacological interventions. The FOXO transcription
factor FOXO3 is a homolog of dFOXO and of daf-16, in
which mutations suppress the life-extending effects of
daf-2 (Kenyon et al., 1993). FOXO transcription factors
are, in fact, part of the same insulin/IGF1/GH pathway
(Fig. 1) that modulates lifespan across organisms (Ke-
nyon, 2010). A strong association between FOXO3 and
human longevity has been reported (Willcox et al., 2008)
and subsequently validated in other populations (for
review, see Kenyon, 2010). FOXO3 was also associated
AGING GENES AS TARGETS FOR DRUG DISCOVERY
with insulin levels and prevalence of cancer, heart dis-
ease, and type 2 diabetes (Willcox et al., 2008). Further
work is necessary to understand the modulation of
FOXO3 and its molecular mechanisms affecting longev-
ity, but it is a promising target for drug development.
To facilitate target gene prioritization, a number of
additional approaches may be employed. For example, in
silico studies of transcriptional regulation can allow the
identification of upstream regulators (for review, see de
Magalha ˜es et al., 2010). Furthermore, an emerging ap-
proach to study the complex interactions between the
multiple components of biological systems is network
biology (Baraba ´si et al., 2011). Given the complexity of
aging, network approaches may be particularly suited to
identify crucial regulators of its modulation by the en-
vironment. For instance, knowing the protein-protein
interaction network of candidate proteins allows the
identification of hubs, proteins with a large number of
interactions, which tend to be more biologically relevant
(Fig. 3). Together with other biological (e.g., kinases and
receptors are often seen as promising drug targets),
medical, and strategic considerations already used for
target selection in drug discovery (for review, see
Knowles and Gromo, 2003), the integrated knowledge of
aging-related pathways can help identify suitable tar-
gets for drug discovery. In addition, the advent of large-
scale databases of compounds and drugs, such as Drug-
Bank (Wishart et al., 2008), STITCH (Kuhn et al., 2008),
and the Connectivity Map (Lamb et al., 2006), paves the
way to cross-linking longevity/CR-associated genes with
drug databases to identify candidate molecules for ef-
fects on aging.
Advances in the integration of biological (including
aging-related) datasets are paralleled by advances in
data integration and network analyses in nutrition and
pharmacology (Hopkins, 2008). Biological systems are
intrinsically complex; for example, CR signaling in-
volves nonlinear pathways, feedback loops, and compen-
satory mechanisms (Fig. 1). Multitarget drugs and com-
binatorial therapies may therefore be more successful
than single-target drugs. A network-based view of drug
discovery is emerging to account for the complexity of
human biology (Schadt et al., 2009; Erler and Linding,
2010). Network approaches allows drug developers to
take advantage of the large volumes of “-omic” datasets
being generated and exploit, rather than dismiss, the
intricacy of biology, disease, and drug responses to de-
velop new therapies (for review, see Cho et al., 2006;
Schadt et al., 2009). Moreover, focusing on drugs that
target multiple proteins, rather than ligands that act on
individual targets, has advantages in terms of efficacy
and toxicity (Hopkins, 2008). Employing combinations of
compounds to target multiple pathways and avoid com-
pensatory mechanisms is another approach, one already
used in cancer therapies (Meric-Bernstam and Gonza-
lez-Angulo, 2009), and in the context of aging is being
explored by companies such as Genescient.
Current progress in genomics, high-throughput meth-
ods, informatics, and systems biology should help to
develop network approaches that test target combina-
tions resulting in the emerging paradigm of network
pharmacology (Keith et al., 2005; Hopkins, 2008). Sys-
tematic drug-design strategies directed against multiple
targets hold much promise in the field of aging
(Csermely et al., 2005), although challenges remain in
developing accurate computer models of relevant path-
ways and suitable in vitro and in vivo models for testing.
In the same vein, progress in personalized medicine and
in predicting individual responses (e.g., using SNPs) to
the environment (including diet, lifestyle, and drugs),
will be key to maximizing environmental interventions
that improve health and counteract aging. Therefore,
network approaches to both aging and pharmacology are
promising future avenues (Simko ´ et al., 2009).
C. Translation to Extend Human Healthspan
Although a number of genes and even a few drugs
have emerged as candidates for targeting the aging pro-
cess pharmacologically, several problems are associated
with translation to human aging. In principle, human
clinical trials on aging cannot be performed. One major
problem is that aging cannot be quantified, and even a
trial running for several years would struggle to identify
endpoints. Lifespan or survival could be quantified, as
well as health biomarkers such as low blood pressure,
insulin sensitivity, inflammatory markers, glucose me-
tabolism, etc., but these may or may not reflect altera-
tions in the aging process.
Another issue is whether long-term interventions are
practical in humans (Kirkland and Peterson, 2009). In-
terventions such as CR mimetics may only be effective in
humans if applied for many years, in which case their
safety and side effects would have to be demonstrated.
For example, aspirin has beneficial anti-inflammatory
and antithrombotic properties and can slightly extend
lifespan in male, but not female, mice (Strong et al.,
2008). Human epidemiological studies suggest its long-
term use can reduce the risk of certain types of cancer
and cardiovascular disease (Strong et al., 2008; Rothwell
et al., 2011), yet it also increases risk of gastrointestinal
bleeding (Derry and Loke, 2000). Therefore, it will be
crucial to understand the long-term effects of com-
pounds in trials associated with antiaging drugs.
Many aging-related genes have pleiotropic effects, and
so targeting them may have beneficial effects in one
disease yet may be detrimental for another age-related
disease. As indicated above, the only gene shown to be
essential for CR in mammals is GHR. Mouse knockouts
are also long-lived (Bonkowski et al., 2006). Therefore,
inhibitors of GHR may be used to decrease insulin/
IGF1/GH signaling and may be deemed to be of potential
therapeutic value. Recent data from subjects with GHR
deficiency showed decreased mortality from cancer and
type 2 diabetes, but cardiac disease mortality appears to
DE MAGALHÃES ET AL.
be increased. Overall mortality does not seem to be
different (Guevara-Aguirre et al., 2011).
One possibility, as touched upon above, is to conduct
clinical trials for specific age-related diseases to obtain
approval for particular drugs from regulatory agencies
(e.g., U.S. Food and Drug Administration). On the basis
of findings in model organisms, people could engage in
long-term use of approved drugs indicated for specific
diseases. Supplements can also be marketed for long-
term effects, though all these can be seen as backdoor
approaches. In addition, short-term studies in humans
may be feasible for disease, followed by individual anal-
ysis of other age-associated endpoints (Kirkland and
Peterson, 2009). Another potential area to translate
findings from the bench to the bedside is focusing on
dysfunction and frailty in the elderly (Kirkland and Pe-
terson, 2009). This would imply clinical studies in el-
derly patients, which has its own problems (Evans,
FIG. 3. Network of CR-related proteins from yeast. Some proteins, such as Sch9 and Sir2 (indicated by red arrows), have a high number of interacting
partners (hubs), whereas others have no interactions. Such analyses could be used to identify candidate regulatory hubs as well as promising new candidate
genes that interact with known CR-related proteins. Sir2 mammalian homologs are the focus of considerable research (see text), whereas Sch9’s mammalian
homolog AKT2 is important in insulin signaling and glucose transport. Figure created using STRING (http://string-db.org/).
AGING GENES AS TARGETS FOR DRUG DISCOVERY
2011), but established frailty indicators could be used as
endpoints (Kirkland and Peterson, 2009).
Overall, demonstrating that a particular intervention
is affecting human aging, as done in model organisms, is
virtually impossible. Interventions, including drugs,
emerging from basic research on aging will probably
target specific age-related pathological conditions and/or
dysfunction. Subsequent studies of health biomarkers
and multiple age-related diseases may reveal broader
effects. Success in animal models or short-term human
studies may be sufficient to convince potential patients
of the usefulness of particular dietary supplements or
approaches, as exemplified by those voluntarily under-
going CR (http://www.crsociety.org/), which can serve as
basis for further studies (Soare et al., 2011).
D. Future Prospects in Epigenetics and Aging
One field of immense untapped potential is epigenet-
ics. Initially defined by Conrad Waddington as “the in-
teraction of genes with their environment, which bring
the phenotype into being,” epigenetics represents an
extra layer of instructions not encoded in the primary
DNA sequence. The role of this extra layer in the regu-
lation of genome-environment interactions is beginning
to emerge. Epigenetics involve chemical modifications of
DNA nucleotide residues (such as cytosine methylation)
and associated proteins such as histones that alter the
DNA’s structure and function and can activate or re-
press genes (Goldberg et al., 2007).
Epigenetic modifications can be the result of stress or
diet (Mathers, 2006; Fraga and Esteller, 2007; Sedivy et
al., 2008). Although precise targets for epigenetic modi-
fications during aging or CR are unknown, this is an
area with great potential, because epigenetic-driven
changes in gene expression as a result of diet or lifestyle
are thought to contribute to lifelong health (Mathers,
2006). In fact, histone deacetylases, like sirtuins, modify
epigenetic patterns (Fraga and Esteller, 2007).
Merry et al. (2008) showed in rats that dietary sup-
plementation with ?-lipoic acid, although by itself un-
able to extend lifespan, allowed animals switched from
CR to ad libitum feeding at 12 months of age to maintain
the survival trajectory and extended longevity charac-
teristic of CR; conversely, animals switching from ad
libitum to CR did not exhibit extended longevity. In
contrast, switching rats not fed lipoic acid between ad
libitum feeding and CR also switched the survival tra-
jectory. These results suggest that supplementation
with lipoic acid induced a “memory effect” on the ani-
mals, locking them into the survival trajectory of the
feeding regimen before the switch (Merry et al., 2008). It
is noteworthy that animals fed lipoic acid and switched
from CR to ad libitum feeding gained weight, just like
animals not fed lipoic acid, and thus it seems that al-
though the longevity effects of CR were preserved, other
effects of CR were not. Because lipoic acid can induce
hyperacetylation of histones and potentially acts as a
histone deacetylase inhibitor, the hypothesis that epige-
netic mechanisms are involved in this memory effect
that specifically influences the life-extending effects of
CR is attractive (Merry et al., 2008), although it is also
possible that changes in energy uptake or utilization
could be involved, and further work is needed to eluci-
date the underlying mechanisms.
Most approaches outlined thus far rely on manipula-
tion of gene activities by diet or drugs to identify genes
in signaling cascades or pathways associated with aging
or its manipulation. Yet difficulties may surface because
our knowledge of these pathways is still incomplete.
Epigenetic modifications can modify hundreds or thou-
sands of genes, so targeting a given epigenetic protein or
modification may be a more powerful approach, al-
though much work remains for this strategy to be feasi-
ble. Therefore, the case for an epigenetic link between
nutrition and longevity is strong, even if the specific
epigenetic role of nutrients in modulating aging remains
unknown (Niculescu and Lupu, 2011).
VI. Concluding remarks
Aging is the major driving factor of disease in the 21st
century. Manipulation of aging-related genes by diet,
lifestyle, and pharmaceuticals could dramatically im-
prove human health and could be used to develop drugs
against age-related diseases such as cancer, heart dis-
ease, type 2 diabetes, obesity, and neurodegenerative
diseases. The hundreds of aging-related genes and genes
related to CR already identified offer enormous oppor-
tunities for target discovery (Fig. 2). Although aging-
related genes cannot be modified in humans, under-
standing how these can be manipulated by diet or
pharmaceuticals can have a profound impact on health.
In other words, work on the genetics of aging allows the
identification of novel genomic targets for drug develop-
ment, opening the door for aging pharmacogenomics.
Marred by decades of “quackery” (including grafting tes-
ticles from young animals into men), the science of aging
Already more than 20 companies worldwide are focusing
specifically on the aging process (http://whoswho.senescence.
info/corp.php), in addition to “big pharma,” with aging-
oriented research and development projects. Although this
number is modest, it shows the growing potential of a field
that is bound to increase. In 2008, GlaxoSmithKline pur-
chased Sirtris for $720 million (Sipp, 2008), a huge amount
for a company with no clinical data; presumably the pur-
chase was based on the extraordinary potential suggested
by a compound capable of delaying aging. Even though
questions have been raised about their efficiency, resvera-
trol and other drugs targeting SIRT1 showcase how a gene
initially identified as a regulator of aging in yeast can be
used as a pharmaceutical target for multiple human dis-
eases. It demonstrates confidence in the field and in the
idea that aging is not immutable. The recent problems
DE MAGALHÃES ET AL.
raised concerning SIRT1 and resveratrol research also
serve as a cautionary tale of the hurdles in translation of
laboratory discoveries to the clinic.
We now know of hundreds of genes that regulate
aging in model organisms, dozens associated with lon-
gevity in humans, and hundreds differentially expressed
with age. This vast amount of information yields in-
creased power for personalized and stratified medicine,
for identifying biomarkers of aging, and for drug devel-
opment to extend lifespan and ameliorate age-related
diseases. Overall, it gives us a blueprint (albeit still
imperfect) of how aging is controlled that we can use to
potentially manipulate the basic aging process, what-
ever its underlying molecular mechanisms may be.
Moreover, our knowledge of nutrient-sensing pathways
that mediate the effects of CR has greatly increased in
recent years, opening new opportunities for drug discov-
ery and ultimately for perhaps developing an antiaging
pill that retards aging with minimal side effects.
In conclusion, we now know of many target genes that
either individually or collectively could be used for
screening molecules (nutritional compounds and drugs)
that may modulate aging. Even if proving that a partic-
ular diet or drug can delay aging is not feasible from a
scientific and regulatory perspective, there is a huge
potential to identify molecules that ameliorate age-re-
lated diseases and/or dysfunction. This represents a tre-
mendous opportunity for companies working in nutri-
tion and pharmacology in a field on an upward
This work was supported by the Biotechnology and Biological
Sciences Research Council [Grant BB/H008497/1] (to J.P.M.); the
Ellison Medical Foundation (to J.P.M.); a Marie Curie International
Reintegration Grant within EC-FP7 (to J.P.M.); the Erasmus pro-
gram (to D.W., M.P.); and the Bundesministerium fu ¨r Bildung und
Forschung (to D.W.). We thank everyone at the GABBA Annual
Symposium in Porto, Portugal, June 2009, for discussions that
spurred this work and all participants at the Lifestyle and Ageing
Conference in Pisa, Italy, October 2010, for fruitful discussions on
these topics. We also thank Brian Merry for valuable discussions and
comments on a draft of the manuscript. We also thank Joana Costa
for helping type the manuscript.
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AGING GENES AS TARGETS FOR DRUG DISCOVERY