Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 467–479

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Best Practice & Research Clinical

Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem

Gender and longevity: Why do men die earlier

than women? Comparative and experimental
evidence
Jennifer C. Regan, PhD, Postdoctoral Fellow a,
Linda Partridge, PhD, Professor a, b, *
a
The Institute of Healthy Ageing, UCL, Gower St., London WC1E 6BT, UK
b
Max Planck Institute for Biology of Ageing, Cologne D-50931, Germany

Keywords:
Sex differences in lifespan exist world-wide, with women outliving
sex men by more than a decade in some countries. The gender gap is
gender not a uniquely human phenomenon; most sexually reproducing
ageing species examined show sex differences in patterns of ageing, yet a
lifespan comprehensive explanation does not exist. Here, we discuss how
evolution ageing responds to natural selection on traits that arise as a
steroid hormones consequence of sexuality. Sexual dimorphisms in vertebrates are
androgens
mediated by sex-steroids, such as androgens and oestrogens, and
estrogens
we examine their regulation of biological processes that can affect
ageing and lifespan. The sexes can respond differently to dietary
restriction and altered activity of nutrient-sensing pathways, with
females showing a greater plasticity for life extension. We suggest
that the cross-regulation of steroid hormone and nutrient-sensing
signalling pathways is a promising process for further study in
understanding the biological basis for the gender gap.
Ó 2013 Elsevier Ltd. All rights reserved.

Introduction

Sex differences in life expectancy are a world-wide phenomenon. In developed nations, women
outlive men by an average of 7 years [1]. However, the past decade has seen a trend towards closure of
this gap; for example, over the last 30 years in the UK, the difference between male and female life
expectancy has narrowed from 6.0 to 4.1 years (Fig. 1; [2]). This trend has largely been attributed to

* Corresponding author.
E-mail address: Partridge@age.mpg.de (L. Partridge).

1521-690X/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.beem.2013.05.016
468 J.C. Regan, L. Partridge / Best Practice & Research Clinical Endocrinology & Metabolism 27 (2013) 467–479

Fig. 1. Life expectancy at birth, UK, 1980–82 to 2008–10. Source: Office of National Statistics (2011) UK Interim Life Tables.

convergence in behaviours such as smoking and drinking, and a lower proportion of the workforce in
dangerous or physically wearing jobs [3,4]. Moreover, it has occurred despite the fact that mortality at
childbirth has fallen significantly in the past century [5], contributing to an increased life expectancy
for women [2]. An important question is whether sex differences in lifespan are underpinned by
further biological differences: will the gender gap remain, or could it eventually be closed simply by
changes in behaviour?
Sex differences in lifespan are observed in diverse animals, including mammals [6,7], birds [8,9]
reptiles [8] and insects [10]; strongly supportive of a biological basis for sex differences in human
lifespan. With the notable exception of many birds [8] and some invertebrates [11], females are usually
longer-lived than males.
Research on laboratory, model organisms has revealed a pivotal role for diet and metabolism in
determining lifespan, with impressive life-extension achieved upon either dietary restriction (DR) or
lowering activity of insulin/insulin-like growth factor-1 signalling (IIS) and target of rapamycin (TOR)
nutrient-sensing pathways [12]. Interestingly, mutations affecting these pathways have different ef-
fects on the sexes, with life-extension greater in females, and a muted or absent response in males [13–
16]. Several studies have indicated that sex hormones have a profound effect on patterns of ageing. For
example, data on castrated men have indicated that testosterone contributes to faster rates of ageing
[17,18]. Steroid hormones, including sex hormones, are major regulators of processes such as growth
and development, metabolism and behaviour. It is possible that sex hormones and nutrient-sensing
pathways interact to produce different outcomes for the sexes in healthspan and lifespan.
Here, we discuss comparative and experimental evidence from human and animal populations for
sex biases in survival and ageing, distinguishing between differences in how natural selection acts on
the sexes, and how ageing responds to natural selection on other traits. We examine the regulation by
androgens and oestrogens of biological mechanisms that may affect lifespan, including their regulation
of nutrient-sensing pathways.

Natural selection and sex differences in lifespan

An index of the maximum potential lifespan of a species is the age at death of the longest-lived 10%
of the population, which gives and indication of the intrinsic limitation on lifespan for that species.
Mortality rates increase during ageing, with a baseline that is age-independent, and an increase with
age given by the slope of the mortality trajectory. This slope, indicating the rate at which things get
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worse with age, is hence one index of the rate of ageing. In humans, the dramatic increase in life ex-
pectancy since 1850 has been attributable to a lowering of the overall mortality trajectory, with no
change in slope, suggesting that health at all ages has improved, but the rate at which people dete-
riorate with age has stayed constant [19,20]. Thus, there are extrinsic causes of mortality, which may
themselves have age-specific effects, and an intrinsic rate of ageing. The two can interact – for example,
ageing may increase vulnerability to infection.
Evolutionary theory of ageing offers an explanation for the paradoxical shaping of a deleterious
trait, such as ageing, by natural selection. Extrinsic hazards (such as predation, infection and the
physical environment) leave progressively fewer individuals alive, so that mutations affecting only
older age classes experience a declining force of natural selection [21]. Ageing can hence evolve by two
routes. First, mutations that lower fitness specifically in older individuals will reach a higher frequency
in the population than those that affect young individuals. Secondly, mutations that increase the fitness
of the young, at a cost of higher subsequent rate of ageing (antagonistic pleiotropy), can enter the
population by natural selection [22,23]. Ageing thus evolves as a side-effect, of mutation pressure or of
benefits to the young, rather than because it confers any selective advantage. If the sexes are exposed to
different hazards, or those hazards affect the sexes differently, then the rate of decline in the force of
natural selection may differ for females and males, and consequently sex differences in the rate of
ageing can be favoured by selection [24].
Slowed ageing could be advantageous, and therefore directly selected, if parents could improve
fertility or survival of their children, grandchildren or other relatives. A contentious theory, known as
the ‘Grandmother Hypothesis’ [25,26], proposes that caregiving by older women, for instance, by
helping to provide nutrition when the mother is investing in a new infant [25], could improve
grandchild survival or allow daughters to reproduce again sooner [27]. The Grandmother Hypothesis
has been challenged on the basis of theoretical analyses showing that, given the high level of baseline
mortality during human evolutionary history, post-reproductive selection pressures were probably too
weak to drive postmenopausal life-extension [27]. Humans and great apes, our closest primate rela-
tives, have a similar age of female reproductive senescence; for example, female chimpanzees cease to
be fertile at 42 years, compared to 45 years in women [28]. Average human lifespan has at least doubled
in the last 2000 years [20], suggesting that survival exceeding reproductive lifespan by decades is a
very recent phenomenon in evolutionary terms. Indeed, there may be selection for delayed menopause
in modern society [29], but features of ovarian development and oogenesis may cause female repro-
ductive lifespan to offer less genetic variation than lifespan per se, potentially contributing to the long
time between menopause and death in modern women [30].

Indirect selection on sex differences in ageing

The prevalence of sex differences in lifespan in the natural world suggests that selection for some
fundamental feature(s) of different roles in sexual reproduction is responsible, indirectly, for this
gender gap.

Consequences of sexuality

Genetic sex
Biological differences between the genders are initiated by the process of sex determination. In
species that have XX/XY chromosomal determination, such as most mammals, the X is ‘unprotected’ in
the male, implying that if he inherits a mutation on the X chromosome, there is no second, wild type
copy of the gene on the Y chromosome to compensate. Thus men are more exposed to recessive X-
linked diseases such as Duchenne muscular dystrophy. The androgen receptor gene is X-linked, and
mutations in this gene cause Androgen Insensitivity Syndrome (AIS), where an XY individual does not
respond to testosterone. In Complete Androgen Insensitivity Syndrome (CAIS), patients are pheno-
typically female and are usually unaware of their condition until they fail to menstruate in their teens
[31]. This could potentially offer insight into the distinct effects of karyotype and androgens on life-
span; however, there are no large-scale studies of the effect of AIS on longevity and, given that this
group of conditions can be psychosexually challenging, and can require surgical and hormonal
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treatment [31], it is possible that in a modern context they have, if anything, a negative impact on
overall health.
Interestingly, skewing of the identity of the active X-chromosome among the two present in fe-
males, from an initial 50:50 ratio, is observed in leukocytes in most women over 60, suggesting that X
inactivation responds to somatic selection, and may even affect ageing and mortality rates [113]. Thus,
women not only have the advantage of a ‘protected’ X chromosome, but may also dynamically select for
cells with an active X chromosome carrying the ‘best’ genes.
In addition, the Y chromosome itself may be bad for males. The Y is inherited from the father in a
haploid manner and, apart from the pseudoautosomal region, it lacks recombination. Consequently, it
is prone to accumulating mutations and hence has an accelerated evolutionary rate [32], through a
combination of mutation pressure, selection and genetic drift [33]: this could be deleterious for health,
and even lifespan, of males [34]. However, comparisons of human and chimpanzee Y chromosomes
have suggested active maintenance by purifying selection [32,35]; thus, the proposed role of the Y as a
bearer of toxicity may be undeserved. In species with heterogametic females (ZW females and ZZ
males) such as birds, butterflies and moths, it is interesting to note the frequent examples of shorter
female lifespan (Ref. [8] and references therein). However, equal lifespan (e.g. Ref. [36]) and higher
male mortality are also observed [8], and diverse mating systems, size dimorphisms and varied levels
of aggressive competition [9] confound direct comparison of karyotype and longevity.

Mother’s curse: asymmetric inheritance of mitochondrial DNA

Similar to the Y chromosome, mitochondrial DNA (mtDNA) does not recombine and is asymmet-
rically inherited, in this case from the mother. The mitochondrial genome should be more subject than
nuclear DNA to genetic drift and, in addition, is particularly prone to mutation due to its high exposure
to oxidants and reduced repair mechanisms. The very fact that mtDNA is inherited only from the
mother implies that the mitochondrial genome is passing through a sex-specific selective sieve [37].
Theoretically, mutations could accumulate that have a negative effect on males if they are neutral or
beneficial to females. These effects may be direct, such as through mitochondrial function [38], or
second-order, such as retrograde regulation of the nuclear genome by mtDNA [37]. This sex-selective
sieve has been experimentally demonstrated in Drosophila, where variation in the mitochondrial
genome had a significant effect on the variation of male, but not female, average lifespan [39]. Mito-
chondrial function and gene regulation may, hence, be optimized for females, but not males. Given that
the metabolic demands of males and females differ, this could represent a significant disadvantage for
males over a lifetime [40]. Mitochondrial dysfunction underpins a range of diseases, commonly
involving tissues with high metabolic requirements, such as neurons and muscle. Often men are more
prone to developing these diseases; for example, a form of adult-onset blindness, Leber’s hereditary
optic neuropathy, is caused by mutations in complex 1 of the mitochondrial respiratory chain and
predominantly affects young men [41].

Gametic sex: anisogamy and investment

The most basic definition of the sexes is anisogamy: the production of different types of gamete. The
evolution of anisogamy from two mating types that contribute identical gametes (isogamy), is thought
to have been driven by two pressures: parental investment of resources in the zygote, which improves
its fitness, and competition for fertilizations. Transport of gametes to their place of fertilization is risky
for their survival, while larger zygotes have a greater chance of survival and eventual reproduction,
driving the co-operative evolution of a small motile cell (sperm), and a large stationary cell (egg) that
must provide all of the nutrients for the zygote [42,43]. In consequence of their small size, individual
sperm are cheap to produce whereas eggs are expensive. Assuming that the energy that an individual
can invest in reproduction is limited, males make a trade-off towards producing many sperm, each
with a low individual chance of successful fertilization, whereas females invest the same amount into
fewer, larger eggs. Making more and smaller sperm can confer a benefit to the male in number of
fertilizations, driving the size of sperm down; as a result, egg size must increase to compensate [44].
This disparity in investment in each individual gamete underlies dimorphisms between the sexes,
including different breeding strategies. For example, a higher rate of mating often increases fitness for
males, but females, instead, may be choosy of males who provide advantages such as protection of the
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female or her offspring [10]. Some breeding systems, especially those in which the sexes have very
different strategies for maximizing reproductive success, result in the evolution of substantial sex
differences in lifespan. In early human evolution, overt polygyny and covert polyandry are thought to
have operated [45,46]. Examination of other animal populations implies that the nature of early human
breeding systems will have had a profound influence on the evolution of sexual dimorphisms,
including maximum lifespan.

Polygynous breeding systems

In polygynous mating systems, individual males can monopolize more than one female, if they are
able to defend them from other males. In this scenario, females are usually assured to breed, but
produce a relatively low number of offspring per breeding attempt. To produce many offspring, females
must engage in several rounds of breeding, which may result in selection for a longer lifespan. Males,
on the other hand, have the potential to generate a large number of offspring, but the chances of failing
to reproduce altogether are higher, so that the variance of mating success is higher in males than in
females [6,10]. Male, but not female, fitness is hence enhanced by higher mating rates.
Defense of female groups is often violent and achieved at great energetic, and sometimes physical,
cost. For example, alpha male elephant seals spend entire breeding seasons engaging in vocal and
physical battles in order to defend a harem, sometimes dying of exhaustion or fatal wounds (Fig. 2;
[47]). It is difficult for juvenile males, whose strength is not yet a match for males in their prime, to
challenge successfully a male monopolizing females. Similarly, as soon as males suffer any age-related
weakening, defense of the female group becomes tenuous. This acts to compress the reproductive
lifespan of males, sometimes to only a few seasons. For example, in red deer, males rarely obtain and
defend a harem before they are six or seven years old while females usually breed as soon as they
become fertile at one or two years [48]. Comparative studies of mammals have demonstrated that the
extent of sex differences in mortality is indeed significantly higher in polygamous than monogamous
species, and increases with the extent of polygyny [6,7,49].
Polygyny has other consequences for males. The extent of polygyny can be correlated with the
magnitude of sexual dimorphism within a species. Where males compete, size is often an advantage, as
is weaponry such as horns [6]. Disease burden is consistently higher in male mammals [49,50], which
may be a consequence of behavioural dimorphisms such as ranging, or physical dimorphisms, such as
size [49]. If energy is a limiting resource, a trade-off with immune investment may have occurred in
order to reach a larger size (or grow bigger weapons or more impressive ornaments; [51]). As larger
animals are more susceptible to energy deprivation and starvation, high mortality in larger animals
may be related to the energy appropriated from the host by the parasite [8,49]. In addition, polygynous

Fig. 2. Bull elephant seals fight for dominance. Source: Thomas B. Roach (2010) Wikimedia Commons.
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males spend less time feeding and often enter challenging seasons (cold or dry) in worse condition
than females [6]. They are also at greater risk of predation due to the requirement for territorial
defence, and the ranging that it demands [6]. All these factors result in lower survival for polygynous
males of all ages [6]. The evolutionary theory of ageing predicts that high mortality and compressed
reproductive lifespan will lead to the evolution of faster rates of ageing and reduced maximum lifespan
for males compared to females.

Monogamy
In sexually monogamous species, females and males mate exclusively with one partner, and often
share responsibility for the care of offspring. In many monogamous bird species, for example, sex
differences in lifespan are not significant, or are reversed (females dying earlier than males [8,9]),
where females are larger. This is interesting, as it suggests that there is not a fundamental necessity for
a physiological difference between males and females that determines lifespan; rather, it is related to
the investment that the sexes make in each reproductive attempt and the resulting sexual di-
morphisms that evolve.

Polyandrous and promiscuous systems

True polyandry, where a female controls the breeding of a number of males, is rare, and little is
known about its effect on lifespan. However, many species are promiscuous; that is, both males and
females mate with multiple partners. Within promiscuous systems, there can be different mating
frequencies for males and females. Indeed, there may be several alternative mating tactics open to
either sex (monogamy, polygamy, cheating), each with their own associated costs and benefits [52].
The act of breeding can be dangerous for females. They can be injured, exposed to infection, and may
even have their physiology directly modified by mates: in Drosophila, proteins contained within the
male ejaculate have been shown to shorten female lifespan [53]. Despite this, multiple matings with
males potentially carry benefits for females, and polyandry has now been uncovered in insects, birds
and mammals [54]. Benefits to females include continuous sperm supply, genetic diversity of offspring
and avoidance of inbreeding [55]. These benefits must outweigh the cost of the trade-off with lifespan
incurred by multiple matings [54].
Studies linking breeding systems with mortality and maximum lifespan (e.g. Ref. [6]) suggest that
having different strategies for successful breeding can result in different maximum lifespan for the
sexes. However, it is unknown exactly how these sex differences are mediated. Recent studies suggest
that sex hormones have a pivotal role, regulating a myriad of biological processes.

Sex hormones as modifiers of physiologies and behaviours that effect lifespan

Androgens and oestrogens are master regulators of sex differences in mammals, affecting a host of
organismal, cellular and biochemical processes that in turn regulate many life-history traits. There is
evidence to suggest that the impact of sex steroid hormones on lifespan is strikingly dimorphic:
oestrogen appears to have many protective and beneficial roles, whereas removal of testosterone by
castration has long been known to extend lifespan in male domestic and laboratory animals (e.g. dogs,
[56]; cats, [57]; rats, [58]). A recent report of striking longevity in eunuchs at the Korean Imperial court
is strongly suggestive of a role for testosterone in limiting male lifespan in humans [18]. Alongside data
on the many health problems suffered by postmenopausal women [59], these data point to androgens
and oestrogens as potent mediators of sex differences in ageing and longevity through several possible
routes.

Sexually dimorphic behaviour

In wild mammal populations, testosterone has a profound effect on male behaviour, which is thought,
at least in part, to contribute to shorter male lifespan. For example, castration of male Soay sheep shortly
after birth stops them taking part in the rut and leads to substantial increases in adult survival relative
both to intact males and to females [60]. Human behaviour is complex and is less amenable to
direct study, but testosterone is ascribed a major role in risky and aggressive behaviour in men [61].
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Mortality rates, largely due to accidents and violence, spike during puberty and early adulthood in
men, at the same time as they experience a surge of testosterone production. Reckless behaviour is
attributed to a tendency for ‘showing off’ to potential partners and rivals, and is also observed in young
male primates, where it can be predictive of adult social dominance [62]. Men remain more at risk from
accidental death or violence than women throughout life [61], usually rating situations as less
dangerous than do their female peers [63]. Men are also far more likely to end their own life: in the UK,
the suicide rate amongst young men is almost four-fold higher than in young women [64]. Further-
more, men are less likely to notice, or admit to, genuine symptoms of illness [61], and to seek help from
a doctor if they do [65]. The gender bias in self-reporting of ill health is offered as one explanation for
the paradox that, although mortality is higher in men at all ages, morbidity is seen to be higher in older
women [66]. Whilst this is likely to have multiple causes, it is understood that male behaviour, such as
a greater reluctance to seek and comply with medical treatment, must have an impact on reported
morbidity and actual mortality, respectively [66].
Nonetheless, the sex difference in maximum lifespan persists despite gender differences in old age
disability, and when deaths due to risk-taking and accidents are removed from the analysis [67],
suggesting that factors besides behavioural dimorphisms are also important.

Immunity

In a wide range of species, males have a higher disease burden [49], potentially contributing to
higher mortality. In humans, women have a more active immune system than males, underlying the
higher incidence of infection in men and higher rates of autoimmunity in women [68].
Immune responses are energetically expensive and may have a negative effect on reproductive or
competitive ability. The costs of evolving immune defences (e.g. in fruitflies [69]) and activating them
(e.g. in bumblebees [70]) have been experimentally demonstrated. This supports the idea that a trade-
off may exist between immune investment and traits that improve competitive success in males [51],
given that high numbers of matings are important for them. In male mammals, this trade-off is
mediated by testosterone, which promotes muscle growth and is a potent immunosuppressant [71].
Testosterone-mediated immunosuppression may affect mortality and lifespan only where the
parasite burden is high. An effective immune response certainly dictates survival in the case of acute
infection. For example, female mice have a more active immune response than do males, and survive
artificially induced sepsis better [72]. Data on human castration are limited, but in a 30-year study of
eunuchs from an institutionalized, mentally retarded population, men castrated at a young age were
found to have a median lifespan 13.5 years higher than intact males from a comparable group;
importantly, intact males were at a far greater risk of death by infection [17]. Sanitary conditions in
institutions such as these, at the beginning of the last century, are likely to have been hazardous. In
intervention studies on wild populations of Soay sheep, sex differences in winter mortality were lost
upon treatment of the herd with antibiotics [73]. In addition, in studies of domesticated cats, castrated
males lived as long as intact females, abolishing the sex difference in lifespan of several years, with
significantly lower death by infection in castrated than in intact males [57].
Yet the immunosuppressive effect of testosterone cannot explain the gender gap that remains in
human populations in developed nations, where infectious diseases are no longer a major cause of
death [1], suggesting that immunity and parasitism are not the whole story.

Reactive oxygen species and the free radical theory of ageing

An influential theory, proposed in the middle of the last century, to explain senescence is the ‘free
radical theory of ageing’ [74]. Briefly, this states that metabolically-derived free radicals and oxidants
are responsible for cellular damage, and this damage promotes ageing. Mitochondria are a major
source of the superoxide anion O$2 and hydrogen peroxide (H2O2) during respiration, and mitochon-
drial macromolecules, including mtDNA, proteins and lipids, suffer oxidative damage with age [75]. A
large body of empirical evidence appeared to bear out this theory; for example, an inverse correlation
was observed between the rate of reactive oxygen species (ROS) production and the maximum lifespan
across taxa [76], and overexpression of antioxidants in mitochondria in mice extended lifespan [77].
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Oestrogen modulates ROS concentration via its nuclear receptor to increase antioxidants and
decrease oxidants [75]. Conversely, testosterone is linked to increased susceptibility to oxidative stress
[78]. This difference between the sexes has been put forward as an underlying molecular mechanism
for gender differences in human lifespan [75].
Although the free radical theory of ageing and derived variations have remained dominant for
decades, major doubts have been raised over whether oxidative damage is really a causal factor in
ageing [79], by studies that have experimentally silenced reductases/antioxidants and observed no
effect on lifespan, despite an increase in vulnerability to oxidative stress itself (e.g. Ref. [80]). These
findings do not completely rule out a function for ROS in ageing. It is possible that oxidative stress has
an impact on lifespan and/or healthspan under suboptimal or stressful conditions [82], or affects
ageing through other functions for ROS such as REDOX signalling or immunity.

Telomeres

Vertebrate telomeres consist of non-coding DNA repeats that protect the ends of chromosomes
from fusion, degradation and recognition by the DNA damage response. Telomeres are degraded due to
incomplete DNA replication and damage by agents such as ROS; critically short telomeres induce
replicative senescence and cell death [83]. Although both short telomeres and increased degradation
rate have been linked to reduced lifespan, whether telomere dynamics are a causative factor for life
expectancy is still under debate [8]. However, it is clear that there are pronounced sex differences in
telomeres in humans, with men having shorter telomeres and a higher rate of degradation than women
[84]. The relationship between telomere length and lifespan is not consistent. For instance, no studies
have yet identified shorter female telomeres, even when female mortality is higher [8]. In addition,
most telomere studies are performed using leukocytes, meaning that infection history (and sex dif-
ferences therein) is a confounding factor: telomere length correlates with lymphocyte replicative
history [85]. Nevertheless, interesting information is emerging on the possible roles for sex in telomere
biology, including differential oxidation by mitochondrial and immune-generated ROS [8] and oes-
trogen regulation of telomere maintenance by direct activation of telomerase [86]. It is yet to be seen
whether these will have causative roles in determining lifespan.

Regulation of cellular and metabolic processes

The positive effects of oestrogen are wide-ranging and include maintaining muscle strength and
promoting skeletal muscle repair [59], glucose and lipid metabolism [87], and lowering the risk of
cardiovascular disease (CVD), particularly atherosclerosis [59,88]. In addition, oestrogen reduces serum
levels of low-density-lipoprotein (LDL or ‘bad cholesterol’) and increases serum levels of high-density
lipoprotein (HDL or ‘good cholesterol’). The converse is true for testosterone, potentially contributing to
the greater risk of heart disease and stroke in men compared to women [89].
However, the picture is not straightforward. Low testosterone levels in ageing men correlate with
health problems and increased risk of death [90] and, in addition, androgen depletion therapy comes
with a battery of adverse side-effects [91]. Obesity induces a drop in testosterone levels [92], and low
testosterone has been linked with a spectrum of health issues in ageing men such as frailty, low muscle
mass and anaemia [93]. Considering that castration extends life most effectively if performed in
adolescence [17,94], the benefits of lowered testosterone may be at least partially attributable to effects
on development and growth.
The many beneficial effects of oestrogen are illustrated by the rapid physiological decline in health
following menopause [59,88], including a risk for CVD in postmenopausal women that is equal to men
of the same age [88]. Oestrogens affect many signalling pathways. The broad expression of oestrogen
receptors, and their role as nuclear receptors that activate expression of many genes [87,88], suggests
that oestrogens can affect many homeostatic and pathological processes, and may influence patterns of
ageing through several routes. Nutrient-sensing signalling pathways are a potential target for sex
steroids. These pathways have been identified as potent regulators of lifespan [79], and clues from
clinical data and research on model organisms linking them with steroid hormones point to an
interesting topic for further study.
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Nutrient-sensing signalling pathways

Mutating single genes in conserved signalling pathways can have a profound effect on lifespan in
laboratory animals such as worms, flies and mice [13,16,95]. These genes are largely linked to sensing
nutritional state, either via insulin and insulin-like growth factor 1 (IGF-1) signalling (IIS) and its key
transcription factor FOXO [12], which modulates expression of hundreds of genes including ones
involved in immunity and stress responses (e.g. Ref. [96]), or via the target of rapamycin (TOR) pathway
[97–99], which interacts extensively with IIS. These pathways are highly conserved among multicel-
lular organisms, and they match energetically expensive processes, such as growth, reproduction and
metabolism, to nutritional state. The biological processes that IIS/TOR affect to modulate lifespan have
not been determined; indeed, the fundamental processes underlying ageing per se are still unknown
[79].
Mutating genes within the IIS/TOR network has different outcomes for the sexes, suggesting that
the baseline state of these pathways may be different in males and females [67]. For example, reduced
activity of the IIS and TOR network in Drosophila leads to a greater extension of lifespan in females, with
only a weak or absent effect in males [13,16] In mice, heterozygous IGF-1R knockouts are long-lived in
females, but not significantly in males [14]; similarly, deletion of ribosomal S6 protein kinase 1, an

Fig. 3. Sex differences in ageing arise as a consequence of sexuality.

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effector of the TOR and IIS network, led to significantly increased lifespan in females only [100]. In mice
fed the TOR pathway inhibitor rapamycin, life extension was achieved in both sexes, but more effi-
ciently in females compared to males [101]. Data from large cohort studies have also implicated IIS and
TOR in human lifespan (e.g. Refs. [102–104]), and interactions with gender are observed. For instance,
polymorphisms in the IGF-1 receptor were correlated with reduced levels of insulin signalling,
diminutive body size and long life in women [105]. Sex hormones are able to regulate IIS in humans
[106] and, in addition, testosterone promotes age-related pathologies such as prostate cancer cell
proliferation [107] and cardiomyocyte hypertrophy [108] through TOR signalling. Conversely, insulin
signalling can regulate androgen biosynthesis [109], suggesting that sex steroids and nutrient-sensing
pathways cross-regulate. Intriguingly, in Drosophila, which has a cell-autonomous mechanism of sex-
determination, other, non-sex steroid hormones interact with IIS [110] and, in addition, steroid hor-
mones have sex-specific effects on lifespan [111,112], suggesting that the regulation of ageing by the
interplay of steroids and nutrient-sensing pathways is conserved, even in organisms that do not have
sex-hormones.

Conclusions

No comprehensive explanation yet exists for the gender gap in ageing and longevity. Here, we have
discussed sex differences in lifespan arising as a consequence of sexuality and distinct breeding stra-
tegies, which ultimately arise from a disparity in gamete cost (Fig. 3). Physiological dimorphisms
regulated by sex steroids are many and varied, and include behaviour, immune competence, and
cellular and metabolic processes. Importantly, sex steroids interact with the IIS/TOR network, which
itself regulates a myriad of biological processes. Given the role for steroid hormones as master regu-
lators of sexual dimorphisms, and IIS/TOR as pivotal to ageing, the interaction of these pathways may
offer a rapid route for evolution of sex differences in lifespan in response to changing sexual strategies.
We suggest that existing data on cross-regulation of steroid hormones and IIS/TOR, and their effects on
lifespan, should be addressed by further research in experimental model systems.

Acknowledgements

We thank David Gems and Helena Cochemé for useful discussions and comments on the manu-
script. Funding from the European Union’s Seventh Framework Programme (FP7/2007-2011) under
grant agreement n 259679 (IDEAL), The Wellcome Trust (WT081394MA) and The Max Planck
Institute.

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