Chronic stress, allostatic load, and aging in nonhuman primates
DARIO MAESTRIPIERI AND CHRISTY L. HOFFMAN
University of Chicago
Allostatic load is the “wear and tear” of the body resulting from the repeated activation of compensatory physiological mechanisms in response to chronic
stress. Allostatic load can significantly affect the aging process and result in reduced longevity, accelerated aging, and impaired health. Although low
ofstressand allostaticload.Female reproductionis associatedwith increasedriskofmortalityand hyperactivation ofthehypothalamic–pituitary–adrenalaxis.
Reproduction is especially stressful and costly for aging females of low rank. Although many indicators of body condition and neuroendocrine and immune
function are influenced by aging, there are marked and stable individual differences among aging females in body condition, plasma cortisol responses to
stress, and cytokine responses to stress. These differences are consistent with the hypothesis that there are strong differences in chronic stress among
individuals, and that allostatic load resulting from chronic stress affects health during aging. Comparisons between captive and free-ranging rhesus monkey
populations may allow us to understand how differences in environmental stress and allostatic load affect rates of aging, and how these in turn translate into
differences in longevity and health.
In order to survive and function properly, organisms must
maintain their physiological parameters (e.g., temperature,
blood pressure,glucose,and hormone concentrations inblood)
within a certain range of values appropriate for their age, gen-
der, and species. The state of equilibrium in which all of an
organism’s physiological parameters are within the normal
range is referred to as homeostasis. The external environment,
which includes both abiotic factors such as ambient tempera-
ture and humidity and biotic factors such as other organisms
and their behavior, can cause perturbations of homeostasis so
that some physiological parameters change and assume values
homeostasis can also be induced by pathological processes
such as infectious diseases or by genetic alterations or physio-
logical malfunction. In response to these perturbations of
homeostasis,the organism makes adjustmentsinits physiolog-
ical processes so as to bring the values of the parameters that
have been altered back into their normal range. This dynamic
process through which an organism adjusts its physiological
parameters in response to perturbations of homeostasis is re-
ferred to as allostasis. Allostatic processes involve feedback
mechanisms that detect a deviation from homeostatic equilib-
rium and trigger the appropriate compensatory responses.
Environmental perturbations of homeostasis are known as
stressors. There are many types of stressors, acute or chronic.
Responses to acute stressors help the individual survive and
sion from a conspecific are good examples of stressors that
can threaten survival or physical well-being. Areas of the
brain such as the amygdala and prefrontal cortex play a cru-
cial role in evaluating the threat and producing an emotional
response that will help copewith it. Signals from thebrain ac-
tivate the release of catecholamines (epinephrine and norepi-
nephrine) from the sympathetic–adrenal–medullary axis and
of glucocorticoid hormones (cortisol or corticosterone)
from the hypothalamic–pituitary–adrenal (HPA) axis. This
allows the organism to mobilize energy and exercise muscle,
increase cardiovascular tone to facilitate energy delivery, and
temporarily inhibit other physiological processes such as
growth, repair, digestion, and reproduction. Immune pro-
tokines can also be part of acute responses to stressors. Al-
though the general aspects of allostatic responses to stress
are the same in all organisms of the same species, and often
also in different species, there are marked individual differ-
ences both in the perception of threats and in the activation
of allostatic mechanisms.
of compensatory allostatic responses. These responses have
Address correspondence and reprint requests to: Dario Maestripieri, Uni-
versity of Chicago, 5730 South Woodlawn Avenue, Chicago, IL 60637;
The research described in this article was supported by NIH Grant R21-
AG029862 (to D.M.) and by an NSF Graduate Fellowship (to C.L.H.). We
thank all of our research collaborators including, in alphabetical order, James
Ayala, ChristopherCoe, MelissaGerald, JamesHigham,Adaris Mas-Rivera,
Karen Parker, Brian Prendergast, and Angelina Ruiz. We also thank the stu-
dents and the staff of the Caribbean Primate Research Center who provided
assistance with data collection.
Development and Psychopathology 23 (2011), 1187–1195
#Cambridge University Press 2011
an immediate benefit but also a cost. The wear and tear of the
body resulting from chronic allostatic activation is referred to
as allostatic load (AL; Juster, McEwen, & Lupien, 2010). Ca-
techolamines, cortisol, and cytokines are considered primary
mediators of AL. These primary mediators have direct effects
on cellular activities as well as activate secondary mediators,
changetheir rangesofactiontomaintain chemical,tissue, and
organ function. Chronic stressand allostasis result in a perma-
nent shift of physiological parameters away from their normal
homeostatic ranges and toward abnormal values. The chronic
activation of primary and secondary mediators of AL results
in tertiaryoutcomes, such as permanent physiological dysreg-
ulation, brain changes (synaptic and dendritic remodeling,
suppressed neurogenesis, structural atrophy/hypertrophy), ac-
celerated aging, disease, or death (McEwen, 2007).
AL can be detected and quantified through the measure-
ment of chronically altered physiological parameters. Specif-
ically, researchers study the interactions between primary
ondary biomarkers, so as to identify individuals who are at
risk of tertiary outcomes. Documenting AL is difficult be-
cause each mediator produces biphasic effects and is regu-
lated by other mediators, often in reciprocal fashion, leading to
nonlinear effects upon many tissues and organs (Juster et al.,
2010). Assessing AL also requires documenting age effects
with cross-sectional or longitudinal experimental designs.
Describing the accumulation of AL over time and in relation
to age, however, is also difficult because fluctuations in phys-
iological mediators induce compensatory remediation over
time (Juster et al., 2010).
Chronic Stress, AL, and Aging
Despite these difficulties, studies using a combination of AL
biomarkers such as cortisol, catecholamines, cholesterol, blood
pressure, and cytokines have shown that higher AL is associ-
related decline in cognitive and physical functioning, greater
risk of cardiovascular disease, and increased mortality risk
inolderadults (e.g.,Gruenewald, Seeman, Ryff, Karlamangla,
& Singer, 2006; Juster et al., 2010; McEwen, 2007). Some
studies have reported genderdifferencesinALsuch that cardi-
ovascular biomarkers of AL are more dysregulated in men
biomarkers or clusters of AL mediators are linked to specific
pathological outcomes, increased risk of mortality is generally
wald et al., 2006).
evidence specifically linking chronic stress and AL is mixed.
For example, one study found no association between stress-
ful life histories (marital status, group participation, coresi-
dence with married son) and neuroendocrine AL parameters
(Gersten, 2008) but reported an association with current per-
ceived stress in women. In another study, subjective per-
ceived stress, as opposed to objective environmental stress,
was correlated to higher AL primary mediators (Clark,
Bond,&Hecker, 2007). Inyet another study,mothers ofchil-
dren with cancer and other diseases showed increased AL
markers (higher norepinephrine, lower cortisol) and also
had a smaller hippocampus (Glover, 2006; Glover, Garcia-
Arcena, & Mohlman, 2008). Finally, it has been recently re-
ported that individuals exposed to chronic psychosocial
stress, such as victims of child maltreatment, exhibit signs
of early cellular aging such as accelerated telomere length re-
duction (see below), presumablyas a result of AL (Epel et al.,
2004; Tyrka et al., 2010).
Chronic stress is also presumed to be the link between low
socioeconomic status (SES) and high AL and its conse-
quences. A large body of research has shown that aging indi-
viduals of low SES are generally more vulnerable to risk of
cardiovascular, respiratory, rheumatoid, and psychiatric dis-
eases, and mortality from all causes than aging individuals
with more financial resources. Moreover, economically and
ican women exhibitreduced life expectancy, accelerated cellu-
lar aging, and increased vulnerability to aging-related diseases
(Crimmins, Kim, & Seeman, 2009; Epel, 2009; Geronimus,
Hicken, Keene, & Bound, 2006; Geronimus, Hicken, Pearson,
Seashols, Brown, & Dawson Cruz, 2010). Consistent with the
ALmodel,olderindividualswithlow SEShavehighvalues of
AL, andAfricanAmerican women show the most consistently
elevated ALacross allage groups. What islessclear,however,
iswhether the highALassociatedwithlow SES istheresultof
psychosocial stress associated with poverty, or of other factors
linked to low SES.
In addition to lacking financial resources, low SES indi-
viduals also lack social support and exhibit unhealthy life-
styles. Lack of social support can contribute to high AL
and its detrimental consequences because individuals who
have strong close ties with relatives and friends and are em-
bedded in largerand supportive social networks are generally
healthier and live longer than individuals who lack these re-
sources (e.g. Holmen & Furukawa, 2002; Kiecolt-Glaser
et al., 1985; Seeman, 2000; Wright & Steptoe, 2005). Fur-
thermore, low SES, at least in Western societies, is associated
with a numberof lifestyle variablesthat mayaffect health and
the aging process such as smoking, alcohol, and drug abuse,
less healthy diets, more sedentary life styles, greaterexposure
to violent crimes, and fewer coping outlets. Finally, econom-
ically and socially disadvantaged minority women also expe-
rience greater reproduction-related chronic stress, as they be-
gin reproducing at an earlier age and overall produce more
children than nonminority women of high SES. Both human
physiological and psychosocial stressor for females, which
may affect longevity, aging, and health.
Pregnancy and lactation entail dramatic increases in hor-
mones of the hypothalamic–pituitary–gonadal and the HPA
axis, along with suppression of immune function. Repeated
D. Maestripieri and C. L. Hoffman
physiological activation in conjunction with frequent repro-
duction may be a significant source of AL in females and
contribute to increased risk of disease and mortality. For ex-
tion is associated with increased risk of mortality (Hoffman
et al., 2008; Penn & Smith, 2007). In addition to neurendo-
crine and immunological processes, oxidative stress, which
occurs when the production of “free radicals” from metabolic
activities exceeds the capacity of antioxidant defenses and
damages DNA, is also another important byproduct of repro-
duction that contributes to AL (Finkel & Holbrook, 2000).
Oxidative stress can damage telomeres, the complex DNA–
integrity (von Zglinicki, 2002). Human and animal studies
suggest that both psychosocial stress (humans: Epel et al.,
stress associated with frequent reproduction (mice: Kotrschal,
Ilmonen, & Penn, 2007) increase the rate of age-related telo-
mere length reduction, thus resulting in accelerated aging.
however, is generally underinvestigated, and studies simul-
taneously addressing the effects of chronic psychosocial and
reproductive stress and their underlying mechanisms, are con-
Primate Research on Chronic Stress and AL
Research with primate models offersthe opportunity to inves-
tigate the effects of chronic stress associated with low social
statusor frequentreproductionwithout theconfounding influ-
ence of life style variables. Moreover, research with primate
models offers the opportunity to investigate AL accumulation
across the life span using longitudinal and experimental ap-
proaches that would be difficult in humans. Finally, research
on AL and aging in primates can be conduced at multiple
neurochemical, and genetic, thus using the approach that has
been advocated for research in human developmental psycho-
pathology (e.g., Cicchetti & Toth, 2009). Therefore, primate
research can extend, complement, and validate current efforts
to understand the relationship between chronic stress, AL,
aging, and health in humans.
Primate research has produced evidence linking status-re-
lated chronic stress and AL, although this relationship has not
been studied in the context of aging. Although low social sta-
mans,insomeprimate societieshighsocial statuscanbeeven
suggested that it is stress, rather than status per se, that results
in high AL. Sapolsky (2005) has argued that low status is as-
high-ranking individuals maintain dominance through threats
and other forms of psychological intimidation (e.g., ma-
caques, baboons, chimpanzees). This is particularly true in
groups in which dominance hierarchies are stable, rank is so-
cially inherited from mothers and difficult to change, and low-
ranking individuals are subjected to high rates of harassment,
so that their daily lives are characterized by lack of control
and predictability. In these species and social situations, how-
psychosocial stress if the hierarchy becomes unstable and their
rank is being challenged. High rank can be associated with
greater stress also in despotic primate species in which high-
ranking individuals frequently reassert their dominance
through physical aggression (e.g., ring-tailed lemurs); in these
species or societies, high-ranking individuals may be more
stressed than their victims. In contrast, in nondespotic primate
dominance hierarchies are loose or nonexistent, social factors
are not a significant source of psychological stress.
In primate species in which low-ranking individuals are
highly stressed, psychosocial stress can be alleviated by the
presence of strong networks of kin and the receipt of social
support (grooming, physical contact, and agonistic aid), the
effective avoidance of high-ranking individuals, or the use
avoid triggering their aggression). Individuals with “relaxed”
personalities, who can effectively discriminate between threa-
tening and neutral stimuli and do not hyperreact to novelty
may also be less vulnerable to status-related psychosocial
stress (Sapolsky, 2005).
The relationship between status-related stress and AL in
primates has been investigated mainly with regard to neu-
roendocrine biomarkers (primarily cortisol; Abbott et al.,
2003), and to a lesser extent with immunological and cardio-
vascular measures. Little is known about the relationship be-
tween status-related psychosocial stress and catecholamines.
With regard to cortisol, work with wild baboons conducted
by Sapolsky (2005) as well as studies of macaques and other
primates have shown that stressed individuals show elevated
other lower cortisol responses to environmental or pharmaco-
logical challenges, and hyper- or hyposensitivity to negative
feedback regulation (i.e., cortisol responsesto dexamethasone
suppression test; e.g., Gust, Gordon, Hambright, & Wilson,
1993). In groups of baboons or macaques that have been
newly formed or in which there have been dominance upheav-
als, all individuals have high cortisol levels regardless of
rank (Abbott et al., 2003). In both captive long-tail macaques
and wild baboons, low-ranking males havelower testosterone
levels, presumably a suppression effect resulting from high
sus macaque females suggested that aging affects the basal
activity of the HPA axis (particularly, circadian variation in
cortisol levels) but this effect can be maskedbyacute psycho-
social stress (Gust et al., 2000). This study, however, provided
no information on social status orother types of chronic stress.
Therefore, the relationship between the HPA axis, chronic
stress, and aging remains uninvestigated in primates. Data on
social behavior in aging macaques indicate that low-ranking
Allostatic load in nonhuman primates
andreduced activitylevels when compared tohigh-ranking fe-
males, possibly due to greater psychosocial stress (Veenema,
pen, & Spruijt, 2001).
In captive long-tailed macaques (a species in which low-
ranking individuals are highly stressed), low rank is associ-
ated with higher basal blood pressure, a sluggish activation
of the cardiovascular stress response after achallenge and de-
layed recovery when it abates, a pathogenic cholesterol pro-
file, and increased vulnerability to the atherogenic effects of
a high-fat diet (e.g., Kaplan, Manuck, Anthony, & Clarkson,
2002). However, there have been no studies of cardiovascular
indicators of AL in aging primates.
Previous studies of immune function inrelation topsycho-
social stress and aging in primates have relied on two assess-
ment methods: in vitro assays of natural killer (NK) cytolytic
activity and quantification of plasma cytokine concentrations
(typically interleukin [IL]-1, -6, and -8; the IL-1 receptor an-
tagonist, or IL-1ra, is also used as a marker of inflammation
and infection; Coe & Laundenslager, 2007). In general, mod-
erate acute stress is expected to enhance immunity, whereas
chronic stress is expected to be immunosuppressive. Studies
ing conditions for captive animals (Coe & Ershler, 2001) or
capture and handling of free-ranging animals (Laudenslager
et al., 1999) are followed by a decline in NK cytotoxicity to-
ward K562 targets in vitro for up to 24 hr later. Coe and col-
laborators (Coe, 1993, 2004; Coe & Ershler, 2001) have also
documented aging-related declines in NK cytolytic cell activ-
ity (both in basal conditions and in response to acute psycho-
social stress) as well as reduction in cytokine release in re-
sponses to antigen challenges. However, they reported a
great deal of interindividual variation in the timing and the
magnitude of this decline in immune function and showed
that this variation is predictive of health and longevity (Coe
& Ershler, 2001). Specifically, monkeys showing low cyto-
lytic activity at 20 years of age lived only a few more years,
whereas those sustaining high lytic responses continued to
live on foras much as a decade longer (Coe & Ershler, 2001).
The brain is a major target of AL (Ganzel, Morris, &
Wethington, 2010; McEwen, 2007). Data from rodents have
shown that chronic stress results in neuronal loss, loss of sy-
naptic connectivity, or impairment of synaptic function in the
hippocampus, amygdala, and prefrontal cortex (McEwen,
2007). A longitudinal study of aging human subjects showed
riod were associated with reduced hippocampal volume and
reduced performance on hippocampal-dependent memory
tasks (Lupien et al., 1998). After preliminary studies by Sa-
polsky and collaborators 20 years ago suggested that chronic
psychosocial stress may damage the hippocampus in vervet
monkeys (Sapolsky, Uno, Rebert, & Finch, 1990; Uno, Ta-
rara, Else, Suleman, & Sapolsky, 1989), no further studies
have been conducted in nonhuman primates. Although re-
search by Morrison and collaborators has investigated many
aspects of brain aging in rhesus monkeys, including the ef-
fects of estrogen (e.g., Hof & Morrison, 2004; Morrison
2003; Morrison & Hof, 2007; Radley & Morrison, 2005),
this work has not investigated the effects of chronic social
stress. Information on aging-related changes in brain func-
tion, rather than in brain structure, in primates has been pro-
vided by measurements of monoamine metabolites and neuro-
peptides. In humans, alterations of the monoamines dopamine,
serotonin, and norepinephrine have been implicated in aging-
relatedchangesin cognitivefunctionaswell asinaging-related
disorders such as Alzheimer’s and Parkinson’s disease (e.g.,
a reduction of monoamine content in various areas of the brain
as well as in cerebral spinal fluid (CSF) concentrations of the
Leahy, Roth, & Redmond, 1987; Goldman-Rakic & Brown,
1981; Mohr et al. 2010; Shelton et al., 1988). Brain oxytocin
and corticotropin-releasing factorare involved in regulating so-
cial, affective, and cognitive processes and are known to be af-
fected by chronic stress; therefore, they are good candidates as
able on the effects of aging on these neuropeptides in primates.
Finally, body condition and metabolic variables provide
information about health and disease, and therefore are
good candidates as biomarkers of tertiary outcomes of AL
during aging in primates. Body weight (BW) and body
mass index (BMI) generally decrease with increasing age
(see below), and are especially low in individuals who are
known to be chronically sick. Being overweight or obese is
also a health risk factor, and there is evidence that the meta-
bolic syndrome occurs in primates (Kaufman et al., 2005;
Schwartz, Kemnitz, & Howard, 1993). Finally, analyses of
blood chemistry variables in rhesus monkeys have shown
that serum albumin and creatinine levels, albumin/globulin
ratio, serum calcium, and total serum proteins exhibit the
greatest magnitude of change in relation to age (Smucny
the relationship between chronic stress and metabolic indica-
tors of AL in nonhuman primates.
Free-Ranging Rhesus Monkeys as Model Organisms
for Research on Chronic Stress, AL, and Aging
aging in many research areas including neurobiology and cog-
nition, skeletal and reproductive aging, dysfunction of the en-
docrine and immune system, and cardiovascular disease and
diabetes (Roth et al., 2004). Most, if not all, biomedical aging
research with rhesus monkeys to date, however, has been con-
ducted in captivity and with individually housed subjects.
has been conducted with free-ranging rhesus monkeys.
Studying aging in free-ranging rhesus monkeys is neces-
sary and important for at least two reasons. The first is that
free-ranging rhesus monkeys do not live as long as their
captive counterparts. In captivity, the median life span of
D. Maestripieri and C. L. Hoffman
rhesus monkeys is 25 years and the maximum life span is 40
years (Roth et al., 2004). In food-provisioned, predator-free
free-ranging populations, however, the median life span is
15 years and less than 5% of individuals reach 25 years of
ability of health care have extended the human life span, cap-
tivity appears to have similarly increased the life span of
cause many of the aging-related disorders that we observe in
both contemporary humans and captive rhesus monkeys are
of these species. Studying the aging process in the environ-
mental conditions in which humans spent most of theirevolu-
tionary history is obviously no longeran option. Free-ranging
rhesus monkeys, however, give us the unique opportunity
to study the aging process in environmental conditions that
closely approximate those in which these primates evolved.
The extent to which the aging process may be qualitatively
and/or quantitativelydifferent in free-ranging and captive rhe-
sus monkeys is unclear. Forexample, it is possible that funda-
free-ranging animals when compared to captive individuals,
due to the greater cumulative effects of physical, ecological,
and psychosocial stressors (i.e., AL) experienced by the
free-ranging monkeys. Variation in aging rates between cap-
tiveandwild animals,aswellasbetween wild populationsex-
demonstrated in other species of mammals (Austad, 1993,
1996; Miller, Harper, Dysko, Durkee, & Austad, 2002).
Therefore, one reason for studying aging in free-ranging rhe-
sus monkeys is that by comparing free-ranging and captive
ferent environments as a result of differences in AL.
A related reason for studying free-ranging monkeys is that
captive monkeys that are individually housed in cages. Rhesus
monkeys are highly social animals that live in large groups, in
which daily social activities depend on complex behavioral
transactions regulated by kinship, dominance, or friendship.
These groups have a strong matrilineal structure and a rigid
dominance hierarchy. Rhesus monkeys are considered one of
the most despotic primate species, in which low-ranking indi-
viduals experience high levels of chronic stress (Maestripieri,
inance rank is socially inherited from mothers and is highly
stable throughout the lifetime. Therefore, young females born
to low-ranking mothers typically remain low ranking for the
threats (Maestripieri, 2007). In addition, low-ranking females
typically have fewer relatives in their group and receive less ef-
fective social support than high-ranking females. Therefore,
low-ranking rhesus females are good model organisms for
on AL during aging.
Rhesus monkey females are also good model organisms
for studying the effects of reproduction-related chronic stress
on AL and aging. Rhesus females begin reproducing at 3 or 4
years of age and continue to do so into their 20s. Pregnancy
lasts 5.5 months, and infants are usually weaned within 6 or
12 months. Some rhesus females produce one infant per year
for 15–20 years, whereas others give birth everyother yearor
with longer interbirth intervals. In addition to the energetic
stress of pregnancy and lactation, motherhood is also associ-
ated with significant psychosocial stress. Rhesus infants are
from other conspecifics; therefore, concerns over infant safety
and the need for protection are acause of significant anxiety in
rhesus mothers (Maestripieri, 1993a, 1993b). Females who
reproduce almost every year probably experience significant
chronic stress, above and beyond status-related stress, and
such reproductive stress should result in physiological AL
and increased risk of disease and mortality during aging.
Chronic Stress, AL, and Aging in the Rhesus Monkey
Population on Cayo Santiago
The Caribbean Primate Research Center of the University of
Puerto Rico maintains a free-ranging population of rhesus
macaques on theisland of Cayo Santiago, Puerto Rico, which
includes approximately 900–1000 individuals. The popula-
tion was established in 1938 and has been under continuous
observation since 1956(Rawlins &Kessler, 1986). The mon-
keys are free-ranging on the island, yet they are easily identi-
fiable and fully habituated to human presence, facilitating be-
havioral observations. They liveinseveral large social groups
and maintain a social structure and behavior very similar to
key chow, which is readily accessible to all members of the
population. Therefore, all monkeys in the population have es-
sentially the same diet and very similar life style. Except for
periodic culling of individuals, mostly juveniles and males,
the social structure of this population has been intact for de-
cades, and all individuals have a fully known genealogical,
reproductive, and clinical history. All matrilineal relatedness
is known for all females in the population from birth records
and observations, whereas paternal relatedness has been de-
termined through genetic analyses. Finally, all monkeys on
the island are trapped once a year, allowing scientists to ob-
tain biological samples or any physical measurements they
might need for their research. In an ongoing study of aging
in this population, we have obtained evidence that low social
that this has consequences for longevity and aging.
Female reproduction is risky, costly, and stressful
Analyses of the long-term colony records of the Cayo San-
tiago population for a period of over 40 years showed that
the median age for females who survive to reproductive age
Allostatic load in nonhuman primates
is about 15 years and maximum life span is about 30 years of
age (Hoffman, Higham, Mas-Rivera, Ayala, & Maestripieri,
2010). Many aging females continue reproducing until they
ing age. One of the costs of reproduction is reduced survival:
females have a higher probability of dying during the period in
which they produce and raise offspring (i.e., the last few weeks
of pregnancy and the first few postpartum months, when fe-
males are lactating and their offspring are fully nutritionally
and socially dependent on them) than at other times of the
year. This was demonstrated by analyzing seasonal fluctua-
tions in births and deaths in adult females and males (Hoffman
males) were recorded in 45 years (1961–2005). Most births
(86%) were concentrated in a 5-month period, from November
mid-May and ended in October. Seasonal reproduction in this
population is regulated by climatic factors; the onset of the
Spring rainy season triggers the beginning of mating activity,
and the birth season begins about 6 months after the onset of
mating (Hoffman et al., 2008; Rawlins & Kessler, 1985). In
the period between 1961 and 2005, the mating season, and
therefore also the birth season, have commenced increasingly
earlier over time, due to the fact that the Spring rainy season
has begunincreasinglyearlier,possiblyasa result ofglobal cli-
mate changes (Hoffman et al., 2008). Data from 922 adult
deaths (526 males, 396 females) in relation to time of the
seasonal fluctuations in their monthly probability of mortality,
and that these fluctuations were significantly different between
the sexes.Female mortality probability peaked in Februaryand
March, that is, the last 2 months of the birth season, whereas
male mortality peaked in August, September, and October,
that is, during the mating season (Hoffman et al., 2008). In ad-
dition to this analysis of mortality probabilities, we also com-
pared the total numberof female and male deaths in the mating
and the birth seasons and found that more females died in the
birth season than in the mating season, whereas more males
died in the mating season than in the birth season. Finally,
we showed that changes in the timing of the onset of the birth
in mortality. As the birth season has commenced increasingly
earlier in the year, the average dates of female and male deaths
have steadily shifted as well (Hoffman et al., 2008). Although
in female mortality during the birth season appeared to be due
which in turn, may have been the result of reproduction-related
stress and impaired immune function (Hoffman et al., 2008).
Increased risk of mortality is one of the costs of female re-
production. Other costs are energetic and metabolic. Sustain-
ing pregnancy and producing milk are expensive activities
that require the use of resources the body normally uses for
its own maintenance or growth. Young females typically
compensate for these costs by increasing their food intake
and body mass. Increasing food intake and body mass may
not be an option for aging females, whose body weight and
body mass are much lower than those of younger adults, and
which continue to decline with advancing age. Aging females
attempt to compensate for the increasing energetic costs of re-
production in three different ways: by resting more and saving
energy,byproducing infantslessfrequently,and by producing
smaller infants that require less nutritional expenditure. We re-
ported that after giving birth, older females spent a higher pro-
portion of time resting than younger females did (Hoffman,
became longer with advancing age, so that between 4 and 18
years of age 85% of females gave birth annually, whereas at
man, Higham, et al., 2010). Finally, there was a tendency for
older females to produce infants that were of low body mass
for their ages. The old females’ compensating strategies allow
them to produce infants even at very late ages, but in doing so
theiroffspring. Infact, the probabilityof offspring survival de-
man, Higham, et al., 2010).
therhood-associatedpsychosocial stress. Inrhesusmonkeysand
elevated anxiety resulting from concerns about the infant’s
safety (Maestripieri, 1993a, 1993b). In addition, motherhood
and lactation are also accompanied bysleep disruption, and ten-
sion and conflict in social relationships with older offspring or
that basal cortisol levels, as measured through assays of fecal
and lactating than in nonpregnant nonlactating females (Hoff-
tation was accompanied by greater plasma cortisol responses to
the stress of capture and individual housing. This was demon-
strated with both between-subject analyses (i.e., by comparing
plasma cortisol responses to stress in lactating and nonpregnant
nonlactating females) and within-subject analyses (i.e., by com-
yearand lactating in another year; Hoffman, Ayala, et al., 2010;
reproducing females have elevated concentrations of cortisol
9–10 months per year, and that females who give birth every
year have elevated glucocorticoid hormones most of their life.
Given the glucocorticoid-cascade hypothesis (Sapolsky, Krey,
& McEwen, 1986), frequent reproduction is a source of signifi-
cant AL in primate females, and its deleterious consequences
should be especially apparent during aging.
Social status, chronic stress, and AL in free-ranging
Despite the effects of changes in female reproductive state
from 1 year to the next, individual differences in plasma
D. Maestripieri and C. L. Hoffman
cortisol responses to stress among aging rhesus monkey fe-
males were highly stable across 2 consecutive years, suggest-
ing that there may have been differences in chronic stress
production (Hoffman, Ayala, et al., 2010). Although domi-
man, Ayala, et al., 2010), high-ranking females had lower
cortisol responses to stress than low-ranking ones. Specifi-
cally, females who belonged to the top matrilines in their re-
spective groups (n ¼ 21) had significantly lower cortisol
ingmatrilines (n ¼ 40;high rank: 29.02+1.81 mg/dl; middle
and low rank: 34.46 + 1.49 mg/dl; U ¼ 272, p ¼ .02). As
mentioned before, rhesus macaque society is highly despotic
and low-ranking females probably live in a state of constant
anxiety and fear given the frequent threats and the unpredict-
able aggression they receive from high-ranking females. On
Cayo Santiago, where social groups are larger than in the
wild, the benefits of high rank seem to be restricted to the
members of the top-ranking matriline. Middle-ranking fe-
males are probably just as stressed as low-ranking females
and that may explain their similarity in cortisol responses to
stress. With regard to the psychosocial stress associated with
lactation, however, low-ranking females seem to be worse
off than middle-ranking females. In fact, low-ranking females
had greater increases in cortisol from the cycling to the lactat-
ingconditionthan didmiddle-orhigh-rankingfemales (Hoff-
man, Ayala, et al., 2010). Therefore, reproduction is particu-
larly costly and stressful for low-ranking females, and low-
statusfemales whoreproducea great deal duringtheir lifetime
may experience particularly high AL during aging. Cortisol
responsesto stress, however, are influenced not only bysocial
status and reproductive condition but also by genotype. We
genotyped aging females for the serotonin transporter gene
polymorphism (a long, l, and a short, s, allele are present in
both rhesus monkey and human populations) and found
that, other things being equal, females with the ls (23% of
the population) or the ss (11%) genotype had higher cortisol
responses to stress than females with the ll (66%) genotype,
suggests that genetic risk factors should be taken into consid-
eration when examining interindividual variation in AL in
both rhesus monkeys and humans.
Although the main focus of our aging study was on endo-
crine markers of AL, we also gathered data on body condi-
markers of AL and aging. Among our aging rhesus monkey
females, we found strong negative correlations between age
and BW and the BMI. In addition, there were strong positive
years, suggesting that differences in body condition among
aging females were stable over time. BW and BMI were pos-
itively correlated with total bilirubin (BW: rs ¼ .31, n ¼ 52,
p ¼ .03; BMI: rs ¼ .27, n ¼ 51, p ¼ .05), total protein (BW:
rs ¼ .27, n ¼ 52, p ¼ .05; BMI; rs ¼ .31, n ¼ 51, p ¼ .03),
and total triglycerides (BW; rs ¼ .29, n ¼ 52, p ¼ .03; BMI;
rs ¼ .31, n ¼ 51, p ¼ .03) and negatively correlated with
levels of gamma-glutamyl transferase (BW; rs ¼ 2.42, n ¼
52, p ¼ .002; BMI: rs ¼ 2.43, n ¼ 51, p ¼ .002). Therefore,
old age and poor body condition were associated with altera-
tions in glucose and lipid metabolism (see also Kessler &
younger controls to measure concentrations of monoamine
metabolites and peptides. The CSF concentrations of seroto-
nin, norepinephrine,and dopaminewerenot significantly dif-
ferent in relation to female age or rank, but CSF concentra-
tions of oxytocin were significantly higher in aging females
(Parker, Hoffman, Hyde, Cummings, & Maestripieri, 2010).
The plasma concentrations of cytokines IL-1ra, IL-6, and
IL-8 measured after the stress of capture and housing in a
cage were generally higher and more variable in older (.15
years) than in younger (,15 years) females (Hoffman
et al., 2011). As with plasma cortisol levels, the concentra-
tions of IL-1ra and IL-8 measured in the same subjects in
2 consecutive years were significantly positively correlated
(IL-1ra; rs ¼ .64, n ¼ 15, p ¼ .01; IL-8; rs ¼ .85, n ¼ 18,
p ¼ .0004), whereas for IL-6 the correlation was not signifi-
cant (rs ¼ .06, n ¼ 19, p ¼ .77). There was no significant
effect of rank or a significant interaction between rank and
age on cytokines. Average concentrations of IL-8 were
significantly positively correlated with those of plasma
cortisol (n ¼ 69, rs ¼ .29, p ¼ .01), whereas cortisol was
not correlated with IL-1ra or IL-6. There were no significant
correlations between cytokine concentrations and CSF con-
centrations of the serotonin metabolite 5-HIAA, the dop-
amine metabolite HVA, or the dopamine precursor tyrosine.
There were, however, significant negative correlations be-
tween the serotonin aminoacid precursor tryptophan and
IL-1ra (r¼ .52, n ¼ 32, p ¼ .002), IL-6 (r¼.38, n ¼ 33,
p ¼ .02), and IL-8 (r ¼ .35, n ¼ 34, p ¼ .04). These correla-
tions were independent of age. One female in particular, had
extremely low levels of CSF tryptophan, suggesting signifi-
cant inflammation associated with activation of indole-3-di-
oxygenase. This female also had very high concentrations
of all three cytokines (IL-1ra ¼ 1530.93; IL-6 ¼ 82; IL-8
Although social status did not significantly affect all phys-
iological markers of AL, we found stability of individual dif-
ferences in BW and BMI, plasma cortisol responses to stress,
and plasma cytokine responses to stress in 2 consecutive
years. These differences are consistent with the hypothesis
that there are strong differences in chronic stress among indi-
viduals, and that chronic stress affects many aspects of the
aging process. Body condition and cytokine concentrations
were affected by age, whereas plasma cortisol concentrations
were affected by rank and genotype. However, there was a
correlation between plasma cortisol and one of the cytokines,
suggesting an interaction between psychosocial stress, HPA
function, and immune function in aging females.
In conclusion, although the study of chronic stress and
AL during aging in free-ranging rhesus monkeys is just be-
Allostatic load in nonhuman primates
ginning, there is already suggestive evidence that stress asso-
ciated with low social status and reproduction influences
different physiological indicators of AL. Being of low dom-
stressful and comparable to having low SES in human soci-
eties. However, primate research suggests that there are
important factors modulating the relationship between social
status,AL, and aging. Low status is morelikelytobe stressful
in despotic than in egalitarian societies, and if such despotic
societies are large and highly stratified, individuals of the
middle class can be as stressed as those at the bottom of the
hierarchy. Primate research also suggests that the stress of re-
production may be higher in low status than in high status fe-
males, and that females of low status who reproduce fre-
quently in their lifetime may experience particularly high
levels of AL during aging, with negative consequences for
health and longevity. Future primate research can address
the cumulative effects of chronic psychosocial and energetic
stress on longevity, the rate of aging, and health using a lon-
gitudinal life span approach. Furthermore, comparing the
aging process in free-ranging and captive rhesus monkeys
can enhance our understanding of variation in aging rates
and longevity in populations of the same species exposed
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Allostatic load in nonhuman primates