Reciprocal Affiliation Among Adolescent Rats During a Mild Group Stressor
Predicts Mammary Tumors and Lifespan
JASON R. YEE, MA, SONIA A. CAVIGELLI, PHD, BERTHA DELGADO, MD, AND MARTHA K. MCCLINTOCK, PHD
Objective: Although the detrimental physical health effects of social isolation have been known for three decades, the answers to
how and why social relationships generally improve health remain elusive. Social relationships are not always beneficial, and we
examined a structural dimension that may bring about their salubrious effects: affiliative reciprocity during a stressor. Methods:
In a lifespan study, female rats lived with their sisters and were tested for temperament, affiliative reciprocity during an everyday
stressor at puberty, corticosterone response to a stressor, mammary tumor development and diagnosis, and death. Results: Rats that
affiliated more reciprocally during a mild group stressor survived longer (p ? .0005), having exhibited a lower corticosterone peak
in response to an acute novel stressor in late adulthood (p ? .0015), and longer time to the development of spontaneous mammary
tumors (p ? .02). These effects could not be explained solely by the number of affiliative interactions or individual temperament.
Indeed, affiliative reciprocity and neophobia were independent and predicted mortality additively (p ? .0002). Conclusions:
Affiliative reciprocity during a stressor, a structural quality of social interactions, protected females from early mammary tumor
development (the primary pathology in Sprague-Dawley rats) and early all-cause mortality. Conversely, lack of reciprocity (whether
disproportionately seeking or receiving attempted affiliation) was as potent a risk factor as neophobia. Thus a social role increased
risk additively with individual temperament. Our data indicate that affiliative reciprocity functions as a buffer for everyday stressors
and are likely mediated by attenuated reactivity of the hypothalamic-pituitary-adrenal axis. Key words: social support structure,
affiliative reciprocity, corticosterone, individual differences, spontaneous mammary tumor, psychosocial risk factors.
AUC ? area under the curve; HR ? hazard ratio; CI ? confidence
comparable to cigarette smoking (1). Yet answers to how and
why this is so remain elusive (5,6). It is widely assumed that
relationships facilitate good health primarily through provid-
ing social support (6). Two pathways have been proposed to
explain how supportive relationships can promote better
health: (1) socio-behaviorally, by promoting the adoption of a
healthier lifestyle consisting of behaviors such as eating a
balanced diet, exercising, and taking regular visits to the
family physician; or (2) psychobiologically, via psychological
mechanisms that coordinate appraisals, emotions, and a sense
of control, and thereby influence biological processes (6–10).
This distinction is often made by referring to the support as
either instrumental or emotional, respectively (11). Supportive
relationships are thought to augment physical health through
psychological mechanisms by organizing the endogenous reg-
ulation of hormones, cytokines, and other chemical mediators.
However, although there is strong evidence that health behav-
iors play a part (12), there is little direct evidence that
psychological mechanisms affect mortality through these
endogenous mediators (5). To address this paucity, we
confine our focus to psychobiological pathways.
ocial isolation is deleterious for physical health (1–4) with
an estimable risk of broad-based morbidity and mortality
House et al.’s (1) seminal report on social relationships and
health proposed that further theorizing would require distin-
guishing between: a) the existence or quantity of relationships,
b) their formal structure, and c) their content. Although an
abundance of research has explored the health impact of
varying amounts of social support, few have examined the
structural features. To our knowledge, in the nearly 30 years
since Berkman and Syme (3) published the first prospective
study linking social isolation with increased mortality, very
little progress has been made toward understanding what
features of the formal structure need to be present for social
relationships to provide their health benefits.
One way to isolate the necessary structural features that
make social relationships salubrious is to closely examine the
quality of group interactions. There are a number of different
dimensions along which social relationships can vary struc-
turally, including, for example, reciprocity (1). If the variation
in a structural dimension can predict the variation in mortality,
all while the number of social partners and content of the
interactions are held constant, then this is strong evidence that
this feature of the formal structure is an integral part of what
makes social relationships beneficial to health.
In the present report, we employ a rat model to study the
structural features of social interactions. To study the social
interactions most salient to support and health, we investigated
social interactions in response to a mild common stressor
experienced simultaneously by the whole group—relocation
of the home cage. Such stressors occur at least daily over the
lifespan for laboratory-housed rats (13), and thus, although
relatively mild, creates a background of chronic stressors
throughout the lifespan (14). Examining interactions during
such a stressor also keeps the content of the interactions within
a narrow range of behaviors that are expressed daily in re-
sponse to common laboratory disruptions. Moreover, the num-
ber of social partners was held constant for each group to
further ensure that we are isolating the effects of relationship
structure. Rats are an excellent model for investigations of the
connection between social relationships and health because
From the Department of Comparative Human Development , University of
Chicago (J.R.Y., M.K.M.); Department of Pathology (B.D.); Center for In-
terdisciplinary Health Disparities Research (J.R.Y., B.D., M.K.M.); Institute
for Mind and Biology (J.R.Y., B.D., M.K.M.), Chicago, Illinois; and Depart-
ment of Biobehavioral Health (S.A.C.), Pennsylvania State University, Uni-
versity Park, Pennsylvania.
Address correspondence and reprint requests to Jason R. Yee, MA, Institute
for Mind and Biology, University of Chicago, 940 E. 57th Street, Chicago, IL
60637. E-mail: firstname.lastname@example.org
Supported by Grants from the National Institutes of Health CA130267 (to
J.R.Y.), HD08693 (to S.A.C.), and ES012382 and AG018911 (to M.K.M.).
Received for publication November 20, 2007; revision received May 16,
Copyright © 2008 by the American Psychosomatic Society
Psychosomatic Medicine 70:1050–1059 (2008)
rats exhibit complex socio-cognitive capacities, such as gen-
eralized reciprocity, previously thought only to exist in
humans (15), and because they are relatively short-lived, al-
lowing us to bring social and temperament characterizations
made early in development to bear on morbidity and mortality.
We first set out to characterize the content of social behav-
iors enacted during the mild stressor of home cage relocation.
We hypothesized that social contact under stressful conditions
would not be equally initiated and received across group
members, resulting in individual differences in reciprocity that
may explain the variation in morbidity and mortality. The
structural dimension of reciprocity has been linked to both
physical and mental health outcomes. For example, in married
couples in which one member develops a serious illness,
targeted intervention to restore the equity of the relationship
resulted in increased relationship quality and less psycholog-
ical distress for the patient (16). Similarly, seriously ill
patients receiving long-term care are less likely to report
depression when they perceive the relationship with their
primary caregiver as more reciprocal (17). In the context of
the workplace, lack of reciprocity has been linked to declines
in physical health. Imbalance in the amount of effort expended
in relation to the rewards reaped is associated with increased
risk of coronary heart disease (18). Given these findings, we
expected that rats whose interactions after a stressor were
reciprocal would experience better health outcomes.
Furthermore, since previous work in our laboratory has
demonstrated that neophobia, a dimension of individual tem-
perament, predicts mammary tumor incidence and mortality
(19,20), we investigate whether social interactions and neo-
phobia are independent risk factors for mammary tumors and
death, or whether one operates solely through an effect on the
other. For example, neophobic individuals might be more
likely to seek the reassurance of affiliation more frequently
than they are approached by their less neophobic cagemates.
Lastly, since we are primarily interested in psychobiolog-
ical mechanisms, and have restricted any opportunity for
individual differences in health behaviors, we examine
whether the structure of social interactions early in life pre-
dicts stress-induced glucocorticoid reactivity or ovarian func-
tion late in life. Overexposure to glucocorticoids throughout
the lifespan is widely thought to exacerbate declining health
(21). Moreover, a history of prior exposure to repeated stres-
sors (i.e., chronic stress) facilitates a heightened glucocorti-
coid response to a novel stressor (22,23). We hypothesized
that reciprocal affiliative interactions with cagemates during
the daily stressors they encounter in the lab over the course of
the lifespan would buffer them from deleterious conse-
quences. Thus, when presented with a novel stressor in adult-
hood, rats that consistently engaged in reciprocity would
exhibit lower glucocorticoid levels than rats that lacked reci-
procity in their interactions. Finally, because social interac-
tions can affect ovarian function, and ovarian steroids modu-
late glucocorticoid levels, we assessed ovarian function in the
weeks before corticosterone measurements as potentially con-
Female Sprague-Dawley rats lived throughout their lives in solid bottom
plastic cages (43.5 ? 23.5 ? 20.5 cm) on a 14L:10D lighting schedule (lights
on at 20:00 hours) with food and water ad libitum. Rooms were maintained
at 22 ? 1°C, with 13 to 15 room air changes an hour and humidity range 40%
to 60%. The rats also contributed to a previous study focusing strictly on the
relationships between temperament, corticosterone responses to stressors, and
lifespan (20). For this reason, methodology concerning the protocol will be
abbreviated with a focus on aspects relevant to the findings presented in this
report. Fifty-four rats were originally in this longitudinal study, but five died
before all data were collected (e.g., corticosterone measured at 15 months of
age). Due to the longitudinal nature of the study, rats that died were not
Females were bred in our laboratory and tested for neophobic or neophilic
temperament at 20 days of age. After weaning at 22 days of age, they
continued to live only with their sisters until 28 days of age, when we
reorganized their home cages; a third remained with two of their sisters, a
third were housed with two strange females, and a third were isolated. This
reorganization did not affect the measures or outcome of this study and thus
need not be discussed further. At 46 days of age, all resumed living with their
sisters in trios, and remained together until death.
Having been reunited with their sisters for a week, each trio was exposed
to home cage relocation at 53 days of age, a mild stressor that is part of
standard husbandry procedures, and one of the common stressors that labo-
ratory rats experience throughout their lives (13). Social interactions during
this stressor were recorded. The home relocation stressor was repeated in
early middle age (8.3 months). At 11 months of age, biweekly health checks
and palpation for mammary tumors, along with daily vaginal smears. In late
middle-age (15 months), during reproductive senescence, when ?89% of the
rats were still disease free, the females were exposed to a 30-minute restraint
stressor and repeated blood samples were collected to assess corticosterone
response dynamics. Health checks continued until death (median ? 22.3
months of age).
At 20 days of age, we measured rats’ willingness to explore a complex
novel environment by quantifying locomotion in a 940 cm2square arena
scattered with a few rat-sized objects. Each rat’s locomotor behavior was
compared against her sisters to create three categories: the two most active
sisters were identified as ‘neophilic,’ the two least active were identified as
‘neophobic,’ and those with values closest to the family mean were identified
as ‘intermediate.’ In the current study, intermediates were not included in
order to assess whether temperament and affiliative reciprocity are indepen-
dent or overlapping constructs with respect to health measures. For details on
the behavioral assay, see Ref. (20).
Each sister represented a different third of the temperament distribution.
As in our previous report (20), which focused on the comparison between
neophobia and neophilia to identify neophobia as a risk factor for early death,
we excluded data from sisters with an intermediate temperament to maintain
a “high risk versus low risk” comparative framework (yielding 54 subjects).
Sisters with an intermediate temperament had lifespans that were roughly
intermediate between their neophobic and neophilic sisters.
Social Interactions During a Common Stressor
Home cage behavior was recorded during the first half of the dark period
(11:00–15:00) after relocating the home cage to another room and setting it
on a table next to a cage of unfamiliar rats, a manipulation designed to mildly
stress each animal simultaneously, while not changing their normal social
context. Affiliative reciprocity scores were established at 53 days of age, and
their stability was quantified by retesting at 8.3 months of age.
Behavior was analyzed using the Noldus Observer (Noldus) video anal-
ysis system. An ethogram (see Table 1) was constructed to quantify the most
RECIPROCAL AFFILIATION AND HEALTH IN OLD AGE
1051 Psychosomatic Medicine 70:1050–1059 (2008)
common social behaviors after cage relocation. Coding for these social
behaviors was corroborated by comparison to the existing literature on rat
social behavior in both captive and naturalistic populations (24–26).
Social behaviors consisted of four general categories, 1) affiliation re-
ceived, 2) affiliation initiated, 3) tandem curiosity in what lies outside the
home cage, and 4) mutual inspection. Since confirmatory factor analysis
verified that initiation and reception of affiliation were factors different from
each other as well as from the joint behaviors of tandem curiosity and
inspection, we were able to quantify the degree to which affiliative interac-
tions were reciprocated. Together, an oblique solution for these four concep-
tually related factors comprised 69.6% of the variance in overall social
behavior (See Table 2).
For affiliative interactions, initiating social contact was relatively inde-
pendent of receiving it. Indeed, initiating and receiving affiliation comprised
different factors (see Table 2), suggesting that asymmetry in affiliative inter-
actions was feasible and occurred. In sharp contrast, Tandem Curiousity and
Mutual Inspection are inherently joint social interactions in which initiating a
behavior is more correlated with receiving that same behavior than with
initiating or receiving other behaviors (see Table 2). Because affiliative
interactions were the only asymmetrical social behavior manifest within the
sister trios, these behaviors were used to construct a reciprocity score to
quantify the primary source of social behavioral asymmetry within the group.
Affiliative reciprocity is defined here as the balance between initiated and
received affiliation. For each member of the triad, the total percent of
receptions was subtracted from the total percent of initiations to create an
Affiliative Role Score, reflecting the overall receptiveness or initiativeness in
all affiliative interactions. This score ranges theoretically from ?1.0 to ?1.0,
with large negative and positive scores indicating a rat that is more receptive
or more initiative, respectively. Scores close to zero indicate a rat that initiated
and received affiliation in a relatively reciprocal manner. We quantified the
reciprocity of affiliative social interactions with an Affiliative Reciprocity
Index: 10 ? (1 ? Affiliative Role Score ). Ranging theoretically from 0 to
10, this Index operationalizes the affiliative reciprocity construct with a
unitary, continuous variable. Values close to 10 reflect an even balance of
social initiations and receptions, and values close to 0 reflect an uneven
balance of social initiations and receptions. Individual reciprocity scores that
were compared with corticosterone production, tumor onset and life span are
from the 53 days measure.
Corticosterone Response to Restraint Stressor
in Middle Adulthood
We used the corticosterone response to restraint stress, a novel stressor, as
a biomarker of the degree to which the daily husbandry events throughout
adulthood had been experienced as stressful or potentially ameliorated by the
buffering of affiliation interactions during these daily stressors. At 15 months
of age, we determined whether females with high and low reciprocal affilia-
tion, measured twice previously, had different corticosterone responses. Five
of the original 54 rats in the study did not survive until this point and were
excluded, yielding a total of 49 individuals that completed the study
(Nneophobic & nonreciprocal?11,Nneophobic & reciprocal?12,Nneophilic & nonreciprocal?13,
Nneophilic & reciprocal? 13).
During the nadir of the corticosterone circadian rhythm at the end of the
rats’ active period (0–3 hours after lights on), we collected repeated blood
samples following a novel, 30-minute restraint stressor at 15 months of age.
Samples were collected at 0, 30, 60, 90, and 150 minutes from the onset of the
restraint period, according to methods described previously (20). Corticoste-
rone was measured using a commercial radioimmunoassay kit (Rat and Mice
Corticosterone kit, MP Biomedicals) as described previously (20).
Touch Places forepaws on conspecifics for less than
Places forepaws on conspecifics for greater
than one second
Walks closely behind conspecific
Rears against cage wall within an arm’s
length of a conspecific rearing against
Uses forepaws or flank to move a
conspecific from its position
Sniffs at the side of conspecific’s mouth.
Sniffing typically involves tilted head
posture and short, repeated head nods
Anogenital inspection Sniffs or licks anogenital region of
conspecific. Sniffing typically involves
tilted head posture and short, repeated
head nods. Conspecific receiver may lift
TABLE 2.Confirmatory Factor Analysis of Categories of Social Interactions During a Mild Stressor
Social Behaviors Initiate or Receive Affiliation-InitiatingAffiliation-ReceivingMutual InspectionTandem Curiosity
Percent of variance
J. R. YEE et al.
1052 Psychosomatic Medicine 70:1050–1059 (2008)
Ovarian Function During Reproductive Senescence
Daily vaginal lavages and cytology analyses were initiated at 60 days of
age and continued through reproductive senescence. To determine whether
different rates of reproductive senescence could account for any observed
differences between groups in corticosterone reactivity to a stressor, we
measured ovarian function during the 3 weeks before administering the late
middle-age restraint stressor according to methods described previously
(20,27). The pattern of estrous cycles indicated the successive reproductive
states of ovarian senescence: regular cycles, irregular cycles, constant estrus,
persistent diestrus and anestrus (27). During regular cycles, prolonged irreg-
ular estrogenized cycles and constant estrus, females spend proportionally
more time in an estrogenized state. In the later stages of reproductive senes-
cence, when the ovaries become atrophic (irregular cycles and persistent
diestrus/anestrus), females are significantly less estrogenized.
Tumor Growth and Mortality
The colony was allowed to undergo natural attrition as a variety of
pathologies spontaneously developed. Mammary neoplasia, the most common
pathology in this strain of rats, was assessed through regular health checks
begun at 11 months of age. We defined onset of tumor detection as the age at
which a growth was first reliably palpable and persisted for 3 weeks. Mam-
mary tumor size averaged across all females was 77.02 g, approximately 19%
of the mean body weight (i.e., 400 g).
At necropsy, tumors were excised, formalin-fixed, and paraffin-embed-
ded. After deparaffinization in xylene, slides were rehydrated through con-
secutive graded alcohols to distilled water. After blocking endogenous
peroxidase activity, sections were heated for antigen retrieval with citrate
buffer. The sections were then incubated with the anti-Glucocorticoid
Receptor primary antibody (3D5, 1:400, Abcam Inc., Cambridge, MA) for
1 hour at room temperature. The slides were then incubated with horse-
radish peroxidase labeled Polymer, and the reactions were completed with
the Envision detection system using 3 to 3? diaminobenzidine as the
chromogen (DakoCytomation, Carpinteria, CA).
Histological diagnosis was validated by concordance of two surgical
pathologists specializing in breast cancer pathology in the Department of
Pathology at the University of Chicago (28). Diagnoses included malignant
cancer (e.g., in situ ductal carcinoma, invasive ductal carcinoma, and carci-
nosarcoma) as well as benign tumors (e.g., fibroadenoma, lactating adenoma,
and papillary cystadenoma). Rats often developed a multiplicity of tumors,
each with independent diagnoses; some tumors contained multiple segments,
each with independent diagnoses.
Health of aging females was monitored biweekly by researchers and the
institutional veterinarian, and weekly if not daily toward the end of life. Half
of the rats died naturally. To preclude suffering, however, 29 of the 49
females were euthanized when they displayed symptoms indicating that they
were within 1 week of death. Primary indicators were: shallowness of breath,
behavioral lethargy, chromodachyrhea, drooping eyelids or partial closure of
the eyes, wheezing or clicking in lungs, and urine-soaked fur (19). Secondary
indicators were: nasal discharge, sticky or un-groomed fur, pale eye and skin
color, and bloating (Cavigelli and McClintock, unpublished data). Decisions
to euthanize based on these symptoms were made independently by a veter-
inarian making weekly health checks and by an observer making daily health
checks. Both were blind to the animals’ temperament and style of social
interaction. Approximately equal numbers of neophobic and neophilic fe-
males (N ? 15, 14, respectively), and reciprocal and nonreciprocal females
(N ? 13, 16, respectively) were sacrificed.
To assess the underlying structure to the social behaviors enacted in the 20
minutes during cage relocation, we analyzed each social behavior, initiated
and received, using principal components factor analysis with orthotran/
varimax rotation. The final factor solution was extracted by considering the
eigenvalues (greater than 1.0), examining the scree plot (29), and verifying
that the overall factor structure was consistent with a priori concepts (30).
To measure the effect of continuous predictors on temporal outcomes, we
used Cox proportional hazards regression. We fulfilled the proportional hazards
assumption—that the ratio of hazards is constant across time for levels of
predictors—by comparing log-minus-log survival plots for all outcomes in which
affiliative reciprocity was a significant predictor. Full versus partial models were
tested with the likelihood ratio test. The nonparametric Kaplan-Meier survival
analysis was used for group comparisons of temporal variables.
When appropriate, the affiliative reciprocity variable is dichotomized
solely for descriptive purposes. Rats with scores above the median are
referred to as “high reciprocity rats,” whereas those with scores below the
median are referred to as “low reciprocity rats.” The dichotomized variable
was never used for statistical purposes.
Reciprocity as a predictor of mammary tumor severity and type of
reproductive senescence was assessed with ordered logistic regression. Mam-
mary tumor severity was classified into three categories: none, benign, or
malignant. The categories for reproductive senescence from most to least
estrogenized were long regular cycles, constant estrus, irregular cycles, per-
sistent diestrus and anestrus.
The amount of corticosterone produced in response to a stressor was
summarized as the area under the curve with respect to ground (AUCG; cite
Pruessner 2003) and the dynamics of its response with baseline (prestressor),
peak (maximal response during 2 hours post-stress), and recovery (final minus
baseline) levels. The effects of reciprocity on these variables were tested with
simple linear regression.
All tests were two-tailed and statistical significance was achieved at p ?
.05. Statistical trends were noted when p ? .10.
The average Affiliative Reciprocity Index score ranged
from 1.67, indicating a large asymmetry between initiating
and receiving affiliative contact, to 10.00, indicating a perfect
balance (colony average ? 6.94 ? 2.31). Each rat’s role in the
balance of initiating or receiving affiliative contact with her
sisters remained relatively consistent from puberty to late
middle age (r ? 0.322, p ? .02). However, we did not
detect stability in the frequency of engaging in tandem curi-
osity and mutual inspection (tandem curiosity: r ? 0.155,
p ? .29; mutual inspection: r ? 0.006, p ? .97), further
indicating that these behaviors are not major indicators of
stable social roles.
Affiliative reciprocity, a social role emergent from group
interactions, might result from individual differences in neopho-
bia, particularly during the mild stressor of home cage relocation
However, females categorized as having high or low affiliative
temperament (48% versus 46% respectively; chi-square [1, N ?
49] ? 0.023, p ? .88). Conversely, neophobic and neophilic rats
did not differ in degree of affiliative reciprocity (t ? 0.13,
p ? .90). Thus, reciprocity of social contact, a style of social
interaction, and infant temperament, an individual trait, are two
independent psychosocial factors.
Females affiliating more reciprocally might be more so-
cially active in general. However, the total number of social
interactions in which a rat engaged was not significantly
associated with her affiliative reciprocity (R2? 0.063, F(1,
47) ? 3.18; p ? .08). Affiliative reciprocity might also reflect
social dominance, although social dominance relationships
among female rats are not typically stable (31). A correlate of
social dominance, body weight, measured when social behav-
ior was observed in puberty, was not associated with social
reciprocity during a mild stressor as would be expected if
RECIPROCAL AFFILIATION AND HEALTH IN OLD AGE
1053 Psychosomatic Medicine 70:1050–1059 (2008)
engaging in reciprocal support were a product of dominance
(R2? 0.040, F(1, 47)?1.95 ; p ? .17). Moreover, body
weight was not associated with a rat’s role in initiating and
receiving affiliation (R2? 0.001, F(1, 47) ? 0.68 ; p ? .80).
Finally, no fights were observed.
Rats that did not have reciprocated affiliative contact dur-
ing the brief group stressor died earlier than those whose
affiliative interactions were reciprocated equally. Affiliative
reciprocity predicted lifespan such that every 10% decrease in
reciprocity resulted in an increased risk of death between 13%
and 51% (HR ? 1.31, 95% CI ? 1.13–1.51; p ? .0005). High
reciprocity rats had a median lifespan of 25.9 months whereas
that of low reciprocity rats was only 20.4 months, a difference
of almost a half-year, one-third of the range in lifespan under
laboratory conditions (1.5–3 years; Figure 1A). To verify that
the effects of affiliative reciprocity were not mediated by the
mere frequency of interactions, but rather its structure, uni-
variate predictions were calculated for the frequency of initi-
ating and receiving affiliative interactions, as well as total
involvement in affiliative behaviors, and affiliative role. Only
the frequency of receiving affiliation decreased the risk of
death, albeit a weaker effect ranging from 0.002% to 5.8% for
each additional affiliative behavior received (HR ? 0.97, 95%
CI ? 0.94–0.99; p ? .04). Moreover, frequency did not
mediate the effect of reciprocity; when reception frequency is
modeled along with affiliative reciprocity, it did not diminish
reciprocity’s predictive power, as indicated by the lack of a
decrease in z score going from the univariate model with
reciprocity alone to a full model including both variables
(Univariate: zreciprocity? 3.62; Full: zreciprocity? 3.75).
Additive Effects of Affiliative Reciprocity
Because affiliative reciprocity and temperament were in-
dependent traits, and neophobic temperament is a risk factor
for early death (20), we sought to determine whether low
affiliative reciprocity is also a risk factor for early death,
acting independently of neophobic temperament. The variance
in lifespan explained by affiliative reciprocity was not merely
mediated by temperament as indicated by the lack of a de-
crease in z-score when temperament is added to the model;
Reciprocity Univariate: zreciprocity? 3.62; Full: zreciprocity?
Indeed, low affiliative reciprocity and neophobia each in-
creased the risk of death and did so additively (multivariate
model, Affiliative reciprocity: HR ? 1.38, 95% CI ? 1.18–
1.61, p ? .00003; Neophobia: HR ? 2.00, 95% CI ? 1.09–
3.66, p ? .025; Full model: Likelihood-ratio chi-square [2,
N ? 49] ? 17.16, p ? .0002). In fact, the full model including
both neophobia and affiliative reciprocity explained more of
the variance in lifespan than affiliative reciprocity alone (like-
lihood ratio test: chi-square [1, N ? 49] ? 4.95, p ? .03). Rats
exhibiting both risk factors died earliest (i.e., low reciproc-
ity and neophobic temperament) and those with neither
lived the longest (median lifespans were 19.0 and 26.8
months, respectively; Figure 2). Rats with only one risk
factor had an intermediate life span (22.0 months), with no
difference between those with a social or a temperament
risk factor (Mantel-Cox logrank chi-square [1, n ? 27] ?
0.24, p ? .62).
Mammary tumors are one of the major forms of pathology
at death in the Sprague-Dawley strain. Of the 49 aging female
rats included in the current study, 32 (65%) developed at least
one palpable mammary tumor by the end of her natural life
span. Rats that did not interact reciprocally during a brief
group stressor developed palpable mammary tumors earlier
than rats engaged in reciprocal affiliation with their cagemate.
Affiliative reciprocity directly predicted the onset of palpable
mammary tumors such that every 10% decrease in reciprocity
resulted in an increased risk of tumor palpation between 3%
Figure 1. Affiliative reciprocity predicts lifespan. A, Rats that affiliate more reciprocally live longer. Median survival for “High reciprocity” rats (dotted line)
(upper 50th percentile of affiliative reciprocity scores) was 776 days; median survival for “Low reciprocity” rats (solid line) (lower 50th percentile) was 612 days.
Affiliative reciprocity scores were dichotomized for graphical purposes only. B, Cox proportional hazards survival analysis was applied to estimate the effect
of affiliative reciprocity on lifespan (HR ? 1.31, 95% CI ? 1.13–1.51; p ? .0005).
J. R. YEE et al.
1054Psychosomatic Medicine 70:1050–1059 (2008)
and 43% (HR ? 1.21, 95% CI ? 1.03–1.43, p ? .02). As with
lifespan, it was social structure that was predictive—tumor
onset was not predicted by the frequency of initiating or
receiving affiliative interactions, total involvement in affilia-
tive behaviors, or affiliative role (i.e., primarily initiating or
primarily receiving) (Univariate models for: Initiation: HR ?
1.02, 95% CI?0.99–1.06, p ? .19; Reception: HR ? 1.02,
95% CI ? 0.98–1.05, p ? .39; Involvement: HR ? 1.01, 95%
CI ? 0.99–1.03, p ? .20; Role: HR ? 1.39, 95% CI ?
0.42–4.63, p ? .58).
The risk of developing at least one tumor by the end of the
lifespan, however, was not predicted by affiliative reciprocity;
17 of the rats with at least one mammary tumor exhibited high
reciprocity, and 15 exhibited low reciprocity (chi-square [1,
n ? 32] ? 0.16, p ? .69). Likewise, overall tumor burden at
the end of life was not predicted by affiliative reciprocity as a
continuous variable (R2? 0.085, F(1, 47) ? 2.78 ; p ? .11).
Although 73% of tumor-bearing low reciprocity rats devel-
oped malignancies compared with 47% of tumor-bearing high
reciprocity rats that developed malignancies, this result was
not statistically significant (Odds ratio ? 3.18; 95% CI ?
0.27–37.00; p ? .35). Affiliative reciprocity did not predict
survival once a mammary tumor had been palpated (HR ?
0.89, 95% CI ? 0.74–1.06, p ? .18).
Corticosterone Response to Restraint Stressor
at Late Middle Age
At 15 months of age, after an adulthood of exposure to
daily mild stressors in the laboratory and yet before 93.9% of
the rats had developed tumors and 7 months before the median
age of death, rats that had been less reciprocally affiliative
since adolescence had larger corticosterone responses to an
acute novel restraint stressor (AUCG) than did rats that had
been more reciprocally affiliative (R2? 0.095; F(1, 47) ?
4.92, p ? .03). On closer examination of individual compo-
nents of the corticosterone response, we found that it was the
peak corticosterone concentration attained within 120 minutes
of the stressor onset that was strongly associated with its
degree of affiliative reciprocity (Figure 3; R2? 0.194; F(1,
47) ? 11.33, p ? .0015). It was not associated with baseline
or recovery concentrations (Figure 3; Baseline: R2? 0.013,
F(1, 47) ? 0.63, p ? .43; Recovery: R2? 0.023, F(1, 47) ?
1.09, p ? .30), which explains the weaker association with the
total amount of corticosterone produced (i.e., AUCG).
There was no difference between high and low affiliative
reciprocity groups in the latency to reach peak corticoste-
rone levels (Mantel-Cox logrank chi-square [1, N ? 49] ?
0.334, p ? .56).
Figure 2. Low affiliative reciprocity and neophobia additively predict shorter
lifespan. Rats exhibiting the risk factors low affiliative reciprocity and neo-
phobia die sooner. Median survival for rats exhibiting no risk factors (dotted
line) was 805 days; median survival for rats exhibiting 1 risk factor (thin solid
line) was 660 days; median survival for rats exhibiting two risk factors (wide
solid line) was 571. Affiliative reciprocity scores were dichotomized for
graphical purposes only. Cox proportional hazards survival analysis was
applied to estimate the effect of affiliative reciprocity and neophobic temper-
ament on lifespan (Affiliative reciprocity: HR ? 1.38, 95% CI ? 1.18–1.61,
p ? .00003; Neophobia: HR ? 2.00, 95% CI ? 1.09–3.66, p ? .025; Full
model: Likelihood-ratio (LR) chi-square ? 17.16, df ? 2, p ? .0002).
Figure 3. Affiliative reciprocity predicts corticosterone response to restraint stress. Rats that affiliate more reciprocally in adolescence exhibit lower peak
corticosterone concentrations in the 2 hours following a restraint stressor in adulthood (R2? 0.194; F(1, 47)) ? 11.33, p ? .0015). Affiliative reciprocity,
however, predicted neither baseline (R2? 0.013, F(1, 47) ? 0.63, p ? .43) nor recovery (R2? 0.023, F(1) ? 1.09, p ? .30) concentrations. Closed circles (F)
represent sisters identified as “Neophilic”; open circles (E) represent sisters identified as “Neophobic”.
RECIPROCAL AFFILIATION AND HEALTH IN OLD AGE
1055 Psychosomatic Medicine 70:1050–1059 (2008)
Ovarian Function During Reproductive Senescence
The larger rise in corticosterone concentration in females
with low reciprocal affiliation could result from higher estro-
gen levels, as is observed during proestrus of a spontaneous
ovarian cycle (20,32). On the day of corticosterone measure-
ment, however, there was no difference in the level of
estrogenization between dichotomized reciprocity groups
(chi-square [1, N ? 49] ? 0.587, p ? .44). Moreover, in
contrast to temperament (20), affiliative reciprocity was not as-
95% CI ? 0.63–1.19; p ? .37), further suggesting that temper-
ament and affiliative reciprocity are independent risk factors.
The results presented here are the first to demonstrate that
affiliative reciprocity, an aspect of the formal structure of
affiliative interactions, can predict the glucocorticoid response
to stress in aging rats, onset of mammary tumors, and longev-
ity. Affiliative reciprocity, a social structural trait measurable
during puberty and maintained into adulthood, predicted mor-
bidity and mortality prospectively. Based on the current evi-
dence, our working hypothesis is that reciprocity of affiliative
interactions, independent of their frequency, buffers the expe-
rience of everyday stressors, attenuates glucocorticoid reac-
tivity over the lifespan, and hence, slows pathophysiological
decline and the rate of aging.
To examine the meaning behind initiating and receiving
affiliative interactions, we carefully considered their situa-
tional context. Reenacting a standard mildly-stressful labora-
tory procedure, each group’s home cage was taken from its
rack and carried to a table where it was placed alongside
another cage of three sisters. Once in the behavioral observa-
tion room, cage lids were removed and replaced with Plexi-
glas. This reenactment was chosen to present the group with
novel and potentially threatening physical and social stimuli,
and to this end, animals experienced unexpected disruptions to
their housing conditions and were confronted with the sights,
sounds, and smells of new conspecifics. In this potentially
threatening context, affiliative contact could be supportive.
Therefore, social contact during this novel and potentially
threatening cage relocation may be conceptualized as social
support insofar as the animals found the situation stressful and
their female littermates a source of comfort (33–35).
The primary objective of this study was to characterize the
pattern of home cage social interactions during this mild
stressor of relocation to a relatively novel physical environ-
ment. Initiations of the affiliative behaviors “touch,” “hold-
fast,” and “follow,” were more highly intercorrelated than
with reception of these same social behaviors. This pattern
contrasted sharply with inspection behavior (oral and anogeni-
tal) and tandem curiosity (push away and stand by), where
initiating and receiving of each these behaviors was highly
correlated. Indeed, the initiation and reception of affiliation
were not distributed equally among group members, and thus,
there was considerable difference among the triad of sisters in
the balance of giving and receiving social contact during the
mild stressor. In other words, some sisters were highly recip-
rocal in initiating and receiving affiliation, whereas others
gave more than they initiated or vice versa.
We construed social contact as affiliative, but also consid-
ered its association with social dominance. Body weight,
however, a measure that is typically highly correlated with
dominance status in rats, did not predict the reciprocity of
females initiating or receiving affiliation. Moreover, the typ-
ical ingredients of antagonistic social relationships were ab-
sent. We never observed interactions that caused an animal to
be physically wounded. This may be a result of the fact that
there were no clear defendable resources. Females comprising
the group were littermates whose access to resources (i.e.,
food and water) was unlimited. They were not allowed to
mate, and in fact, were never exposed to colony rooms in
which males were also housed. Dominance hierarchies have
been known to manifest through more subtle behaviors in
groups of female rats (31), but the semi-natural housing con-
ditions necessary to elicit those behaviors were not available
in this experiment. Moreover, behaviors that we labeled
affiliative did not resemble these female-typic dominance
Although further study of the temporal stability of affilia-
tive reciprocity is necessary, we were able to show that affili-
ative reciprocity was stable across a long time interval (7
months), which spanned different developmental stages, from
adolescence to adulthood. Recent progress has been made in
the study of animal personality (36). For those studies on
individual differences in rat behavior, few have assessed tem-
poral stability in individual differences as was done in the
current study (19,20,37). One such study reported that insect
predation (a behavior involving interaction with another or-
ganism) in female rats exhibits a significant correlation (r ?
0.447, p ? .05) when testing 1 month apart (38). In the current
study where we found behavioral stability across 7 months,
the stability may have been due to the fact that cage compo-
sition was stable. Social groups were stable between affiliative
reciprocity measurements and until natural death, thus provid-
ing little stimulus for behavioral fluctuation or change over
time. This social stability is similar to the maintenance of
dominance hierarchies among female baboons (Papio cyno-
cephalus) as long as the group composition does not change
(39,40). However, this is not to say that our methods were not
strict enough to detect a lack of stability since two other types
of behaviors measured in our study (tandem curiosity and
mutual inspection) were not correlated across timepoints.
Lastly, it is known that, in human personality research, there
is fluctuation from one measure to the next, even when the
interval between measures is day-to-day, or within-day (41).
If affiliative contact during group duress can be construed
as social support, then our model provides an opportunity to
prospectively contrast the health effects of the quantitative and
qualitative aspects of social support. House et al.’s seminal
reports (1,5) on social relationships and health indicated that
further elucidation would require the clear distinction between
1) the existence or quantity of relationships, 2) their formal
J. R. YEE et al.
1056 Psychosomatic Medicine 70:1050–1059 (2008)
structure, and 3) their content. In our model, the size of each
animal’s social network was held constant, and the frequency
of engaging in affiliative behaviors did not predict morbidity
and mortality. The content of social interactions was held
relatively constant by observing social behaviors strictly while
the group was experiencing a stressor, and analyzing only
social behaviors that occurred in this context. Although hold-
ing these factors relatively constant, we found that affiliative
reciprocity, an aspect of a relationship’s formal structure,
predicted later health outcomes. To our knowledge, this is the
first report directly comparing quantitative and qualitative
aspects of social interactions that also demonstrates that it is
the structural feature of social relationships that predicts mor-
bidity and mortality.
Previously, we have shown that neophobic temperament is
a risk factor for early death (20). Here, we show that low
affiliative reciprocity during a mild group stressor is an
equally potent risk factor. Moreover, low affiliative reciproc-
ity can be regarded as a risk factor independent from
neophobia since it is distributed evenly across tempera-
ments. Furthermore, it can be considered an additive risk
factor since models including both risk factors are significantly
more predictive than either partial model. It is noteworthy that
neophobia and nonreciprocal affiliation are independent, ad-
ditive risk factors. This independence suggests that reciprocal
social relationships could ameliorate early-appearing psycho-
logical predispositions toward mortality (e.g., neophobia).
In this rat model, we can think of no ways in which sibling
cagemates could have provided sociobehavioral (i.e., instru-
mental) support. Rather, our data support psychobiological
mediation whereby social support enhances physical health
through psychological states affecting neuroendocrine and
neuroimmune mechanisms, including the hypothalamic-pitu-
itary-adrenal axis. Affiliative reciprocity during late puberty
was associated with a low stress-induced rise in corticosterone
in adulthood. This suggests that regular reciprocal relation-
ships serve to alleviate everyday stressors, perhaps by altering
perceptions of stressor severity. This finding is in line with the
stress-buffering hypothesis that states that social support pro-
tects against the harmful physiological effects of repeated
stressors. It is unlikely that the well-known effects of estrogen
on glucocorticoid secretion (32,42,43) mediate the association
between affiliative reciprocity and corticosterone since neither
level of estrogenization on the day of restraint (indicated by
vaginal cytology) or the state of reproductive senescence
preceding restraint was associated with reciprocity.
It is beyond the scope of this study to describe the mech-
anism through which reciprocity influences corticosterone re-
sponses to stress, but future work could start by examining
brain regions known to modulate the meaning of a stressor,
such as the medial prefrontal cortex (44). It is worth noting
that the results of this study do not diminish the contribution
of sociobehavioral types of support; rather, by creating an
animal model devoid of these influences, we show that psy-
chobiological mechanisms may confer salubrious benefits on
their own without the influence of sociobehavioral mecha-
Our data indicate that low affiliative reciprocity predicts
not only early death but also early mammary tumor growth,
the most common pathology at the time of death in this rat
strain. There is accumulating evidence that stress and glu-
cocorticoids could be involved in tumor growth processes.
Conzen and coworkers have demonstrated in a xenograph
mouse model of human breast cancer cells, that dexametha-
sone inhibits chemotherapy-induced apoptosis and also in
vitro regulates genes mediating cell survival pathways
(45,46). In a mouse model of spontaneous carcinomas, Tausk
and coworkers demonstrated that repeated chronic stressors
increased skin cancer risk (47). Kiecolt-Glaser and coworkers
have shown that psychological stress suppresses apoptosis in
cells that have sustained DNA damage in vitro (48,49). Fi-
nally, a lifespan study of isolated rats, which are at risk for
spontaneous early development of rapidly growing mammary
tumors (50), implicated a heightened corticosterone response
to stressors (G.L. Hermes, MD, PhD, unpublished data, Jan-
uary 2008) and among group-housed rats the dynamics of the
corticosterone stress response predicted not only tumor onset,
but also malignancy and growth (JRY, unpublished data,
2008). Since females low in affiliative reciprocity in this study
exhibited heightened corticosterone responses to a stressor, we
examined whether affiliative reciprocity could predict mam-
mary tumorigenesis, a process that is dependent on the sup-
pression of apoptosis in damaged cells. This was indeed the
case—females with a relative lack of reciprocal support de-
veloped tumors earlier. This finding adds to a growing liter-
ature implicating stress in the development and progression of
neoplastic disease (51–53).
The study of reciprocity in social interactions has primarily
fallen under the purview of human research given its complex
nature. However, human studies are limited in a number of
ways. Few are prospective in relation to predicting health
outcomes. Surely, none can take a prospective lifespan ap-
proach where attributes early in life are used to predict health
during senescence. In addition, few studies examine naturally-
occurring reciprocity among individuals who already have a
significant personal relationship (54), even though these rela-
tionships may be the most frequent and/or important social
interactions an individual experiences. In patient contexts,
separating emotional from instrumental support is difficult, if
not unethical, to achieve. It is perhaps the inability to achieve
conceptual precision that has made further mechanistic preci-
sion difficult. Objective measures of the structural qualities of
social relationships are nearly impossible since self-report is
preferred over time-intensive behavioral observations.
The current report aimed to address and improve each of
these issues. By developing a rat model we were able to take
a prospective lifespan approach, showing that social psycho-
logical characteristics present in adolescence could predict age
of mammary tumor development and natural death. We ex-
amined the social interactions of sisters whose behavior was in
response to a mild stressor not unlike those that commonly
RECIPROCAL AFFILIATION AND HEALTH IN OLD AGE
1057 Psychosomatic Medicine 70:1050–1059 (2008)
occur in the laboratory on a daily basis (e.g., cage change,
transport) (13). Since there was no conceivable opportunity
for sisters to exchange instrumental support, we were able to
isolate the effect of what we have argued above to be akin to
emotional support from other group members. Moreover, we
were able to directly compare the quantity of affiliation to the
quality of it, finding that affiliative reciprocity, a measure that
represents a qualitative dimension of social relationships, pre-
dicts mammary tumor development and death while the raw
number of affiliative interactions was unable to predict either
outcome. The operational precision with which we defined
reciprocity may have strengthened the mechanistic line of
inquiry. We found that reciprocity is associated with the
corticosterone response to an acute stressor during adulthood,
and that this effect was not mediated by ovarian functioning.
Future studies must determine if these associations are indeed
It has been argued that rats are not capable of such complex
sociality as to warrant the study of reciprocity. However,
recent evidence indicates that rats are capable of generalized
reciprocity, a social ability that has only been previously
demonstrated in humans (15). Female rats were more likely
provide food for another rat if they had received such instru-
mental support themselves in the past. Here we show behavior
among sisters that is consistent with reciprocal emotional
support. Until research demonstrates the contrary, we find no
good reason not to assume that the behavior observed can be
construed as emotional support and serve as a good animal
model for human psychosocial amelioration of stress and its
pathophysiological consequences. Future studies will hope-
fully characterize more fully the conditions that enable affili-
ative reciprocity, as well as achieve a higher level of mecha-
nistic precision explicating the neuroendocrine systems and
cellular pathways in this form of social modulation of disease
We thank Dr. L. Pyter for helpful comments on drafts of the manu-
script, Dr. M. Kocherginsky for statistical assistance, and T. Brawn,
J. Clarke, K. Eisenman, J. Hoffman, A. Lindner, E. Shaw-Taylor, M.
Tsakalis, T. Whitney, H. You, and A. Wiley for their expert technical
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