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Loneliness, an interpersonally stressful state of perceived social isolation, enhances risk for cognitive difficulties. For example, loneliness has been linked to the development of cognitive impairment and dementia among older adults. Lonelier adults ages 65 and above experienced more cognitive impairment, as assessed by the Abbreviated Mental Test, than those who were less lonely (1). Lonelier adults ages 75 and older had larger cognitive declines over 10 years than their less lonely counterparts, as measured by the Mini-Mental State Examination (2). In addition, lonelier adults who were an average of 81 years old were twice as likely to develop Alzheimer’s disease during a 6-year period compared with those who were less lonely (3). Recent research has also addressed the relationship between loneliness and specific types of cognitive function. A report from the English Longitudinal Study of Ageing demonstrated that lonelier adults who were an average of 65 years old had larger declines in verbal episodic memory, but not verbal fluency, over a 4-year period compared with those who were less lonely (4). Accordingly, it is important to understand the factors that could reduce loneliness-related cognitive difficulties over time, particularly memory problems, which lonely people experience as adults. The current study investigated whether omega-3 supplementation could alleviate loneliness-related cognitive declines. Mechanistically, omega-3 polyunsaturated fatty acids (PUFAs), commonly found in oily fish, are essential to normal brain development and maintenance. For example, omega-3 PUFAs help prevent neuronal apoptosis (5,6). Omega-3 PUFAs also reduce inflammation (7), which could have downstream effects on cognitive function (8). Epidemiological and observational studies of dietary intake support the link between omega-3 and cognitive function, particularly global indices of cognitive impairment; people with higher dietary intake of omega-3 had a reduced risk of new-onset dementia, and less global cognitive decline over time than people with lower omega-3 intake (9–11). A large population-based study demonstrated that older adults who ate more fish had better cognitive performance, as measured by a neuropsychological test battery, than those who ate less fish (12). Adults who reported higher marine-based PUFA intake had better overall cognitive function, as reflected by a better composite score across the Kendrick Object Learning Test, the Trail Making Test (Part A), and a variety of other cognitive tests, compared with those who reported lower marine-based PUFA intake (13). Indeed, a recent meta-analysis concluded that people with high adherence to a typical Mediterranean diet, which is high in fish, had a lower risk of both mild and advanced global cognitive impairment than their less adherent counterparts (14). Studies examining the cognitive benefits of omega-3 supplementation also support the link between omega-3 and cognition, although the effects are much less consistent. A number of randomized controlled trials (RCTs) demonstrate better cognitive function, including less global cognitive impairment and better attention, in omega-3 supplemented groups compared with placebo (15–17). In addition, healthy adults who received an omega-3 supplement were faster at both working and episodic memory tasks than those who received a placebo (18). Although some studies report null effects (e.g., 19,20), the supplementation literature suffers from methodological inconsistencies such as varied supplementation doses, supplementation regimen lengths, and sample characteristics (e.g., cognitively healthy versus Alzheimer’s disease patients) which could contribute to the contradictory results. Emerging evidence from the omega-3 literature suggests that supplementation improves cognitive function for people experiencing mild cognitive problems. For instance, a recent meta-analysis of 10 RCTs concluded that immediate verbal recall, attention, and processing speed were better among people receiving an omega-3 supplement compared with placebo, but only for people experiencing mild cognitive impairment (21). No supplementation effects were found for cognitively healthy participants or people with Alzheimer’s disease. Similarly, among healthy older adults with age-related cognitive decline, those in the omega-3 supplementation group had better visuospatial and immediate and delayed verbal memory compared with their counterparts in the placebo condition; there was no effect of supplementation on executive function or working memory (17). In addition, a recent RCT demonstrated that among adults with mild cognitive impairment, those who received an omega-3 supplement had improved working memory, immediate visual episodic memory, and delayed verbal episodic memory compared with those who received a placebo (22). The present study is a secondary analysis of a RCT assessing the anti-inflammatory effects of omega-3 supplementation (7; ClinicalTrials.gov identifier: NCT00385723). The consort diagram and other RCT-related documents are available in the primary report. This study explored the impact of loneliness and omega-3 supplementation on secondary outcomes in our RCT: verbal episodic memory, working memory, executive function, and verbal fluency/processing speed. Taken together, prior research suggests that lonely adults may develop memory difficulties over time and omega-3 intake could lessen these risks. However, the existing literature linking loneliness, omega-3 supplementation, and cognitive function is in its infancy and many questions remain unanswered. Accordingly, exploratory questions and analyses are needed to begin joining these diverse literatures. The clearest preliminary hypothesis derived from prior research was that lonelier participants would have poorer verbal episodic memory than less lonely participants, and that omega-3 supplementation would attenuate these effects. We also explored the effects of loneliness and omega-3 supplementation on working memory, executive function, and verbal fluency/processing speed.

Inflammation is a robust and reliable predictor of all-cause mortality in older adults (1). Proinflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive protein (CRP) play a role in cardiovascular disease, type II diabetes, arthritis, osteoporosis, Alzheimer’s disease, periodontal disease, and frailty and functional decline (2–3). In addition, inflammation is now regarded as a risk factor for most cancers because of the evidence that inflammation influences tumor promotion, survival, proliferation, invasion, angiogenesis, and metastases (4). Behavioral lifestyle factors can substantially influence inflammation. Obesity has been characterized as a state of chronic inflammation because of the elevated plasma levels of IL-6, TNF-α, and CRP (5). One obvious mechanism is provided by the fact that adipocytes (fat cells) are capable of producing and secreting IL-6 and TNF-α; in fact, up to 30% of IL-6 may be derived from adipose tissue (6). Physical activity is also an important behavioral cofactor; people who describe themselves as active have lower levels of inflammatory biomarkers than their sedentary counterparts (7). Indeed, when physical or cardiorespiratory fitness is assessed rigorously and objectively by maximal exercise testing, fitness is inversely associated with inflammation, even after adjusting for confounds including age, smoking, medications, and visceral fat (8–11). Although regular physical activity is associated with lower levels of IL-6 and other proinflammatory cytokines, acute exercise transiently boosts production and release of IL-6 from skeletal muscles; the IL-6 that is released during physical activity inhibits TNF-α production and can induce IL-10 production, one mechanism underlying exercise’s anti-inflammatory function (1). Lower levels of circulating IL-6 at rest as well as following exercise appear to be the normal adaptation to training (12) In addition to exercise and obesity, behavior affects inflammation through other pathways; even relatively modest levels of anxiety and depressive symptoms can raise proinflammatory cytokine production (13). Additionally, psychological stressors can directly provoke transient increases in proinflammatory cytokines (14–15), and chronic stressors have been linked to sustained overproduction of IL-6 (16–17). Yoga’s reputation for stress reduction and mental health benefits has bolstered its popularity in recent years, and data from randomized trials suggest that yoga reduces symptoms of anxiety and depression (18–19). Hatha yoga, the most common form practiced in the western world, combines body postures or asanas, breath control or pranayama, and meditation (20). Mechanistic explanations for yoga’s potential mental and physical health benefits have highlighted reductions in sympathetic nervous system tone (21–22), and increases in vagal activity (22), both of which could have favorable endocrine and immune consequences, including lower inflammation. In fact, one recent randomized trial suggested that yoga might have positive benefits for inflammation; 9 heart failure patients randomized to a two-month hatha yoga intervention showed a 22% reduction in IL-6 and a 20% reduction in CRP compared to minimal change in the 10 patients who received standard medical care (23). In contrast, CRP did not change following a 6-week nonrandomized trial in 33 individuals both with and without established coronary artery disease, but the group did show significant reductions in blood pressure, heart rate, and body mass index (BMI) (24). Surprisingly few studies have attempted to relate endocrine or immune function to yoga practice, even though some hatha yoga postures are characterized as immune enhancing or restorative (25). We assessed cardiovascular, inflammatory, and endocrine responses in novice and expert yoga practitioners before, during, and after a hatha yoga session, as well as in two control conditions. To test yoga's restorative potential, stressors preceded each of the three conditions, providing data on the extent to which yoga speeded an individual's physiological recovery. In addition, tape stripping a small area of forearm skin before each of the conditions provided data on the course of skin barrier repair, a stress-sensitive process modulated by both cortisol and cytokine production (26–27). The ability to minimize autonomic and inflammatory responses in stressful situations undoubtedly influences the burden that stressors place on an individual. Thus, we designed this study to assess yoga’s ability to promote recovery from a stressor. We elected to conduct the yoga session after the stressor, rather than prior to the stressor, for several reasons. First, anticipation of a stressor following the yoga session could reduce participants’ ability to fully relax and concentrate during the yoga session, particularly among novices; completing the stressor prior to the yoga session could allow for a more relaxing yoga experience, providing greater power to detect effects of yoga. In addition, our ability to track changes in physiological markers of interest during the yoga session was improved by eliciting a physiological response prior to the session. Finally, using a stressor prior to the yoga session allowed us to examine whether regular yoga practice resulted in differential magnitude of reactivity to the stressor, independent of the effects of a recent yoga session. We hypothesized that: (1) experienced yoga practitioners would have lower levels of inflammation, and smaller autonomic, endocrine, and inflammatory responses to the stressors than novices. (2) During and following the yoga session, subjects would demonstrate more rapid declines (recovery) in stress hormones and proinflammatory cytokine production, and better skin barrier repair than evidenced following either of the control conditions. Mood measures would reflect greater positive change following yoga compared to the control conditions.

Objective Two studies using cross-sectional designs explored four possible mechanisms by which loneliness may have deleterious effects on health: health behaviors, cardiovascular activation, cortisol levels, and sleep. Methods In Study 1, we assessed autonomic activity, salivary cortisol levels, sleep quality, and health behaviors in 89 undergraduate students selected based on pretests to be among the top or bottom quintile in feelings of loneliness. In Study 2, we assessed blood pressure, heart rate, salivary cortisol levels, sleep quality, and health behaviors in 25 older adults whose loneliness was assessed at the time of testing at their residence. Results Total peripheral resistance was higher in lonely than nonlonely participants, whereas cardiac contractility, heart rate, and cardiac output were higher in nonlonely than lonely participants. Lonely individuals also reported poorer sleep than nonlonely individuals. Study 2 indicated greater age-related increases in blood pressure and poorer sleep quality in lonely than nonlonely older adults. Mean salivary cortisol levels and health behaviors did not differ between groups in either study. Conclusions Results point to two potentially orthogonal predisease mechanisms that warrant special attention: cardiovascular activation and sleep dysfunction. Health behavior and cortisol regulation, however, may require more sensitive measures and large sample sizes to discern their roles in loneliness and health.

Objective: Influenza and pneumonia account for significant morbidity and mortality, particularly in older individuals. Previous studies have shown that spousal caregivers of patients with dementia have poorer antibody and virus specific T cell responses to an influenza virus vaccine relative to noncaregiving control subjects. This study tested the hypothesis that stress can also significantly inhibit the IgG antibody response to a pneumococcal bacterial vaccine. Method: We measured antibody titers of current caregivers, former caregivers, and control subjects after vaccination with a pneumococcal bacterial vaccine. Results: Caregivers showed deficits relative to controls and former caregivers in their antibody responses to vaccination. Although the groups did not differ before vaccination or in the rise in antibody 2 weeks or 1 month after vaccination, current caregivers had lower antibody titers 3 and 6 months after vaccination than either former caregivers or controls. Conclusions: These data, the first evidence that chronic stress can inhibit the stability of the IgG antibody response to a bacterial vaccine for pneumonia, provide additional evidence of health risks associated with dementia caregiving. Key words: stress, immune response, vaccinations.

Objective: Postmenopausal status increases some aspects of women's physiological responses to psychological stress; however, the influences of chronic hormone replacement with estrogen and progestogen on these responses are not known. We investigated possible effects of long-term estrogen replacement therapy (ERT). both with and without progestogen, on physiological reactivity to brief laboratory stressors. Method: We studied three groups of postmenopausal women: 16 on estrogen alone, 14 on estrogen and progestogen, and 25 control participants receiving no replacement therapy. Cardiovascular, neuroendocrine, and immune data were collected at baseline and after speech and math tasks. Results: In all groups, the stressors reduced vagal cardiac control (indexed by respiratory sinus arrhythmia); increased heart rate and plasma epinephrine, adrenocorticotropic hormone, and cortisol levels; and altered T lymphocyte response (measured by mitogen-induced cell proliferation), natural killer cell lysis, and circulating leukocyte subsets. Women on either type of ERT had higher total cortisol levels (reflecting an estrogen effect on cortisol binding globulin) and greater mitogen-induced blastogenesis across measurement periods than controls. They also showed greater vagal withdrawal and less decline in mitogen-stimulated blastogenesis in response to the stressors. Combined estrogen and progestogen was associated with higher epinephrine and lower circulating total lymphocytes, T cells, and CD4+ T cells across measurement periods, and with intermediate levels of vagal withdrawal in response to the stressors. Conclusions: Long-term ERT was associated with enhanced parasympathetic responsiveness to stress, suggesting possible reduced demand for potentially detrimental sympathetic activation; and with higher overall levels and smaller stress-induced reductions of mitogen-stimulated blastogenesis, suggesting

Human responses to brief psychological stressors are characterized by changes and large individual differences in autonomic, neuroendocrine, and immune function. The authors examined the effects of brief psychological stressors on cardiovascular, neuroendocrine, and cellular immune response in 22 older women to investigate the common effects of stress across systems. They also used interindividual variation in heart rate reactivity, cardiac sympathetic reactivity (as indexed by preejection period reactivity in their reactivity paradigm), and cardiac vagal reactivity (as indexed by respiratory sinus arrhythmia reactivity) to explore the heterogeneity in human responses to brief psychological stressors. The results revealed that brief psychological stressors heightened cardiac activation, elevated plasma catecholamine concentrations, and affected the cellular immune response. It was also found that individuals characterized by high, relative to low, cardiac sympathetic reactivity showed higher stress-related changes in adrenocorticotropic hormone and cortisol plasma levels but comparable changes in epinephrine and norepinephrine concentrations. These data suggest that the effects of psychological stressors on cardiovascular and cellular immune response are governed by coordinated regulatory mechanism(s) and that going beyond the simple notion of heart rate reactivity to examine neural substrates may shed light on the interrelationships among and the regulatory mechanisms for the autonomic, endocrine, and immune responses to stressors.

Although increased morbidity and mortality have been reliably associated with social isolation and less satisfying personal relationships, relatively little is known about the underlying biopsychosocial mechanisms. We assessed problem-solving behaviors and changes in immune function in 90 newlywed couples who were admitted to a hospital research unit for 24 hours. Subjects who exhibited more negative or hostile behaviors during a 30-minute discussion of marital problems showed greater decrements over 24 hours relative to low negative subjects on four functional immunological assays (natural killer cell lysis, blastogenic response to two mitogens, and the proliferative response to a monoclonal antibody to the T3 receptor), as well as larger increases in the numbers of total T lymphocytes and helper T lymphocytes. High negative subjects had higher antibody titers to latent Epstein-Barr virus than low negative subjects, consistent with down-regulated immune function. Women were more likely to show negative immunological changes than men. The discussion of marital problems also led to larger increases in blood pressure that remained elevated longer in high negative subjects than low negative subjects. Positive or supportive problem-solving behaviors were not related to either immunological or blood pressure changes. These physiological differences were particularly noteworthy because marital satisfaction was high in both groups, and couples had been selected on the basis of stringent mental and physical health criteria. These data provide additional support for the link between personal relationships and immune function.

To address the question of whether childhood abuse and other adversities have lasting, detectable consequences for inflammation and cell aging late in life, and whether the effects are large enough to be discernible beyond that of a major chronic stressor, dementia family caregiving. Previous research on the physical health consequences of childhood abuse and other adversities has been based on data from young or middle-aged adults.In this community sample of 132 healthy older adults (mean age = 69.70 years; standard deviation = 10.14), including 58 dementia family caregivers and 74 non-caregivers, blood samples were analyzed for interleukin (IL)-6, tumor necrosis factor (TNF)-α, and telomere length, a measure of cell aging. Depressive symptoms were assessed by the Center for Epidemiological Studies Depression Scale.After controlling for age, caregiving status, gender, body mass index, exercise, and sleep, the presence of multiple childhood adversities was related to both heightened IL-6 (0.37 ± 0.03 log10 pg/mL versus 0.44 ± 0.03 log10 pg/mL) and shorter telomeres (6.51 ± 0.17 Kb versus 5.87 ± 0.20 Kb), compared with the absence of adversity; the telomere difference could translate into a 7- to 15-year difference in life span. Abuse was associated with heightened IL-6 and TNF-α levels; for TNF-α, this relationship was magnified in caregivers compared with controls. Moreover, abuse and caregiving status were associated significantly and independently with higher levels of depressive symptoms.Adverse childhood events are related to continued vulnerability among older adults, enhancing the impact of chronic stressors. Childhood adversities cast a very long shadow.

Objective To assess endocrinological and immunological correlates of marital conflict and marital satisfaction, 31 older couples (mean age 67 years) who had been married an average of 42 years were studied. Method Couples were admitted to the Clinical Research Center and a catheter was placed in each subject's arm. Blood was drawn on entry for immunological assays; for hormone analyses, five blood samples were drawn during a 30-minute conflict discussion and a 15-minute recovery session. The conflict session was recorded on videotapes that were later coded for problem-solving behaviors using the Marital Interaction Coding System (MICS). Results Among wives, escalation of negative behavior during conflict and marital satisfaction showed strong relationships to endocrine changes, accounting for 16% to 21% of the variance in the rates of change of cortisol, adrenocorticotropic hormone (ACTH), and norepinephrine (but not epinephrine). In contrast, husbands' endocrine data did not show significant relationships with negative behavior or marital quality. Both men and women who showed relatively poorer immunological responses across three functional assays (the blastogenic response to two T-cell mitogens and antibody titers to latent Epstein-Barr virus) displayed more negative behavior during conflict; they also characterized their usual marital disagreements as more negative than individuals who showed better immune responses across assays. Conclusion Abrasive marital interactions may have physiological consequences even among older adults in long-term marriages.

We evaluated hormonal changes and problem-solving behaviors in 90 newlywed couples who were admitted to a hospital research unit for 24 hours. The subjects were selected on the basis of stringent mental and physical health criteria, and admissions were scheduled during the follicular phase of the woman's menstrual cycle. For frequent, unobtrusive endocrine sampling during the interaction tasks, a long polyethylene tube was attached to a heparin well, allowing nurses to draw blood samples at set intervals, out of subjects' sight. Five blood samples were obtained before, during, and after a 30-minute structured problem-solving or conflict task. The conflict session was recorded on videotapes that were later scored for problem-solving behaviors using the Marital Interaction Coding System (MICS). Marital conflict and MICS-coded hostile or negative behavior during conflict was closely linked to changes in serum hormonal levels across five of the six hormones we studied, in spite of the high marital satisfaction of our newlywed couples and the healthy lifestyles demanded by our exclusion criteria. Hostile behavior was associated with decreased levels of prolactin (PRL) and increases in epinephrine (EPI), norepinephrine (NEPI), ACTH, and growth hormone (GH), but not cortisol. These data suggest that the endocrine system may be an important mediator between personal relationships and health.

Each of a series of three hepatitis B (Hep B) inoculations was given to 48 second-year medical students on the 3rd day of a 3-day examination series to study the effect of academic stress on the ability to generate an immune response to a primary antigen. Those students who seroconverted after the first injection (25%) were significantly less stressed and anxious than those who did not seroconvert at that time. In addition, students who reported greater social support demonstrated a stronger immune response to the vaccine at the time of the third inoculation, as measured by antibody titers to Hep B surface antigen (HBsAg) and the blastogenic response to a HBsAg peptide (SAg).