Associations between sedentary behavior and allostatic load: The 1970 British Cohort Study.

Discrepancies in loneliness and social isolation predict cognitive impairment through chronic disease burden.

Social determinants of health (SDoHs) are increasingly recognized as important contributors to the development, course, and outcomes of psychiatric disorders. However, their integration into clinical psychiatry and mechanistic models remains limited. This overview synthesizes emerging evidence on the biopsychosocial mechanisms through which SDoHs influence mental health. There is a need to distinguish between individual-level, clinically actionable health-related social needs and family-, community-, and society-level structural SDoHs, and to consider both adverse and protective social factors. Converging research demonstrates that social experiences are biologically embedded through interacting pathways, including exposomics, epigenetics, allostatic load, accelerated inflammaging, immune dysregulation, and gut-brain-microbiome signaling. These mechanisms influence neural circuitry underlying stress regulation, reward processing, and social cognition. Psychological processes-including individual differences in resilience, wisdom, compassion, and purpose in life-shape responses to SDoHs and are supported by identifiable neurobiological substrates. Social connection has emerged as a central, potentially modifiable SDoH that is strongly associated with whole health and longevity. Loneliness and social isolation have become major global public health challenges. The authors propose a biopsychosocial framework that integrates social exposures, biological mechanisms, neural systems, and psychological processes to better understand the risk, course, and prevention of mental illnesses. Clinical and public health implications include the need for routine assessment of SDoHs, incorporation of protective factors at individual and societal levels, and development of pragmatic, multidomain interventions. Finally, rapidly evolving digital technologies, including artificial intelligence, offer new opportunities but also require careful governance. Advancing toward human-centered "artificial wisdom" may enhance the capacity of technology to promote whole health in individuals with mental illnesses globally.

Germline deletions of UDP-glycosyltransferase (UGT) UGT2B17 and UGT2B28 genes are common in human populations, yet their association with aging remains unclear. In this exploratory study, we analyzed data from 12,934 participants, mostly Caucasian, in the Canadian Longitudinal Study on Aging (CLSA) to assess cross-sectional and prospective associations between UGT deficiencies and aging-related health outcomes, including mortality, multimorbidity, allostatic load, disease burden and polypharmacy. Sex-specific associations emerged from cross-sectional analyses: UGT2B17-deficient males were less likely to report arthritis (adjusted odds ratio (ORadj) = 0.73, 95% confidence interval (0.58-0.92), P = 0.008), UGT2B17-deficient females were less likely to report neurological problems (ORadj = 0.69 (0.51-0.91), P = 0.01), and UGT2B28-deficient females were less likely to report thyroid disorders (ORadj = 0.50 (0.29-0.82), P = 0.009). Despite these associations, multimorbidity remained prevalent across all groups and no significant associations were observed with all-cause mortality or longevity. Physiological dysregulation, assessed by the allostatic load index, was more prevalent in males. Among males aged ≥ 65, UGT2B28-deficiency was associated with reduced high dysregulation compared to UGT-proficient males (40.0% vs. 53.0%, P = 0.05), whereas UGT2B17 deficiency was associated with a higher prevalence in males (60.4% vs. 53.0%, P = 0.03). In addition, UGT2B17-deficient males had a lower prevalence of polypharmacy than UGT-proficient males (9.3% vs. 13.9%; P = 0.02). Overall, these findings indicate sex-specific associations between UGT2B17 and UGT2B28 deletions and selected healthspan-related phenotypes, suggesting that UGT-related genetic variation may modulate physiological pathways relevant to aging. Given the exploratory nature of this study and its reliance on prevalence data, the results are intended to be hypothesis-generating and will require confirmation in longer-term longitudinal studies.

Corticotropin-Releasing Factor-Dependent Synaptic Plasticity In Acute Stress: From Rapid Signaling To Circuit Remodeling And Allostatic Load.

Elevated allostatic load, adverse body composition, and reduced overall survival in a retrospective cohort of men with newly diagnosed metastatic prostate cancer.

Stress is an umbrella term indicating increased allostatic load with the potential to reach a pathological state of the organism. In this context, cortisol concentration and neutrophil granulocytes-to-lymphocyte ratio (NEU: LYM) are expected to increase. On the functional pathway, stress reduces the oxidative burst capacity of neutrophils and therefore, the leucocyte coping capacity (LCC) quantifying this oxygen radical generation of neutrophils. Therefore, we hypothesized that in ponies subjected to repetitive handling, LCC will decrease and will be negatively correlated with cortisol concentration and NEU: LYM ratio. Thus, LCC was measured over 90min by a portable chemiluminometer in nine university owned ponies involved in a vaccination study that included handling and sampling over 42 days. The area under the curve for LCC (AUCLCC) and LCC: NEU (AUCLCC: NEU), cortisol concentration measured by a validated EIA and NEU: LYM ratio were compared before and at days 1, 3, 28, 31 and 42 after immunization by linear mixed models. Pearson correlation coefficients were calculated between AUCLCC, AUCLCC: NEU, cortisol concentration and NEU: LYM ratio. AUCLCC, AUCLCC: NEU and cortisol concentration showed a significant decrease. AUCLCC was moderately positively correlated with NEU: LYM and weakly positively correlated with cortisol concentration, but no correlations were found for AUCLCC: NEU. The progressive decrease of AUCLCC, AUCLCC: NEU, and cortisol concentration might indicate an increasing stress load. However, this was not supported by the time course of NEU: LYM ratio or by the correlations between these parameters. While the slight decrease in LCC over time partially supported our hypothesis, we found no evidence of correlations among AUCLCC: NEU and the other measured stress parameters. This may indicate that different stress markers reflect distinct endpoints within the physiological pathways of the stress response. Future studies should confirm these preliminary results and also incorporate ethograms to obtain a more comprehensive understanding of the stress response and to further evaluate the value of LCC as a stress marker in horses.

Endometrial cancer incidence and mortality are increasing, particularly among Black women and for aggressive subtypes. Allostatic load (AL), a composite measure of physiologic dysregulation across metabolic, cardiovascular, and immune systems, varies by racial category and tumor subtype in other cancers. Endometrial cancer is strongly associated with obesity, and it is unknown whether AL scores maintain sufficient heterogeneity to evaluate differences across subgroups or with clinical outcomes. To describe the performance of AL scoring in endometrial cancer patients and examine associations with tumor characteristics (grade/histology) and survival outcomes. We evaluated AL among 398 participants newly diagnosed with endometrial cancer. AL score was calculated by assigning 1 point for each "high-risk" value (by clinical reference range or distribution-based) for 15 biologic variables for vital signs, anthropometrics, blood-based biomarkers, and medical comorbidities. Distribution-based thresholds for variables were used to preserve heterogeneity in this obesity-dominant context. Overall, 68.7% of Black women had high AL compared to White (56.7%), Hispanic (56.7%), and other race (32.3%) women. Decision tree analyses revealed grade-dependent associations between AL and survival. For women with low-grade tumors, higher AL was associated with poorer overall survival. For high-grade tumors, intermediate AL (≥4, <8) were associated with shortest overall survival. Black women with low-grade disease experienced shorter progression-free survival regardless of AL. AL scoring maintains heterogeneity despite high obesity prevalence in endometrial cancer. Varying relationships between AL and survival by tumor grade and ethnoracial group suggest cumulative physiologic burden and social/structural factors may jointly shape endometrial cancer disparities.

Allostatic load (AL) is a composite measure of cumulative physiological burden from chronic stress, quantifying multisystem dysregulation. Whether AL may alter the risk of overall, cause-specific mortality, and premature mortality remains unclear. We analyzed UK Biobank participants aged 40-69 years (mean 56.6; 53.8% female) with complete data of AL metrics. AL was assessed by integrating 12 commonly applied metrics covering cardiovascular, metabolic, immune, and kidney systems (score range: 0-12), with higher scores indicating greater physiological dysregulation. Associations of AL scores with mortality from all cause and cause-specific mortality were examined. Stratified analyses assessed effect modification by premature mortality (< 70 years at death) and age at recruitment. Over a median follow-up of 15.4 years, 39,804 deaths were recorded, including 14,852 from cancer, 7118 from cardiovascular disease, 1938 from respiratory disease, and 1521 from digestive disease. Higher AL scores were significantly associated with increased risks of all-cause and cause-specific mortality in a dose-response manner (all P-trend < 0.001). Among specific causes, each one-point rise in AL score yielded stronger associations with digestive disease mortality (subdistribution hazard ratio [sHR] = 1.25, 95% confidence interval [CI]: 1.21-1.29) and cardiovascular disease mortality (sHR = 1.20, 95% CI: 1.18-1.21) than for cancer mortality (sHR = 1.08, 95% CI: 1.07-1.09) and respiratory disease mortality (sHR = 1.11, 95% CI: 1.09-1.14). Age significantly modified these associations (all P-interaction < 0.01), with higher HRs for premature mortality (age at death < 70 years) or younger individuals (age at enrollment < 50 years). Higher AL scores were associated with increased risks of all-cause and cause-specific mortality. Such associations were particularly pronounced for digestive and cardiovascular disease mortality, and appeared stronger for premature deaths and among younger individuals. These findings suggest that AL may serve as a marker of early physiological dysregulation and may help identify individuals at elevated risk of premature mortality.

Allostatic load as a moderating factor between child maltreatment exposure and mental health challenges in children and adolescents: a study based on the EPI_Young_Stress Project.

To identify culturally grounded well-being practices among Black men in midlife and examine their associations with physiological health. Analyzing data from the 2004-2005 Midlife in the United States (MIDUS) study, we examined, 116 open-ended responses to the question, "What do you do to make your life go well?" Network topic modeling identified six topics: (1) interpersonal kindness and positive mindset; (2) caring for children; (3) practicing spirituality and faith; (4) maintaining social connections and well-being; (5) avoiding stress; and (6) meaningful work and daily activities. Topic scores, reflecting participants' tendency to discuss these themes, predicted allostatic load and inflammation in structural equation models adjusting for body mass index, chronic conditions, psychological and subjective well-being, age, income, and education. Greater emphasis on meaningful work and daily activities predicted lower inflammation and allostatic load, independent of demographic and psychological covariates (p<.05). Other topics were not associated with physiological dysregulation. Everyday narratives of meaningful work and engagement among Black men are closely linked to physiological health markers, highlighting strengths-based, culturally grounded pathways for public health intervention and health equity.

The precise contribution of visceral obesity to the pathogenesis of low back pain (LBP) is still uncertain. The aim of this study was to understand the relationship between central obesity determined using the waist-to-weight index (WWI) and LBP prevalence and how biological ageing acceleration (BAA) exerts an indirect effect in such an association. Data were obtained from the National Health and Nutrition Examination Survey (NHANES) 1999-2004 and 2009-2010 databases, with 11,737 participants aged ≥ 18 years. The WWI was calculated as the ratio of waist circumference to the square root of weight, and BAA was assessed using the Klemera-Doubal method (KDM)-BAA, phenotypic age (PhenoAge) acceleration, and the allostatic load index (ALI). A greater WWI was significantly positively associated with greater odds of LBP (OR per 1-SD increase: 1.132; 95% CI: 1.082-1.185; p < 0.001). Mediation analysis revealed significant influences of BAA, where KDM-BAA, PhenoAge acceleration, and the ALI mediated 9.238%, 8.573%, and 8.046% of the associations, respectively (p < 0.001 for all). The indirect effects of BA on the association between the WWI and the odds of LBP were also nonnegligible in females, accounting for 8.762%, 19.171%, and 17.321% of the intermediary association mediated by KDM-BAA, PhenoAge acceleration, and the ALI, respectively. This study provides evidence of the significant associations between the WWI and LBP prevalence and highlights the indirect effects of BAA in these associations.

Life course predictors of allostatic load among sexual and gender minority (SGM) midlife & older adults.

We are seeing an exploding expansion of antisemitic attacks worldwide, raising concerns about their potential impact on biological stress regulation and health. Antisemitism is a historically persistent and structurally embedded form of social exclusion that may contribute to chronic psychosocial stress exposure. Building on research into intergenerational trauma, including neuroendocrine alterations in Holocaust survivors and their descendants, this commentary integrates psychometric, empirical, and conceptual approaches to propose a biologically grounded framework linking antisemitism to endocrine and cardiometabolic processes. Preliminary findings from a pilot study using a Checklist of Antisemitic Perception instrument, in combination with established psychometric measures, indicate an increased psychological burden associated with antisemitic experiences, with clinically relevant symptom levels observed across groups. Mechanistically, chronic stress is mediated by neuroendocrine pathways involving the hypothalamic-pituitary-adrenal axis, autonomic nervous system, and immune regulation, contributing to allostatic load and cardiometabolic risk. Emerging evidence suggests that stress responses are heterogeneous and influenced by individual coping styles, with distinct allostatic set-points and associated neurobiological adaptations, including alterations in striatal glutamatergic signaling. Institutional and discursive contexts may further modulate exposure to antisemitic stressors, as reflected in heterogeneous professional engagement and variations in thematic emphasis within medical discourse. Taken together, these observations support the conceptualization of antisemitism as a chronic stressor with potential biological consequences and highlight the importance of integrating psychometric and biological approaches in future research.

ABSTRACTIntroductionEndometrial cancer (EC) mortality is rising, with increasing rates of advanced disease and high‐risk histologic subtypes. Allostatic load (AL), a biomarker of cumulative physiologic stress, has been linked to cancer‐associated outcomes. We evaluated the association between baseline AL and overall survival among patients with EC.MethodsPatients diagnosed with EC at a single academic center were retrospectively identified. Baseline demographic, clinical, and laboratory values were used to calculate the primary exposure of interest, AL, based on ten physiologic biomarkers. A cohort‐defined threshold classified patients as having high versus low AL. Data were analyzed using unadjusted and adjusted models and Kaplan–Meier curves.ResultsA total of 2174 patients (mean age = 63.1 years, SD = 11.2) with EC were assessed for allostatic load at baseline, 69.2% met criteria for high AL (n = 1505). The median follow up time was 49.5 months (IQR = 25.7, 76.4). High AL was associated with worse overall survival (unadjusted HR: 1.70 (95% CI, 1.28, 2.24), adjusted HR 1.58; 95% CI, 1.19, 2.11). Patients with high AL had a 52% higher rate of death compared to the low AL group. High AL was more prevalent among Black patients, those who were not married, and those without private insurance (all p < 0.001).ConclusionsElevated allostatic load was associated with worse overall survival in this cohort of patients with EC, consistent with the hypothesis that physiological stress may impact survival outcomes. These findings are hypothesis‐generating and suggest that physiologic stress and social disadvantage may contribute to survival differences warranting further study.

The association between allostatic load (AL) and breast carcinoma in situ (BCIS) remains unclear. We investigated this relationship in the UK Biobank while also assessing its role in invasive breast cancer (IDC) for comparison. Using data from the UK Biobank, we included 159,240 women (40-69years). AL was derived from 12 biomarkers. Cox proportional hazards models, restricted cubic splines (RCS), and time-dependent ROC curves were used to assess associations with BCIS and IDC. Over a median follow-up of 13.65years, 1,320 BCIS and 7,197 IDC cases occurred. In fully adjusted models, AL was not associated with BCIS (HR per 1-point increase = 1.004; 95% CI: 0.966-1.042; p = 0.854). RCS confirmed no non-linear relationship (p = 0.605). Conversely, AL was significantly associated with IDC (HR = 1.018; 95% CI: 1.002-1.035; p = 0.026), indicating a 1.8% increased risk per unit increase. Predictive utility was minimal (AUC < 0.58), and sensitivity analyses using quintile-based AL scoring validated these findings. While AL is an independent risk factor for IDC, it shows no association with BCIS. These findings suggest that the biological drivers of in-situ lesions differ from those of invasive progression, highlighting AL as an etiologic factor for malignancy rather than a screening tool for early-stage localization.

Breast cancer survivors frequently experience persistent and co-occurring symptoms, yet the role of allostatic load (AL), a measure of cumulative physiological stress, in shaping these outcomes remains unclear. We examined the associations of AL with physical and mental health outcomes, symptom burden profiles, and socioeconomic disparities among breast cancer survivors using data from the UK Biobank. The study included 1,444 breast cancer survivors and 1,444 age-matched women without cancer who completed baseline (2006–2010) and follow-up (2022) assessments. AL was derived from 11 biomarkers and analyzed as a continuous measure. Survivorship outcomes included sleep quality, fatigue, depression, anxiety, cognitive function, functional limitation, and self-rated mental health. Latent class analysis was used to identify symptom burden profiles, and multivariable regression and mediation analyses were performed. Among breast cancer survivors (mean age 58 years), higher AL was associated with poorer sleep quality (β = 0.18, 95% CI 0.06–0.29), greater fatigue (β = 0.23, 95% CI 0.12–0.35), increased functional limitation (β = 0.28, 95% CI 0.09–0.47), higher depressive symptoms (β = 0.15, 95% CI 0.02–0.28), higher anxiety (β = 0.12, 95% CI 0.01–0.23), and poorer self-rated mental health (β = −0.09, 95% CI - 0.13 to - 0.05), but not cognitive function. These associations were weaker or absent among women without cancer. Higher AL was also associated with increased likelihood of adverse symptom burden profiles. Mediation analyses indicated that AL partially mediated associations of income and education with multiple outcomes, accounting for approximately 6–15% and 8–9% of these associations, respectively. These findings suggest that elevated AL is associated with worse survivorship outcomes and contributes to socioeconomic disparities in symptom burden among breast cancer survivors. Chronic physiological stress may represent an important mechanism underlying survivorship heterogeneity and a potential target for intervention.

To compare the sleep behavior, cortisol, and immunoglobulin A responses between 2 conditions; an experimental condition consisting of 2 consecutive weeks of school and training commitments with low- and high-load training and a 3-day control condition without school and training obligations. Objective sleep characteristics were monitored using ActiGraphy in 11 female water polo athletes (age: 12.9 [1.2]y) during both conditions. In the experimental condition, a low-load training week was followed by a high-load training week. Salivary cortisol and immunoglobulin-A were measured before training. Sleep duration was lower and awakenings were fewer in experimental condition compared to control condition (duration: 464.1 [20.6] vs 501.3 [85.0]min, P = .02, d = 0.66; awakenings: 17.4 [8.4] vs 21.1 [10.2], P = .02, d = 0.71). Sleep characteristics were similar between training conditions; however, variability in time in bed and total sleep time was lower during high- (12.34% [6.46%] and 13.32% [7.59%]) than low-load training (16.30% [7.43%] and 17.32% [5.50%]) (P < .01, d = 1.12 and P = .04, d = 0.70). Salivary cortisol and immunoglobulin-A levels were higher during high-load than low-load training (P < .01, d = 1.02 and P < .01, d = 1.38). School and sports training commitments reduce sleep duration but improve sleep quality in adolescent water polo athletes, while high-load training reduces sleep variability and increases allostatic load without altering sleep characteristics.

BackgroundMetabolic stressors, including metabolic syndrome (MetS), circadian syndrome (CircS), and allostatic load (AL), measure the metabolic and stress‐related physiological dysregulations that are associated with the risk of frailty and cardiovascular mortality in the adult population.AimTo assess the effects of MetS, CircS, and AL on all‐cause mortality in U.S. adults by age and sex.MethodsWe performed a retrospective cohort analysis using the National Health and Nutrition Examination Survey (NHANES) data, including 7 cycles (2005–2018). The associations between metabolic stressors and mortality were evaluated using stratified Cox regression analyses.ResultsThe study included 37434 adults for analysis of CircS and MetS, while 26480 adults were included for AL analysis. All exposures, including CircS (hazard ratio [HR]: 1.29; 95% confidence interval [CI] 1.18–1.42), MetS (HR: 1.09; 95% CI 1.00–1.18), and AL (HR: 1.25; 95% CI 1.11–1.41), were associated with all‐cause mortality in the entire cohort. In adjusted analyses, CircS (HR: 1.55; 95% CI 1.34–1.80), MetS (HR: 1.32; 95% CI 1.14–1.53), and AL (HR: 1.44; 95% CI 1.21–1.70) were only associated with all‐cause mortality in individuals with age < 70 years. In subgroup analyses by sex, all three exposures were strongly associated with mortality in males as well as in the subgroup of males with age < 70 years. The CircS was found to be a strong marker for all‐cause mortality in individuals aged < 70 and in both sexes.ConclusionThe strength of association between CircS and all‐cause mortality was stronger than that of MetS and AL, irrespective of sex. Our findings indicate that metabolic biomarkers, specifically CircS, may help refine risk stratification and prognostic evaluation among adults aged less than 70 years.

Objective Research on allostatic load (AL) and depression has been increasing, but has lacked attention on perimenopausal women. This study aimed to explore the dual trajectories of AL and depression in perimenopausal women and identify their common influencing factors. Method Data from seven follow-up sites of the Study of Women’s Health Across the Nation (SWAN) were used, and 1185 perimenopausal women aged 42–52 years were eventually included. Trajectories of AL and depression were identified by fitting different group-based trajectory models. A dual trajectory model was used to estimate the probability of the correlation between different level trajectory groups of AL and depression, and multivariate logistic regression was used to estimate the degree of association of demographic characteristics of perimenopausal women with AL and depression. Results In a dual trajectory model of AL and depression, AL and depression showed an interactive association, with high AL trajectories increasing the likelihood of high depression trajectories (14.65%) and high depression trajectories increasing the likelihood of high AL trajectories (41.2%). After considering demographic characteristics, age, race, income level, social support, hot flashes and night sweats were found to be common influences on AL and depression. Conclusion Interventions should be tailored according to the different trajectory groups of AL and depression, with a focus on high-vulnerability subgroups (high AL without depression, low AL with high depression, high AL with high depression). AL monitoring should also be integrated into perimenopausal depression management. In addition, care should be taken to address the common risk factors behind these trajectories and develop interventions based on relevant determinants.