What Explains the Link Between Hearing and Vision Impairment and Cognitive Function? Analysis of Mediating Effects in the USA, England and Ireland.

OBJECTIVES: Hearing and vision impairments are associated with cognitive decline and dementia risk. Explanations for this include age-related processes impacting on sensory and cognitive function (common cause), or sensory impairments having a direct or indirect impact on cognition via social engagement, depression and physical activity (cascade). We tested whether associations between hearing, vision and episodic memory were mediated by allostatic load, social engagement, depression and physical activity. METHODS: We used structural equation modelling with cross-sectional data from the USA (n = 4746, aged 50-101), England (n = 4907, aged 50-89) and Ireland (4292, aged 50-80) to model factors related to the common cause (indexed by allostatic load) and the cascade hypothesis with respect to cognitive ability (episodic memory). RESULTS: Poorer hearing/vision was associated with lower social engagement, depression and sedentary lifestyle. Poor vision was not related to allostatic load, and poor hearing was associated with allostatic load in only one data set, contributing to a common-cause hypothesis. Lower social engagement, depression and a sedentary lifestyle were associated with poorer episodic memory, contributing to the cascade hypothesis. Using effect estimates to calculate the proportion of the total effects mediated by the combined mediator variables, up to two fifths of the relationship between hearing and vision with episodic memory can be explained by the mediators. CONCLUSIONS: The association between hearing, vision and episodic memory is mediated by allostatic load, social engagement, depression, and physical activity. The finding that social engagement, depression, and physical activity mediate the association between sensory abilities and cognitive function supported the cascade hypotheses. Interventions to improve healthy lifestyle, reduce depression and foster social engagement of older people with sensory impairments are likely to be beneficial in preventing cognitive decline and dementia.

Biologic Correlates and Consequences of the Social Determinants of Health and Disease.

The consequences of experiences and exposures suffered by those living in poverty can last a lifetime and can even be passed on to the next generation. The challenges associated with poverty have been labeled the "social determinants of health" (SDoH), but this is something of a misnomer. A more appropriate label would be the "social determinants of disease." This essay is a broad overview of the processes, including allostatic load and epigenetic aging, that might contribute to prolonging the adverse effects of the social determinants of disease.

Homeostasis to Allostasis: Prefrontal Astrocyte Roles in Cognitive Flexibility and Stress Biology.

In the intricate landscape of neurophysiology, astrocytes have been traditionally cast as homeostatic cells; however, their mechanistic involvement in allostasis-particularly how they modulate the adaptive response to stress and its accumulative impact that disrupts cognitive functions and precipitates psychiatric disorders-is now starting to be unraveled. Here, we address the gap by positing astrocytes as crucial allostatic players whose molecular adaptations underlie cognitive flexibility in stress-related neuropsychiatric conditions. We review how astrocytes, responding to stress mediators such as glucocorticoid and epinephrine/norepinephrine, undergo morphological and functional transformations that parallel the maladaptive changes. Our synthesis of recent findings reveals that these glial changes, especially in the metabolically demanding prefrontal cortex, may underlie some of the neuropsychiatric mechanisms characterized by the disruption of energy metabolism and astrocytic networks, compromised glutamate clearance, and diminished synaptic support. We argue that astrocytes extend beyond their homeostatic role, actively participating in the brain's allostatic response, especially by modulating energy substrates critical for cognitive functions.

Examining emotion regulation and inflammation as predictors of maternal mental health after fetal anomaly diagnosis.

OBJECTIVE: Fetal anomalies occur in approximately 3% of pregnancies and receiving the diagnosis may be a potentially traumatic experience for families. The mental health of mothers receiving diagnoses and what predicts resilience or poor mental health is understudied. Emotion regulation is an important, modifiable, transdiagnostic factor of mental health, and may be protective post-diagnosis. Evaluating biomarkers of stress, including IL-6 and Allostatic Load (AL), can also serve as early indicators of risk, indicative of early intervention. This study assessed whether reappraisal, suppression, IL-6, and AL was associated with mental health outcomes and resilience in women after receiving a fetal anomaly diagnosis. METHODS: Pregnant women (N=108) presenting to a fetal concerns clinic for initial consultation completed measures of emotion regulation (i.e., reappraisal and suppression), depression, anxiety, posttraumatic stress symptoms, and resilience between 2019-2022. A blood draw was used to assess IL-6 and create composite allostatic load measure including: IL-6, blood pressure, heart rate, glucose, cortisol, and body mass index. RESULTS: Linear regressions controlling for age, gestational age, and perceived fetal diagnosis severity, demonstrated that IL-6 was negatively associated with resilience and positively associated with depression. Reappraisal was positively associated to resilience and negatively associated with depression, anxiety, and PTSD, whereas state insurance status was positively associated to anxiety and PTS symptoms. Suppression and allostatic load were not significant. CONCLUSIONS: Women experiencing fetal anomaly diagnosis represent an understudied population with unaddressed mental health needs. Reappraisal serves as not only a protective factor, but one that can be enhanced to promote maternal resilience and mental health. Furthermore, elevated IL-6 may be a critical early indicator of potential intervention needs among women who are pregnant, to mitigate negative psychological states and enhance resilience.

Disturbed glucose homeostasis and its increased allostatic load in response to individual, joint and fluctuating air pollutants exposure: Evidence from a longitudinal study in prediabetes.

We investigated the effect of individual, joint and fluctuating exposure to air pollution (PM2.5, BC, NO3-, NH4+, OM, SO42-, PM10, NO2, SO2, O3) on glucose metabolisms among prediabetes, and simultaneously explored the modifying effect of lifestyle. We conducted a longitudinal study among prediabetes during 2018-2022. Exposure windows within 60-days moving averages and their variabilities were calculated. FBG, insulin, HOMA-IR, HOMA-B, triglyceride glucose index (TyG), glucose insulin ratio (GI) and allostatic load of glucose homeostasis system (AL-GHS) was included. Linear mixed-effects model and BKMR were adopted to investigate the individual and overall effects, respectively. We also explored the preventive role of lifestyle. Individual air pollutant was associated with increased FBG, insulin, HOMA-IR, HOMA-B, TyG, and decreased GI. People with FBG ≥6.1 mmol/L were more susceptible. Air pollutants mixture were only associated with increased HOMA-B, and constituents have the highest group-PIP. Air pollutants variation also exert harmful effect. We observed similar diabetic effect on AL-GHS. Finally, the diabetic effect of air pollutants disappeared if participants adopt a favorable lifestyle. Our findings highlighted the importance of comprehensively assessing multiple air pollutants and their variations, focusing on metabolic health status in the early prevention of T2D, and adopting healthy lifestyle to mitigate such harmful effect.

Affect regulation and allostatic load over time.

OBJECTIVE: Emerging work suggests that affect regulation strategies (e.g., active coping, anger expression) predict disease and mortality risk, with sometimes divergent estimates by sex or education levels. However, few studies have examined potential underlying biological mechanisms. This study assessed the longitudinal association of affect regulation with future allostatic load. METHOD: In 2004-2006, 574 participants from the Midlife in the United States study completed validated scales assessing use of nine general and emotion-specific regulatory strategies (e.g., denial, anger expression). As a proxy for how flexibly participants regulate their affect, variability in the use of regulatory strategies was operationalized using a standard deviation-based algorithm and considered categorically (i.e., lower, moderate, greater variability) to assess non-linear effects. Participants also provided data on relevant covariates and 24 allostatic load biomarkers (e.g., cortisol, blood pressure). In 2017-2021, these biomarkers were again collected. Linear regressions modeled betas (ß) and 95 % confidence intervals (CI) examining associations of affect regulatory constructs with future allostatic load. RESULTS: In fully-adjusted models including initial allostatic load, general regulatory strategies were unrelated to future allostatic load. Yet, greater versus moderate affect regulation variability levels predicted lower allostatic load (ß=-0.14; 95 %CI: -0.27, -0.01). Only among more educated participants, greater use of anger expression predicted lower allostatic load, while the reverse was noted with anger control (ßexpression=-0.12; 95 %CI: -0.20, -0.05; ßcontrol=0.14; 95 %CI: 0.05, 0.24). CONCLUSIONS: While general regulatory strategies appeared unrelated to allostatic load, greater variability in their use and anger-related strategies showed predictive value. Subsequent studies should examine these associations in larger, more diverse samples.

Chronic Work Discrimination, Allostatic Load, and HbA1c in Older Workers.

BACKGROUND AND OBJECTIVE: Work discrimination is an important public health problem with consequences for health. This study examined the effect of chronic work discrimination on 4-year changes in HbA1c, as a reflection of glucose control and type 2 diabetes risk in older workers and assessed whether allostatic load (AL) affected the strength of this association. RESEARCH DESIGN AND METHODS: We used Health and Retirement Study data (2010-2016, n = 3,246). Conditional change multinomial logistic regression examined the association between chronic work discrimination, high AL (4 or more out of 8 high-risk biomarkers), and HbA1c, while accounting for relevant covariates. RESULTS: Black participants had the highest rates of baseline (22.7%) and follow-up (28%) HbA1c levels, AL (38%), and chronic work discrimination (39%; p < .01). Severe chronic work discrimination was associated with elevated HbA1c (relative risk ratio [RRR] = 1.61, 95% confidence interval [CI] = 1.07, 2.43). AL was associated with elevated HbA1c (RRR = 1.49, 95% CI = 1.04, 2.14). Relative to White participants, Hispanic (RRR = 1.52, 95% CI = 1.07, 2.16, RRR = 1.81, 95% CI = 1.051, 3.12), and Black (RRR = 2.42, 95% CI = 1.82, 3.23; RRR = 3.00, 95% CI = 1.97, 4.56) participants had an increased risk of intermediate and elevated HbA1c, respectively. Among those with long job tenure (≥5 years), both moderate (RRR = 1.81, 95% CI = 1.11, 2.96) and severe (RRR = 1.90, 95% CI = 1.15, 3.12) chronic work discrimination was associated with elevated HbA1c. DISCUSSION AND IMPLICATIONS: Chronic work discrimination was associated with HbA1c; however, no moderating effects of AL were observed. Findings underscore a need for organizational and public health measures to establish strong anti-discrimination laws in the workplace to improve the work environment of older workers and reduce diabetes risk.

Elevated allostatic load is associated with poorer response to repetitive transcranial magnetic stimulation in treatment-resistant depression.

This cohort study investigated whether allostatic load (AL) is associated with treatment response to repetitive transcranial magnetic stimulation (rTMS) in treatment-resistant depression (TRD). Pre-treatment blood samples measured AL across multiple systems. Pre- and post-treatment mood changes were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS). Associations between AL and treatment outcomes were explored. Higher pre-treatment AL was significantly associated with poorer post-treatment response status but was not significantly associated with smaller reduction in MADRS score after 4 weeks of treatment. Identifying biomarker profiles informed by the AL model could enhance treatment decisions in TRD, reducing risks associated with prolonged, ineffective rTMS trials and emphasizing the need for reliable predictive biomarkers.

Allostatic Load/Chronic Stress and Cardiovascular Outcomes in Patients Diagnosed With Breast, Lung, or Colorectal Cancer.

BACKGROUND: Cardiovascular disease and cancer share a common risk factor: chronic stress/allostatic load (AL). A 1-point increase in AL is linked to up to a 30% higher risk of major cardiac events (MACE) in patients with prostate cancer. However, AL's role in MACE in breast cancer, lung cancer, or colorectal cancer remains unknown. METHODS AND RESULTS: Patients ≥18 years of age diagnosed with the mentioned 3 cancers of interest (2010-2019) and followed up at a large, hybrid academic-community practice were included in this retrospective cohort study. AL was modeled as an ordinal measure (0-11). Adjusted Fine-Gray competing risks regressions estimated the impact of AL precancer diagnosis on 2-year MACE (a composite of heart failure, ischemic stroke, acute coronary syndrome, and atrial fibrillation). The effect of AL changes over time on MACE was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after cancer diagnosis). Among 16 467 patients, 50.5% had breast cancer, 27.9% had lung cancer, and 21.4% had colorectal cancer. A 1-point elevation in AL before breast cancer diagnosis corresponded to a 10% heightened associated risk of MACE (adjusted hazard ratio, 1.10 [95% CI, 1.06-1.13]). Similar findings were noted in lung cancer (adjusted hazard ratio, 1.16 [95% CI, 1.12-1.20]) and colorectal cancer (adjusted hazard ratio, 1.13 [95% CI, 1.08-1.19]). When considering AL as a time-varying exposure, the peak associated MACE risk occurred with a 1-point AL rise between 6 and 12 months post- breast cancer, lung cancer, and colorectal cancer diagnosis. CONCLUSIONS: AL warrants investigation as a potential marker in these patients to identify those at elevated cardiovascular risk and intervene accordingly.

Association Between Uveal Melanoma and Allostatic Load.

BACKGROUND/AIM: Allostatic load (AL) is a measure of chronic stress that is associated with worse cancer outcomes. The purpose of this retrospective cohort study was to investigate the relationship between AL and uveal melanoma (UM) clinical features. PATIENTS AND METHODS: AL score was calculated as a composite of ten biomarkers in 111 patients with UM from the University of Illinois Hospital. One point was assigned to an AL score for each biomarker based on predetermined cutoff values. Linear and logistic regression analyses evaluated the relationship between AL score and several tumor clinical characteristics. RESULTS: High AL score had a significant relationship with extraocular extension (p=0.015). There was also a significant difference in mean blood glucose levels between the different tumor size groups (p=0.029). Higher AL scores also had a trend of being associated with a smaller tumor size (p=0.069). CONCLUSION: AL score was significantly associated with the presence of extraocular extension for uveal melanoma, while the smallest tumor size group was associated with the highest blood glucose level. No other significant correlations were found between AL and other clinical features of UM. The relationship between AL score and extraocular extension warrants further investigation. Additional research is needed to evaluate socioeconomic factors and their effect on the relationship between chronic stress and the clinical features of UM.

Defining the brain control of physiological stability.

The last few decades have seen major advances in neurobiology and uncovered novel genetic and cellular substrates involved in the control of physiological set points. In this Review, I discuss the limitations in the definition of homeostatic set points established by Walter B Canon and highlight evidence that two other physiological systems, namely rheostasis and allostasis provide distinct inputs to independently modify set-point levels. Using data collected over the past decade, the hypothalamic and genetic basis of regulated changes in set-point values by rheostatic mechanisms are described. Then, the role of higher-order brain regions, such as hippocampal circuits, for experience-dependent, allostatic induced changes in set-points are outlined. I propose that these systems provide a hierarchical organization of physiological stability that exists to maintain set-point values. The hierarchical organization of physiology has direct implications for basic and medical research, and clinical practice.

Assessing the Correlation between Allostatic Load and False-Positive Image-Guided Breast Biopsies.

Background: Allostatic load (AL) is the accumulation of physiological dysregulation attributed to repeated activation of the stress response over a lifetime. We assessed the utility of AL as a prognostic measure for high-risk benign breast biopsy pathology results. Method: Eligible patients were women 18 years or older, with a false-positive outpatient breast biopsy between January and December 2022 at a tertiary academic health center. AL was calculated using 12 variables representing four physiological systems: cardiovascular (pulse rate, systolic and diastolic blood pressures, total cholesterol, high-density lipoprotein, and low-density lipoprotein); metabolic (body mass index, albumin, and hemoglobin A1C); renal (creatinine and estimated glomerular filtration rate); and immune (white blood cell count). Multivariable logistic regression was used to assess the association between AL before biopsy and breast biopsy outcomes controlling for patients' sociodemographics. Results: In total, 170 women were included (mean age, 54.1 ± 12.9 years): 89.4% had benign and 10.6% had high-risk pathologies (radial scar/complex sclerosing lesion, atypical ductal or lobular hyperplasia, flat epithelial atypia, intraductal papilloma, or lobular carcinoma in-situ). A total of 56.5% were White, 24.7% Asian, and 17.1% other races. A total of 32.5% identified as Hispanic. The mean breast cancer risk score using the Tyrer-Cuzick model was 11.9 ± 7.0. In multivariable analysis, with every one unit increase in AL, the probability of high-risk pathology increased by 37% (odds ratio, 1.37; 95% confidence interval, 1.03, 1.81; p = 0.03). No significant association was seen between high-risk pathology and age, ethnicity, breast cancer risk, or area deprivation index. Conclusion: Our findings support that increased AL, a biological marker of stress, is associated with high-risk pathology among patients with false-positive breast biopsy results.

Association of allostatic load with overall survival in epithelial ovarian cancer.

OBJECTIVE: Elevated allostatic load (AL), an integrated, cumulative marker of physiologic damage due to socioenvironmental stress, is associated with increased mortality in patients with breast, lung, and other cancers. The relationship between allostatic load and mortality in ovarian cancer patients remains unknown. We examined the relationship between allostatic load and overall survival in ovarian cancer patients. METHODS: This cross-sectional study used data from 201 patients enrolled in a prospective observational ovarian cancer cohort study at a National Cancer Institute-designated Comprehensive Cancer Center from October 2012 through June 2022. All patients underwent debulking surgery and completed a full course of standard-of-care platinum-based chemotherapy. Follow-up was completed through January 2024. Allostatic load was calculated as a summary score by assigning one point to the worst sample quartile for each of ten biomarkers measured within 45 days before the ovarian cancer diagnosis. High allostatic load was defined as having an allostatic load in the top quartile of the summary score. A Cox proportional hazard model with robust variance tested the association between allostatic load and overall survival. RESULTS: There were no associations between allostatic load and ovarian cancer clinical characteristics. After accounting for demographic, clinical, and treatment factors, high allostatic load was associated with a significant increase in mortality (hazard ratio 2.17 [95%CI, 1.13-4.15]; P = 0.02). CONCLUSION: Higher allostatic load is associated with worse survival among ovarian cancer patients. Allostatic load could help identify patients at risk for poorer outcomes who may benefit from greater socioenvironmental support during treatment.

Retrospective operationalization of allostatic load in patients with cancer: A systematic review.

Allostatic load (AL) has been shown to impact cancer outcomes. At present, no gold standard exists surrounding AL computation. As such, a systematic review of the literature was performed to identify studies that retrospectively calculated AL in patients with cancer. The following variables were collected for each study: AL calculation method, including the biomarkers used and their cutoff values, number of biosystems represented, definition of high AL, and the use of proxy biomarkers. Thirteen articles were included for full-text review. The number of biomarkers used in the calculation of AL varied considerably, ranging from 6 to 16. Considerable variability was also observed in terms of utilized biomarkers and biosystem representation. This lack of standardization complicates retrospective AL calculation among patients with cancer. Nonetheless, determining AL in patients with cancer presents an important step in the optimization of patient care and outcomes.

Allostatic load measures in older adults with subjective cognitive decline and mild cognitive impairment: A cross-sectional analysis from the Brazilian Memory and Aging Study.

INTRODUCTION: An increasing body of research suggests that stress and allostatic load are related to cognitive dysfunction and neurodegeneration. OBJECTIVES: to determine the relationship between allostatic load (AL) and cognitive status in older adults classified with subjective cognitive decline (SCD) and mild cognitive impairment (MCI). METHODOLOGY: Using the Brazilian Memory and Aging Study (BRAMS) database, we analyzed data from 57 older adults with SCD and MCI. Blood neuroendocrine (cortisol, DHEA-s), inflammatory (C-reactive protein, fibrinogen), metabolic (HbA1c, HDL-cholesterol, total cholesterol, creatinine), and cardiovascular (blood pressure, waist/hip ratio) were transformed into an AL index. RESULTS: Despite a significant difference in the univariate analysis between waist/hip ratio (0.94 in the MCI group vs. 0, 88 in the SCD group, p = 0.03), total cholesterol levels (194 vs. 160, p = 0.02), and AL index (36.9 % in the MCI group vs. 27.2 % in the SCD group, p = 0.04), AL was not associated with SCD or MCI in the multivariate analysis. CONCLUSION: Our data suggest that different profiles of AL in MCI compared to individuals with SCD could be due to cofounding factors. These findings need to be confirmed in longitudinal studies investigating profiles of AL changes at preclinical and prodromal stages of Alzheimer's disease.

Associations between allostatic load and hepatic steatosis and liver fibrosis: evidence from NHANES 2017-2020.

BACKGROUND: Allostatic load, the cumulative strain resulting from chronic stress responses, has been linked to disease occurrence and progression, yet research quantifying this relationship is limited. This study aimed to explore the relationship between allostatic load score (ALS) levels and the degree of hepatic steatosis and fibrosis. METHODS: Data from the National Health and Nutrition Examination Survey 2017-2020 were analyzed. The ALS was based on the statistical distribution, assigning one point for each biomarker if it was in the highest risk quartile, and then summing them to generate the ALS score (range, 0-8). The multivariate linear regression was employed to analyze the association between the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) with ALS. Additionally, multinomial logistic regression was used to investigate the association between ALS and the degree of hepatic steatosis and fibrosis. RESULTS: Participants had a weighted mean age of 52.69 years and 56.14% were female. In the multivariate linear regression analysis, ALS showed a significant positive correlation with CAP (ß = 15.56, 95% CI: 14.50-16.62) and LSM (ß = 0.58, 95% CI: 0.48-0.67). Age, healthy dietary level, and PIR had significant interactions with this positive correlation. In the multinomial logistic regression analysis, ALS exhibited a significant positive correlation with different degrees of hepatic steatosis and fibrosis. Consistency of the results was observed in sensitivity analyses using clinical thresholds of ALS. CONCLUSIONS: Comprehensive clinical assessment targeting load adaptation may enhance the effectiveness of risk assessment in patients with hepatic steatosis and fibrosis.

Allostasis, health, and development in Latin America.

The lifespan is influenced by adverse childhood experiences that create predispositions to poor health outcomes. Here we propose an allostatic framework of childhood experiences and their impact on health across the lifespan, focusing on Latin American and Caribbean countries. This region is marked by significant social and health inequalities nested in environmental and social stressors, such as exposure to pollution, violence, and nutritional deficiencies, which critically influence current and later-life health outcomes. We review several manifestations across cognition, behavior, and the body, observed at the psychological (e.g., cognitive, socioemotional, and behavioral dysfunctions), brain (e.g., alteration of the development, structure, and function of the brain), and physiological levels (e.g., dysregulation of the body systems and damage to organs). To address the complexity of the interactions between environmental and health-related factors, we present an allostatic framework regarding the cumulative burden of environmental stressors on physiological systems (e.g., cardiovascular, metabolic, immune, and neuroendocrine) related to health across the life course. Lastly, we explore the relevance of this allostatic integrative approach in informing regional interventions and public policy recommendations. We also propose a research agenda, potentially providing detailed profiling and personalized care by assessing the social and environmental conditions. This framework could facilitate the delivery of evidence-based interventions and informed childhood-centered policy-making.

Harmonizing the assessment of allostatic load across cycles of the Canadian Health Measures Survey: Variable selection and calculation method.

Background: The availability of measures to operationalize allostatic load - the cumulative toll on the body of responding to stressor demands - in population health surveys may differ across years or surveys, hampering analyses on the entire sampled population. Here, impacts of variable selection and calculation method were evaluated to generate an allostatic load index applicable across all cycles of the Canadian Health Measures Survey (CHMS). Methods: Data from CHMS cycles 1 to 4 were used to compare allostatic load scores when replacing the most prevalent risk factor, waist-to-hip ratio - available in cycles 1 to 4 but not 5 and 6 - with body mass index (BMI), waist circumference, waist circumference within BMI groups (classified as normal, overweight, or obese), or waist-to-height ratio. Indexes were generated using clinical or sex-specific empirically defined risk thresholds and as count-based or continuous scores. Logistic regression models that included age and sex were used to relate each potential index to socioeconomic indicators (educational attainment, household income). Results: Of the variables assessed, waist-to-height ratio and waist circumference were closest to waist-to-hip ratio according to an individual's percentile ranking and in classifying "at risk" using either clinical or empirically defined cut-offs. Allostatic load profiles generated using waist-to-height ratios most closely resembled profiles constructed using waist-to-hip ratios. Sex-dependent associations with educational attainment and household income were maintained across constructs whether indexes were count-based or continuous. Interpretation: Allostatic load profiles and associations with socioeconomic indicators were robust to variable substitution and method of calculation, supporting the use of a harmonized index across survey cycles to assess the cumulative toll on health of stressor exposure.

Enriched housing differentially alters allostatic load and cardiopulmonary responses to wildfire-related smoke in male and female mice.

Living conditions are an important modifier of individual health outcomes and may lead to higher allostatic load (AL). However, housing-induced cardiovascular and immune effects contributing to altered environmental responsiveness remain understudied. This investigation was conducted to examine the influence of enriched (EH) versus depleted housing (DH) conditions on cardiopulmonary functions, systemic immune responses, and allostatic load in response to a single wildfire smoke (WS) exposure in mice. Male and female C57BL/6J mice were divided into EH or DH for 22 weeks, and cardiopulmonary assessments measured before and after exposures to either one-hr filtered air (FA) or flaming eucalyptus WS exposure. Male and female DH mice exhibited increased heart rate (HR) and left ventricular mass (LVM), as well as reduced stroke volume and end diastolic volume (EDV) one week following exposure to WS. Female DH mice displayed significantly elevated levels of IL-2, IL-17, corticosterone and hemoglobin A1c (HbA1c) following WS, while female in EH mice higher epinephrine levels were detected. Female mice exhibited higher AL than males with DH, which was potentiated post-WS exposure. Thus, DH increased susceptibility to extreme air pollution in a gender-dependent manner suggesting that living conditions need to be evaluated as a modifier of toxicological responses.