M. Austin Argentieri

Circulating plasma proteins play key roles in human health and can potentially be used to measure biological age, allowing risk prediction for age-related diseases, multimorbidity and mortality. Here we developed a proteomic age clock in the UK Biobank (n = 45,441) using a proteomic platform comprising 2,897 plasma proteins and explored its utility to predict major disease morbidity and mortality in diverse populations. We identified 204 proteins that accurately predict chronological age (Pearson r = 0.94) and found that proteomic aging was associated with the incidence of 18 major chronic diseases (including diseases of the heart, liver, kidney and lung, diabetes, neurodegeneration and cancer), as well as with multimorbidity and all-cause mortality risk. Proteomic aging was also associated with age-related measures of biological, physical and cognitive function, including telomere length, frailty index and reaction time. Proteins contributing most substantially to the proteomic age clock are involved in numerous biological functions, including extracellular matrix interactions, immune response and inflammation, hormone regulation and reproduction, neuronal structure and function and development and differentiation. In a validation study involving biobanks in China (n = 3,977) and Finland (n = 1,990), the proteomic age clock showed similar age prediction accuracy (Pearson r = 0.92 and r = 0.94, respectively) compared to its performance in the UK Biobank. Our results demonstrate that proteomic aging involves proteins spanning multiple functional categories and can be used to predict age-related functional status, multimorbidity and mortality risk across geographically and genetically diverse populations.

HPA axis genes implicated in glucocorticoid regulation play an important role in regulating the physiological impact of social and environmental stress, and have become a focal point for investigating the role of glucocorticoid regulation in the etiology of disease. We conducted a systematic review to critically assess the full range of clinical associations that have been reported in relation to DNA methylation of CRH, CRH-R1/2, CRH-BP, AVP, POMC, ACTH, ACTH-R, NR3C1, FKBP5, and HSD11β1/2 genes in adults. A total of 32 studies were identified. There is prospective evidence for an association between HSD11β2 methylation and hypertension, and functional evidence of an association between NR3C1 methylation and both small cell lung cancer (SCLC) and breast cancer. Strong associations have been reported between FKBP5 and NR3C1 methylation and PTSD, and biologically-plausible associations have been reported between FKBP5 methylation and Alzheimer's Disease. Mixed associations between NR3C1 methylation and mental health outcomes have been reported according to different social and environmental exposures, and according to varying gene regions investigated. We conclude by highlighting key challenges and future research directions that will need to be addressed in order to develop both clinically meaningful prognostic biomarkers and an evidence base that can inform public policy practice.

Previous longitudinal studies have consistently shown an association between attendance at religious services and lower all-cause mortality, but the literature on associations between other measures of religion and spirituality (R/S) and mortality is limited. We followed 36,613 respondents from the Black Women's Health Study from 2005 through December 31, 2013 to assess the associations between R/S and incident all-cause mortality using proportional hazards models. After control for numerous demographic and health covariates, together with other R/S variables, attending religious services several times per week was associated with a substantially lower mortality rate ratio (mortality rate ratio = 0.64, 95% confidence interval: 0.51, 0.80) relative to never attending services. Engaging in prayer several times per day was not associated with mortality after control for demographic and health covariates, but the association trended towards a higher mortality rate ratio when control was made for other R/S variables (for >2 times/day vs. weekly or less, mortality rate ratio = 1.28, 95% confidence interval: 0.99, 1.67; P-trend < 0.01). Religious coping and self-identification as a very religious/spiritual person were associated with lower mortality when adjustment was made only for age, but the association was attenuated when control was made for demographic and health covariates and was almost entirely eliminated when control was made for other R/S variables. The results indicate that service attendance was the strongest R/S predictor of mortality in this cohort.

Both environmental exposures and genetics are known to play important roles in shaping human aging. Here we aimed to quantify the relative contributions of environment (referred to as the exposome) and genetics to aging and premature mortality. To systematically identify environmental exposures associated with aging in the UK Biobank, we first conducted an exposome-wide analysis of all-cause mortality (n = 492,567) and then assessed the associations of these exposures with a proteomic age clock (n = 45,441), identifying 25 independent exposures associated with mortality and proteomic aging. These exposures were also associated with incident age-related multimorbidity, aging biomarkers and major disease risk factors. Compared with information on age and sex, polygenic risk scores for 22 major diseases explained less than 2 percentage points of additional mortality variation, whereas the exposome explained an additional 17 percentage points. Polygenic risk explained a greater proportion of variation (10.3-26.2%) compared with the exposome for incidence of dementias and breast, prostate and colorectal cancers, whereas the exposome explained a greater proportion of variation (5.5-49.4%) compared with polygenic risk for incidence of diseases of the lung, heart and liver. Our findings provide a comprehensive map of the contributions of environment and genetics to mortality and incidence of common age-related diseases, suggesting that the exposome shapes distinct patterns of disease and mortality risk, irrespective of polygenic disease risk.

Background: The few studies of the relationship between religion and/or spirituality (R/S) and hypertension are conflicting. We hypothesized that R/S may reduce the risk of hypertension by buffering adverse physiological effects of stress. Methods: We prospectively assessed the association of R/S with hypertension within the Black Women's Health Study (BWHS), a cohort study initiated in 1995 that follows participants through biennial questionnaires. The 2005 questionnaire included four R/S questions: (i) extent to which one's R/S is involved in coping with stressful situations, (ii) self-identification as a religious/spiritual person, (iii) frequency of attending religious services, and (iv) frequency of prayer. Incidence rate ratios (IRRs) and 95% confidence intervals were calculated for each R/S variable in relation to incident hypertension using Cox proportional hazards regression models, controlling for demographics, known hypertension risk factors, psychosocial factors, and other R/S variables. Results: During 2005-2013, 5,194 incident cases of hypertension were identified. High involvement of R/S in coping with stressful events compared with no involvement was associated with reduced risk of hypertension (IRR: 0.87; 95% CI: 0.75, 1.00). The association was strongest among women reporting greater levels of perceived stress (IRR: 0.77; 95% CI: 0.61, 0.98; p interaction = .01). More frequent prayer was associated with increased risk of hypertension (IRR: 1.12; 95% CI: 0.99, 1.27). No association was observed for the other R/S measures. Conclusion: R/S coping was associated with decreased risk of hypertension in African American women, especially among those reporting higher levels of stress. Further research is needed to understand the mechanistic pathways through which R/S coping may affect health.