Relationships of depression and antidepressant use with epigenetic age acceleration and all-cause mortality among postmenopausal women

Abstract

We investigated relations of depressive symptoms, antidepressant use, and epigenetic age acceleration with all-cause mortality risk among postmenopausal women. Data were analyzed from ≤1,900 participants in the Women's Health Initiative study testing four-way decomposition models. After a median 20.4y follow-up, 1,161 deaths occurred. Approximately 11% had elevated depressive symptoms (EDS + ), 7% were taking antidepressant medication at baseline (ANTIDEP + ), while 16.5% fell into either category (EDS_ANTIDEP + ). Baseline ANTIDEP + , longitudinal transition into ANTIDEP + and accelerated epigenetic aging directly predicted increased mortality risk. GrimAge DNA methylation age acceleration (AgeAccelGrim) partially mediated total effects of baseline www.aging-us.com AGING 2024, Vol. 16, No. 10 AGING specific regions of the genome [29]. "DNAm age"also known as "epigenetic age"represents innate aging processes at the cellular level which have been linked to functional decline with age [30]. Epigenetic age can be estimated using multivariable regression models of DNAm profiles, and a discrepancy between DNAm age and chronological age, known as epigenetic age acceleration (EAA), has been associated with adverse health outcomes [28-30, 41]. A higher "DNAm age" compared to chronological age suggests faster biological aging than expected [30]. Epigenetic age acceleration is linked to obesity, early menopause, Down syndrome, Werner syndrome, HIV infection, lung cancer, Alzheimer's and Parkinson's diseases, and is determined partly by genetic factors and partly by environmental, psychosocial, and behavioral factors [40, 41]. Two epigenetic clocks, blood-based Hannum (71 CpGs) and pan-tissue Horvath (353 CpGs), can be used to derive extrinsic and intrinsic epigenetic age acceleration (EEAA and IEAA) by calculating the difference between DNAm and chronologic ages [28, 42]. Age-related changes in methylation of 353 CpGs included in the Horvath epigenetic clock, are known to influence DNA replication and repair, lipid metabolism, oxidative stress, and other processes linked to chronic diseases [42, 43], while epidemiologic evidence suggests that the Horvath estimator may predict cognitive function, lung function, physical strength, and premature mortality [42]. PhenoAge and GrimAge are next-generation epigenetic clocks from which EAA can also be estimated [29, 30].