Epigenetic Clocks and Allostatic Load Reveal Potential Sex-Specific Drivers of Biological Aging

Abstract

Allostatic load (AL) and epigenetic clocks both attempt to characterize the accelerated aging of biological systems, but at present it is unclear whether these measures are complementary or distinct. This study examines the cross-sectional association of AL with epigenetic age acceleration (EAA) in a subsample of 490 community-dwelling older adults participating in The Irish Longitudinal study on Aging (TILDA). A battery of 14 biomarkers representing the activity of four different physiological systems: immunological, cardiovascular, metabolic, renal, was used to construct the AL score. DNA methylation age was computed according to the algorithms described by Horvath, Hannum, and Levine allowing for estimation of whether an individual is experiencing accelerated or decelerated aging. Horvath, Hannum, and Levine EAA correlated 0.05, 0.03, and 0.21 with AL, respectively. Disaggregation by sex revealed that AL was more strongly associated with EAA in men compared with women as assessed using Horvath’s clock. Metabolic dysregulation was a strong driver of EAA in men as assessed using Horvath and Levine’s clock, while metabolic and cardiovascular dysregulation were associated with EAA in women using Levine’s clock. Results indicate that AL and the epigenetic clocks are measuring different age-related variance and implicate sex-specific drivers of biological aging.

The Socioeconomic Gradient in Epigenetic Aging Clocks: Evidence from the Multi-Ethnic Study of Atherosclerosis and the Health and Retirement Study

“…SES-epigenetic clock associations have been shown to differ by sex, age and race. 48, 61, 70 Figure 4 displays SES index-clock associations stratified by ancestry, sex, and age, and adjusted for lifestyle behaviors (full results with and without adjustments for lifestyle behaviors are provided in Tables S14 and S15 ). Clock associations appear to be most significant in European ancestry individuals.…”

“…to differ by sex, age and race. 48,61,70 66,74 The IEAA and EEAA terminology has been used to refer to the observation that clocks trained in whole blood may be more reflective of age-related changes in leukocyte composition, whereas multi-tissue clocks are independent of these changes. For example, multi-tissue epigenetic clocks like the Horvath 66,68 to approximately 40% for pedigree-based estimates .…”

Weight management intervention identifies association of decreased DNA methylation age with improved functional age measures in older adults with obesity

“…Because of the limited sample size, we did not conduct locus-bylocus comparisons or any subgroup analysis. As there are potential sex differences in DNA methylation age clocks and allostatic load [22] the relationship between functional measures and DNA methylation age may be impacted by sex. While allosteric load can be measured in multiple ways there could be a relationship between these and functional measures.…”

Aging and Allostasis: Using Bayesian Network Analytics to Explore and Evaluate Allostatic Markers in the Context of Aging

“…The process of aging typically implies a funnel of steadily declining (neuro)endocrine, physiological, and psychophysiological variance components: with time, the natural variance in independent (bio)markers decreases significantly, and consequently, the cumulative overall variance (e.g., captured in constructs like Allostatic Load), reflecting a steadily decrease of the adaptive capability of an individual. This process will inevitably lead to critical transitions in health status (towards (chronic) disease and/or mortality), that might likely, though not yet proven, follow specific mathematical trajectories of decay [ 17 ], and is recently even linked to (epi-)genetic effects [ 18 , 19 , 20 ]. However, this would render biomarkers typically used to define an Allostatic Load Index less useful for application in elderly populations, as sufficient systemic variance to effectively monitor changes in health status declines over time.…”