Objective: This study aims to investigate the bidirectional associations between frailty and DNA methylation (DNAm) age acceleration (AgeAccel), and further test whether epigenetic aging mediates the pathway linking frailty to adverse health outcomes.

Background: The interplay of frailty with epigenetic aging remains largely underexplored so far.

Method: We used biennial data from the Health and Retirement Study (2006–2022, N=4018) to detect the bidirectional relationship between 13 DNAm aging clocks and corresponding AgeAccel measures with frailty. Frailty was quantified using a 32-item deficit Frailty index (FI), 5-item Fried Phenotype (FP) and 5-item intrinsic capacity (IC) simultaneously. AgeAccel measures were calculated as residuals from regressing epigenetic age on chronological age for each clock. Physical disability was assessed using self-reported activities of daily living (ADL) and instrumental ADL (IADL). To evaluate associations of epigenetic aging with frailty prevalence, history, and incidence, we applied logistic (cross-sectional), linear (retrospective), and Cox (prospective) regression models, respectively. Furthermore, we implement mediation analyses to quantify epigenetic aging’s role in mediating frailty-driven disability and mortality. All above models were progressively adjusted for key covariates.

Results: Participants with historical or prevalent FI and FP were epigenetically older as measured by eight DNAm clocks and AgeAccel, indicating accelerated aging both prior to and during frailty episodes. Additionally, one standard deviation increase in epigenetic age was associated with 9% to 41% higher odds of experiencing frailty onset in the next six years (eg. FI, GrimAge: HR=1.41, 95%CI=1.16-1.71), suggesting epigenetic aging was not only a consequence by also a predictor of frailty. There were no similar significant associations between DNAm clocks and IC. The four second-generation clocks accounted for 2-6% of frailty-driven disability and 12-26% of mortality. Sensitivity analyses confirmed robustness of these results.

Conclusion: Accelerated epigenetic aging may precede and accompany frailty progression, mediating its adverse effect on functional dysfunction and mortality. Targeting frailty would attenuate biological aging, while DNAm clocks could serve as biomarkers for intervention efficacy.

Baseline characteristics of HRS participants by FI

Forest plot of association between DNAm age and FI

Forest plot of association between DNAm age and FP

Forest plot of association between DNAm age and IC

Mediating effect of DNAm age on health outcomes

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MDS Abstracts - https://www.mdsabstracts.org/abstract/bidirectional-relationships-between-frailty-and-dnam-age-acceleration-and-its-mediation-effects-on-physical-disability-and-mortality/