Hormone Replacement Therapy Exhibits a Complex Relationship with Aging Clocks
Hormone replacement therapy is a popular treatment for women leading up to or following menopause. Manipulating sex hormones is a very blunt strategy, with potentially significant downsides, and a high variation in outcomes between patients, but the medical community has accumulated a great deal of experience in delivering this class of therapy. In the matter of assessing how this sort of approach affects aging, the research community is presently engaged in a process of gathering as much data as possible on how aging clocks interact with various therapies thought to influence aging or age-related disease. The accuracy of the clocks in the environment of any given therapy is unknown, and the effect of the therapy on the clock is unknown, and so the way forward is to obtain as much data as possible to illuminate the space of the possible and enable better judgements on how to move ahead. The clocks and the therapies are being calibrated against one another simultaneously.
Epigenetic age acceleration (EAA) is a critical biomarker of aging. Hormone replacement therapy (HRT) is commonly used to alleviate age-related diseases, while glycemic status also influences the aging process. We aimed to investigate the association between estrogen and EAA, and the effects of HRT, EAA, and glycemic status on mortality. Mendelian randomization (MR) established causal relationships between genetically predicted estrogen receptor expression and EAA markers (HorvathAA, HannumAA, PhenoAA, and GrimAA). Using data from the National Health and Nutrition Examination Survey, we employed Cox proportional hazards models to analyze the association between HRT and mortality, exploring whether it was modified by EAA and glycemic status.
Elevated estrogen receptor α (ESR1) expression significantly decelerated PhenoAA (β -1.26). HRT significantly correlated with a reduced risk of all-cause (hazard ratio, HR: 0.65) and cardiovascular (HR: 0.52) mortality. Additionally, there was a significant three-way interaction among HRT, two types of EAA (HorvathAA and PhenoAA), and abnormal glucose status. Stratified analyses showed no significant interaction in the normal glucose subgroup; however, a significant antagonistic interaction emerged between HRT and both HorvathAA and PhenoAA in the abnormal glucose subgroup. Consequently, although HRT exhibited a protective main effect in patients with abnormal glucose, its survival benefits were significantly attenuated as their epigenetic aging accelerated.