Abstract
BACKGROUND: The age-specific magnitude of the impact of hormones on aging and the role of hormone replacement therapy (HRT) remain unclear. METHODS: We used data from UK Biobank participants for our analysis. Linear and logistic regression models were employed to investigate the associations and its differences between estradiol/testosterone and biological age acceleration (BAA) across different age group. Then, females were divided into HRT and non-HRT groups, and restricted cubic splines were used to evaluate HRT initiation age and duration. RESULTS: A total of 54,912 participants (71.99% females, 28.01% males) were enrolled, with 39,303 females assessed for the impact of HRT on aging. Estradiol decline in females was linked to a 0.18-0.29-year BAA increase, while testosterone decline in males was linked to a 0.07-0.71-year BAA increase. It showed estradiol protected against aging in females (most prominent at 41-55 years) while elevated testosterone accelerated aging. In males, testosterone was protective (most significant at 56-70 years) and estradiol had no notable effect. Quartile and age-stratified analyses confirmed these findings. In contrast, the decrease of estradiol was associated with biological age younger. Hormone replacement therapy (HRT) in females resulted in sustained BAA reduction (-4.5 to -6.0, 41-70 years) superior to non-HRT (-4.0 to -5.5). HRT initiated at 56-60 years showed optimal efficacy, with longer duration associated with more pronounced aging deceleration. CONCLUSIONS: The impact of per standard deviation (SD) decrease in sex hormone levels on aging (BAA) varies by age, with significant effects observed in females aged 50-55 years and males aged 65-70 years. These findings may facilitate the optimization of HRT timing to maximize anti-aging benefits and enable personalized treatment strategies.