The role of frailty in the association between testosterone levels and mortality risk in older men

BACKGROUND: Testosterone plays an important role in male aging, yet its impact on mortality remains unclear. Frailty, a syndrome of physiological decline, may mediate this relationship. This study investigates the mediating role of frailty in the association between testosterone levels and both all-cause and cardiovascular disease mortality in older men. METHODS: We analyzed data from 1478 men aged 60 years or more in the National Health and Nutrition Examination Survey (2011-2016). Cox proportional hazards models evaluated the direct association between testosterone and mortality. Mediation analysis on the log-hazard scale was conducted using the product-of-coefficients approach and Sobel tests to quantify indirect effects via the frailty index, and the proportion mediated was calculated as the ratio of the indirect to total effect. RESULTS: Higher testosterone levels were associated with lower risks of all-cause mortality (hazard ratio (HR) 0.892, 95% confidence interval (CI) 0.830-0.959; P = 0.002) and cardiovascular disease mortality (HR 0.820, 95% CI 0.716-0.939; P = 0.004). Frailty score was strongly associated with both all-cause (HR 1.648 per 0.1 increase) and cardiovascular disease mortality (HR 1.723 per 0.1 increase). Mediation analysis demonstrated that frailty substantially explained the association between testosterone and mortality. For all-cause mortality, the indirect pathway through frailty accounted for 35.9% of the total effect. After adjustment for frailty, the residual direct effect of testosterone was attenuated and no longer statistically significant, a pattern consistent with near-complete mediation. For cardiovascular disease mortality, frailty accounted for 21.7% of the association. Although the direct effect was reduced, its effect size and confidence interval indicated the possibility of remaining direct pathways, supporting a partial rather than complete mediation. CONCLUSION: Frailty mediates the relationship between testosterone and mortality in older men. Targeting frailty may enhance the survival benefits associated with testosterone, offering potential strategies for aging-related health interventions.