Longer duration of intact hypothalamic–pituitary–gonadal (HPG) axis buffers the adverse impact of late-life frailty in male dogs

Research on physical frailty has focused primarily on understanding the factors that lead to frailty development and on discovering strategies that might prevent or postpone the onset of frailty. In contrast, relatively little attention has focused on biological factors that may influence resilience to frailty once it occurs. It has been demonstrated that low serum testosterone and other markers of hypothalamic-pituitary-gonadal (HPG) axis deterioration may contribute significantly to frailty development in older men. Here, we test the hypothesis that lifetime HPG axis integrity provides a critical physiological context that can contribute to enhanced frailty resilience, i.e., buffer the adverse consequences of late-life frailty. Late-life frailty scores were generated using a 34-item clinical frailty index in a cohort of 87 geriatric male dogs with a broad range of lifetime testis exposure. These dogs were followed from time of frailty scoring until death. Mortality risk associated with frailty index was estimated using Cox proportional hazard models in the overall cohort and in three subgroups differing in lifetime testis exposure. Dogs with the shortest duration of testis exposure had a very high risk of mortality associated with late-life frailty, whereas the mortality consequence of increasing frailty was absent in males with the longest duration of intact HPG axis. The results suggest that disruption of the HPG axis early in life by gonadectomy can impact the lethality of late-life frailty. It follows from this new understanding that the adverse consequences of frailty are context-dependent and future studies of the timing of neutering in companion dogs may yield vital insights by applying a life course approach to assess the importance of early-life events as determinants of late-life frailty and lifelong health.