Background: Frailty refers to a state of increased vulnerability to mortality and other adverse outcomes as a consequence of age-related physiological decline. Sex differences in frailty have been reported; women are usually more frail than men. Physical frailty in men and women is the result of both sociobehavioral and biological factors, making the deciphering of the biology of sex differences in frailty challenging. Investigators have measured frailty in aging animals, including mice and dogs. We posited that companion dogs provide a useful opportunity to study sex differences in the biology of frailty, circumventing many of the sociobehavioral determinants of frailty that complicate human studies.
Methods: Male-female differences in the relationship between lifetime gonad hormone exposure and late-life robustness were studied in the Exceptional Aging in Rottweilers Study (EARS), a lifetime cohort study of companion dogs with a broad range of lifetime gonad exposure. Late-life frailty was assessed by scoring dogs (135 females, 87 males) for deficit accumulation using a 34-item clinical frailty index previously developed and validated in dogs. The study outcome, late-life robustness, was defined as the lowest tertile of frailty index in the study population. Logistic regression models were constructed to assess differences in the likelihood of late-life robustness in dogs stratified into low, middle, and high lifetime gonad exposure groups. Male-female differences were probed after controlling for age at frailty scoring, gonad exposure, and other covariates.
Results: In both male and female dogs, there was a strong association between longer lifetime gonad exposure and increased likelihood of late-life robustness. Compared to dogs in the lowest gonad exposure group, dogs with highest gonad exposure had a statistically significant 3-fold (females) to 10-fold (males) higher likelihood of late-life robustness. Notably, after controlling for gonad exposure and age at frailty scoring, no male-female difference in late-life robustness was found.
Conclusions: The research extends current interest in the biology of sex differences in frailty and provides rationale for further inquiry into the role that the hypothalamic-pituitary-gonadal axis plays in supporting late-life robustness. Studies with companion dogs represent a unique investigative opportunity to enhance our understanding of biological factors that impact sex differences and to spur the development of sex-specific anti-frailty interventions.
Keywords: Aging; Companion dogs; HPG axis; Male-Female differences; Neutering; Preclinical models; Sex hormones; Spay; Timing of gonadectomy; Translational.
In people, “frail” is the descriptor given to individuals with higher vulnerability to adverse future health outcomes. Differences in the degree of frailty versus robustness can be determined by using a clinical tool called frailty index to measure the number of health deficits in each individual. Frailty is diagnosed more often in women than men. Here, we tested in companion dogs whether differences in the occurrence of frailty could be explained by differences in the lifetime duration of sex hormone exposure, i.e., age at gonad removal. We report our experience examining male-female frailty differences in a group of long-lived companion dogs that scientists are utilizing to obtain biological clues on what it takes to achieve extreme longevity. The study outcome, late-life robustness, was defined as those dogs in the study population with the fewest (i.e., lowest tertile) health deficits based on frailty scores. In both males and females, we found a strong association between longer lifetime sex hormone exposure and late-life robustness. Compared to dogs in the shortest sex hormone exposure group, dogs with the longest sex hormone exposure had a statistically significant 3 to 10-fold increased likelihood of late-life robustness, in females and males, respectively. After controlling for differences in sex hormone exposure and age at frailty scoring, no male-female difference in the likelihood of robustness was found. This research indicates the critical role sex hormones may play in retaining late-life robustness and expands our understanding of the importance of early life events in determining lifelong health.
© 2025. The Author(s).