Applying a life course approach to elucidate the biology of sex differences in frailty: early-life gonadectomy diminishes late-life robustness in male and female dogs in the Exceptional Aging in Rottweilers Study

Abstract

Abstract 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

• Preclinical models
• Aging
• HPG axis
• Male-Female differences
• Sex hormones
• Translational