Sex differences in frailty: Comparisons between humans and preclinical models

Frailty can be viewed as a state of physiological decline that increases susceptibility to adverse health outcomes. This loss of physiological reserve means that even small stressors can lead to disability and death in frail individuals. Frailty can be measured with various clinical tools; the two most popular are the frailty index and the frailty phenotype. Clinical studies have used these tools to show that women are frailer than men even though they have longer lifespans. Still, factors responsible for this frailty-mortality paradox are not well understood. This review highlights evidence for male-female differences in frailty from both the clinical literature and in animal models of frailty. We review evidence for higher frailty levels in female animals as seen in many preclinical models. Mechanisms that may contribute to sex differences in frailty are highlighted. In addition, we review work that suggests frailty may play a role in susceptibility to chronic diseases of aging in a sex-specific fashion. Additional mechanistic studies in preclinical models are needed to understand factors involved in male-female differences in frailty in late life.