The influence of genetics and epigenetics on sex disparities in frailty: a narrative review

Sex and gender influence health trajectories and disease occurrence of individuals, thus contributing to sig- nificant differences lifespan between males and females. Despite living longer, women tend to spend a larger propor- tion of their later years in poorer health, accumulating more deficits than men. This increases their risk of experiencing frailty, a condition at the forefront between healthy and un- healthy aging, characterized by a decrease in homeostasis and functional reserve, leading to physical and cognitive decline with adverse outcomes such as disability, hospitaliza- tion, and death. Various biological factors may contribute to sex differences in frailty susceptibility, including inflamma- tion, hormones, genetic and epigenetic mechanisms as well as behavioural and social factors. In this review, we have collected evidence on sex-specific genetic and epigenetic signatures of frailty and closely re- lated phenotypes, such as sarcopenia. Although studies on this issue are largely underrepresented, likely because sta- tistical analyses are often not performed separately by sex, the evidence here reported suggests that different mecha- nisms affect frailty progression in the two sexes. In females, the top-ranked pathways associated with frailty, as retrieved by both genetic association studies and transcriptome anal- ysis, were involved in immune cell infiltration and inflamma- tion, while musculoskeletal structure, oxidative stress, and metabolism were the top-ranked pathways in males. Overall, the data presented here unveil the knowledge gap still pres- ent in the literature about sex-specific mechanistic drivers of frailty, and strongly encourage future studies in multi- center cohorts with equal sex representation. These studies will be crucial for developing sex-specific interventions to reduce frailty progression, promote healthy aging, and im- prove the quality of life in older men and women.