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

Paolina Crocco, Rossella La Grotta, Giuseppina Rose, Serena Dato

Abstract. Sex and gender influence health trajectories and disease occurrence of individuals, thus contributing to significant differences of lifespan between males and females. Despite living longer, women tend to spend a larger proportion 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 unhealthy aging, characterized by a decrease in homeostasis and functional reserve, leading to physical and cognitive decline with adverse outcomes such as disability, ospitalization, and death. Various biological factors may contribute to sex differences in frailty susceptibility, including inflammation, 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 related phenotypes, such as sarcopenia. Although studies on this issue are largely underrepresented, likely because statistical analyses are often not performed separately by sex, the evidence here reported suggests that different mechanisms 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 analysis, were involved in immune cell infiltration and inflammation, while musculoskeletal structure, oxidative stress, and metabolism were the top-ranked pathways in males. Overall, the data presented here unveil the knowledge gap still present in the literature about sex-specific mechanistic drivers of frailty, and strongly encourage future studies in multicenter cohorts with equal sex representation. These studies will be crucial for developing sex-specific interventions to reduce frailty progression, promote healthy aging, and improve the quality of life in older men and women.
Keywords.Sex, gender, frailty, genetics, epigenetics.