By definition, aging is a natural, gradual and continuous process. On the other hand, frailty reflects the increase in vulnerability to stressors and shortens the time without disease (health span) while longevity refers to the length of life (lifespan). The average life expectancy has significantly increased during the last few decades. A longer lifespan has been accompanied by an increase in frailty and decreased independence in older adults, with major differences existing between men and women. For example, women tend to live longer than men but also experience higher rates of frailty and disability. Sex differences prevent optimization of lifestyle interventions and therapies to effectively prevent frailty. Sex differences in frailty and aging are rooted in a complex interplay between uncontrollable (genetic, epigenetic, physiological), and controllable factors (psychosocial and lifestyle factors). Thus, understanding the underlying causes of sex differences in frailty and aging is essential for developing personalized interventions to promote healthy aging and improve quality of life in older men and women. In this review, we have discussed the key contributors and knowledge gaps related to sex differences in aging and frailty.

The mechanisms underlying neuropeptide signaling regulation of lifespan in Caenorhabditis elegans ( C. elegans ) remain unclear. FRPR-18 is a mammalian orexin/hypocretin-like receptor and modulates C. elegans arousal behavior by acting as a receptor for FLP-2 neuropeptide signaling, which is also associated with the systemic activation of the mitochondrial unfolded protein response (mitoUPR). Here we report our preliminary findings on the role of the frpr-18 gene in regulating lifespan and healthspan parameters, including stress resistance. Our results showed that frpr-18(ok2698) null mutants had a shorter lifespan and reduced survivability against thermal stress and paraquat treatment. On the other hand, loss of flp-2 function did not affect lifespan or paraquat tolerance but was necessary for normal thermal stress tolerance. These findings suggest that frpr-18 could play a role in regulating lifespan and stress resistance, possibly through flp-2 independent or parallel neuropeptide signaling pathways.