Germ cells are hidden contributors of sex differences in vertebrate lifespan

Abstract

Aging is a complex biological process whose regulatory mechanisms remain incompletely understood. Accumulating evidence indicates that germ cells play pivotal roles in the systemic regulation of aging. The link between germ cells and somatic aging was first established in invertebrate models, where germ cells positively regulate the rate of organismal aging. However, whether and how this relationship operates in vertebrates has remained unresolved for nearly a quarter of a century. Recently, using the short-lived vertebrate model Nothobranchius furzeri, we demonstrated that germ cells exert sex-dependent effects on somatic aging. In males, germ cell ablation improved healthspan and extended lifespan, accompanied by enhanced vitamin D signaling. In contrast, germ cell removal in females shortened lifespan, associated with increased IGF-1 signaling and reduced estrogen signaling. These findings suggest a vertebrate-specific mechanistic link between germ cells and somatic tissues mediated by sex-specific endocrine signaling. Such a mechanism may contribute to sexual dimorphism in reproductive strategies and potentially underlie the female longevity advantage observed across many species. In this review, we synthesize current evidence for germ cell–mediated regulation of systemic aging, propose that germ cells act as central endocrine orchestrators coordinating reproduction and lifespan, and discuss their potential contribution to sex differences in lifespan.

Graphical Abstract