Signals from the reproductive system regulate somatic regeneration and vertebrate lifespan

The conserved correlation between the timing of life history traits such as puberty and maximal lifespan, proposes a species-specific pace of life. However, little is known about the underlying molecular mechanisms. Exploring this phenomenon is experimentally challenging, due to the relatively long lifespans of classical vertebrate models (mouse and zebrafish). Therefore, we used the turquoise killifish (Nothobranchius furzeri), which undergoes the fastest recorded maturity among vertebrates (3-4 weeks), and a naturally compressed lifespan (4-6 months). We have first reconstructed the killifish’s gonadal architecture by identifying primary gonadal cell-types using single-cell RNA-sequencing. We then systematically perturbed pubertal mechanisms by mutating key pituitary hormones (i.e. FSHB, LHB) and their respective gonadal receptors (i.e. FSHR, LHR), ultimately manipulating puberty by inhibiting germline differentiation at a sex- and stage-specific manner. Additionally, we completely ablated the killifish germline by mutating the DND1 gene. Next, we were curious to explore the possible link between the state of the germline and vertebrate aging. Therefore, we tested whether somatic maintenance (i.e., tail regeneration following genotoxic stress) is enhanced by blocking germline differentiation (FSHR mutants), or by germline depletion (DND1 mutants). Interestingly, we observed a sex-specific physiological phenotype, as germline-depleted females displayed enhanced regeneration and lifespan shortening, while germline-depleted males experienced lifespan extension. We further used single cell RNA-seq to identify potential pathways by which these signals could be mediated. Our findings suggest that signals from the reproductive system are indeed involved in vertebrate lifespan and somatic maintenance in a sex-specific manner.