Sexual interactions negatively impact healthspan in many species. This research uses *C. elegans* to systematically investigate the conserved genes involved in male-induced demise of hermaphrodites. Transcriptomic profiling and targeted screens identified genes whose knockdown protects against male-induced death (*delm-2*, *acbp-3*) and others extending lifespan regardless of male presence (*sri-40*). Classical long-lived mutants showed increased susceptibility to male presence, highlighting the importance of sexual environment. Male-induced genes are triggered by specific components (seminal fluid, sperm, pheromones), and their combined manipulation provides stronger protection. The ion channel *delm-2* regulates lipid metabolism in the nervous system and intestine. This study reveals substantial longevity differences between single-sex and mixed-sex environments, uncovering sophisticated strategies elicited by sexual interactions with potential implications for other species.

Lauren N. Booth, Cheng Shi, Cindy Tantilert, Robin W. Yeo, Jason W. Miklas, Katja Hebestreit, Cecilia N. Hollenhorst, Travis J. Maures, Matthew T. Buckley, Coleen T. Murphy, Anne Brunet