Sex‐Specific Regulation of the Turandot Gene Family Modulates Temperature‐Dependent Lifespan in Drosophila melanogaster

ABSTRACT Ambient temperature is a primordial determinant of longevity across the animal kingdom, yet the molecular transducers that couple thermal cues to aging rates remain elusive. Here, we interrogate the transcriptomic and metabolomic landscapes of Drosophila melanogaster to decode the mechanisms of temperature‐dependent lifespan extension. We find that thermal stress drives a profound remodeling of the transcriptome that surprisingly outpaces metabolic adaptation. Through this multi‐omics integration, we identify the Turandot ( tot ) gene family as a significant factor in the thermal longevity response. Intriguingly, tot genes are not merely passive responders to temperature; rather, they actively regulate lifespan. We demonstrate that RNAi‐mediated knockdown of tot expression is sufficient to extend longevity across a range of temperatures, uncoupling the survival benefit from the thermal environment. Furthermore, this extension exhibits distinct sexual dimorphism, suggesting a sex‐specific strategy in stress‐response allocation. These findings establish the Turandot family as a novel, genetically separable regulator of aging, challenging the view that temperature‐mediated longevity is solely a passive thermodynamic consequence.