Rapamycin's lifespan effect is modulated by mito‐nuclear epistasis in <i>Drosophila</i>

The macrolide drug rapamycin is a benchmark anti-ageing drug, which robustly extends lifespan of diverse organisms. For any health intervention, it is paramount to establish whether benefits are distributed equitably among individuals and populations, and ideally to match intervention to recipients' needs. However, how responses to rapamycin vary is surprisingly understudied. Here we investigate how among-population variation in both mitochondrial and nuclear genetics shapes rapamycin's effects on lifespan. We show that epistatic "mito-nuclear" interactions, between mitochondria and nuclei, modulate the response to rapamycin treatment. Differences manifest as differential demographic effects of rapamycin, with altered age-specific mortality rate. However, a fitness cost of rapamycin early in life does not show a correlated response, suggesting that mito-nuclear epistasis can decouple costs and benefits of treatment. These findings suggest that a deeper understanding of how variation in mitochondrial and nuclear genomes shapes physiology may facilitate tailoring of anti-ageing therapy to individual need.