Genome-wide analysis reveals distinct genetic mechanisms of diet-dependent lifespan and healthspan inD. melanogaster

Dietary restriction (DR) robustly extends lifespan and delays age-related diseases across species. An underlying assumption in aging research has been that DR mimetics extend both lifespan and healthspan jointly, though this has not been rigorously tested in different genetic backgrounds. Furthermore, nutrient response genes important for lifespan or healthspan extension remain underexplored, especially in natural populations. To address these gaps, we utilized over 150 DGRP strains to measure nutrient-dependent changes in lifespan and age-related climbing ability to measure healthspan. DR extended lifespan and delayed decline in climbing ability on average, but there was no evidence of correlation between these traits across individual strains. Through GWAS, we then identified and validatedjugheadandFerredoxinas determinants of diet-dependent lifespan, andDaedalusfor diet-dependent physical activity. Modulating these genes produced independent effects on lifespan and climbing ability, further suggesting that these age-related traits are likely to be regulated through distinct genetic mechanisms.