GWAS for Lifespan and Decline in Climbing Ability in Flies upon Dietary Restriction Reveal decima as a Mediator of Insulin-like Peptide Production
Kenneth A. Wilson current biol. 2020.05.020
Dietary restriction (DR) is the most robust means to extend lifespan and delay age-related diseases across
species. An underlying assumption in the aging field is that DR enhances both lifespan and physical activity
through similar mechanisms, but this has not been rigorously tested in different genetic backgrounds.
Furthermore, nutrient response genes responsible for lifespan extension or age-related decline in functionality remain underexplored in natural populations. To address this, we measured nutrient-dependent changes in lifespan and age-related decline in climbing ability in the Drosophila Genetic Reference Panel
fly strains.
On average, DR extended lifespan and delayed decline in climbing ability, but there was a lack of correlation between these traits across individual strains, suggesting that distinct genetic factors modulate these traits independently and that genotype determines response to diet. Only 50% of strains showed
positive response to DR for both lifespan and climbing ability, 14% showed a negative response for one trait
but not both, and 35% showed no change in one or both traits.
Through GWAS, we uncovered a number of genes previously not known to be diet responsive nor to influence lifespan or climbing ability. We validated
decima as a gene that alters lifespan and daedalus as one that influences age-related decline in climbing
ability. We found that decima influences insulin-like peptide transcription in the GABA receptor neurons
downstream of short neuropeptide F precursor (sNPF) signaling. Modulating these genes produced independent effects on lifespan and physical activity decline, which suggests that these age-related traits can be regulated through distinct mechanisms.