Curr Biol. 2020 Jul 20;30(14):2749-2760.e3. doi: 10.1016/j.cub.2020.05.020. | PubMed

Kenneth A Wilson¹, Jennifer N Beck², Christopher S Nelson³, Tyler A Hilsabeck¹, Daniel Promislow⁴, Rachel B Brem⁵, Pankaj Kapahi⁶

1. Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA; Davis School of Gerontology, University of Southern California, University Park, Los Angeles, CA 90007, USA.
2. Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA; Department of Urology, University of California, San Francisco, 400 Parnassus Avenue, Room A-632, San Francisco, CA 94143, USA.
3. Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA.
4. Department of Pathology, University of Washington, Seattle, WA 98195, USA; Department of Biology, University of Washington, Seattle, WA 98195, USA.
5. Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA; Davis School of Gerontology, University of Southern California, University Park, Los Angeles, CA 90007, USA; Department of Plant and Microbial Biology, University of California, Berkeley, 111 Koshland Hall, Berkeley, CA 94720, USA. Electronic address: rbrem@buckinstitute.org.
6. Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, USA; Davis School of Gerontology, University of Southern California, University Park, Los Angeles, CA 90007, USA; Department of Urology, University of California, San Francisco, 400 Parnassus Avenue, Room A-632, San Francisco, CA 94143, USA. Electronic address: pkapahi@buckinstitute.org.

Abstract

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.

Presented By Kenneth Wilson