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Dietary restriction (DR) extends lifespan and healthspan, by mechanisms that remain incompletely understood. To identify new genes with a role in dietary response, we developed a screening strategy harnessing genetic variation among wild fruit flies. We quantified the lifespan of lines of the Drosophila Genetic Reference Panel on protein-rich and DR diets, and mapped polymorphisms associated with diet-dependent longevity. Among the hits was CG34351/decima, an ortholog of the mammalian GABA-receptor regulator RGS7BP. In validation experiments, pan-neuronal knockdown of decima extended lifespan and elicited repression of Drosophila insulin-like peptides, in flies on the rich diet but not on DR. Knockdown of decima in GABA neurons rescued fat storage and energy availability defects that derive from overnutrition. We propose that decima tunes signaling in these neurons upstream of the insulin pathway to rewire metabolism. These results establish decima as a determinant of the toxic effects of the rich diet in the fly.

Vitamin D has multiple roles including the regulation of bone and calcium homeostasis. Deficiency of 25-hydroxyvitaminD, the major circulating form of vitamin D, is associated with an increased risk of age-related chronic diseases including Alzheimer’s disease, Parkinson’s disease, cognitive impairment, and cancer. In this study, we utilized Caenorhabditis elegans to examine the mechanism by which vitamin D influences aging. We found that Vitamin D3-induced lifespan extension requires the stress response pathway genes SKN-1, IRE-1, and XBP-1. Vitamin D3 (D3) induced expression of SKN-1 target genes, but not canonical targets of IRE-1/XBP-1. D3 suppressed an important molecular pathology of aging, that of widespread protein insolubility, and prevented toxicity caused by human β-amyloid. Our observation that D3 improves protein homeostasis and slows aging highlights the importance of maintaining appropriate vitamin D serum levels, and may explain why such a wide variety of human age-related diseases are associated with vitamin D deficiency.

Aging is a root cause of many chronic diseases and associated morbidity and mortality. A number of interventions have been suggested to improve overall lifespan and health, with one of the most successful being dietary restriction. Despite the generally well-demonstrated health and longevity benefits of dietary restriction, cases remain in model organisms where some genotypes are not affected or are negatively impacted. With the use of the Drosophila Genetic Reference Panel, we have identified a new set of genes that regulate health or longevity either diet-dependently or diet-independently. Associated with longevity are the genes CG34351 and Fdxh. We have also revealed CG33690, a previously uncharacterized gene, as being a regulator of health in response to diet. Through alteration of the expression of these genes via RNAi and gene disruption, we have validated their roles in impacting on lifespan or climbing ability independently. In addition to ascribing novel functions to these genes, our results demonstrate that lifespan and healthspan depend on a complex set of inputs including genetic polymorphisms and diet.