Sirt6 regulates lifespan in <i>Drosophila melanogaster</i>.

Abstract

Sirt6 is a multifunctional enzyme that regulates diverse cellular processes such as metabolism, DNA repair, and aging. Overexpressing Sirt6 extends lifespan in mice, but the underlying cellular mechanisms are unclear. <i>Drosophila melanogaster</i> are an excellent model to study genetic regulation of lifespan; however, despite extensive study in mammals, very little is known about Sirt6 function in flies. Here, we characterized the <i>Drosophila</i> ortholog of Sirt6, dSirt6, and examined its role in regulating longevity; dSirt6 is a nuclear and chromatin-associated protein with NAD⁺-dependent histone deacetylase activity. <i>dSirt6</i> overexpression (OE) in flies produces robust lifespan extension in both sexes, while reducing <i>dSirt6</i> levels shortens lifespan. <i>dSirt6</i> OE flies have normal food consumption and fertility but increased resistance to oxidative stress and reduced protein synthesis rates. Transcriptomic analyses reveal that <i>dSirt6</i> OE reduces expression of genes involved in ribosome biogenesis, including many dMyc target genes. <i>dSirt6</i> OE partially rescues many effects of <i>dMyc</i> OE, including increased nuclear size, up-regulation of ribosome biogenesis genes, and lifespan shortening. Last, <i>dMyc</i> haploinsufficiency does not convey additional lifespan extension to <i>dSirt6</i> OE flies, suggesting <i>dSirt6</i> OE is upstream of <i>dMyc</i> in regulating lifespan. Our results provide insight into the mechanisms by which Sirt6 OE leads to longer lifespan.