期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：5
DOI：10.1073/pnas.2111176119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Sirt6 is well known for its role in regulating the aging process, particularly for its ability to extend lifespan in mice when overexpressed. However, the underlying molecular mechanisms responsible for lifespan regulation by Sirt6 are not well understood. Here, we characterized dSirt6 in fruit flies (
Drosophila melanogaster). We found that dSirt6 functions very similarly to mammalian Sirt6 at the molecular and biochemical levels. Furthermore, overexpressing dSirt6 increased lifespan in flies.
dSirt6 overexpression extends lifespan, in part, by opposing the activity of Myc, a master regulator of protein synthesis, which is associated with decreased protein synthesis. These findings have relevance for the treatment of age-related disease by modulating Sirt6 activity.
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.
Drosophila melanogaster 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
Drosophila 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.
dSirt6 overexpression (OE) in flies produces robust lifespan extension in both sexes, while reducing
dSirt6 levels shortens lifespan.
dSirt6 OE flies have normal food consumption and fertility but increased resistance to oxidative stress and reduced protein synthesis rates. Transcriptomic analyses reveal that
dSirt6 OE reduces expression of genes involved in ribosome biogenesis, including many dMyc target genes.
dSirt6 OE partially rescues many effects of
dMyc OE, including increased nuclear size, up-regulation of ribosome biogenesis genes, and lifespan shortening. Last,
dMyc haploinsufficiency does not convey additional lifespan extension to
dSirt6 OE flies, suggesting
dSirt6 OE is upstream of
dMyc in regulating lifespan. Our results provide insight into the mechanisms by which Sirt6 OE leads to longer lifespan.
