Increased expression of Drosophila Sir 2 extends life span in a dose-dependent manner

Abstract

Sir2, a member of the sirtuin family of protein acylases, deacetylates lysine residues within many proteins and is associated with lifespan extension in a variety of model organisms. Recent studies have questioned the positive effects of Sir2 on lifespan in Drosophila. Several studies have shown that increased expression of the Drosophila Sir2 homolog (dSir2) extends life span while other studies have reported no effect on life span or suggested that increased dSir2 expression was cytotoxic. To attempt to reconcile the differences in these observed effects of dSir2 on Drosophila life span, we hypothesized that a critical level of dSir2 may be necessary to mediate life span extension. Using approaches that allow us to titrate dSir2 expression, we describe here a strong dose-dependent effect of dSir2 on life span. Using the two transgenic dSir2 lines that were reported not to extend life span, we are able to show significant life span extension when dSir2 expression is induced between 2 and 5-fold. However, higher levels decrease life span and can induce cellular toxicity, manifested by increased expression of the JNK-signaling molecule Puc phosphatase and induction of dnaJ-H. Our results help to resolve the apparently conflicting reports by demonstrating that the effects of increased dSir2 expression on life span in Drosophila are dependent upon dSir2 dosage.

Chromatin-modifying genetic interventions suppress age-associated transposable element activation and extend life span in Drosophila

“…4C), using the conditional inducible GeneSwitch system, was able to extend life span, with flies fed the gene-activating drug RU486 outliving a genetically identical control cohort fed only the diluent control EtOH. Together with previously published data (21,25), these observed life span extensions suggest a coordinated response integrating maintenance of heterochromatin structure, TE suppression, and longevity.…”

“…In addition to their effects of delaying age-related heterochromatin gene and TE silencing loss, both increased Sir2 expression and decreased Adar expression have been shown to extend life span in flies (21,25), whereas Dicer-2 and Ago2 mutants are short-lived (15,24). Given our findings presented earlier, we examined whether increased expression of Su(var)3-9 or Dicer-2 also have a positive effect on life span.…”

“…Decreasing activity of the siRNA pathway through Ago2 and Dicer-2 mutants leads to derepression of TE activity and shortened life span (15,24). Sir2 has a central role in aging, with increased gene dosage shown to extend life span in yeast (2) and in nine of 10 studies in nematodes and flies (25)(26)(27)(28). Hypomorphs of Adar, a negative regulator of the siRNA pathway, also exhibit an extension of life span (21).…”

Age‐associated de‐repression of retrotransposons in the Drosophila fat body, its potential cause and consequence

“…Importantly, overexpression of Sir2, a histone deacetylase required for heterochromatin formation and gene silencing, induces an increased lifespan in yeast (Kaeberlein et al ., 1999). The connection between heterochromatin maintenance and lifespan extension is further strengthened by studies in Caenorhabditis elegans and Drosophila (Rogina & Helfand, 2004; Hashimoto et al ., 2010; Jiang et al ., 2013; Whitaker et al ., 2013). Disruption of UTX‐1, a histone demethylase that reduces the heterochromatin epigenetic modification called histone H3 K27 trimethylation (H3K27me3), in C. elegans leads to increased H3K27me3 levels and prolonged lifespan (Jin et al ., 2011; Maures et al ., 2011).…”

Sirtuins: not only animal proteins

“…The yeast SIR2 belongs to class I and is involved in chromatin silencing, DNA damage repair and chromosome condensation during meiosis (Huang et al 2007). In D. melanogaster, it was demonstrated that the increased expression of genes encoding sirtuins may affect the length of their life cycle (Whitaker et al 2013). In C. elegans, four genes have been identified, encoding proteins related to yeast sirtuins.…”