RPD3 histone deacetylase and nutrition have distinct but interacting effects on Drosophila longevity

Abstract

Single-gene mutations that extend longevity have revealed regulatory pathways related to aging and longevity. RPD3 is a conserved histone deacetylase (Class I HDAC). Previously we showed that Drosophila rpd3 mutations increase longevity. Here we tested the longevity effects of RPD3 on multiple nutrient levels. Dietary restriction (DR) has additive effects on RPD3-mediated longevity extension, but the effect may be modestly attenuated relative to controls. RPD3 and DR therefore appear to operate by distinct but interacting mechanisms. Since RPD3 regulates transcription, the mRNA levels for two proteins involved in nutrient signaling, 4E-BP and Tor, were examined in rpd3 mutant flies. 4E-BP mRNA was reduced under longevity-increasing conditions. Epistasis between RPD3 and 4E-BP with regard to longevity was then tested. Flies only heterozygous for a mutation in Thor, the 4E-BP gene, have modestly decreased life spans. Flies mutant for both rpd3 and Thor show a superposition of a large RPD3-mediated increase and a small Thor-mediated decrease in longevity at all food levels, consistent with each gene product having distinct effects on life span. However, DR-mediated extension was absent in males carrying both mutations and lessened in females. Our results support the view that multiple discrete but interacting mechanisms regulate longevity.

Rpd3 interacts with insulin signaling in Drosophila longevity extension

“…These data suggest that reduction in rpd3 levels facilitates female adaptation to starvation, most likely by increasing efficiency in using metabolic reserves [25]. This is supported by our findings that rpd3 P-UTR /+ flies have increased starvation resistance and consistent with our recent report that rpd3 P-UTR /+ flies live longer compared to controls in conditions similar to starvation [11]. …”

“…Metabolic adaptation to starvation in rpd3 mutant flies is illustrated by the findings that rpd3 reduction prevents a fasting-induced decrease in triglycerides in female rpd3 P-UTR /+ flies. This is consistent with our recent report that rpd3 P-UTR /+ flies live longer compared to controls in conditions similar to starvation and findings that heart-specific Rpd3 downregulation increases fly resistance to starvation at age 2 days [11, 12]. To get insights into the mechanism associated with rpd3 reduction we examined if these changes are mediated by IIS.…”

“…Longevity extension in rpd3 mutant flies has been linked to dSir2, 4E-BP, dFOXO, and CR longevity pathways [9, 11, 12, 30]. The data presented here add to our understanding of the mechanism of rpd3 's effects on longevity by identifying a novel genetic link between rpd3 reduction and IIS (Fig.…”

“…Deletion of rpd3 in yeast extends their replicative lifespan [7]. Flies heterozygous for a null or a hypomorphic rpd3 mutant alleles had an extended lifespan compared to genetic controls [9, 11]. Moreover, heart-specific rpd3 downregulation in flies increases heart function, stress resistance, and extends longevity [12].…”

Epigenetics and aging

“…Deletion of genes expressing components of the histone H3 deacetylase complex Rpd3 extends replicative life span of yeast ( 103 ) and organismal life span of flies ( 104 ). Rpd3-mediated deacetylation appears to limit longevity through multiple pathways ( 105 ), highlighting the pleiotropic effects of altering levels of histone acetylation. Further studies are required to fully understand the molecular mechanisms used by these HATs and HDACs to influence life span.…”