Longer lifespan in the Rpd3 and Loco signaling results from the reduced catabolism in young age with noncoding RNA

Zachary Kopp,Yongkyu Park

doi:10.18632/aging.101744

Abstract

Downregulation of Rpd3 (histone deacetylase) or Loco (regulator of G-protein signaling protein) extends Drosophila lifespan with higher stress resistance. We found rpd3-downregulated long-lived flies genetically interact with loco-upregulated short-lived flies in stress resistance and lifespan. Gene expression profiles between those flies revealed that they regulate common target genes in metabolic enzymes and signaling pathways, showing an opposite expression pattern in their contrasting lifespans. Functional analyses of more significantly changed genes indicated that the activities of catabolic enzymes and uptake/storage proteins are reduced in long-lived flies with Rpd3 downregulation. This reduced catabolism exhibited from a young age is considered to be necessary for the resultant longer lifespan of the Rpd3- and Loco-downregulated old flies, which mimics the dietary restriction (DR) effect that extends lifespan in the several species. Inversely, those catabolic activities that break down carbohydrates, lipids, and peptides were high in the short lifespan of Loco-upregulated flies. Long noncoding gene, dntRL (CR45923), was also found as a putative target modulated by Rpd3 and Loco for the longevity. Interestingly, this dntRL could affect stress resistance and lifespan, suggesting that the dntRL lncRNA may be involved in the metabolic mechanism of Rpd3 and Loco signaling.

Highlights

Rpd3, a Drosophila histone deacetylase (HDAC), modulates chromatin structures and affects signaling pathways by interacting with several chromatin remodeling complexes [1,2,3]
In contrast to the higher stress resistance shown with the rpd3 downregulation (Figure 1A-B), the loco upregulation (Loco-Up: UAS-loco/actG4) reduced survivorship by 33% under oxidative stress compared to the common control (UAS-loco/+ in Figure 1A-B) [19]
To find the target genes that both Loco and Rpd3 modulate for stress resistance and lifespan, we examined gene expression profiles of the rpd3 downregulation (Rpd3-Down: rpd3-UAS-loco/+) or the loco upregulation (Loco-Up: UAS-loco/actG4) versus the common control (UAS-loco/+) flies, independently (Figure 1E)

Summary

Introduction

A Drosophila histone deacetylase (HDAC), modulates chromatin structures and affects signaling pathways by interacting with several chromatin remodeling complexes [1,2,3]. The Rpd protein is known to mediate epigenetic effects like long-term memory and lifespan. It has been reported that Rpd interacts partially with the insulin signaling longevity pathway [8]. As several long-lived mutant flies display increased resistance to numerous stressors including oxidation, starvation, and heat compared to wild-type flies [9,10,11,12], Rpd downregulation enhances stress resistance with extended lifespan [6]. It was recently reported that decreased Rpd expression in Drosophila heart tissue enhances cardiac function (decreased heart failure and accelerated heart recovery) and resistance against stressors [6]

Methods

Results

Conclusion