Heart-specific Rpd3 downregulation enhances cardiac function and longevity.

Zachary A Kopp,David Fan,Dhelni T Bhatt,Veevek Shah,Radhika Ragam,Rachel Wu,Kunwoo Park,Yuh-Ru Lin,Hardik Parikh,Kristen Park,Jo-Lin Hsieh,Angela Lee,Ayush Parikh,Dev Ardeshna,Yongkyu Park,Sae Yeon Kim,Emaad Siddiqui,Andrew Li,William Wang

doi:10.18632/aging.100806

Abstract

Downregulation of Rpd3, a homologue of mammalian Histone Deacetylase 1 (HDAC1), extends lifespan in Drosophila melanogaster. Once revealed that long-lived fruit flies exhibit limited cardiac decline, we investigated whether Rpd3 downregulation would improve stress resistance and/or lifespan when targeted in the heart. Contested against three different stressors (oxidation, starvation and heat), heart-specific Rpd3 downregulation significantly enhanced stress resistance in flies. However, these higher levels of resistance were not observed when Rpd3 downregulation was targeted in other tissues or when other long-lived flies were tested in the heart-specific manner. Interestingly, the expressions of anti-aging genes such as sod2, foxo and Thor, were systemically increased as a consequence of heart-specific Rpd3 downregulation. Showing higher resistance to oxidative stress, the heart-specific Rpd3 downregulation concurrently exhibited improved cardiac functions, demonstrating an increased heart rate, decreased heart failure and accelerated heart recovery. Conversely, Rpd3 upregulation in cardiac tissue reduced systemic resistance against heat stress with decreased heart function, also specifying phosphorylated Rpd3 levels as a significant modulator. Continual downregulation of Rpd3 throughout aging increased lifespan, implicating that Rpd3 deacetylase in the heart plays a significant role in cardiac function and longevity to systemically modulate the fly's response to the environment.

Highlights

As a histone deacetylase (HDAC), Rpd3 modulates chromatin structures, including the heterochromatin of Drosophila telomeres, by interacting with several chromatin remodeling complexes [1]
Rpd3-/- homozygous mutant flies are lethal, we found that the rpd3-/+ heterozygous flies (46% of rpd3 expression in Fig. 1A) can increase survivorship up to 31% under the oxidative stress compared to wild type (+/+) flies (Fig. 1B-C)
This mild rpd3 downregulation of Rpd3 downregulation (rpd3Ri)/armG4 flies extended lifespan (16% in SFig. 1C-D), implying that the mild decrease of rpd3 expression in the whole body is favorable for enhancement of both stress resistance and lifespan

Summary

Introduction

As a histone deacetylase (HDAC), Rpd modulates chromatin structures, including the heterochromatin of Drosophila telomeres, by interacting with several chromatin remodeling complexes [1]. Systemic Rpd downregulation extends lifespan in rpd3-/+ heterozygous mutants [3] rpd3-/- homozygotes are lethal. This longer lifespan is detected in yeast with Rpd downregulation [4]. Feeding Drosophila 4-phenylbutyrate (PBA, an inhibitor of histone deacetylase) throughout adulthood could significantly increase lifespan [5]. Several long-lived mutant flies have displayed increased resistance to numerous stressors including oxidation, starvation and heat over wild-type flies, indicating a positive correlation between stress resistance and lifespan extension [6,7,8,9]. Downregulation of Rpd has been known to extend lifespan in Drosophila [3], its relationship to stress resistance has not yet been characterized

Methods

Results

Conclusion