Heart-specific Rpd3 downregulation enhances cardiac function and longevity

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

doi:10.18632/aging.100806

Cited by 12 publications

(25 citation statements)

References 42 publications

(72 reference statements)

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“…Using a UAS-rpd3-dsRNAi transgene and different drivers it was shown that strong whole body rpd3 -reduction is lethal, consistent with previous findings of lethality associated with rpd3 −/− mutation (Kopp et al, 2015). However, use of a weaker actGAL4 driver resulted in 60% reduction of rpd3 mRNA and extended fly longevity.…”

Section: Effects Of Rpd3 On Longevitysupporting

confidence: 87%

“…However, use of a weaker actGAL4 driver resulted in 60% reduction of rpd3 mRNA and extended fly longevity. Additionally, specific rpd3 downregulation in fly heart tissue extends fly longevity and increases fly resistance to oxidation, starvation, and heat (Kopp et al, 2015). Consistently, increased resistance to stress is associated with longer life in many other long-lived flies, such as mth and Indy mutants (Lin et al, 1998; Rogers and Rogina, 2014).…”

Section: Effects Of Rpd3 On Longevitymentioning

confidence: 99%

“…Genetic manipulations that decrease yeast and fly rpd3 levels extend longevity (Kim et al, 1999; Rogina et al, 2002; Rogina and Helfand, 2004; Pallos et al, 2008; Cao et al, 2014; Kopp et al, 2015; Frankel et al, 2015). On the other hand, overexpression of Sir2 genetically or pharmacologically in yeast, worm, fly, and mice extends healthspan and/or longevity (Kaeberlain et al, 1999; Imai et al, 2000; Tissenbaum and Guarente, 2001; Rogina and Helfand, 2004; Wood et al, 2004; Frankel et al, 2011; Whitaker et al, 2013, Banerjee et al, 2012; Kanfi et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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The effects of Rpd3 on fly metabolism, health, and longevity

Woods

Rogina

2016

Experimental Gerontology

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The epigenetic regulation of DNA structure and function is essential for changes in gene expression involved in development, growth, and maintenance of cellular function. Epigenetic changes include histone modifications such as methylation, acetylation, ubiquitination, and phosphorylation. Histone deacetylase (HDAC) proteins have a major role in epigenetic regulation of chromatin structure. HDACs are enzymes that catalyze the removal of acetyl groups from lysine residues within histones, as well as a range of other proteins including transcriptional factors. HDACs are highly conserved proteins divided into two families and based on sequence similarity in four classes. Here we will discuss the roles of Rpd3 in physiology and longevity with emphasis on its role in flies. Rpd3, the Drosophila HDAC1 homologue, is a class I lysine deacetylase and a member of a large family of HDAC proteins. Rpd3 has multiple functions including control of proliferation, development, metabolism, and aging. Pharmacological and dietary HDAC inhibitors have been used as therapeutics in psychiatry, cancer, and neurology.

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Section: Effects Of Rpd3 On Longevitysupporting

confidence: 87%

Section: Effects Of Rpd3 On Longevitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The effects of Rpd3 on fly metabolism, health, and longevity

Woods

Rogina

2016

Experimental Gerontology

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“…We used only thoraces of rpd3 P-UTR because their genetic controls rpd3 P-1.8 flies have reduced levels of rpd3 mRNA in the eyes. Similarly, increased expression of dfoxo mRNA was found in whole body RNA isolated from heart-specific rpd3 downregulation [12]. …”

Section: Resultsmentioning

confidence: 99%

“…Rpd3, an orthologue of mammalian HDAC1, can also deacetylate lysine residues of various other proteins, such as P53, or bind to promoter region of other genes ( p21 and p57 ) and affect their transcription [6]. Reduced expression of Rpd3 extends lifespan in yeast, worms and fruit flies [7–12]. Similar effects on Drosophila lifespan were achieved by feeding fruit flies 4-phenylbutyrate (PBA), a histone deacetylase inhibitor [3].…”

Section: Introductionmentioning

confidence: 99%

Rpd3 interacts with insulin signaling in Drosophila longevity extension

Woods

Ziafazeli

Rogina

2016

Aging

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Histone deacetylase (HDAC) 1 regulates chromatin compaction and gene expression by removing acetyl groups from lysine residues within histones. HDAC1 affects a variety of processes including proliferation, development, metabolism, and cancer. Reduction or inhibition of Rpd3, yeast and flyHDAC1 orthologue, extends longevity. However, the mechanism of rpd3's effects on longevity remains unclear. Here we report an overlap between rpd3 and the Insulin/Insulin-like growth factor signaling (IIS) longevity pathways. We demonstrated that rpd3 reduction downregulates expression of members of the IIS pathway, which is associated with altered metabolism, increased energy storage, and higher resistance to starvation and oxidative stress. Genetic studies support the role of IIS in rpd3 longevity pathway, as illustrated with reduced stress resistance and longevity of flies double mutant for rpd3 and dfoxo, a downstream target of IIS pathway compared to rpd3 single mutant flies. Our data suggest that increased dfoxo is a mediator of rpd3's effects on fly longevity and intermediary metabolism, and confer a new link between rpd3 and IIS longevity pathways.

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Heart-specific Rpd3 downregulation enhances cardiac function and longevity

Cited by 12 publications

References 42 publications

The effects of Rpd3 on fly metabolism, health, and longevity

The effects of Rpd3 on fly metabolism, health, and longevity

Rpd3 interacts with insulin signaling in Drosophila longevity extension

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