Overexpression of Sir2 in the adult fat body is sufficient to extend lifespan of male and female Drosophila

Hoffmann, Julia; Romey, Renja; Fink, Christine; Yong, Li; Roeder, Thomas

doi:10.18632/aging.100553

Cited by 76 publications

(59 citation statements)

References 39 publications

(76 reference statements)

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“…This latter experiment illustrates the role of dSir2 in mediating dietary effects on longevity, discussed in greater detail below. A second recent study confirms that dSir2 overexpression increases the life span in flies (Hoffmann et al 2013). …”

Section: Sirtuins and Agingmentioning

confidence: 67%

Calorie restriction and sirtuins revisited

2013

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Calorie or dietary restriction (CR) has attracted attention because it is the oldest and most robust way to extend rodent life span. The idea that the nutrient sensors, termed sirtuins, might mediate effects of CR was proposed 13 years ago and has been challenged in the intervening years. This review addresses these challenges and draws from a great body of new data in the sirtuin field that shows a systematic redirection of mammalian physiology in response to diet by sirtuins. The prospects for drugs that can deliver at least a subset of the benefits of CR seems very real.

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Section: Sirtuins and Agingmentioning

confidence: 67%

Calorie restriction and sirtuins revisited

2013

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“…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).…”

mentioning

confidence: 99%

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

Wood

Jones

Jiang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

156

183

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Transposable elements (TEs) are mobile genetic elements, highly enriched in heterochromatin, that constitute a large percentage of the DNA content of eukaryotic genomes. Aging in Drosophila melanogaster is characterized by loss of repressive heterochromatin structure and loss of silencing of reporter genes in constitutive heterochromatin regions. Using next-generation sequencing, we found that transcripts of many genes native to heterochromatic regions and TEs increased with age in fly heads and fat bodies. A dietary restriction regimen, known to extend life span, repressed the age-related increased expression of genes located in heterochromatin, as well as TEs. We also observed a corresponding age-associated increase in TE transposition in fly fat body cells that was delayed by dietary restriction. Furthermore, we found that manipulating genes known to affect heterochromatin structure, including overexpression of Sir2, Su(var)3-9, and Dicer-2, as well as decreased expression of Adar, mitigated age-related increases in expression of TEs. Increasing expression of either Su(var)3-9 or Dicer-2 also led to an increase in life span. Mutation of Dicer-2 led to an increase in DNA double-strand breaks. Treatment with the reverse transcriptase inhibitor 3TC resulted in decreased TE transposition as well as increased life span in TE-sensitized Dicer-2 mutants. Together, these data support the retrotransposon theory of aging, which hypothesizes that epigenetically silenced TEs become deleteriously activated as cellular defense and surveillance mechanisms break down with age. Furthermore, interventions that maintain repressive heterochromatin and preserve TE silencing may prove key to preventing damage caused by TE activation and extending healthy life span.aging | heterochromatin | transposable elements | dietary restriction | silencing

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“…For example, overexpression of antioxidant enzymes such as SOD1, SOD2 and catalase caused lifespan extension (Orr and Sohal, 1994;Sun and Tower, 1999;Parkes et al, 1998;Sun et al, 2002). Overexpression of a Drosophila homolog of Sirtuin 2 (Sir2) (NAD+-dependent protein deacetylase) in fat bodies also led to an extended lifespan (Banerjee et al, 2012;Hoffmann et al, 2013). Although Sir2 orthologs are considered to be involved in the determination of lifespan in other organisms (Kaeberlein et al, 1999;Tissenbaum and Guarente, 2002), the ubiquitous overexpression of Drosophila Sir2 failed to extend the Drosophila adult lifespan (Burnett et al, 2011).…”

Section: O V E R E X P Re Ss Io N O F D Ro S O Ph I L a O G G1 U S I N Gmentioning

confidence: 99%

<i>Drosophila</i> Ogg1 is required to suppress 8-oxo-guanine accumulation following oxidative stress

et al. 2015

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Reactive oxygen species (ROS) generated during energy production processes are a major cause of oxidative DNA damage. A DNA glycosylase encoded by the Ogg1 gene removes oxidized guanine bases and is widely conserved. However, the biological role of the gene in individual organisms has not yet been characterized in Drosophila, which is a suitable model to study the influence of oxidative damage on senescence. Here, we performed a genetic analysis to confirm that Ogg1 plays an essential role in the removal of 8-oxo-guanines from nuclei. We first confirmed by quantitative real-time PCR that Ogg1 mRNA expression was reduced by 30-55% in Ogg1 mutants and in flies expressing inducible Ogg1 dsRNA compared to control flies. We then showed that additional accumulation of 8-oxo-guanines occurred in the nuclei of epithelial midgut cells after paraquat feeding in flies with downregulated Ogg1 expression. We confirmed that a transposon possessing the UAS sequence was integrated in the 5′-UTR of the Ogg1 alleles and that it is oriented in the same transcriptional direction as the gene. Using the Gal4/UAS system, which enables us to induce ectopic expression in Drosophila, we induced overexpression of Ogg1 by 40-fold. We observed a lower amount of 8-oxo-guanine in the midgut epithelial cells of adults overexpressing Ogg1. These genetic data strongly suggest that the Drosophila Ogg1 ortholog CG1795 plays an essential role in the suppression of 8-oxo-guanines, consistent with its role in other organisms. Although adult flies with reduced Ogg1 expression failed to show elevated sensitivity to paraquat, those with Ogg1 overexpression showed resistance to oxidative stress by paraquat feeding and had a significantly longer lifespan in normal feeding conditions. These observations are consistent with the hypothesis that oxidative DNA damage by ROS accumulation is a major contributor to senescence.

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Overexpression of Sir2 in the adult fat body is sufficient to extend lifespan of male and female Drosophila

Cited by 76 publications

References 39 publications

Calorie restriction and sirtuins revisited

Calorie restriction and sirtuins revisited

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

<i>Drosophila</i> Ogg1 is required to suppress 8-oxo-guanine accumulation following oxidative stress

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