<i>Drosophila</i> lifespan control by dietary restriction independent of insulin‐like signaling

Min, Kyung‐Jin; Yamamoto, Rochele; Buch, Susanne R.; Pankratz, Michael J.; Tatar, Marc

doi:10.1111/j.1474-9726.2008.00373.x

Cited by 182 publications

(203 citation statements)

References 31 publications

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“…Dietary restriction (DR) increases lifespan in diverse organisms, including Drosophila (4) where the increased longevity from DR is dFOXO-independent (18). Interestingly, we found that flies subjected to DR were not resistant to DDT (Fig.…”

Section: Resultsmentioning

confidence: 69%

Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila

Afschar

Toivonen

Hoffmann

et al. 2016

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

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Lifespan of laboratory animals can be increased by genetic, pharmacological, and dietary interventions. Increased expression of genes involved in xenobiotic metabolism, together with resistance to xenobiotics, are frequent correlates of lifespan extension in the nematode worm Caenorhabditis elegans, the fruit fly Drosophila, and mice. The Green Theory of Aging suggests that this association is causal, with the ability of cells to rid themselves of lipophilic toxins limiting normal lifespan. To test this idea, we experimentally increased resistance of Drosophila to the xenobiotic dichlordiphenyltrichlorethan (DDT), by artificial selection or by transgenic expression of a gene encoding a cytochrome P450. Although both interventions increased DDT resistance, neither increased lifespan. Furthermore, dietary restriction increased lifespan without increasing xenobiotic resistance, confirming that the two traits can be uncoupled. Reduced activity of the insulin/Igf signaling (IIS) pathway increases resistance to xenobiotics and extends lifespan in Drosophila, and can also increase longevity in C. elegans, mice, and possibly humans. We identified a nuclear hormone receptor, DHR96, as an essential mediator of the increased xenobiotic resistance of IIS mutant flies. However, the IIS mutants remained long-lived in the absence of DHR96 and the xenobiotic resistance that it conferred. Thus, in Drosophila IIS mutants, increased xenobiotic resistance and enhanced longevity are not causally connected. The frequent co-occurrence of the two traits may instead have evolved because, in nature, lowered IIS can signal the presence of pathogens. It will be important to determine whether enhanced xenobiotic metabolism is also a correlated, rather than a causal, trait in long-lived mice.lifespan | xenobiotic resistance | IIS | nuclear hormone receptor | DHR96

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Section: Resultsmentioning

confidence: 69%

Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila

Afschar

Toivonen

Hoffmann

et al. 2016

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

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“…Min et al . (2008) showed evidence that the diet‐dependent effects of dFoxO overexpression on fly's lifespan are associated with reduction of dilp2.…”

Section: Animal Modelsmentioning

confidence: 99%

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

2015

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SummaryAging constitutes the key risk factor for age‐related diseases such as cancer and cardiovascular and neurodegenerative disorders. Human longevity and healthy aging are complex phenotypes influenced by both environmental and genetic factors. The fact that genetic contribution to lifespan strongly increases with greater age provides basis for research on which “protective genes” are carried by long‐lived individuals. Studies have consistently revealed FOXO (Forkhead box O) transcription factors as important determinants in aging and longevity. FOXO proteins represent a subfamily of transcription factors conserved from Caenorhabditis elegans to mammals that act as key regulators of longevity downstream of insulin and insulin‐like growth factor signaling. Invertebrate genomes have one FOXO gene, while mammals have four FOXO genes: FOXO1, FOXO3, FOXO4, and FOXO6. In mammals, this subfamily is involved in a wide range of crucial cellular processes regulating stress resistance, metabolism, cell cycle arrest, and apoptosis. Their role in longevity determination is complex and remains to be fully elucidated. Throughout this review, the mechanisms by which FOXO factors contribute to longevity will be discussed in diverse animal models, from Hydra to mammals. Moreover, compelling evidence of FOXOs as contributors for extreme longevity and health span in humans will be addressed.

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“…The state of insulin signaling provides one measure of the nutritional status of the fly. Under conditions of a nutrient challenge, such as CR, insulin signaling is decreased (17,22). An indirect method for assessing the state of insulin signaling is the level of mRNA expression for the 3 Drosophila insulin-like peptides (Dilps) found in the neurosecretory insulinproducing cells (IPCs) of the brain: Dilp2, Dilp3, and Dilp5.…”

Section: Decreases In the Calorie Content Of Food Induce A Decrease Imentioning

confidence: 99%

“…In nematodes, long-lived daf-2/InR and daf-16/dFOXO mutants live even longer when subject to CR (16). In flies, knockdown of dilps using RNAi does not decrease the life span-extending effects of CR and dFoxO null mutations continue to have a CR responsive life span extension, suggesting that CR and IISmediated life span extension may be unrelated (17). However, CR fails to further increase the life span extension of long-lived chico (InR substrate) mutant flies, suggesting CR and IIS mediated life span extension may be related (18).…”

mentioning

confidence: 99%

Long-lived Indy and calorie restriction interact to extend life span

Wang

Neretti²,

Whitaker³

et al. 2009

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

101

160

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Calorie restriction (CR) improves health and extends life span in a variety of species. Despite many downstream molecules and physiological systems having been identified as being regulated by CR, the mechanism by which CR extends life span remains unclear. The Drosophila gene Indy (for I'm not dead yet), involved in the transport and storage of Krebs cycle intermediates in tissues important in fly metabolism, was proposed to regulate life span via an effect on metabolism that could overlap with CR. In this study, we report that CR down regulates Indy mRNA expression, and that CR and the level of Indy expression interact to affect longevity. Optimal life span extension is seen when Indy expression is decreased between 25 and 75% of normal. Indy long-lived flies show several phenotypes that are shared by long-lived CR flies, including decreased insulin-like signaling, lipid storage, weight gain, and resistance to starvation as well as an increase in spontaneous physical activity. We conclude that Indy and CR interact to affect longevity and that a decrease in Indy may induce a CR-like status that confers life span extension.Drosophila ͉ insulin ͉ physical activity ͉ triglyceride A ging is a complex biological process that causes deteriorative changes over time. It has been suggested that the interplay between environmental factors and genetic alterations may affect this near universal process. Calorie restriction (CR) is the most widely recognized life span-extending intervention, and it has been shown to extend lifespan in a variety of different organisms (1, 2). Progress has been made in identifying genes that regulate longevity, and many of them appear to belong to pathways related to nutrient sensing, metabolism or nutrient/ metabolic signaling (3-7). The life span extending effects of a subset of these longevity genes has been shown to be associated with, and in some cases, causally related to CR life span extension (chico, Sir2, p53). Studies have suggested that alterations in the activity of these genes may mediate elements of the normal CR life span extending effect. Despite these advances little is understood about the molecular and genetic mechanisms underlying the healthy life span extension of CR.In Drosophila melanogaster, mutations in the Indy gene dramatically extend life span (8). The INDY protein is a transmembrane transporter of Krebs cycle intermediates (citrate, succinate, fumarate, and alpha-ketoglutarate) predominantly found at the plasma membrane of cells in the midgut, fat body, and oenocytes, tissues important for the uptake, utilization, and storage of nutrients and the principal sites of intermediary metabolism in the fly (8-10). Several independently derived lines, each with a P-element in the non-coding region of the Indy locus leading to decreased expression of Indy mRNA, have been shown to extend life span. It has been reported that life span extension is seen even when the Indy mutation is crossed into different genetic backgrounds (e.g., Hyperkinetic, Shaker, drop dead, and the lo...

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Drosophila lifespan control by dietary restriction independent of insulin‐like signaling

Cited by 182 publications

References 31 publications

Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila

Nuclear hormone receptor DHR96 mediates the resistance to xenobiotics but not the increased lifespan of insulin-mutant Drosophila

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

Long-lived Indy and calorie restriction interact to extend life span

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