The role of glucose-6-phosphate dehydrogenase in the evolution of longevity in Drosophila melanogaster

Luckinbill, Leo S.; Riha, V.F.; Rhine, Samuel A.; Grudzien, Thaddeus A.

doi:10.1038/hdy.1990.66

Cited by 32 publications

(18 citation statements)

References 44 publications

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“…Glucose‐6‐phosphate dehydrogenase overexpression increased median life span in Drosophila and female mice . Longer‐lived strains of Drosophila were shown to possess higher glucose‐6‐phosphate dehydrogenase activity than shorter lived strains . By increasing flux through NADP‐dependent forms of the enzyme, knocking out or knocking down NAD‐dependent isocitrate dehydrogenase increased life span in yeast and C. elegans .…”

Section: Aging Oxidative Stress and The Nadph‐linked Antioxidant Symentioning

confidence: 99%

Ketone bodies mimic the life span extending properties of caloric restriction

Veech

Bradshaw

Clarke³

et al. 2017

IUBMB Life

139

109

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The extension of life span by caloric restriction has been studied across species from yeast and Caenorhabditis elegans to primates. No generally accepted theory has been proposed to explain these observations. Here, we propose that the life span extension produced by caloric restriction can be duplicated by the metabolic changes induced by ketosis. From nematodes to mice, extension of life span results from decreased signaling through the insulin/insulin-like growth factor receptor signaling (IIS) pathway. Decreased IIS diminishes phosphatidylinositol (3,4,5) triphosphate (PIP 3 ) production, leading to reduced PI3K and AKT kinase activity and decreased forkhead box O transcription factor (FOXO) phosphorylation, allowing FOXO proteins to remain in the nucleus. In the nucleus, FOXO proteins increase the transcription of genes encoding antioxidant enzymes, including superoxide dismutase 2, catalase, glutathione peroxidase, and hundreds of other genes. An effective method for combating free radical damage occurs through the metabolism of ketone bodies, ketosis being the characteristic physiological change brought about by caloric restriction from fruit flies to primates. A dietary ketone ester also decreases circulating glucose and insulin leading to decreased IIS. The ketone body, D-b-hydroxybutyrate (D-bHB), is a natural inhibitor of class I and IIa histone deacetylases that repress transcription of the FOXO3a gene. Therefore, ketosis results in transcription of the enzymes of the antioxidant pathways. In addition, the metabolism of ketone bodies results in a more negative redox potential of the NADP antioxidant system, which is a terminal destructor of oxygen free radicals. Addition of D-bHB to cultures of C. elegans extends life span. We hypothesize that increasing the levels of ketone bodies will also extend the life span of humans and that calorie restriction extends life span at least in part through increasing the levels of ketone bodies. An exogenous ketone ester provides a new tool for mimicking the effects of caloric restriction that can be used in future research. The ability to power mitochondria in aged individuals that have limited ability to oxidize glucose metabolites due to pyruvate dehydrogenase inhibition suggests new lines of research for preventative measures and treatments for aging and aging-related disorders. V C 2017 The Authors IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 69(5): [305][306][307][308][309][310][311][312][313][314] 2017 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Abbreviations: D-bHB, D-b-hydroxybutyrate; HIF-1a, hypoxia-inducible factor 1-alpha; IGF, insulin/insulin-like growth factor; FOXO, forkhead box transcription factor; HDAC, histone deacetylase; IIS, insulin/insulin-like growth factor receptor signaling pathway; ILP, insulin l...

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Section: Aging Oxidative Stress and The Nadph‐linked Antioxidant Symentioning

confidence: 99%

Ketone bodies mimic the life span extending properties of caloric restriction

Veech

Bradshaw

Clarke³

et al. 2017

IUBMB Life

139

109

View full text Add to dashboard Cite

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“…The major function of PPP is to generate nicotinamide adenine dinucleotide phosphate (NADPH) to provide more reduced form of glutathione to counteract the damaging effects of ROS. Long-lived flies contain higher glucose-6-phosphate dehydrogenase (G6PD) activity, a rate limiting enzyme in pentose phosphate pathway (Luckinbill et al 1990). In addition, Hsp27 can increase G6PD activity (Preville et al 1999), and Hsp27 overexpression transgenic flies extend lifespan and exhibit better resistance to oxidative stress (Wang et al 2004; Liao et al 2008).…”

Section: Introductionmentioning

confidence: 99%

Reduced neuronal expression of ribose‐5‐phosphate isomerase enhances tolerance to oxidative stress, extends lifespan, and attenuates polyglutamine toxicity in Drosophila

et al. 2011

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Summary Aging and age-related diseases can be viewed as the result of the lifelong accumulation of stress insults. The identification of mutant strains and genes which are responsive to stress and can alter longevity profiles provides new therapeutic targets for age-related diseases. Here we reported that a Drosophila strain with reduced expression of ribose-5-phosphate isomerase (rpi), EP2456, exhibits increased resistance to oxidative stress and enhanced lifespan. In addition, the strain also displays higher levels of NADPH. The knockdown of rpi in neurons by double-stranded RNA interference recapitulated the lifespan extension and oxidative stress resistance in Drosophila. This manipulation was also found to ameliorate the effects of genetic manipulations aimed at creating a model for studying Huntington’s disease by overexpression of polyglutamine in the eye, suggesting that modulating rpi levels could serve as a treatment for normal aging as well as for polyglutamine neurotoxicity.

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“…The pentose pathway absolutely requires carbons derived from glucose, so for this essential source of cytoplasmic NADPH to function in the presence of low glucose, alternative metabolic pathways for glucose carbons must be inhibited by low glucose, which they robustly are at several rate-limiting steps. Indeed, polymorphisms in the gene for glucose-6-phosphate dehydrogenase are strikingly correlated with life span across strains of Drosophila: the longest-lived strain exhibited a 64% higher activity of glucose-6-phosphate dehydrogenase than the shortest-lived strain [94]. Similarly, the NADP-dependent form of isocitrate dehydrogenase is a major source of NADPH in mitochondria, and elevation of this enzyme protects against oxidative stress in vitro [95] and even increases replicative life span [95].…”

Section: Glucose Regulates Its Own Metabolic Fate: the Glucose Switchmentioning

confidence: 99%

“…Other than two studies linking life span to expression levels of glucose-6-phosphate dehydrogenase [94] or to variants in NADP-dependent isocitrate dehydrogenase [97], very few studies have directly linked variations in levels of glucose-sensitive genes to life span. We therefore examined the correlation between hypothalamic expression of glucose-sensitive genes and average life span across 5 strains of mice.…”

Section: Genetic Correlation Between Gene Expression and Life Spanmentioning

confidence: 99%

Secrets of the lac Operon

Mobbs¹,

Mastaitis²,

Zhang³

et al. 2006

Interdisciplinary Topics in Gerontology

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Elevated blood glucose associated with diabetes produces progressive and apparently irreversible damage to many cell types. Conversely, reduction of glucose extends life span in yeast, and dietary restriction reduces blood glucose. Therefore it has been hypothesized that cumulative toxic effects of glucose drive at least some aspects of the aging process and, conversely, that protective effects of dietary restriction are mediated by a reduction in exposure to glucose. The mechanisms mediating cumulative toxic effects of glucose are suggested by two general principles of metabolic processes, illustrated by the lac operon but also observed with glucose-induced gene expression. First, metabolites induce the machinery of their own metabolism. Second, induction of gene expression by metabolites can entail a form of molecular memory called hysteresis. When applied to glucose-regulated gene expression, these two principles suggest a mechanism whereby repetitive exposure to postprandial excursions of glucose leads to an age-related increase in glycolytic capacity (and reduction in ␤-oxidation of free fatty acids), which in turn leads to an increased generation of oxidative damage and a decreased capacity to respond to oxidative damage, independent of metabolic rate. According to this mechanism, dietary restriction increases life span and reduces pathology by reducing exposure to glucose and therefore delaying the development of glucose-induced glycolytic capacity.

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The role of glucose-6-phosphate dehydrogenase in the evolution of longevity in Drosophila melanogaster

Cited by 32 publications

References 44 publications

Ketone bodies mimic the life span extending properties of caloric restriction

Ketone bodies mimic the life span extending properties of caloric restriction

Reduced neuronal expression of ribose‐5‐phosphate isomerase enhances tolerance to oxidative stress, extends lifespan, and attenuates polyglutamine toxicity in Drosophila

Secrets of the lac Operon

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