Overexpression of Glutamate-Cysteine Ligase Extends Life Span in Drosophila melanogaster

Orr, William C.; Radyuk, Svetlana N.; Prabhudesai, Leena; Toroser, Dikran; Benes, Judith; Luchak, James M.; Mockett, Robin J.; Rebrin, Igor; Hubbard, James G.; Sohal, Rajindar S.

doi:10.1074/jbc.m508272200

Cited by 120 publications

(143 citation statements)

References 26 publications

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“…Thus, a higher GSH content in DCAexposed flies might be a consequence of its de novo synthesis stimulated by the elevated expression of gclc and gclm, which is in agreement with earlier studies wherein DCA-induced upregulation of GSH via induction of GCL was observed in mice (Theodoratos et al 2012). Parallel to the above discussion, overexpression of gclc and gclm was reported to extend life span of Drosophila (Orr et al 2005) and de novo synthesis of GSH was also reported against long-term low-dose γ-irradiation in mice (Lee et al 2013).…”

Section: Discussionsupporting

confidence: 79%

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

Pandey

Vimal

Chandra

et al. 2014

AGE

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Dichloroacetic acid (DCA), a water disinfection by-product, has attained emphasis due to its prospect for clinical use against different diseases including cancer along with negative impact on organisms. However, these reports are based on the toxicological as well clinical data using comparatively higher concentrations of DCA without much of environmental relevance. Here, we evaluate cellular as well as organismal effects of DCA at environmentally and mild clinically relevant concentrations (0.02-20.0 μg/ml) using an established model organism, Drosophila melanogaster. Flies were fed on food mixed with test concentrations of DCA for 12-48 h to examine the induction of reactive oxygen species (ROS) generation, oxidative stress (OS), heat shock genes (hsps) and cell death along with organismal responses. We also examined locomotor performance, ROS generation, glutathione (GSH) depletion, expression of GSH-synthesizing genes (gclc and gclm), and hsps at different days (0, 10, 20, 30, 40, 50) of the age in flies after prolonged DCA exposure. We observed mild OS and induction of antioxidant defense system in 20.0 μg/ml DCA-exposed organism after 24 h. After prolonged exposure to DCA, exposed organism exhibited improved survival, elevated expression of hsp27, gclc, and gclm concomitant with lower ROS generation and GSH depletion and improved locomotor performance. Conversely, hsp27 knockdown flies exhibited reversal of the above end points. The study provides evidence for the attenuation of cellular and functional decline in aged Drosophila after prolonged DCA exposure and the effect of hsp27 modulation which further incites studies towards the therapeutic application of DCA.

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Section: Discussionsupporting

confidence: 79%

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

Pandey

Vimal

Chandra

et al. 2014

AGE

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“…Another gene was Gclm , which codes for the modulatory subunit of glutamate–cysteine ligase (GCL), the rate‐limiting enzyme in de novo glutathione biosynthesis. Global overexpression of GCLm in flies extended the mean lifespan by 24%, and neuronal overexpression of the catalytic subunit (GCLc) increased mean and maximum lifespans by up to 50% (Orr et al., 2005). …”

Section: Resultsmentioning

confidence: 99%

Comparative transcriptomics across 14 Drosophila species reveals signatures of longevity

Avanesov

Porter

et al. 2018

Aging Cell

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SummaryLifespan varies dramatically among species, but the biological basis is not well understood. Previous studies in model organisms revealed the importance of nutrient sensing, mTOR, NAD/sirtuins, and insulin/IGF1 signaling in lifespan control. By studying life‐history traits and transcriptomes of 14 Drosophila species differing more than sixfold in lifespan, we explored expression divergence and identified genes and processes that correlate with longevity. These longevity signatures suggested that longer‐lived flies upregulate fatty acid metabolism, downregulate neuronal system development and activin signaling, and alter dynamics of RNA splicing. Interestingly, these gene expression patterns resembled those of flies under dietary restriction and several other lifespan‐extending interventions, although on the individual gene level, there was no significant overlap with genes previously reported to have lifespan‐extension effects. We experimentally tested the lifespan regulation potential of several candidate genes and found no consistent effects, suggesting that individual genes generally do not explain the observed longevity patterns. Instead, it appears that lifespan regulation across species is modulated by complex relationships at the system level represented by global gene expression.

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“…Indeed, the role of oxidative stress resistance in aging is controversial, and the data presented here may provide new avenues for determining whether there is a causal link between the two (28,29). Irrespective of the role of oxidative stress resistance in aging, alterations in redox homeostasis alone can impact cell-signaling pathways in many ways (30,31).…”

Section: Discussionmentioning

confidence: 99%

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

Kabil

Banerjee

et al. 2011

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

132

154

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The mechanisms through which dietary restriction enhances health and longevity in diverse species are unclear. The transsulfuration pathway (TSP) is a highly conserved mechanism for metabolizing the sulfur-containing amino acids, methionine and cysteine. Here we show that Drosophila cystathionine β-synthase (dCBS), which catalyzes the rate-determining step in the TSP, is a positive regulator of lifespan in Drosophila and that the pathway is required for the effects of diet restriction on animal physiology and lifespan. dCBS activity was up-regulated in flies exposed to reduced nutrient conditions, and ubiquitous or neuron-specific transgenic overexpression of dCBS enhanced longevity in fully fed animals. Inhibition of the TSP abrogated the changes in lifespan, adiposity, and protein content that normally accompany diet restriction. RNAi-mediated knockdown of dCBS also limited lifespan extension by diet. Diet restriction reduced levels of protein translation in Drosophila, and we show that this is largely caused by increased metabolic commitment of methionine cycle intermediates to transsulfuration. However, dietary supplementation of methionine restored normal levels of protein synthesis to restricted animals without affecting lifespan, indicating that global reductions in translation alone are not required for diet-restriction longevity. Our results indicate a mechanism by which dietary restriction influences physiology and aging.hydrogen sulfide | essential amino acids | metabolism | healthspan F or a broad range of taxonomically diverse organisms, the quality of their diet acts as a powerful modulator of health and longevity through molecular mechanisms that are largely unknown. Lifespan is extended, for example, when food is restricted to an extent that falls short of inducing starvation. In mammals, this manipulation, which is often called dietary restriction (DR), not only increases lifespan but also imparts a broad-spectrum improvement in health during aging. In humans, for example, DR reduces risk factors for diabetes, cardiovascular disease, and cancer (1).Transsulfuration is an evolutionarily ancient metabolic process that involves a network of enzymes responsible for the metabolism of sulfur-containing amino acids. The transsulfuration pathway (TSP) has been studied extensively in mammals, in which it has been shown to direct the conversion of homocysteine to cysteine following the breakdown of methionine, an essential amino acid. Flux through the TSP is known to affect overall cellular metabolism by directly influencing cysteine and methionine levels. Methionine availability affects protein synthesis and methylation, and it has been implicated in murine aging (2). Cysteine availability controls the synthesis of glutathione (GSH), which is the chief regulator of cellular redox homeostasis and an important agent in xenobiotic detoxification (Fig. 1A). Patients with genetic defects in the TSP are characterized by high levels of homocysteine, low levels of GSH, and increased incidence of age-related path...

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Overexpression of Glutamate-Cysteine Ligase Extends Life Span in Drosophila melanogaster

Cited by 120 publications

References 26 publications

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

Comparative transcriptomics across 14 Drosophila species reveals signatures of longevity

Increased transsulfuration mediates longevity and dietary restriction in Drosophila

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