Non-linear impact of glutathione depletion on C. elegans life span and stress resistance

Abstract

The redox environment in cells and organisms is set by low-molecular mass and protein-bound thiols, with glutathione (GSH) representing a major intracellular redox buffer. Subtle thiol oxidation elicits signal transduction processes and adaptive responses to cope with stressors, whereas highly oxidizing conditions may provoke cell death. We here tested how thiol depletion affects life span, stress resistance and stress signaling in the model organism Caenorhabditis elegans. Diethyl maleate (DEM), an α,β-unsaturated carbonyl compound that conjugates to GSH and other thiols, decreased C. elegans life span at a concentration of 1 mM. In contrast, low and moderate doses of DEM (10–100 µM) increased mean and maximum life span and improved resistance against oxidative stress. DEM-induced life span extension was not detectable in worms deficient in either the FoxO orthologue, DAF-16, or the Nrf2 orthologue, SKN-1, pointing to a collaborative role of the two transcription factors in life span extension induced by thiol depletion. Cytoprotective target genes of DAF-16 and SKN-1 were upregulated after at least 3 days of exposure to 100 µM DEM, but not 1 mM DEM, whereas only 1 mM DEM caused upregulation of egl-1, a gene controlled by a p53-orthologue, CEP-1. In order to test whether depletion of GSH may elicit effects similar to DEM, we suppressed GSH biosynthesis in worms by attenuating γ-glutamylcysteine synthetase (gcs-1) expression through RNAi. The decline in GSH levels elicited by gcs-1 knockdown starting at young adult stage did not impair viability, but increased both stress resistance and life expectancy of the worms. In contrast, gcs-1 knockdown commencing right after hatching impaired nematode stress resistance and rendered young adult worms prone to vulval ruptures during egg-laying. Thus, modest decrease in GSH levels in young adult worms may promote stress resistance and life span, whereas depletion of GSH is detrimental to freshly hatched and developing worms.

Glucose as a Major Antioxidant: When, What for and Why It Fails?

“…Consistent with this is recent data generated on C. elegance model regarding integration of stress induced responses of nervous system with metabolic adaptations [34]. It was shown that the flight response mediated by tyramine (worm analog of catecholamines) in the end leads to stimulation of insulin-IGF-1 signaling and have the opposite effect to longevity-promoting stress responses to heat, starvation, glucose restriction or exercise [35][36][37]. If hypothetically translated to modern humans it can provide accurate mechanistical explanations why emotional stress accompanied with sedentary behaviors may have detrimental health consequences associated with both excessive insulin and adrenaline signaling causing atherosclerosis [23], contributing among the other factors to insulin resistance and accelerated aging [38] but can be reversed by exercise or fasting [39].…”

“…On the other hand, glycogen clearly protects against the oxidative stress and at the same time decreases lifespan and healthspan [40,100]. Starvation and stress induced gluconeogenesis clearly support survival and improve health-and lifespans [100,101], but are associated with increase generation of reactive oxygen species [35]. Thus, healthy aging requires certain degree of oxidative stress that leads to metabolic shift to catabolism and activate endogenous protective mechanisms that include enhanced protein quality control, stimulation of endogenous antioxidant defense including gluconeogenesis [47,99,102].…”

Glucose as a Major Antioxidant: When, What for and Why It Fails?

“…Consistent with this is recent data generated on C. elegance model regarding integration of stress induced responses of nervous system with metabolic adaptations [39]. It was shown that the flight response mediated by tyramine (worm analog of catecholamines) in the end leads to stimulation of insulin-IGF-1 signaling and have the opposite effect to longevity-promoting stress responses to heat, starvation, glucose restriction or exercise [40][41][42]. If hypothetically translated to modern humans it can provide accurate mechanistical explanations why emotional stress accompanied with sedentary behaviors may have detrimental health consequences associated with both excessive insulin and adrenaline signaling causing atherosclerosis [24], contributing among the other factors to insulin resistance and accelerated aging [43] but can be reversed by exercise or fasting [44].…”

Ferrous-glutathione coupling mediates ferroptosis and frailty inCaenorhabditis elegans

“…Deletion of four C. elegans homologs of GPX4 decreases lifespan 28 , but whether ferroptosis is responsible is unknown. We tested whether acute depletion of glutathione can initiate ferroptosis in adult C. elegans using diethyl maleate (DEM), which conjugates glutathione 29,30 . We found that DEM induced death in 4-day old worms (at the end of their reproductive phase) in a dose-and time-dependent manner, with ≈50% lethality occurring after 24-hour exposure to 10 mM DEM ( Figure 1A) associated with ≈50% depletion of glutathione ( Figure 1B).…”