Lifelong Glutathione Deficiency in Mice Increased Lifespan and Delayed Age-Related Motor Declines

Glutathione (GSH) is a crucial redox scavenger, essential for maintaining cellular redox balance. This study explores the long-term effects of chronic GSH deficiency on lifespan, motor function, cognitive performance, redox status and inflammation. GCLM^-/- mice, with a 70-90% reduction in GSH levels, were compared to GCLM^+/+ controls across their lifespan (5, 10 and 20 months). We assessed lifespan, motor performance using balance and coordination tests, cognitive function through anxiety and memory tests, redox markers, and inflammation markers, particularly TNF-α and IL-6. Biochemical analyses of GSH levels in peripheral tissues and brain regions were conducted to evaluate redox state changes. GCLM^-/- mice displayed extended lifespans and improved motor function at young and adult stages, with a delayed onset of motor decline with age. Cognitive function remains largely unaffected, although there are reductions in anxiety-related behaviors and minor deficits in fear-associated memory. Age-related increases in TNF-α, an inflammatory marker, are observed in both genotypes, with GCLM^-/- mice showing a less pronounced increase, particularly in females. There were significant GSH reductions in peripheral tissues, with sporadic changes in brain regions. This stress likely triggers compensatory antioxidant responses, modulating inflammation and redox-sensitive pathways. The data suggests that lifelong GSH deficiency provides protective effects against inflammation and motor decline in younger animals but exacerbates these issues in older mice. The study offers insights into potential therapeutic strategies that leverage mild oxidative stress to promote healthy aging, emphasizing the importance of redox state and antioxidant defenses in the aging process.