#1

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

J Thomas Mock et al. Aging Dis. 2024.

Abstract

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. [PMID: 39656492]

From the full text:

“GCLM-/- mice exhibited both extended median and maximum lifespans.”

“GCLM-/- mice were also found to have deficits in pre-pulse inhibition, a phenomenon associated with psychological diseases such as schizophrenia and anxiety-disorders. GCLM has been strongly associated with schizophrenia in some case-control studies with genetic and functional evidence of impairment of GSH synthesis in schizophrenia.”

PubMed Abstract

Full Text - Open Access

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#2

So one should only supplement with GSH or GlyNAC in old age but not in young age?

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#4

I posted it here earlier today: GLYNAC Stimulates Mitochondrial Biogenesis - #50 by adssx

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#5

Seeing how both astaxanthin and sulforaphane increase median lifespan in male mice in the ITP, most likely through NRF2 activation, I believe that supersedes alternative mice studies.

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#6

Or maybe just high dose glycine when not yet in advanced age, which may extend lifespan through a different mechanism than boosting glutathione, such as reducing methionine toxicity. It extended median and maximum lifespan in rats by about 30%, compared to 6% in mice. Rats are genetically more similar to humans. And rats may be a better model for gerontological research than mice. I’m of the opinion that ITP should be using rats instead of mice in their research despite the higher cost and longer study duration.

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#7

Sulforaphane has never been tested in the ITP, has it?

#8

I believe it was part of a properiertary supplement that contained multiple ingredients.

#9

If you’re talking about Protandim: it does not contain sulforaphane. But it contains other Nrf2 activators.

Still, I don’t understand your point related to the current topic. NRF2 activation increases GSH so GSH is good?

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