Mitochondria are the power plants of the cell, turning out the chemical energy store molecule ATP that is needed to power cellular processes. Mitochondrial function declines with age, and this faltering of energy production is an important contribution to degenerative aging. A broad range of proximate causes have been identified, changes in gene expression that directly or indirectly disrupt the supply of rate-limiting molecules necessary for mitochondria to carry out their work. Researchers identified loss of NAD+ as one of those issues some years ago, and supplementation with precursor compounds derived from vitamin B3 (such as nicotinamide riboside) has been shown to increase NAD+ levels and improve mitochondrial function. Today's research materials report on an analogous effort to raise levels of the antioxidant glutathione, also lost with age, by supplementing with a combination of precursor compounds glycine and N-acetylcysteine.
Antioxidants are important to mitochondrial function and cell health. Creating ATP is an energetic process, producing reactive oxidizing molecules as a necessary side-effect. Too much oxidation harms the cell, though some oxidation is needed as a signaling mechanism. Cells employ antioxidants to soak up the excess. Researchers have in the past shown benefits in mice through genetic engineering to upregulate the natural mitochondrial antioxidant catalase, while mitochondrially targeted antioxidant compounds such as MitoQ and SKQ1 have also resulted in animal studies showing improvements in health and a modest extension of life span.
The results reported in this small pilot human study of glycine and N-acetylcysteine supplementation appear interesting, particularly given that the intervention doesn't just improve mitochondrial function, but also improves markers of age-related chronic inflammation. Exercise is more effective at increasing NAD+ levels than the present methods of NAD+ precursor supplementation, at least in published clinical trial data. Exercise is known to increase glutathione levels as well, but is it better for glutathione levels than this approach to precursor supplementation? Looking at blood samples or red blood cells, a 2007 study shows a ~25% increase in glutathione via exercise, which is considerably smaller than the ~100% increase via supplementation claimed in the present study. That suggests it to be worth the expense to replicate this outcome in a larger study.
For those who are minded to responsibly repeat this study as a self-experiment at home, hopefully also discussing with a physician beforehand and taking blood tests before and after to see how the metrics hold up, I should note that glycine and N-acetylcysteine are both easily obtained. They are existing supplements, widely used. Shop around, prices vary considerably. Per the papers, the daily intake of each supplement is large: ~100 mg/kg for glycine (~6 grams for a 60kg human) and ~130 mg/kg for N-acetylcysteine (~8 grams for a 60kg human), split into two doses.
A pilot human clinical trial in eight older adults 70 to 80 years of age reveals that supplementation with GlyNAC - a combination of glycine and N-acetylcysteine as precursors of the natural antioxidant glutathione - could improve many age-associated defects in older humans to improve muscle strength and cognition, and promote healthy aging. The study participants taking GlyNAC for 24 weeks saw improvements in many characteristic defects of aging, including glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, body fat, genomic toxicity, muscle strength, gait speed, exercise capacity, and cognitive function. The benefits declined after stopping supplementation for 12 weeks. GlyNAC supplementation was well tolerated during the study period.
As mitochondria generate energy, they produce waste products such as free radicals. These highly reactive molecules can damage cells, membranes, lipids, proteins, and DNA. Cells depend on antioxidants, such as glutathione, the most abundant antioxidant in our cells, to neutralize these toxic free radicals. Failing to neutralize free radicals leads to harmful and damaging oxidative stress that can affect mitochondrial function. Interestingly, glutathione levels in older people are much lower than those in younger people, and the levels of oxidative stress are much higher. Animal studies have shown that restoring glutathione levels by providing GlyNAC reverses glutathione deficiency, reduces oxidative stress, and fully restores mitochondrial function in aged mice.
Glycine and N-acetylcysteine (GlyNAC) supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial
Oxidative stress (OxS) and mitochondrial dysfunction are implicated as causative factors for aging. Older adults (OAs) have an increased prevalence of elevated OxS, impaired mitochondrial fuel-oxidation (MFO), elevated inflammation, endothelial dysfunction, insulin resistance, cognitive decline, muscle weakness, and sarcopenia, but contributing mechanisms are unknown, and interventions are limited/lacking. We previously reported that inducing deficiency of the antioxidant tripeptide glutathione (GSH) in young mice results in mitochondrial dysfunction, and that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improves naturally-occurring GSH deficiency, mitochondrial impairment, OxS, and insulin resistance.
This pilot trial in OA was conducted to test the effect of GlyNAC supplementation and withdrawal on intracellular GSH concentrations, OxS, MFO, inflammation, endothelial function, genotoxicity, muscle and glucose metabolism, body composition, strength, and cognition. A 36-week open-label clinical trial was conducted in eight OAs and eight young adults (YAs). OAs were studied again after GlyNAC supplementation for 24 weeks, and GlyNAC withdrawal for 12 weeks.
GlyNAC supplementation for 24 weeks in OA corrected red blood cell GSH deficiency, OxS, and mitochondrial dysfunction; and improved inflammation, endothelial dysfunction, insulin-resistance, genomic-damage, cognition, strength, gait-speed, and exercise capacity; and lowered body-fat and waist-circumference. However, benefits declined after stopping GlyNAC supplementation for 12 weeks.