Glutathione declines during aging. To illustrate that point, let’s take a look at 3 different studies.

First, when comparing people in the 21 to 61y+ age range, blood GSH levels declined by about 50% (Yang et al. 1995). Second, 70yr olds have 15% less glutathione when compared with newborns (Inal et al. 2002). Third, GSH was 33% reduced when comparing the youngest group, 20-29y, vs the oldest, > 60y (Qui-lin et al. 2005).

With these data in mind, can restoring glutathione levels in older adults improve health-related measures?

To optimize GSH, first we need to know what it’s made of. Glutathione is a tripeptide, which means that it’s made from 3 amino acids, including cysteine, glycine, and glutamate. When considering that glycine and cysteine levels (in blood) decline during aging (Sekhar et al. 2011), strategies aimed at restoring levels of these amino acids may be an important approach for restoring GSH in GSH-deficient older adults.

In 2021, Kumar et al. utilized this approach in a a relatively small (8 older adults, 71-80y, 8 younger adults, 21-30y), 24-week randomized controlled trial (RCT), and found that glycine + N-acetylcysteine (NAC, as a source of cysteine) supplementation (100 mg each for glycine and NAC/kg body weight) impacted multiple health-related parameters, including GSH restoration, reduced oxidative stress, oxidative DNA damage, inflammation, insulin resistance, and endothelial dysfunction, whereas mitochondrial function, body composition (including less fat mass), muscle strength, exercise capacity, and cognition were improved.

In 2022, similar data was published by the same research group (Kumar et al.). In that study, glycine + NAC (again using 100 mg each for glycine and NAC/kg body weight) supplementation in 61-80yr olds (n=11) for 16-weeks improved the same markers that were published in 2021, and impacted others, including improved markers of cell senescence, stem cells, mitophagy, blood pressure, waist size, and gait speed.

When considering the data from these 2 RCTs, GSH restoration may be a promising approach for improving health-related outcomes in GSH-deficient in older adults.

But, that’s not the purpose of this post. Can GSH restoration increase lifespan? Also, do centenarians (people older than 100y) have relatively higher or lower levels of GSH in blood?

First, glycine + NAC (GlyNAC) supplementation extends lifespan (in mice; Kumar et al. 2022). In that study, there were 2 groups of C57BL/6J mice, which were fed a either regular diet (no GlyNAC; 8 males, 8 females), or the regular diet supplemented with GlyNAC (8 males, 8 females), with amounts that were similar to that used in the 2 human RCTs. Supplementation started at 65 weeks of age (equivalent to starting ~40y in people), and when comparing 50% survival, which is the time when half the colony was dead and half was still alive, GlyNAC-supplemented mice had a 24% increased median survival, when compared with control-fed mice.

However, this study had some limitations. 16 mice per group is relatively small for lifespan studies-for example, see my 2 recent CR, fasting, and/or circadian alignment videos, where > 40 mice per group were used to evaluate lifespan. Additionally, no info was published about food consumption or body weight, which is important because if GlyNAC-supplemented mice ate less food than controls, that can explain the lifespan-extending effect. Mild calorie restriction (5%) can impact lifespan, so omission of food intake or body weight is potentially important.

In contrast, this study had strengths, including measuring GSH levels is several tissues-heart, liver and kidney. In those organs, there was a clear, age-related decline for GSH, but, aged mice that were supplemented with GlyNAC had significantly higher GSH when compared with unsupplemented controls. From this we can conclude that the lifespan-extending effect of GlyNAC supplementation is associated with GSH restoration in multiple tissues.

What about the data in centenarians? Earlier, we saw that GSH levels decline during aging, so is it reasonable to expect further declines in people that are 100yrs old (or older)?

In contrast, blood GSH levels were 48% higher in close-to-centenarians (average age, 97y, n=116) when compared with their offspring (average age, 67y, n=232; Xu et al. 2022). Collectively, when considering these data, the 2 human RCTs, and the mouse lifespan study, it suggests that relatively higher levels of GSH may be an important part of a pro-longevity strategy. Interestingly, each of GSH’s component amino acids were also significantly higher in the 97-yr olds, and likely explain the higher levels of GSH found in the centenarians of the Xu study.

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References:

Inal et al: Age-related changes in the glutathione redox system https://pubmed.ncbi.nlm.nih.gov/11835271/

Kumar et al 2021: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 https://pubmed.ncbi.nlm.nih.gov/33783984/

Kumar et al 2022: Supplementing Glycine and N-Acetylcysteine (GlyNAC) in Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, and Aging Hallmarks: A Randomized Clinical Trial https://pubmed.ncbi.nlm.nih.gov/35975308/

Kumar et al 2022: GlyNAC (Glycine and N-Acetylcysteine) Supplementation in Mice Increases Length of Life by Correcting Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Abnormalities in Mitophagy and Nutrient Sensing, and Genomic Damage https://pubmed.ncbi.nlm.nih.gov/35268089/

Nguyen et al: Impaired mitochondrial fatty acid oxidation and insulin resistance in aging: novel protective role of glutathione https://pubmed.ncbi.nlm.nih.gov/23534396/

Qui-lin et al: Age-related changes of the redox state of glutathione in plasma https://pubmed.ncbi.nlm.nih.gov/16232335/

Sekhar et al: Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation https://pubmed.ncbi.nlm.nih.gov/21795440/

Xu et al: Metagenomic and metabolomic remodeling in nonagenarians and centenarians and its association with genetic and socioeconomic factors https://www.nature.com/articles/s43587-022-00193-0

Yang et al: Effect of ageing on human plasma glutathione concentrations as determined by high-performance liquid chromatography with fluorimetric detection https://pubmed.ncbi.nlm.nih.gov/8749248/