The Power of Three, Redux: Glycine and N-Acetylcysteine (GlyNAC) Increases Mouse Lifespan By 24%

Aging better doesn’t always mean aging longer. For example, while traditional aging theories claim that oxidative stress and dysfunction of mitochondria – our cellular power generators – play a role in the aging process, it's uncertain if these two processes also affect longevity. Curiously, the most prevalent intracellular antioxidant, glutathione, shields cells against oxidative stress and is required for mitochondrial function, but glutathione levels diminish with age.

Building on their previous research in humans showing that supplementing with glycine and N-acetylcysteine (GlyNAC) can improve glutathione deficiency, oxidative stress, and mitochondrial dysfunction, researchers from Baylor College of Medicine now show that GlyNAC supplementation resulted in mice living 24% longer than untreated mice. Just like the human results, GlyNAC supplementation in mice corrected defective glutathione synthesis, glutathione shortage, oxidative stress, mitochondrial dysfunction, nutrient sensing, and genomic damage. These studies show that GlyNAC supplementation can enhance the lifespan and improve a variety of age-related abnormalities, providing the theoretical basis for this unique and easy dietary supplement to help people live longer and healthier lives.

“There is growing interest in being able to improve both healthy aging and longer life, but this is not an easy task. We have investigated aging in mice and in human studies for two decades, and our studies show that GlyNAC supplementation successfully and consistently improves many age-related defects,” said senior author Rajagopal V. Sekhar, M.D. “It is exciting that something as simple as GlyNAC can improve several important defects in aging and also extend life.”

GlyNAC and The Power of Three

Glutathione – composed of glycine, cysteine, and glutamic acid – is the most prevalent endogenous intracellular antioxidant tripeptide. Glutathione levels tend to fall as people become older, which coincides with an increase in age-related oxidative stress and mitochondrial dysfunction. Shekar and co-author Premranjan Kumar previously published that glutathione adequacy is crucial for optimal mitochondrial fuel oxidation. 

In human studies, adding GlyNAC not only repaired glutathione shortage, oxidative stress, and mitochondrial dysfunction, but the glutathione precursor enhanced nutrition sensing, lessened genomic damage, and reversed premature aging in HIV patients. In doing so, they developed the expression 'the power of three' to describe how the combined actions of glycine, NAC, and glutathione resulted in benefits.

GlyNAC Increased Mouse Lifespan

Since GlyNAC supplementation improves multiple fundamental defects associated with human aging, Kumar, Osahon, and Sekhar predicted that GlyNAC supplementation could improve longevity by improving glutathione deficiency, oxidative stress, mitochondrial dysfunction, nutrient sensing abnormalities, and genomic damage at the organ level. To test this, the Baylor College of Medicine researchers supplemented mice with GlyNAC from the age of 65-weeks – representing humans in their late 40s and early 50s – for the rest of their natural life, finding that GlyNAC supplementation in mice increases life span by 24%.

What caused this to happen? The solutions likely lie in rectifying several problems, including glutathione shortage as well as oxidative stress, mitochondrial dysfunction, aberrant nutrition sensing, and genomic damage – the latter of which are hallmarks of aging. In this study, Kumar, Osahon, and Sekhar show that GlyNAC supplementation reverses these abnormalities in three important organs: heart, liver, and kidneys. This is consistent with previous studies showing that GlyNAC supplementation can support healthy heart, liver, and kidney function.

GlyNAC supplementation can reverse premature aging and increase muscular strength, exercise capacity, insulin resistance, cognition, blood pressure, body composition, and quality of life, according to published human research. GlyNAC supplementation increases cognition in elderly individuals and HIV-infected people, as the Baylor College of Medicine showed in previous research. These findings imply that GlyNAC may support the health of various organ systems, including the brain and neurological system, and that more research is needed.

Why was this research done on mice rather than humans?

“But mice are not humans. Could this happen in people? There is published evidence from our human studies showing that GlyNAC supplementation improves similar defects in people,” Sekhar said.

The time it takes to confirm or refute the tested intervention is an obstacle to conducting human clinical trials to test the effect on length of life. Studying rodents or other models can practically provide a proof-of-concept because they can be done in a time-sensitive manner. These results on the effects of GlyNAC on people have substantial implications for longevity.

GlyNAC Is Not the Same as Glycine or NAC on Their Own

If you’re thinking about supplementing with GlyNAC, you have to do just that – you cannot use either glycine or cysteine. Glycine is not provided by NAC alone, and only GlyNAC contains both the glycine and cysteine required for glutathione production. GlyNAC supplementation enhances glutathione synthesis and concentrations to address glutathione deficit in various important organs of the body, according to results from this study. There has been no evidence of NAC-alone extending mammalian life while feeding NAC-alone in roundworms (C. elegans) has been shown to accelerate aging and diminish longevity. GlyNAC supplementation, on the other hand, extends the life of mice, as revealed in this paper.

What About Supplementing With Glutathione?

Glutathione supplementation has not been shown to improve mammalian longevity in investigations. In fact, glutathione supplementation, on the other hand, was observed to accelerate aging and decrease life in C. elegans. Supplemental glutathione is connected with the risk of generating reductive stress because various organs maintain varied quantities of glutathione.

GlyNAC avoids this issue by enabling cells to autoregulate and maintain their needed glutathione balance; GlyNAC does not interfere with cellular autoregulation, allowing cells to produce the required quantity of glutathione depending on a cell’s requirement. This is significant because the cellular demand for glutathione in each organ changes continually and dynamically and is impacted by changes in metabolic activity induced by feeding/fasting, rest/activity, and waking/sleep.

What’s Next for GlyNAC?

The key disadvantage of this pilot exploratory study is that it was done in a minimal number of mice. Also, the data is not presented from every organ in the body, despite showing proof-of-concept that GlyNAC supplementation from a younger age can improve life span. The favorable findings of this study suggest the necessity for more significant numbers of mice of both genders in future studies and investigation of the effects in other organs in male and female mice to discover gender differences. 

References:

Kumar P, Liu C, Hsu JW, et al. 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. Clin Transl Med. 2021;11(3):e372. doi:10.1002/ctm2.372

Kumar P, Osahon OW, Sekhar RV. 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. Nutrients. 2022;14(5):1114. Published 2022 Mar 7. doi:10.3390/nu14051114