The results of a pilot human clinical trial conducted by researchers at Baylor College of Medicine suggest that taking a supplement known as GlyNAC—a combination of glycine and N-acetylcysteine (NAC) as precursors of the natural antioxidant glutathione (GSH)—could improve many age-associated deficiencies in older people, to improve muscle strength and cognition, and promote healthy aging.

The small-scale study showed that older humans taking GlyNAC for 24 weeks demonstrated improvements in many characteristic defects of aging, including glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, body fat, muscle strength, genomic toxicity, gait speed, exercise capacity, and cognitive function.

“The overall findings of the current study are highly encouraging,” said Rajagopal Sekhar, MD, associate professor of medicine in the Section of Endocrinology, Diabetes and Metabolism at Baylor. “They suggest that GlyNAC supplementation could be a simple and viable method to promote and improve healthy aging in older adults. We call this the ‘Power of 3’ because we believe that it takes the combined benefits of glycine, NAC and glutathione to reach this far reaching and widespread improvement.”

Sekhar and colleagues reported on their findings in a paper in Clinical and Translational Medicine, in which they concluded, “Dietary supplementation of GlyNAC could improve the cellular, mitochondrial, and metabolic health of OA, improve strength and cognition, and thereby promote healthy aging.” Their report is titled, “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.”

Mitochondrial dysfunction and oxidative stress (OxS) are believed to play a causal role in the aging process, the authors wrote. “Aging in older adults (OA) is associated with declining cognition, declining physical function, elevated inflammation, endothelial dysfunction, insulin resistance, and central obesity.” However as Sekhar pointed out, “there is limited understanding as to why these defects occur in older humans, and effective interventions to reverse these defects are currently limited or lacking.”

To help try and understand what causes unhealthy aging, scientific research has identified nine hallmark defects that are believed to contribute to the aging process. “The field of geroscience has identified at least nine hallmark defects of aging which are believed to contribute to the aging process,” the team explained. “These hallmark defects of aging include mitochondrial dysfunction, dysregulated nutrient sensing (which includes insulin resistance), altered intercellular communication (which includes inflammation), genomic instability, loss of proteostasis, epigenetic alterations, cellular senescence, telomere attrition, and stem cell exhaustion.”

Sekhar said, “It is believed that correcting these aging hallmarks could improve or reverse many age-related disorders and help people age in a healthier way. However, we do not fully understand why these hallmark defects happen, and there are currently no solutions to fix even a single hallmark defect in aging.”

For the last 20 years, Sekhar and his team have been studying natural aging in older humans and aged mice. Their prior work has highlighted the links between mitochondria and aging. Mitochondria generate energy needed for supporting cellular functions by burning fat and sugar from foods, so mitochondrial health is critically important for life. Sekhar believes that improving the health of malfunctioning mitochondria in aging is the key.

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—which is the most abundant antioxidant in our cells—to neutralize these toxic free radicals. “During the process of fuel oxidation, mitochondria generate toxic reactive oxygen species (ROS) which results in harmful OxS, and therefore mitochondria depend on antioxidants for protection from the damaging effects of OxS,” the team noted. Failing to neutralize free radicals leads to harmful and damaging oxidative stress that can affect mitochondrial function. Interestingly, glutathione (GSH) levels in older people are much lower than those in younger people, and the levels of oxidative stress are much higher.

Animal studies conducted in the Sekhar lab had previously shown that lack of GSH even in young mice was linked with mitochondrial dysfunction, while restoring glutathione levels by providing GlyNAC reversesd glutathione deficiency, reduced oxidative stress and fully restored mitochondrial function in aged mice. “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,” they wrote.

The team’s previous work had also shown that supplementing HIV patients with GlyNAC improved multiple deficits associated with premature aging observed in those patients, Sekhar added. “In this study, we wanted to understand the effects of GlyNAC supplementation on many age-associated defects in older adults.”

To further understand whether GlyNAC might hold the key to mitochondrial recovery, Sekhar and colleagues conducted their pilot clinical trial in older humans. “We worked with eight older adults 70 to 80 years of age, comparing them with gender-matched younger adults between 21 and 30 years old,” Sekhar said. “We measured glutathione in red blood cells, mitochondrial fuel-oxidation, plasma biomarkers of oxidative stress and oxidant damage, inflammation, endothelial function, glucose and insulin, gait-speed, muscle strength, exercise capacity, cognitive tests, gene-damage, glucose-production and muscle-protein breakdown rates and body composition. Before taking GlyNAC, all these measurements were abnormal in older adults when compared with those in younger people.”

The older participants took GlyNAC for 24 weeks, and then stopped it for 12 weeks. Sekhar and his colleagues repeated the measurements at the halfway point at 12 weeks, after 24 weeks of taking GlyNAC, and again after stopping GlyNAC for 12 weeks. GlyNAC supplementation was well tolerated during the study period. The benefits declined after stopping GlyNAC supplementation for 12 weeks.

Encouragingly, the results showed that continued GlyNAC supplementation for 24 weeks appeared to improve four of the nine aging hallmark defects. “… it is exciting that this study finds that GlyNAC supplementation appears to improve the components of four aging hallmarks (i.e., improvements in mitochondrial dysfunction, inflammation, insulin resistance and genomic damage) …” the authors wrote. “The results of this trial suggest that GlyNAC supplementation in OA is well tolerated and could play a novel role in improving healthy aging in OA by correcting GSH deficiency, OxS, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, body fat, muscle strength, gait speed, and cognitive function.”

Sekhar further stated, “We are very excited by the results. After taking GlyNAC for 24 weeks, all these defects in older adults improved and some reversed to the levels found in young adults … I am particularly encouraged by the improvements in cognition and muscle strength. Alzheimer’s disease and mild cognitive impairment (MCI) are serious medical conditions affecting memory in older people and leading to dementia, and there are no effective solutions for these disorders. We are exploring the possibility that GlyNAC could help with these conditions by conducting two pilot randomized clinical trials to test whether GlyNAC supplementation could improve defects linked to cognitive decline in Alzheimer’s disease and in MCI, and possibly improve cognitive function. We also have completed a randomized clinical trial on supplementing GlyNAC vs. placebo in older adults and those results will be forthcoming soon.”

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