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.

BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial. METHODS: Twenty-four OA and 12 young adults (YA) were studied. OA was randomized to receive either GlyNAC (N = 12) or isonitrogenous alanine placebo (N = 12) for 16-weeks; YA (N = 12) received GlyNAC for 2-weeks. Participants were studied before, after 2-weeks, and after 16-weeks of supplementation to assess GSH concentrations, OxS, MFO, molecular regulators of energy metabolism, inflammation, endothelial function, IR, aging hallmarks, gait speed, muscle strength, 6-minute walk test, body composition, and blood pressure. RESULTS: Compared to YA, OA had GSH deficiency, OxS, mitochondrial dysfunction (with defective molecular regulation), inflammation, endothelial dysfunction, IR, multiple aging hallmarks, impaired physical function, increased waist circumference, and systolic blood pressure. GlyNAC (and not placebo) supplementation in OA improved/corrected these defects. CONCLUSION: GlyNAC supplementation in OA for 16-weeks was safe and well-tolerated. By combining the benefits of glycine, NAC and GSH, GlyNAC is an effective nutritional supplement that improves and reverses multiple age-associated abnormalities to promote health in aging humans. Clinical Trials Registration Number: NCT01870193.

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.

Determinants of length of life are not well understood, and therefore increasing lifespan is a challenge. Cardinal theories of aging suggest that oxidative stress (OxS) and mitochondrial dysfunction contribute to the aging process, but it is unclear if they could also impact lifespan. Glutathione (GSH), the most abundant intracellular antioxidant, protects cells from OxS and is necessary for maintaining mitochondrial health, but GSH levels decline with aging. Based on published human studies where we found that supplementing glycine and N-acetylcysteine (GlyNAC) improved/corrected GSH deficiency, OxS and mitochondrial dysfunction, we hypothesized that GlyNAC supplementation could increase longevity. We tested our hypothesis by evaluating the effect of supplementing GlyNAC vs. placebo in C57BL/6J mice on (a) length of life; and (b) age-associated GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage in the heart, liver and kidneys. Results showed that mice receiving GlyNAC supplementation (1) lived 24% longer than control mice; (2) improved/corrected impaired GSH synthesis, GSH deficiency, OxS, mitochondrial dysfunction, abnormal mitophagy and nutrient-sensing, and genomic-damage. These studies provide proof-of-concept that GlyNAC supplementation can increase lifespan and improve multiple age-associated defects. GlyNAC could be a novel and simple nutritional supplement to improve lifespan and healthspan, and warrants additional investigation.

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.

BACKGROUND: 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. METHODS: A 36-week open-label clinical trial was conducted in eight OAs and eight young adults (YAs). After all the participants underwent an initial (pre-supplementation) study, the YAs were released from the study. OAs were studied again after GlyNAC supplementation for 24 weeks, and GlyNAC withdrawal for 12 weeks. Measurements included red-blood cell (RBC) GSH, MFO; plasma biomarkers of OxS, inflammation, endothelial function, glucose, and insulin; gait-speed, grip-strength, 6-min walk test; cognitive tests; genomic-damage; glucose-production and muscle-protein breakdown rates; and body-composition. RESULTS: GlyNAC supplementation for 24 weeks in OA corrected RBC-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. CONCLUSIONS: GlyNAC supplementation for 24-weeks in OA was well tolerated and lowered OxS, corrected intracellular GSH deficiency and mitochondrial dysfunction, decreased inflammation, insulin-resistance and endothelial dysfunction, and genomic-damage, and improved strength, gait-speed, cognition, and body composition. Supplementing GlyNAC in aging humans could be a simple and viable method to promote health and warrants additional investigation.