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. 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 provided capsules of glycine (1.33 mmol/kg/day) and cysteine (0.81 mmol/kg/day, provided as N‐acetylcysteine [NAC]) prepared by a licensed pharmacist, and replenished every 4 weeks for 24 weeks. Compliance with GlyNAC supplementation was assessed with phone calls and capsule counting every 4‐weeks when OA returned to collect GlyNAC capsules for the next 4‐weeks and to have blood drawn for monitoring renal (creatinine) and liver function (as ALT and AST).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.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.