Supplementing Glycine and N-acetylcysteine (GlyNAC) in Aging HIV Patients Improves Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Endothelial Dysfunction, Insulin Resistance, Genotoxicity, Strength, and Cognition: Results of an Open-Label Clinical Trial

Abstract

Background: Patients with HIV (PWH) develop geriatric comorbidities, including functional and cognitive decline at a younger age. However, contributing mechanisms are unclear and interventions are lacking. We hypothesized that deficiency of the antioxidant protein glutathione (GSH) contributes to multiple defects representing premature aging in PWH, and that these defects could be improved by supplementing the GSH precursors glycine and N-acetylcysteine (GlyNAC). Methods: We conducted an open label clinical trial where eight PWH and eight matched uninfected-controls were studied at baseline. PWH were studied again 12-weeks after receiving GlyNAC, and 8-weeks after stopping GlyNAC. Controls did not receive supplementation. Outcome measures included red-blood cell and muscle GSH concentrations, mitochondrial function, mitophagy and autophagy, oxidative stress, inflammation, endothelial function, genomic damage, insulin resistance, glucose production, muscle-protein breakdown rates, body composition, physical function and cognition. Results: PWH had significant defects in measured outcomes, which improved with GlyNAC supplementation. However, benefits receded after stopping GlyNAC. Conclusions: This open label trial finds that PWH have premature aging based on multiple biological and functional defects, and identifies novel mechanistic explanations for cognitive and physical decline. Nutritional supplementation with GlyNAC improves comorbidities suggestive of premature aging in PWH including functional and cognitive decline, 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

“…GSH levels have been reported to be inversely related to multimorbidity in OA 49 . OAs have an increased prevalence of GSH deficiency 42–44 .…”

“…GSH levels have been reported to be inversely related to multimorbidity in OA. 49 OAs have an increased prevalence of GSH deficiency. [42][43][44] GlyNAC supplementation for 24 weeks corrected GSH deficiency, OxS and oxidant damage, but improvement in GSH and OxS reverted to pre-supplementation levels 12 weeks after stopping GlyNAC, suggesting that continued supplementation of GlyNAC is necessary for maintenance of benefits.…”

GlyNAC (Glycine and N-Acetylcysteine) Supplementation Improves Impaired Mitochondrial Fuel Oxidation and Lowers Insulin Resistance in Patients with Type 2 Diabetes: Results of a Pilot Study

“…Plasma insulin concentrations were measured using a commercially available, highly specific radioimmunoassay kit for human insulin (Linco Research, St. Charles, MO, USA). Insulin resistance was calculated (as HOMA-IR) as reported by us in prior studies [ 42 , 43 , 44 ]. Plasma free-fatty acid concentrations were measured using a spectrophotometric assay (Wako Chemicals, Neusse, Germany).…”

“…The results of these rodent studies suggest that GSH adequacy is critically important for optimal and efficient mitochondrial function, and that GlyNAC supplementation could be important for improving mitochondrial dysfunction and lowering IR. We tested this in human clinical trials involving older humans and in HIV-infected patients, and found that GlyNAC supplementation for a short duration of 2 weeks was sufficient to improve mitochondrial dysfunction and lower IR in both trials [ 41 , 42 ], but also that GlyNAC supplementation over longer durations ranging from 12–24 weeks reversed, corrected and normalized mitochondrial dysfunction compared to controls, also further improved IR [ 43 , 44 ]. However, stopping GlyNAC supplementation in both trials resulted in a recurrence of mitochondrial dysfunction and worsening of IR [ 43 , 44 ].…”

“…We tested this in human clinical trials involving older humans and in HIV-infected patients, and found that GlyNAC supplementation for a short duration of 2 weeks was sufficient to improve mitochondrial dysfunction and lower IR in both trials [ 41 , 42 ], but also that GlyNAC supplementation over longer durations ranging from 12–24 weeks reversed, corrected and normalized mitochondrial dysfunction compared to controls, also further improved IR [ 43 , 44 ]. However, stopping GlyNAC supplementation in both trials resulted in a recurrence of mitochondrial dysfunction and worsening of IR [ 43 , 44 ]. These observations indicate causality where defects improve with GlyNAC supplementation, and recur after stopping GlyNAC.…”