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.
Highlights
Effective antiretroviral therapy has improved the health and life expectancy of people with HIV (PWH) [1,2]
In a small pilot study in such ‘older’ Patients with HIV (PWH) with premature aging, we investigated the mechanisms contributing to GSH deficiency and its link with mitochondrial fat and glucose oxidation, and reported that (a) GSH deficiency in PWH occurs due to diminished synthesis caused by deficiency of its precursor amino-acids glycine and cysteine [13]; (b) supplementing glycine and N-acetylcysteine (GlyNAC)
This study found that compared to controls, PWH with premature aging have elevated muscle protein breakdown rate (MPBR), and that GlyNAC supplementation lowered the Muscle protein breakdown rate (MPBR) to levels seen in controls
Summary
Effective antiretroviral therapy has improved the health and life expectancy of people with HIV (PWH) [1,2]. Premature aging in PWH is being recognized as a new, significant public health challenge, there is limited knowledge about underlying causal mechanisms, and effective interventions are lacking. Patients with HIV (PWH) develop geriatric comorbidities, including functional and cognitive decline at a younger age. 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). Results: PWH had significant defects in measured outcomes, which improved with GlyNAC supplementation. 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
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