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Reversing Accelerated Aging in HIV patients: Metabolic and Mitochondrial Mechanisms
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Reported by Jules Levin
CROI 2018 March 4-7 Boston, MA
Sekhar RV1,2, Hsu JW3, Suliburk J3, Liu R2, Minard C3, Yechoor V2, Jahoor F3, Liu C1,2,3 1Translational Metabolism Unit, 2Division of Endocrinology, Diabetes and Metabolism, 3Baylor College of Medicine, Houston, TX
Program Abstract:
HIV-infected patients are reported to have 'accelerated aging' based on rapid physical and functional decline. Such patients have muscle weakness, decreased exercise capacity, fat accumulation, muscle loss and impaired mitochondrial fuel oxidation (MFO), but underlying mechanisms are unknown and interventions lacking. We investigated deficiency of the intracellular antioxidant glutathione, GSH) and impaired MFO as metabolic and mitochondrial mechanisms contributing to accelerated aging and functional decline in HIV patients.
An open-label clinical trial (NCT02348775) in 8 older GSH-deficient HIV-infected patients of both genders (aged 50-64y), compared to 8 age, gender and BMI-matched non-HIV controls. HIV subjects were studied before and after 12-weeks of oral supplementation with N-acetylcysteine plus glycine (NAC-Gly, provided as GSH precursors), and again 8-weeks after stopping supplementation. Controls were not supplemented. All subjects underwent muscle biopsy, calorimetry, physical function measures (gait speed, chair-rise test, 6-min walk, grip strength), DEXA scan, anthropometry, and infusion of 2H3-3-methylhistidine tracer to measure the following: glutathione levels in muscle and red-cells, MFO, muscle strength, exercise capacity, body composition, waist-circumference and rate of muscle protein breakdown.
Compared to non-HIV controls, 'older' HIV patients had significantly lower intracellular GSH, impaired MFO, lower gait speed, grip strength and 6-min walk times, higher fat mass and waist circumference, and increased muscle protein breakdown. Molecular analyses indicate a post-translational defect in genes regulating mitochondrial fuel oxidation. With NAC-Gly supplementation over 12weeks all these defects improved significantly; GSH, MFO and gait speed normalized to levels seen in non-HIV controls. Benefits began to recede on stopping supplementation. Results are summarized in attached table.
In HIV patients, deficiency of GSH and impaired mitochondrial fuel oxidation contribute to accelerated aging with decreased muscle strength and exercise capacity, increased muscle breakdown and fat accumulation. Supplementing NAC-Gly fully corrected intracellular GSH deficiency, impaired MFO and gait speed, and also improved strength, exercise capacity, fat mass, waist circumference and muscle loss. These findings suggest a key role for NAC-Gly supplementation and GSH on reversing accelerated aging in HIV, and warrants further investigation.
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