RANDOMIZED CLINICAL TRIAL OF SUPPLEMENTING GLYNAC IN TYPICAL OLDER ADULTS TO PROMOTE HEALTHY AGING - The population of older adults (OA) is rapidly rising and anticipated to exceed 2 billion by 2050 causing an exponential rise in age-related comorbidities and healthcare costs. Age-related defects include mitochondrial dysfunction, inflammation, oxidative stress (OxS), insulin resistance (IR), genomic damage and endothelial dysfunction and result in declining physical function (gait speed and muscle strength), elevated blood pressure (BP) and higher waist circumferences. Via studies in OA and old mice (OM), we identified that deficiency of the body’s most abundant antioxidant Glutathione (GSH) plays a key contributory role for these defects in aging. GSH is an intracellular tripeptide composed of glycine, cysteine and glutamic acid, and declines with age. We found that GSH deficiency in OA occurs due to diminished synthesis caused by deficiency of glycine and cysteine (and not glutamic acid), and that GSH deficiency can be corrected by supplementing GlyNAC (combination of oral glycine, and N-acetyl-cysteine (NAC) as a cysteine donor because oral cysteine is absorbed poorly). In OM and OA, we discovered that GSH adequacy is critically necessary for efficient mitochondrial fuel (fatty-acid) oxidation (MFO) and for lowering OxS. In a small NIH-funded double-blinded, placebo-controlled, proof-of-concept pilot randomized clinical trial (RCT) in 24 highly selected, healthy OA and 12 young adults (YA) we reported that OA had (a) GSH deficiency in muscle and red blood cells; (b) impaired mitochondrial function; (c) deficient nutrient sensing; (d) increased inflammation; (e) elevated IR; (f) endothelial dysfunction; (g) genomic damage; (h) stem cell fatigue; and (i) cellular senescence. These abnormalities were associated with: (i) physical decline in gait speed, strength and exercise capacity; (ii) increased waist circumference; and (iii) higher blood pressure. GlyNAC (and not placebo) supplementation: (a) normalized RBC GSH concentrations, mitochondrial fuel oxidation, molecular regulators of energy metabolism, nutrient sensors, genomic damage, stem cells and cellular senescence; (b) lowered OxS, proinflammatory cytokines (IL6, TNFa, hsCRP); IR; endothelial dysfunction; (c) improved gait speed, strength, exercise capacity, body composition and systolic BP. GlyNAC supplementation in young humans had no impact. These data provide proof-of-concept that supplementing GlyNAC in OA corrects GSH deficiency and improves 7 aging hallmarks, and was not associated with any adverse effects. Could GlyNAC supplementation introduce a transformational change to improve the health of aging humans by promoting healthy aging? Although our completed RCT provides proof-of-concept for this, the sample size was small. Critically, the RCT was conducted in a rigorously screened cohort of healthy OA, using a high dose of GlyNAC. Therefore, it is important to definitively establish the validity and effectiveness of GlyNAC supplementation in a larger RCT conducted in a more typical population of OA, and also determine whether a lower GlyNAC dose, with lesser pill burden, could be effective. We propose a less invasive, less restrictive RCT in 150 more typical OA to determine the effects of supplementing GlyNAC on intracellular GSH, OxS, mitochondrial function, inflammation, IR, endothelial function, genomic damage, physical function, body composition and QoL. The proposed RCT will also test and compare two doses of GlyNAC to determine whether a lower dose of GlyNAC can be as effective as a higher dose on measured outcomes after 24-weeks.
