Trial of GlyNAC in Older Adults with COVID-19: Glutathione, Inflammation and Recovery

The global pandemic caused by the novel Coronavirus SARS-Cov-2 results in COVID-19 and is associated with a very high mortality rate ranging from 3% (in USA) to 14% (in Italy) Increased age is identified as a high-risk group for COVID-19due to significantly high mortality in older adults (OA). It is not clear why COVID-19 is associated with high mortality, but emerging evidence from hospitalized patients has identified a `cytokine storm' with severely elevated inflammatory cytokines (especially IL-6) as a potential contributor. Increased inflammation in patients with COVID-19 is reported to correlate negatively with peripheral lymphocyte populations, and contributes to immune dysfunction. We have studied aging for >20 years, and found that correcting the deficiency of the endogenous antioxidant protein glutathione (GSH) is critically important to lower inflammation, elevated oxidative stress (OxS) and impaired mitochondrial fatty-acid oxidation (MFO)in OA. GSH is the most abundant endogenous, intracellular, antioxidant protein and functions by protecting cells from toxic OxS generated during mitochondrial energy production. OA are deficient in GSH. We have identified and validated an effective, simple and safe nutritional intervention called GlyNAC (combination of GSH precursors glycine and NAC-N-acetylcysteine) to correct GSH deficiency in OA. GSH is identified as a potential candidate to combat COVID-19, but has not been studied in OA with COVID-19.We recently completed a 16-week NIH-funded double-blind placebo-controlled randomized clinical trial in OA with outcomes measured at 2-weeks and 16-weeks. GlyNAC supplementation for 14-days led to: (1) RBC-GSH ­40%; (2) lowered inflammation; (3) lower OxS; (4) improved mitochondrial function.In earlier pilot studies in OA we found that: (1) OA had striking GSH deficiency, elevated OxS and impaired MFO; (2) GSH deficiency in OA occurs due to diminished synthesis, caused by decreased availability of its precursor amino-acids glycine and cysteine, and can be improved by supplementing GlyNAC for 14-days [; (3) GlyNAC supplementation improved inflammation, OxS , MFO, cognition and function.These results are highly relevant to OA with COVID-19 because: (1) OA with COVID-19 have a high mortality risk; (2) increased inflammation is associated with high mortality in COVID-19; (3) GSH is identified as a potential candidate tocombat COVID-19; (4) OA have GSH deficiency, chronic inflammation and cognitive impairment and GlyNAC corrects these defects in OA; (5) GlyNAC has a strong safety profile in our trials; (6) GlyNAC, GSH and OxS have not been studiedin COVID-19. (7) GSH prevents replication of the influenza virus in rodents. Based on these data, we propose an exploratory pilot randomized clinical trial to test the effect of supplementing GlyNACvs. placebo for 14-days in hospitalized in OA with COVID-19 to determine the impact on clinical improvement, recovery,survival, cognition, function, inflammation, immune and mitochondrial function, GSH concentrations and oxidative stress.If successful, this could identify GlyNAC as a novel nutritional supplement to improve the health of patients with COVID.