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Cellular increases in oxidative stress (OxS) and decline in mitochondrial function are identified as key defects in aging, but underlying mechanisms are poorly understood and interventions are lacking. Defects linked to OxS and impaired mitochondrial fuel oxidation, such as inflammation, insulin resistance, endothelial dysfunction, and aging hallmarks, are present in older humans and are associated with declining strength and cognition, as well as the development of sarcopenic obesity. Investigations on the origins of elevated OxS and mitochondrial dysfunction in older humans led to the discovery that deficiencies of the antioxidant tripeptide glutathione (GSH) and its precursor amino acids glycine and cysteine may be contributory. Supplementation with GlyNAC (combination of glycine and N-acetylcysteine as a cysteine precursor) was found to improve/correct cellular glycine, cysteine, and GSH deficiencies; lower OxS; and improve mitochondrial function, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, and multiple aging hallmarks; and improve muscle strength, exercise capacity, cognition, and body composition. This review discusses evidence from published rodent studies and human clinical trials to provide a detailed summary of available knowledge regarding the effects of GlyNAC supplementation on age-associated defects and aging hallmarks, as well as discussing why GlyNAC supplementation could be effective in promoting healthy aging. It is particularly exciting that GlyNAC supplementation appears to reverse multiple aging hallmarks, and if confirmed in a randomized clinical trial, it could introduce a transformative paradigm shift in aging and geriatrics. GlyNAC supplementation could be a novel nutritional approach to improve age-associated defects and promote healthy aging, and existing data strongly support the need for additional studies to explore the role and impact of GlyNAC supplementation in aging. [ABSTRACT FROM AUTHOR]