Glycine and N-acetylcysteine supplementation, with or without exercise, in brain health and functional aging: implications for sarcopenia and frailty in older adults.

Aging is closely associated with oxidative stress, mitochondrial dysfunction, chronic inflammation, and progressive declines in muscle and cognitive function. Exercise is widely recognized as the most effective non-pharmacological strategy to counteract these processes; however, its benefits may be potentiated by targeted nutritional interventions. Glycine and N-acetylcysteine (NAC), both precursors of the antioxidant glutathione, have emerged as promising candidates for maintaining redox balance, supporting mitochondrial metabolism, and improving physiological resilience in older adults. Evidence on NAC suggests context-dependent effects, with supplementation improving glutathione availability, fatigue resistance, and exercise performance in individuals with low baseline glutathione, while results remain inconsistent in healthy populations. Glycine and its derivatives, such as glycine propionyl-L-carnitine, show potential to enhance anaerobic performance and reduce lactate accumulation, though findings are mixed and require confirmation in older cohorts. Increasingly, studies on combined glycine and NAC supplementation (GlyNAC) provide compelling proof-of-concept: clinical and preclinical trials demonstrate improvements in oxidative stress, mitochondrial dysfunction, insulin resistance, inflammation, muscle strength, cognition, and even lifespan extension in animal models. These results suggest that GlyNAC, especially when paired with exercise, may represent a novel paradigm to mitigate aging hallmarks and extend healthspan.