Glycine ameliorates aging-related dysfunctions associated with Nmdmc-mediated mitochondrial one-carbon metabolism

INTRODUCTION: Aging is characterized by the progressive decline of physiological integrity, and its driving factors include mitochondrial dysfunction, epigenetic changes and metabolic imbalance. Although some studies have shown that glycine (Gly) has anti-aging protection, its mechanism has not been clarified. OBJECTIVES: The purpose of this study is to explore the mechanism of Gly in anti-aging and improving aging-related phenotype, and to clarify the molecular pathway of Gly promoting healthy aging. METHODS: Fruit fly and aged rat models were used to evaluate the effect of Gly supplementation. Life span, stress resistance and functional phenotype were evaluated in fruit flies, and biochemical, histological and physiological indexes related to aging were detected in aged rats. Transcriptomic and metabolomic profiling, along with gene knockdown approaches, were used to identify key pathways and targets involved in Gly-mediated effects. RESULTS: In fruit flies, Gly extended lifespan and ameliorating aging-related phenotypes, with Gly dose-dependently upregulated the expression of Nmdmc, whose knockdown abolished these beneficial effects, indicating the essential role of Nmdmc in Gly-mediated activation of one-carbon metabolism (OCM). Metabolomic identified glyceric acid as a key metabolite linked to improved mitochondrial energy metabolism. In aged rats, Gly also upregulated Mthfd2 (the mammalian ortholog of Nmdmc) and reduced neuronal damage in the hippocampus, restored hepatic cell architecture, and increased muscle fiber density, accompanied by enhanced mitochondrial biogenesis and methylation markers. CONCLUSION: Gly supplementation alleviated aging-related dysfunction by up-regulating Nmdmc and remodeling mitochondrial OCM, which could help to improve DNA repair, mitochondrial function and oxidative stress resistance.