Plasma glycine decelerates biological aging via the redox-inflammatory axis: A large-scale study modulated by sex and...

Glycine serves as a critical substrate for glutathione synthesis and a critical modulator of redox homeostasis. However, whether plasma glycine is associated with biological aging, and the underlying interplay between oxidative stress, inflammation, and dietary context remains unclear.

We analyzed the UK Biobank data to investigate the association between plasma glycine and biological aging, primarily assessed by the Klemera-Doubal Method (KDM) residuals. Restricted cubic splines were used to assess the nonlinear relationships. Mediation analysis assessed the roles of inflammatory and oxidative stress markers. Interactive analysis was applied to explore the relationship between comprehensive dietary patterns and glycine-related aging.

Higher plasma glycine was negatively associated with KDM residuals (β: -0.729, 95%CI: -0.815, -0.643). Mediation analysis demonstrated that the inverse glycine-aging association was partially explained by reduced systemic inflammation and modulation of redox biomarkers (mediation proportions: 3.9% to 25.6%). Exploratory in silico Gene Ontology (GO) analysis provided supportive evidence implicating oxidative stress and inflammatory responses in these pathways. Notably, we identified a sex-specific diet interaction, the inverse association between glycine and KDM residuals was attenuated in males consuming a pro-inflammatory and pro-oxidative diet (β: -0.757, 95%CI: -1.294, -0.220) compared to the anti-inflammatory and anti-oxidative diet group (β: -0.939, 95%CI: -1.402, -0.476) (p for interaction = 0.014). No such interaction was observed in females.

Plasma glycine negatively correlated with biological aging, partly through modulation of the redox-inflammatory axis. The male-specific vulnerability to pro-oxidative and pro-inflammatory diets highlights that glycine's efficacy is contingent upon a favorable nutritional context. These results support for precision interventions integrating glycine optimization with anti-inflammatory dietary patterns to extend healthy longevity.