Decipher aging related skin microbiome and metabolites crosstalk from a chronologically matched cohort

Aging has shown close link to shifts in the skin microbiome in population cohort study. However, how variations in microbial communities relate to divergent skin aging within individuals of the same chronological ages remains unclear. In this study, we performed phenotypic, metabolomic and metagenomic analyses on 103 women aged 39-41 to investigate how skin microbiota mediate metabolic pathways influencing divergent skin aging. The younger group (based on AI-predicted age and skin elasticity) exhibited fewer wrinkles and higher microbial diversity with more potential probiotics. Meanwhile, the older group displayed increased antibiotic resistance genes in microbiota, exacerbating skin aging vulnerability. Using skin metabolomics and genome-scale metabolic models (GEM), our study revealed that S. maltophilia, enriched in younger individuals, utilizes the glutathione cycle for antioxidant defense and protein thiol maintenance. In Vitro experiments and transcriptome analysis further demonstrated that S. maltophilia upregulates key genes, including GCLM, PGD, SOD2 and NQO1, to enhance GSH synthesis and alleviate oxidative stress-induced skin aging. Additionally, S. maltophilia was significantly correlated with WCSC, and GEM analysis further uncovered its potential anti-aging functions in betaine, lysolecithin and porphyrin metabolism. Moreover, we found that A. guillouiae modulates melanin precursor DA and 3-MT, suggesting a potential therapeutic strategy to mitigate pigmentation during skin aging. Together, our findings illustrate the dynamic regulation between skin microbiota and the host in skin aging, independent of chronological age. This study offers new insights for designing targeted anti-aging interventions.