Systemic aging alters ocular structures and plasma metabolome, yet relationships between multidimensional biological aging, environmental exposomes, plasma metabolism, and retinal changes remain uncharacterized. This study evaluated how these phenotypic networks align with retinal structural variations. Following rigorous screening, 45,542 UK Biobank participants (2006-2010) were analyzed. Systemic aging was quantified using PhenoAge acceleration, Klemera-Doubal method age acceleration (KDM-BA), and a frailty index (FI). Plasma metabolic signatures were derived from nuclear magnetic resonance profiling via elastic net regression, and exposome factors (lifestyle, diet, pollution, mental health) were assessed via phenotypic data. Mediation analyses evaluated the intermediary roles of plasma metabolites. Biological age acceleration and frailty showed significant inverse associations with macular thickness across all inner subfields (standardized β range -1.386 to -0.421, all FDR-adjusted P < 0.001). Metabolic signatures accounted for substantial proportions of these associations: 81.14% for PhenoAge acceleration, 19.92% for KDM-BA acceleration, and 32.27% for FI (all FDR-adjusted P < 0.001). Integrative analyses demonstrated that adverse exposomes-including tobacco exposure, poor diet, air pollution, and negative psychosocial states-correlated with reduced macular thickness, with systemic aging and metabolic dysregulation serving as significant statistical intermediaries within these multidimensional pathways. These findings demonstrate a robust link between systemic senescence and retinal structure, suggesting that plasma metabolism is a key correlate of neurosensory retinal integrity.
