Malnutrition and age-related macular degeneration: mechanistic insights from UK Biobank metabolomic and imaging data

Abstract Background Malnutrition, characterized by degeneration of body composition due to reduced intake or inflammation, shares some common mechanisms with age-related macular degeneration (AMD), while their associations remain unexplored. Methods This cohort study utilized data from the UK Biobank. Participants without pre-existing AMD and with complete malnutrition data were included. Cox regression was employed to evaluate the longitudinal association. An ElasticNet model was used to derive a metabolomic signature of malnutrition, which was subsequently assessed for association with AMD. Malnutrition and the metabolomic signature were further tested for associations with photoreceptor thinning. Structural equation modeling was applied to delineate underlying mechanisms. Results A total of 444 681 participants (mean age: 56.4 ± 8.1 years; 45.8% male) were included, with 32 086 (7.2%) diagnosed with malnutrition at baseline. Over a median follow-up of 13.6 years, 10 009 AMD cases were identified. Malnutrition was associated with an increased risk of AMD (hazard ratio [HR]: 1.221, 95% CI, 1.144-1.304, p < .001). The metabolomic signature of malnutrition, derived from 127 metabolites, was significantly associated with AMD risk (per SD increase: HR: 1.073, 95% CI, 1.037-1.110, p < .001) and thinner photoreceptor layer (β = −.214, 95% CI, −0.314 to −0.114, p < .001). Structural equation modeling revealed that malnutrition increased AMD risk partially through metabolomic changes that induced photoreceptor thinning. Conclusions Malnutrition in middle-aged adults was significantly associated with increased risk of AMD, which was mediated by metabolomic alterations that impaired photoreceptor health.