A lipidomic based metabolic age score for monitoring the effects of lifestyle and diet on metabolic disease risk.

Abstract

Biological age scores capture ageing heterogeneity beyond chronological age but are often dominated by lifestyle and environmental exposures, limiting clinical interpretability. We developed an environmentally adjusted metabolic age score (EAmAge) to isolate intrinsic ageing biology relevant to neurodegeneration and chronic disease. Major environmental influences were statistically removed from plasma lipidomic profiles before constructing an age-prediction model using ridge regression. EAmAge was derived in the AusDiab cohort (n = 10,339) and validated across three independent cohorts (BHS, ADNI and ASPREE; total n = 9,835). Compared with an unadjusted lipidomic age model (mAge_orig), EAmAge showed stronger and more consistent associations with incident Alzheimer s disease-related dementia, cardiovascular events and all-cause mortality. EAmAge was also associated with Alzheimer s disease-related biomarkers, including amyloid burden, reduced glucose metabolism and hippocampal atrophy. These findings establish EAmAge as a robust and partially modifiable biomarker that improves risk stratification by disentangling intrinsic metabolic ageing from environmental confounding.