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Background: Metabolomic scores based on age (MetaboAge) and mortality (MetaboHealth) are considered indicators of overall health, but their association with cognition in the general population is unknown. Therefore, the association between MetaboAge/MetaboHealth and level and decline in cognition was studied, as were differences between men and women., Methods: Data of 2821 participants (50% women, age range 45-75) from the Doetinchem Cohort Study was used. MetaboAge and MetaboHealth were calculated from 1H-NMR metabolomics data at baseline. Cognitive domain scores (memory, flexibility and processing speed) and global cognitive functioning were available over a 10-year period. The association between MetaboAge/MetaboHealth and level of cognitive functioning was studied using linear regressions while for the association between MetaboAge/MetaboHealth and cognitive decline longitudinal linear mixed models were used. Analyses were adjusted for demographics and lifestyle factors., Results: Higher MetaboAge, indicating poorer metabolomic ageing, was only associated with lower levels of processing speed in men. Higher MetaboHealth, indicating poorer immune-metabolic health, was associated with lower levels of cognitive functioning for all three domains and global cognitive functioning in both men and women. Only in men, MetaboHealth was also associated with 10-year decline in flexibility, processing speed and global cognition. Metabolites that contributed to the observed associations were in men mainly markers of protein metabolism, and in women mainly markers of lipid metabolism and inflammatory metabolites., Conclusions: MetaboHealth, not MetaboAge, was associated with cognitive functioning independent of conventional risk factors. Individual metabolites affect cognitive functioning differently in men and women, suggesting sex-specific pathophysiological pathways underlying cognitive functioning., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.)

Biological age uses biophysiological information to capture a person's age-related risk of adverse outcomes. MetaboAge and MetaboHealth are metabolomics-based biomarkers of biological age trained on chronological age and mortality risk, respectively. Lifestyle factors contribute to the extent chronological and biological age differ. The association of lifestyle factors with MetaboAge and MetaboHealth, potential sex differences in these associations, and MetaboAge's and MetaboHealth's sensitivity to lifestyle changes have not been studied yet. Linear regression analyses and mixed-effect models were used to examine the cross-sectional and longitudinal associations of scaled lifestyle factors with scaled MetaboAge and MetaboHealth in 24,332 middle-aged participants from the Doetinchem Cohort Study, Rotterdam Study, and UK Biobank. Random-effect meta-analyses were performed across cohorts. Repeated metabolomics measurements had a ten-year interval in the Doetinchem Cohort Study and a five-year interval in the UK Biobank. In the first study incorporating longitudinal information on MetaboAge and MetaboHealth, we demonstrate associations between current smoking, sleeping ≥8 hours/day, higher BMI, and larger waist circumference were associated with higher MetaboHealth, the latter two also with higher MetaboAge. Furthermore, adhering to the dietary and physical activity guidelines were inversely associated with MetaboHealth. Lastly, we observed sex differences in the associations between alcohol use and MetaboHealth., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)