This cross-sectional study of 27,375 UK Biobank adults (ages 40–70) examined whether metabolic syndrome (MetS) is associated with accelerated brain aging, measured as brain age gap (BAG = MRI-estimated brain age minus chronological age), and whether plasma metabolites mediate this association. MetS required ≥3 of 5 components; brain age was modeled from 1,079 MRI phenotypes across 6 modalities using LASSO regression.
MetS was associated with a BAG of +1.26 years (β = 1.13; 95% CI: 0.99–1.27). BAG rose dose-dependently from 0.13 years (1 component) to 2.30 years (all 5 components). All five individual MetS components were independently associated with higher BAG, with the strongest effects from hyperglycemia (β = 1.08) and elevated blood pressure (β = 1.10). Eight plasma metabolites significantly mediated the MetS–BAG link, with PUFA% (16.5%), Ω-6% (14.0%), and GlycA (11.1%) accounting for the largest shares.
- UK Biobank healthy volunteer bias likely underestimates the true MetS–BAG association; the imaging subsample was younger and metabolically healthier than the broader cohort. - Cross-sectional design with MetS and metabolites measured at baseline (~9 years before MRI) prevents causal inference or longitudinal tracking of brain aging pace. - Sample is 93% White, limiting generalizability to non-European populations.
Even having just one or two MetS components is linked to meaningfully older-appearing brains, so clinicians should treat MetS components early and collectively—not only to reduce cardiovascular risk but to protect brain health. Monitoring inflammatory markers (GlycA) and lipid profiles (ApoB, PUFA ratios) may help identify patients at greatest risk for accelerated brain aging.
