Metabolomic signatures of mid-life obesity persist into old age in association with cardiac ageing

Abstract Background Obesity and co-morbid metabolic conditions accelerate cardiac ageing. The extent and mechanisms of a "legacy effect" of elevated mid-life body mass index (BMI) on future cardiovascular function in old age have not been investigated. Hypothesizing that mid-life obesity is associated with a distinct metabolomic signature that persists into old age, we investigated longitudinal patterns in circulating metabolomics and their impact on cardiovascular structure and function in old age. Methods In a prospective cohort of community adults, we analyzed longitudinal targeted metabolomic profiles (acylcarnitines and amino acids) based on sera collected at mid-life and later-life, in association with echo assessments of left ventricular mass and diastolic function|expressed as the ratio of early (E) to late (A) diastolic mitral filling velocities|in later-life. After standardizing metabolite concentrations using z-scoring, mean differences between normal vs. elevated BMI (23kg/m2) groups at both time points were compared using Wilcoxon rank sum test; and displayed using volcano plots, which highlight metabolites with the greatest differences in terms of fold-change or p values from Wilcoxon rank sum test. Results We studied 367 subjects (mean age 59±4 years; 48.5% women; 6% diabetic; 30% hypertensive; and 28% smokers) with mean BMI 23±3 kg/m2. After 15 years, their mean BMI was 24±4 kg/m2. At mid-life, the branched-chain amino acid valine along with its acyl-carnitine metabolites C4- and C5-carnitine as well as related amino acids phenylalanine and tyrosine showed positive associations with BMI; and glycine, an inverse association, independent of age, sex, hypertension, diabetes, and smoking status. These associations at mid-life persisted into later-life, except for glycine (Table). Subjects with elevated vs. normal BMI at mid-life had 30 and 2 metabolites with higher and lower concentrations, respectively, whereas subjects categorized by later-life BMI had only 5 differentially abundant metabolites (Figure). Mid-life BMI was positively and inversely associated with left ventricular mass index (β = 1.16, 95% CI 0.041, 2.279, p = 0.042) and E/A ratio (β = -0.014, 95% CI -0.027, -0.001, p = 0.039), respectively, assessed in later-life. Conclusion Mid-life BMI is associated with cardiac structural and diastolic functional alterations in old age. Markers of branched chain amino acids and one-carbon metabolism pathways associate with BMI in mid-life and later-life. Glycine serves as a one-carbon donor for many metabolic pathways, including anti-oxidant defence; its impact on these is more prominent for elevated BMI at mid-life than in old age. These findings broaden our understanding into specific metabolic pathways that may be altered by mid-life BMI, attesting to the legacy effect of mid-life obesity on adverse cardiovascular function in ageing.