Plasma metabolites of a healthy lifestyle in relation to mortality and longevity: Four prospective US cohort studies

Abstract

Background: A healthy lifestyle is associated with a lower premature mortality risk and with longer life expectancy. However, the metabolic pathways of a healthy lifestyle and how they relate to mortality and longevity are unclear. We aimed to identify and replicate a healthy lifestyle metabolomic signature and examine how it is related to total and cause-specific mortality risk and longevity.

Methods: In four large cohorts with 13,056 individuals and 28-year follow-up, we assessed five healthy lifestyle factors, used liquid chromatography mass spectrometry to profile plasma metabolites, and ascertained deaths with death certificates. The unique healthy lifestyle metabolomic signature was identified using an elastic regression. Multivariable Cox regressions were used to assess associations of the signature with mortality and longevity.

Findings: The identified healthy lifestyle metabolomic signature was reflective of lipid metabolism pathways. Shorter and more saturated triacylglycerol and diacylglycerol metabolite sets were inversely associated with the healthy lifestyle score, whereas cholesteryl ester and phosphatidylcholine plasmalogen sets were positively associated. Participants with a higher healthy lifestyle metabolomic signature had a 17% lower risk of all-cause mortality, 19% for cardiovascular disease mortality, and 17% for cancer mortality and were 25% more likely to reach longevity. The healthy lifestyle metabolomic signature explained 38% of the association between the self-reported healthy lifestyle score and total mortality risk and 49% of the association with longevity.

Conclusions: This study identifies a metabolomic signature that measures adherence to a healthy lifestyle and shows prediction of total and cause-specific mortality and longevity.

Funding: This work was funded by the NIH, CIHR, AHA, Novo Nordisk Foundation, and SciLifeLab.

Keywords: BMI; Translation to population health; alcohol; diet; lifestyle; longevity; metabolome; metabolomics; mortality; physical activity; smoking.

Figure 1.. Flow diagram.

NHS, Nurses’ Health Study I; NHSII, Nurses’ Health Study II; HPFS, Health Professionals Follow-up Study; BMI, body mass index; CVD, cardiovascular disease.

Figure 2.. Metabolome-wide associations for the healthy lifestyle adherence.

A.) Top 40 positive and inverse associations between individual metabolites and healthy lifestyle adherence. Results are from multivariable linear regressions adjusted for age, fasting status, ethnicity, multivitamin use, diabetes, hypertension, antihypertensive medication use, hypercholesterolemia, lipid-lowering medication use, total energy intake, study cohorts, original sub-studies, and the case/control status within the original sub-study. P values are corrected for multiple testing using a Bonferroni adjustment. B.) Normalized enrichment score of pre-defined metabolite sets with adherence to a healthy lifestyle. Results are from metabolite set enrichment analysis (MSEA) based on individual multivariable-adjusted linear regression β coefficients. P values are corrected for multiple testing using a false discovery rate (FDR) adjustment. β, standardized beta coefficient; CI, confidence interval; CE, cholesteryl esters; PC, phosphatidylcholine; TAG, triacylglycerols; PE, phosphatidylethanolamine. * P value <0.05

Figure 3.. Associations between individual metabolites, and healthy lifestyle adherence and its components.

This heatmap shows the 101 metabolites retained in the healthy lifestyle signature and their weight from regularized elastic net regressions, β coefficient from multivariable-adjusted linear regression (self-reported healthy lifestyle adherence) and odds ratios (OR) from multivariable-adjusted logistic regressions (alcohol, BMI, diet, physical activity, smoking). Results are adjusted for age, fasting status, ethnicity, multivitamin use, diabetes, hypertension, antihypertensive medication use, hypercholesterolemia, lipid-lowering medication use, total energy intake, study cohorts, original sub-studies, and the case/control status within the original sub-study. Results for each healthy lifestyle factor are further adjusted for the other healthy lifestyle factors. P values are corrected for multiple testing using a Bonferroni adjustment. Dark pink indicates a strong positive association and dark blue a strong negative association. * P value < 0.05, ** P value < 0.001

Figure 4.. Correlation between the healthy lifestyle metabolomic signature and the self-reported score by cohorts.

A.) Correlation in the HPFS, B.) Correlation in the NHS, C.) Correlation in the NHSII, D.) Correlation in the WHI. For each of the number of healthy factors (0, 1, 2, 3, 4, 5; x-axis), boxplots represent the interquartile range and median of the corresponding number of factors estimated by the metabolomic signature (y-axis). R is the Pearson correlation coefficient.