In a recent study published in the journal Med, researchers used a collated dataset comprising four American sample cohorts to identify the metabolomic markers of a healthy lifestyle and, potentially, the mechanisms underlying their production. They used a combination of analytical techniques, particularly liquid chromatography-mass spectrometry, on the 13,056 datasets and observed that the healthy lifestyle metabolomic signature was largely reflective of lipid metabolism pathways.
Shorter and more saturated di—and triacylglycerol metabolite sets were found to be inversely associated with healthy lifestyles, while phosphatidylcholine plasmalogens and cholesteryl esters were directly associated with the condition. Encouragingly, the relative concentrations of these biomarkers accounted for a 17% lower risk of all-cause mortality, a 19% reduced risk of cardiovascular disease-related mortality, a 17% lower risk of cancer-related mortality, and a 25% improved probability of attaining longevity.
The relationship between lifestyle choices and metabolic health
Chronic, non-transmissible disease prevalence is currently higher than it has ever been and has primarily been attributed to the increased adoption of sub-optimal health behavioral choices, including diets (e.g., the Western-style diet) and physical activity levels (e.g., the sedentary lifestyle). Previous research has highlighted the profound benefits of adopting a healthy lifestyle, with research on American cohorts revealing 55-71% reduced all-cause mortality risk in individuals who maintained their body mass index (BMI) between 18.5-24.9 kg/m2, consumed alcohol in moderation, partook in physical activity, and abstained from smoking.
Unfortunately, the mechanisms underpinning these interactions remain largely unknown. Some studies have suggested that individuals’ health behavior components such as body weight, diet, alcohol consumption, physical activity, and smoking may have associated metabolomic signatures indicative of their current and historical health. Still, these hypotheses have rarely been tested within a scientific framework. The limited information in the field, despite being at times confounding, suggests that polyunsaturated fatty acids (PUFAs), phosphatidylcholines (PCs), and glutamate and similar amino acids (AAs) are associated with improved health outcomes, while triacylglycerols (TAG), sphingomyelins (SMs), and carnitines are associated with suboptimal ones.
“However, most studies only examined diet and physical activity factors, with small sample sizes and limited sets of metabolites profiled. Thus, a comprehensive understanding of the metabolic pathways underlying healthy lifestyle behaviors remains to be discovered. By studying several modifiable lifestyle factors simultaneously, a better understanding of the common biological mechanisms as well as the key differences may be acquired.”
About the study
In the present study, researchers used lifestyle, metabolomic, and clinical information from four American cohorts comprising more than 13,000 individuals to compute a metabolomic-based combined healthy lifestyle score during mid-life and further examine the relationship between this score and mortality and longevity outcomes. Outcome follow-up was extensive and had a mean duration of 28 years. The cohorts included the Nurses’ Health Study (NHS; 1976), the second iteration of the same prospective cohort (NHSII; 1989), the Women’s Health Initiative (WHI; 1993), and the Health Professionals Follow-up Study (HPFS; 1986). They comprised primarily middle-aged (mean 54.3 years) women (85.8%) belonging to the White ethnicity (96.7%).
Lifestyle information was participant-reported, clinical information was obtained from the prospective cohort database, and metabolomic information was derived from (fasting) blood plasma samples obtained at the time of study initiation and subsequent follow-up. Individuals lacking data on measured outcomes (BMI, alcohol consumption, metabolomic profiling, diets, physical activity levels, smoking status) were excluded. The WHI cohort was used as an external validation cohort for results obtained from the three remaining cohorts.
Plasma metabolomic profiling was carried out using acetonitrile/methanol/formic acid extraction followed by hydrophilic interaction liquid chromatography (HILIC) and positive ionization mass spectrometry (MS) for polar compounds (e.g., amino acids) and isopropanol extraction followed by octyl high-performance liquid chromatography (HPLC) and positive ionization MS for lipids. The Metabolite Standard Initiative (MSI) database was used to identify obtained metabolites.
Lifestyle factors (treatments) were of five main categories – diet, alcohol consumption, physical activity, smoking, and BMI, and were assessed using questionnaires and the Alternative Healthy Eating Index (AHEI). Mortality and longevity (outcomes) were obtained from family-member reports (for death), State statistics records, and the National Death Index database. Multivariable linear regressions, logistic regression, and elastic linear regressions were used for statistical data analyses. Cox proportional hazard ratios were computed to translate these results into relative disease risk.
Results reveal that the metabolomic signature most reflective of healthy lifestyles is the lipid metabolism pathway comprising PC, TAG, CE, and DAG metabolite families. Diet composition and BMI were found to be the best predictors of positive metabolite signatures. Metabolite characterization identified more than 400 metabolites associated with lifestyle choices. Elastic regression analyses identified 187 of these metabolites as descriptive of healthy lifestyle behaviors – 58 were positively associated, while 129 were inversely associated with beneficial mortality and longevity outcomes.
“…the MSEA revealed CEs, mainly of PUFAs, and PCs as the most enriched metabolite sets positively associated with a healthy lifestyle. CEs serve as a mean for the storage and transportation of cholesterol and other lipids in the blood and were shown to be reflective of dietary fat intake. PCs are naturally found in the body but also in foods such as eggs, fatty fish, and soybeans. They are well known for their essential role in cell membranes and membrane signaling.”
Animo acids and metabolites involved in purine metabolism were also highlighted as signatures of healthy lifestyles. Vegetarian diets that are rich in circulating glycine, trigonelline, asparagine, hippurate, and glutamine and poor in valine, isoleucine, and leucine were found beneficial over dietary intakes of red meats, chicken, and energy drinks.
Outcome analyses revealed a surprising fact – the metabolomic signatures identified herein were more accurate predictors of mortality and longevity than patient-reported fitness and health levels.
“Indeed, the metabolomic signature explained 38.0% of the association between the self-reported healthy lifestyle score and mortality, pointing to unique biological pathways captured by metabolomics. Consistent with the literature and with our mortality results, we found an association of the healthy lifestyle metabolomic signature with longevity, and the signature explained 48.6% of the association between self-reported healthy lifestyle score and longevity.”
The present study uses a large combined American cohort comprising more than 13,000 participants to identify metabolomic signatures associated with positive mortality and longevity outcomes as a consequence of healthy lifestyle and dietary choices. Study findings reveal that more than 100 metabolites are associated with (positive or negative) health lifestyle outcomes, most of which are involved in the lipid metabolism pathways.
“…our findings suggest that greater adherence to a healthy lifestyle may lead to alterations in the metabolome that are associated with lower premature mortality risk and higher likelihood of longevity. We identified a metabolomic signature associated with a combined healthy lifestyle in US adults that is strongly reflective of lipid metabolism pathways. We found that those with a higher multimetabolite score had a lower risk of total and cause-specific mortality and a greater likelihood of living longer.”
- Tessier, A.-J., Wang, F., Liang, L., Wittenbecher, C., Haslam, D. E., Eliassen, A. H., Tobias, D. K., Li, J., Zeleznik, O. A., Ascherio, A., Sun, Q., Stampfer, M. J., Grodstein, F., Rexrode, K. M., Manson, J. E., Balasubramanian, R., Clish, C. B., Martínez-González, M. A., Chavarro, J. E., … Guasch-Ferré, M. (2024). Plasma metabolites of a healthy lifestyle in relation to mortality and longevity: Four prospective US cohort studies. In Med. Elsevier BV, DOI – 10.1016/j.medj.2024.01.010, https://www.cell.com/med/fulltext/S2666-6340(24)00040-0