Plasma metabolite signature of healthy lifestyle factors in midlife in relation to all-cause mortality
Background:
A healthy lifestyle has been associated with a lower risk of premature death. Metabolic pathways of a healthy lifestyle and their association with mortality remain to be understood. This study aimed to identify the metabolomic signature of a healthy lifestyle score and examine its prospective association with all-cause mortality.
Method:
The population included 12,146 participants from the Nurses’ Health Study, Nurses’ Health Study II and Health Professionals Follow-Up Study (83% women, 97% white, aged 54.9 ± 9.3 years). Plasma metabolites were profiled using high-throughput liquid chromatography mass-spectrometry at baseline. The healthy lifestyle score was computed by summing the total number of baseline healthy lifestyle factors. Factors included the Alternative Healthy Eating Index (upper 40%), moderate alcohol intake (women: 5-15 g/day; men: 5-30 g/day) and moderate-to-vigorous physical activity (≥30 minutes/day) assessed using validated questionnaires; and self-reported smoking (never) and BMI (18.5-24.9 kg/m2). The multi-metabolite signature was identified using elastic net regressions with train test validation split (70-30%). Metabolic pathways were determined using enrichment analysis. Multivariable Cox proportional hazards regression was used to examine the association between the healthy lifestyle metabolite signature and subsequent mortality risk.
Results:
The identified signature encompassed 88 metabolites and correlated with the healthy lifestyle score (Pearson r=0.43 and 0.44 in the training and test sets; p<0.001). While C18:0 sphingomyelin, creatine, N2,N2-dimethylguanosine were inversely associated with a healthy lifestyle (p<0.001), beneficial glycerophospholipids showed positive associations (p<0.001). The methylhistidine metabolic pathway, reflective of muscle protein breakdown and dietary protein source, emerged as the most enriched metabolite set. Among individual healthy lifestyle factors, the signature was most strongly associated with normal BMI (p<0.001). During up to 32y of follow-up, 3,851 deaths were documented. The healthy lifestyle metabolite signature score was inversely associated with mortality risk (HR=0.79 [95% CI 0.73, 0.85]) and remained significant after mutual adjustment for the healthy lifestyle score (HR=0.84 [95% CI 0.77, 0.91]).
Conclusions:
In US middle-aged adults, a plasma metabolite signature related to a healthy lifestyle was associated with lower subsequent mortality risk. Findings provide novel insights into potential metabolic pathways underlying the association between a healthy lifestyle and lower premature mortality.
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