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Background <p>Lifestyle factors play a critical role in the prevention and management of hypertension, while metabolomics provides valuable insights into the biological mechanisms underlying disease development. However, the relationships among lifestyle-related metabolic signatures, lifestyle behaviors, and hypertension risk remain incompletely understood.</p> Methods <p>This prospective cohort study used data from the UK Biobank. A composite healthy lifestyle score was calculated, and a lifestyle-related metabolic signature was developed using nuclear magnetic resonance (NMR)-based metabolomics and elastic net regression. Multivariable-adjusted Cox proportional hazards models were used to evaluate the associations between the healthy lifestyle score and the metabolic signature and incident hypertension. Causal mediation analysis based on a counterfactual framework (CMAverse package) was performed to quantify the mediating effect of the metabolic signature on the association between lifestyle and hypertension. Subgroup, interaction, and sensitivity analyses were also conducted.</p> Results <p>A total of 126,677 eligible participants (mean age, 54.92 ± 8.12 years; 46.47% male; 96.09% White) were included. During a median follow-up of 13.43 years, 18,720 participants developed hypertension. A healthy lifestyle-related metabolic signature comprising 76 metabolites was identified and showed a strong correlation with the healthy lifestyle score. Both a higher healthy lifestyle score (HR: 0.927; 95% CI: 0.913–0.940) and a higher metabolic signature level (HR: 0.675; 95% CI: 0.641–0.711) were independently associated with a significantly lower risk of incident hypertension, with significant inverse dose-response trends. These associations remained generally consistent across subgroups stratified by age, education, and income. Mediation analysis indicated that the metabolic signature explained 57.08% (95% CI: 31.89%–83.15%) of the protective association between a healthy lifestyle and hypertension risk. The primary findings remained robust across multiple sensitivity analyses.</p> Conclusion <p>A healthy lifestyle is associated with a distinct metabolomic profile that substantially mediates its protective association with hypertension. These findings provide new insights into the metabolic mechanisms linking lifestyle behaviors to hypertension risk and highlight the importance of metabolic health in hypertension prevention.</p>

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Association of NMR metabolic signatures of healthy lifestyle with hypertension: a prospective cohort study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Xi Zhang,
  • Li Zhang,
  • Zhixing Fan,
  • Chuying Huang,
  • Jie Xiang

摘要

Background

Lifestyle factors play a critical role in the prevention and management of hypertension, while metabolomics provides valuable insights into the biological mechanisms underlying disease development. However, the relationships among lifestyle-related metabolic signatures, lifestyle behaviors, and hypertension risk remain incompletely understood.

Methods

This prospective cohort study used data from the UK Biobank. A composite healthy lifestyle score was calculated, and a lifestyle-related metabolic signature was developed using nuclear magnetic resonance (NMR)-based metabolomics and elastic net regression. Multivariable-adjusted Cox proportional hazards models were used to evaluate the associations between the healthy lifestyle score and the metabolic signature and incident hypertension. Causal mediation analysis based on a counterfactual framework (CMAverse package) was performed to quantify the mediating effect of the metabolic signature on the association between lifestyle and hypertension. Subgroup, interaction, and sensitivity analyses were also conducted.

Results

A total of 126,677 eligible participants (mean age, 54.92 ± 8.12 years; 46.47% male; 96.09% White) were included. During a median follow-up of 13.43 years, 18,720 participants developed hypertension. A healthy lifestyle-related metabolic signature comprising 76 metabolites was identified and showed a strong correlation with the healthy lifestyle score. Both a higher healthy lifestyle score (HR: 0.927; 95% CI: 0.913–0.940) and a higher metabolic signature level (HR: 0.675; 95% CI: 0.641–0.711) were independently associated with a significantly lower risk of incident hypertension, with significant inverse dose-response trends. These associations remained generally consistent across subgroups stratified by age, education, and income. Mediation analysis indicated that the metabolic signature explained 57.08% (95% CI: 31.89%–83.15%) of the protective association between a healthy lifestyle and hypertension risk. The primary findings remained robust across multiple sensitivity analyses.

Conclusion

A healthy lifestyle is associated with a distinct metabolomic profile that substantially mediates its protective association with hypertension. These findings provide new insights into the metabolic mechanisms linking lifestyle behaviors to hypertension risk and highlight the importance of metabolic health in hypertension prevention.