Phenotypic Age Mediates Effects of Life’s Essential 8 on Reduced Mortality Risk in US Adults
Aging is one of the major risk factors for a variety of chronic diseases and death. However, chronological age does not fully reflect individual differences in the biological aging process. Phenotypic age is a composite score based on routine clinical markers, used to differentiate individuals within the same age group who have varying risks of disease and mortality. In recent years, growing evidence suggests that lifestyle factors such as diet, physical activity, smoking, alcohol consumption, obesity, and sleep are closely related to the acceleration or deceleration of biological aging. Life’s Essential 8 (LE8), recommended by the American Heart Association (AHA), is a set of health behaviors aimed at achieving ideal cardiovascular health (CVH) through lifestyle improvements. However, it remains unclear whether phenotypic age can effectively mediate the impact of LE8 on mortality.
This study aimed to explore whether phenotypic age mediates the protective effects of a healthy lifestyle on mortality and to quantify the mediating effect of phenotypic age between LE8 and mortality.
Source of the Paper
The research was conducted by scholars from Peking University Health Science Center, Tulane University, Harvard T.H. Chan School of Public Health, and other institutions. The main authors include Yuxuan Zhao and Haiming Yang, among others. The paper was published on September 16, 2024, in the journal Precision Clinical Medicine, with the DOI 10.1093/pcmedi/pbae019.
Research Process
Study Participants and Data Source
The study used data from the National Health and Nutrition Examination Survey (NHANES) 2005-2010, including 17,132 adults aged ≥20 years. Participants with incomplete follow-up data or those unable to calculate phenotypic age and LE8 scores were excluded, resulting in a final sample of 15,320 participants. All participants provided written informed consent, and the study protocol was approved by the ethics committee of the National Center for Health Statistics.
Calculation of Phenotypic Age
Phenotypic age was calculated based on 10 variables, including chronological age and nine routine clinical biomarkers (serum albumin, creatinine, glucose, C-reactive protein, lymphocyte percentage, mean cell volume, red cell distribution width, alkaline phosphatase, and white blood cell count). The calculation method was based on a linear combination model proposed by Levine et al. Additionally, the researchers calculated phenotypic age acceleration, the difference between phenotypic age and chronological age, to reflect an individual’s relative health status and disease susceptibility.
Calculation of LE8 Scores
LE8 includes four modifiable cardiovascular health behaviors (not smoking, healthy diet, physical activity, and healthy sleep) and four cardiovascular health factors (body mass index, blood pressure, non-high-density lipoprotein cholesterol, and blood glucose). Each metric was scored from 0 to 100, and the LE8 total score was the average of the eight metric scores. Based on the scores, LE8 levels were categorized as high (80-100), moderate (50-79), and low (0-49).
Determination of Mortality
Mortality data, including all-cause mortality and cardiovascular disease mortality, were obtained from the National Death Index, with follow-up until December 31, 2019. Cardiovascular disease mortality was defined as death caused by heart disease or cerebrovascular disease.
Statistical Analysis
Cox proportional hazard models were used to assess the associations between phenotypic age, LE8 scores, and all-cause and cardiovascular disease mortality. Mediation analysis was employed to quantify the mediating effect of phenotypic age between LE8 and mortality. All analyses were adjusted for covariates such as chronological age, sex, ethnicity, marital status, education level, family income, and disease history.
Research Findings
Relationship Between Phenotypic Age and Mortality
The study found that for each 1-year increase in phenotypic age, the risk of all-cause mortality and cardiovascular disease mortality increased by 4% (HR = 1.04, 95% CI: 1.04-1.05). Phenotypic age acceleration was also significantly associated with mortality risk, indicating that phenotypic age is an independent predictor of mortality risk beyond chronological age.
Relationship Between LE8 and Phenotypic Age
High levels of LE8 (scores 80-100) were associated with a younger phenotypic age, with phenotypic age acceleration being 3.30 years younger compared to the low LE8 group. This suggests that adherence to LE8 recommendations significantly slows the progression of phenotypic age.
Relationship Between LE8 and Mortality
High levels of LE8 were associated with lower all-cause mortality and cardiovascular disease mortality. For each 1-standard deviation increase in LE8, the risk of all-cause mortality and cardiovascular disease mortality decreased by 21% and 29%, respectively. Mediation analysis showed that phenotypic age mediated 36% of the effect of LE8 on all-cause mortality and 22% of its effect on cardiovascular disease mortality.
Single-Metric Analysis
Among the individual metrics of LE8, the effects of healthy diet, not smoking, blood pressure control, and physical activity on reducing all-cause mortality were partially mediated by phenotypic age. Healthy diet had the largest mediating effect, accounting for 30%.
Research Conclusion
The study demonstrated that adherence to LE8 recommendations significantly slows the progression of phenotypic age, thereby reducing all-cause mortality and cardiovascular disease mortality. Phenotypic age plays an important mediating role between LE8 and mortality. This finding supports the value of phenotypic age as a potential indicator for promoting long-term cardiovascular health and well-being.
Research Highlights
- Innovation: This study is the first to quantify the mediating effect of phenotypic age between LE8 and mortality, revealing the mechanism by which a healthy lifestyle reduces mortality risk by slowing biological aging.
- Application Value: Phenotypic age can serve as an effective health indicator to assess individual adherence to a healthy lifestyle and provide a basis for public health interventions.
- Comprehensiveness: The study not only evaluated the relationship between LE8 total scores and mortality but also analyzed the effects of individual metrics, providing scientific evidence for targeted health interventions.
Other Valuable Information
The study also conducted several sensitivity analyses, such as re-evaluating the relationship between LE8 and phenotypic age after excluding blood glucose and using phenotypic age acceleration instead of phenotypic age in mediation analysis. The results were consistent with the main analysis, further validating the robustness of the findings.
Through this research, we have deepened our understanding of the relationship between a healthy lifestyle and biological aging, while also providing new insights and tools for future public health interventions.