Phenotypic Age Mediates the Effects of Life's Simple 7 on Reduced Mortality Risk in the US

Background: Phenotypic age, a newly developed marker for biological aging, improves risk prediction for adverse health events than chronological age. "Life’s Simple 7" (LS7) is a set of 7 recommended healthy lifestyle metrics proposed by the AHA to improve cardiovascular health. It is unknown, however, whether phenotypic age mediates the protective effects of healthy lifestyles on cardiovascular disease (CVD)- and all-cause mortality. Methods: Prospective analyses were performed using NHANES 1999-2010 data (6 cycles) on 9842 adults with linked death records till Dec 31, 2015. Adjusted hazard ratios (aHR) were estimated for phenotypic age, LS7-score, and LS7’s individual components for all-cause and cardiovascular mortality. Mediation analyses were performed using structural equation modeling. Results: One point increment in LS7-score was associated with a 0.92 (95% CI 0.87-0.98) year younger in phenotypic age, independent of general demographic characteristics and chronological age. During a median of 10.33-year follow-up, 1616 deaths were recorded, 323 being cardiovascular. One year increment in phenotypic age was associated with a higher risk of all-cause (aHR=1.05, 95% CI 1.04-1.05) and cardiovascular (1.04 [1.03-1.06]) mortality. The mediation analysis revealed that phenotypic age was estimated to mediate 66% and 42% of the total effects of LS7 on all-cause and cardiovascular mortality, respectively. Conclusion: Our data indicate that adherence to LS7 guidelines significantly slows down biological aging, which results in a prolonged lifespan as well as a reduced risk of cardiovascular mortality.