Modifiable risk factors attenuated longevity genetic predisposition on life expectancy in the oldest old.

Abstract

In this prospective cohort study of 1545 participants aged 80 years and older from the China Hainan Centenarian Cohort Study, we investigated the independent and joint associations of modifiable risk factors and genetic predisposition with life expectancy. A weighted modifiable risk factor score (MRFS) based on 11 factors and a polygenic risk score (PRS) for longevity were constructed. A favorable modifiable risk factor profile (low MRFS) was associated with a 40.7% lower death risk (HR 0.593, 95%CI 0.505-0.696) compared with high MRFS. Genetic predisposition to longer lifespan (high PRS) conferred a 13.0% lower risk (HR 0.870, 95%CI 0.768-0.986). Participants with both low MRFS and high PRS had the lowest mortality (HR 0.544, 95%CI 0.432-0.686), with a borderline significant multiplicative interaction (P = 0.040). Life expectancy gains from a low MRFS were more pronounced in those with high PRS (6.92 years at age 80) than low PRS (5.35 years). Among the oldest-old Han Chinese, favorable modifiable risk profiles and genetic predisposition independently and jointly contribute to substantially longer life expectancy. Importantly, an unfavorable modifiable profile may largely negate genetic longevity benefits, emphasizing the critical role of managing these factors even in advanced age and irrespective of genetic inheritance.