Genetic predisposition, modifiable lifestyles, and their joint effects on human lifespan: evidence from multiple cohort studies

Objective To investigate the associations across genetic and lifestyle factors with lifespan. Design A longitudinal cohort study. Setting UK Biobank. Participants 353 742 adults of European ancestry, who were recruited from 2006 to 2010 and were followed up until 2021. Exposures A polygenic risk score for lifespan with long (highest quintile) risk categories and a weighted healthy lifestyle score, including no current smoking, moderate alcohol consumption, regular physical activity, healthy body shape, adequate sleep duration, and a healthy diet, categorised into favourable, intermediate, and unfavourable lifestyles. Main outcome measures Lifespan defined as the date of death or the censor date minus the date of birth. Results Of the included 353 742 participants of European ancestry with a median follow-up of 12.86 years, 24 239 death cases were identified. Participants were grouped into three genetically determined lifespan categories including long (20.1%), intermediate (60.1%), and short (19.8%), and into three lifestyle score categories including favourable (23.1%), intermediate (55.6%), and unfavourable (21.3%). The hazard ratio (HR) of death for individuals with a genetic predisposition to a short lifespan was 1.21 (95% CI 1.16 to 1.26) compared to those with a genetic predisposition to a long lifespan. The HR of death for individuals in the unfavourable lifestyle category was 1.78 (95% CI 1.71 to 1.85), compared with those in the favourable lifestyle category. Participants with a genetic predisposition to a short lifespan and an unfavourable lifestyle had 2.04 times (95% CI 1.87 to 2.22) higher rates of death compared with those with a genetic predisposition to a long lifespan and a favourable lifestyle. No multiplicative interaction was detected between the polygenic risk score of lifespan and the weighted healthy lifestyle score (p=0.10). The optimal combination of healthy lifestyles, including never smoking, regular physical activity, adequate sleep duration, and a healthy diet, was derived to decrease risk of premature death (death before 75 years). Conclusion Genetic and lifestyle factors were independently associated with lifespan. Adherence to healthy lifestyles could largely attenuate the genetic risk of a shorter lifespan or premature death. The optimal combination of healthy lifestyles could convey better benefits for a longer lifespan, regardless of genetic background. Data are available in a public, open access repository. NHANES data are available at . UK Biobank study was under Application Number 66354. The UK Biobank is an open access resource and bona fide researchers can apply to use the UK Biobank dataset by registering and applying at . Further information is available from the corresponding author upon request.