Genetic predisposition to longer lifespan, lifestyle factors, and all-cause mortality: a 17-year prospective cohort study

BackgroundWe used a genome-wide polygenic lifespan score (PLS) to investigate whether genetic predisposition to a longer lifespan is associated with lower mortality risk and how this association compares with associations between long-term lifestyle factors and mortality. MethodsA PLS was computed for the Older Finnish Twin Cohort (mean age 57{middle dot}4 years; 45{middle dot}2% males; N=5575). Cox regression models were used to analyse the effects of the PLS on all-cause mortality risk before and after adding covariates (sex, physical activity, BMI, alcohol consumption, smoking, and education level). Differences between concordance indices (C-indices) were used to evaluate each predictors contribution to the models discriminatory performance. FindingsOver a mean follow-up of 17{middle dot}5{+/-}8{middle dot}3 years, 1405 deaths (25{middle dot}2%) were recorded. A one standard deviation increase in the PLS was statistically significantly associated with a lower all-cause mortality risk (hazard ratio [HR]=0{middle dot}838, 95% confidence interval [CI]=0{middle dot}792-0{middle dot}887) and remained relatively unchanged after adding all covariates (HR=0{middle dot}863, 95% CI=0{middle dot}816-0{middle dot}912). Smoking 20 or more cigarettes per day showed the strongest association with increased mortality risk (HR=3{middle dot}341, 95% CI=2{middle dot}751-4{middle dot}056), whereas female sex was linked to the greatest risk reduction (HR=0{middle dot}678, 95% CI=0{middle dot}597-0{middle dot}770). Smoking had the largest impact on model discrimination ({Delta}C-index=0{middle dot}027), whereas all other covariates increased the C-index by less than 0{middle dot}006. InterpretationGenetic predisposition to a longer lifespan was associated with a small decrease in all-cause mortality risk. This association remained after adjusting for lifestyle factors and covariates. Smoking behaviour and female sex were stronger predictors of mortality than genetic scores for lifespan. FundingThis study was funded by the Research Council of Finland (341750, 346509, and 361981 for ES) and the Juho Vainio, and Paivikki and Sakari Sohlberg Foundation (ES). Finnish Twin Cohort data collection was supported by the Research Council of Finland (264146, 308248, 336823, and 352792 for JK), the Wellcome Trust Sanger Institute, the Broad Institute, ENGAGE, and FP7-HEALTH-F4-2007 (201413). Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe systematically searched PubMed and Google Scholar for studies related to the association of polygenic scores of lifespan/longevity and lifestyle factors with the risk of mortality from inception to November 30, 2024, and published in the English language. The search revealed three noteworthy publications on the effects of lifestyle factors and genetic predisposition to lifespan on mortality risk. However, the results regarding sex-specific results and information on the contribution of different factors in predicting deaths were scarce. While lifespan may be influenced by both genetic and lifestyle factors, it remains unclear how separate lifestyle factors affect the relationship between the genetic determinants of lifespan and mortality. Additionally, understanding how well genes and lifestyle factors predict all-cause mortality is crucial for evaluating their contribution to human lifespan. Added value of this studyOur work presents results on the interplay between genetic predisposition to lifespan and lifestyle factors in all-cause mortality. We demonstrate the relative contribution of genetic and lifestyle factors and mortality-related demographics in predicting all-cause mortality. Furthermore, we provide sex-specific associations. Implications of all the available evidenceBased on this study, the association between genetic predisposition to a longer lifespan and lower risk of all-cause mortality remains relatively independent of lifestyle factors and known covariates. However, female sex and smoking behaviour remain important, albeit opposing, factors in all-cause mortality. The findings of this study can be used to guide future research on lifespan and longevity in the field of genetics.