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

We examined whether a genome-wide polygenic lifespan score (PLS) is associated with all-cause mortality and how this association compares with associations between long-term lifestyle factors and mortality. The PLS was computed for the older Finnish Twin Cohort (mean age 57.4 years; 45.2% men; N = 5575). Cox regression was used to estimate the effects of the PLS on all-cause mortality risk, before and after adding sex, physical activity, BMI, alcohol consumption, smoking behavior, and education level. Concordance indices (C-indices) were used to assess each predictor's contribution to the model's discriminatory performance. Over a mean follow-up of 17.5 ± 8.3 years, 1405 deaths (25.2%) occurred. A one standard deviation increase in the PLS was statistically significantly associated with a lower all-cause mortality risk (hazard ratio [HR] = 0.838, 95% confidence interval [CI] = 0.792-0.887). This association remained relatively unchanged after adding all covariates (HR = 0.863, 95% CI = 0.816-0.912). Smoking 20 or more cigarettes per day showed the strongest association with increased mortality risk (HR = 3.341, 95% CI = 2.751-4.056), while female sex was associated with the greatest risk reduction (HR = 0.678, 95% CI = 0.597-0.770). Smoking behavior had the largest impact on model performance (ΔC-index = 0.027); other covariates contributed less (ΔC-index < 0.006). In conclusion, genetic predisposition to a longer lifespan was associated with a modest reduction in all-cause mortality risk, independent of lifestyle and other factors. Smoking behavior and female sex were stronger predictors of mortality than the PLS.