Abstract

Aims It is unknown whether long‐term low‐density lipoprotein cholesterol (LDL‐c) lowering increases lifespan and longevity in a general population not selected for elevated cardiovascular risk. The present study aimed to investigate the overall and gene‐specific effect of circulating LDL‐c levels on lifespan and longevity in a general population. Methods Leveraging data from the Global Lipids Genetics Consortium (n = 173 082), we identified genetic variants to proxy LDL‐c levels generally, and also through perturbation of particular drug targets (HMGCR, NPC1L1 and PCSK9). We investigated their association with lifespan (n = 1 012 240) using Mendelian randomization, and replicated results using the outcome of longevity to the 90th vs. 60th percentile age (11 262 cases/25 483 controls). Results A 1‐standard deviation increase in genetically proxied LDL‐c was associated with 1.2 years lower lifespan (95% confidence interval [CI] −1.55, −0.87; P = 3.83 × 10−12). Findings were consistent in statistical sensitivity analyses, and when considering the outcome of longevity (odds ratio for survival to the 90th vs 60th percentile age 0.72, 95% CI 0.64, 0.81, P = 7.83 × 10−8). Gene‐specific Mendelian randomization analyses showed a significant effect of LDL‐c modification through PCSK9 on lifespan (−0.99 years, 95% CI −1.43, 0.55, P = 6.80 × 10−6); however, estimates for HMGCR and NPC1L1 were underpowered. Conclusions This genetic evidence supports that higher LDL‐c levels reduce lifespan and longevity. In a general population that is not selected for increased cardiovascular risk, there is likely to be a net lifespan benefit of LDL‐c lowering therapies, particularly for PCSK9 inhibitors, although randomized controlled trials are necessary before modification of clinical practice.