Genetics
Mendelian randomisation across nine drug targets and half a million lifespans finds genetically proxied CETP inhibition extends life expectancy (Lipids Health Dis 2023)
Original title: Genetic insights into the association of statin and newer nonstatin drug target genes with human longevity: a Mendelian randomization analysis
A two-sample Mendelian randomisation study tested causal associations between nine lipid-lowering drug target genes (LDLR, HMGCR, PCSK9, NPC1L1, APOB, CETP, LPL, APOC3, ANGPTL3) and human lifespan, using genome-wide association summary data covering up to 500,193 European individuals, with sensitivity tests and eQTL validation. Genetically proxied LDLR enhancement, mimicking LDL-C lowering, was associated with extended lifespan, replicated and confirmed in blood and liver eQTL data, and mediated 22.8% by reduced coronary heart disease risk. Genetically proxied CETP and APOC3 inhibition also showed causal effects on increased life expectancy across both outcome datasets. HMGCR, PCSK9, LPL and APOB variants were associated with longer average lifespan but not with extreme longevity, and no evidence supported an NPC1L1-lifespan association. The authors flag CETP, alongside PCSK9 and APOC3, as a promising target for longevity-oriented drug development, a genetic signal rather than a trial result.
Original abstract
Background: It remains controversial whether the long-term use of statins or newer nonstatin drugs has a positive effect on human longevity. Therefore, this study aimed to investigate the genetic associations between different lipid-lowering therapeutic gene targets and human longevity.
Methods: Two-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCKS9, NPC1L1, APOB, CETP, LPL, APOC3, and ANGPTL3). Two large-scale genome-wide association study (GWAS) summary datasets of human lifespan, including up to 500,193 European individuals, were used as outcomes. The inverse-variance weighting method was applied as the main approach. Sensitivity tests were conducted to evaluate the robustness, heterogeneity, and pleiotropy of the results. Causal effects were further validated using expression quantitative trait locus (eQTL) data.
Results: Genetically proxied LDLR variants, which mimic the effects of lowering low-density lipoprotein cholesterol (LDL-C), were associated with extended lifespan. This association was replicated in the validation set and was further confirmed in the eQTL summary data of blood and liver tissues. Mediation analysis revealed that the genetic mimicry of LDLR enhancement extended lifespan by reducing the risk of major coronary heart disease, accounting for 22.8% of the mediation effect. The genetically proxied CETP and APOC3 inhibitions also showed causal effects on increased life expectancy in both outcome datasets. The lipid-lowering variants of HMGCR, PCKS9, LPL, and APOB were associated with longer lifespans but did not causally increase extreme longevity. No statistical evidence was detected to support an association between NPC1L1 and lifespan.
Conclusion: This study suggests that LDLR is a promising genetic target for human longevity. Lipid-related gene targets, such as PCSK9, CETP, and APOC3, might potentially regulate human lifespan, thus offering promising prospects for developing newer nonstatin therapies.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.