Effects of LDLR Variants on Longevity via Lowered Cardiovascular Disease
The development of atherosclerosis leading to stroke or heart attack is the primary cause of human mortality, accounting for ~26% of deaths worldwide. It also contributes meaningfully to as much as another 15% of deaths through narrowing of blood vessels, heart failure, and so forth. It is well known that lowered LDL-cholesterol in the bloodstream, when maintained over a lifetime, pushes back the tipping point at which atherosclerotic lesions form. So genetic variants that affect LDL-cholesterol levels tend to also affect longevity to some degree, as demonstrated in this study. Unfortunately, therapies that lower LDL-cholesterol levels have nowhere near the same effect size, as (a) these treatments are not maintained over the full lifespan, and (b) lowering LDL-cholesterol has little effect on established atherosclerotic plaque in most patients.
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. Two-sample Mendelian randomization analyses were conducted. The exposures comprised genetic variants that proxy nine drug target genes mimicking lipid-lowering effects (LDLR, HMGCR, PCSK9, 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.
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.
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.