Utilizing genetics and proteomics to assess the role of antihypertensive drugs in human longevity and the underlying pathways: a Mendelian randomization study.

Background: Antihypertensive drugs are known to lower cardiovascular mortality, but the role of different types of antihypertensive drugs in lifespan has not been clarified. Moreover, the underlying mechanisms remain unclear.

Methods and results: To minimize confounding, we used Mendelian randomization to assess the role of different antihypertensive drug classes in longevity and examined the pathways via proteins. Genetic variants associated with systolic blood pressure (SBP) corresponding to drug-target genes were used as genetic instruments. The genetic associations with lifespan were obtained from a large genome-wide association study including 1 million European participants from UK Biobank and LifeGen. For significant antihypertensive drug classes, we performed sex-specific analysis, drug-target analysis, and colocalization. To examine the mediation pathways, we assessed the associations of 2291 plasma proteins with lifespan, and examined the associations of drug classes with the proteins affecting lifespan. After correcting for multiple testing, genetically proxied beta-blockers (BBs), calcium channel blockers (CCBs), and vasodilators were related to longer life years (BBs: 2.03, 95% CI 0.78-3.28 per 5 mmHg reduction in SBP, CCBs: 3.40, 95% CI 1.47-5.33, and vasodilators: 2.92, 95% CI 1.08-4.77). The beneficial effects of BBs and CCBs were more obvious in men. ADRB1, CACNA2D2, CACNB3, CPT1A, CPT2, and EDNRA genes were related to extended lifespan, with CPT2 further supported by colocalization evidence. Eighty-six proteins were related to lifespan, of which four proteins were affected by CCBs. CDH1 may mediate the association between CCBs and lifespan.

Conclusions: Beta-blockers, CCBs, and vasodilators may prolong lifespan, with potential sex differences for BBs and CCBs. The role of CCBs in lifespan is partly mediated by CDH1. Prioritizing the potential protein targets can provide new insights into healthy aging.