Identifying <scp>PDAP1</scp> as a Biological Target on Human Longevity: Integration of Mendelian Randomization, Cohort, and Cell Experiments Validation Study

Identifying factors affecting lifespan, including genes or proteins, enables effective interventions. We prioritized potential drug targets and provided insights into biological pathways for healthy longevity by integrating Mendelian randomization, cohort, and experimental studies. We identified causal effects of tissue‐specific genetic transcripts and serum protein levels on three longevity outcomes: the parental lifespan, the top 1% and 10% extreme longevity, utilizing Mendelian randomization and multi‐traits colocalization, combining the latest genetics data of gene expression (eQTLGen and GTEx) and proteomics (4746 proteins from five studies). We then evaluated associations of these potential genetic targets with mortality risk and life expectancy in the UK Biobank cohort. We performed in vitro cellular senescence experiments to confirm their effects. Fourteen plasma proteins and nine transcripts in whole blood had independent causal effects on longevity, where a cascading effect of both the tissue‐specific transcripts and plasma proteins of LPA, PDAP1, DNAJA4, and TMEM106B showed negative effects on longevity. PDAP1 (PDGFA‐associated protein 1) with the strongest genetic evidence might reduce lifespan by modifying sex hormones, adiposity, and epigenetic aging acceleration. In the prospective cohort, blood PDAP1 levels were significantly associated with higher all‐cause mortality and more years of loss. In vitro, cellular senescence is accompanied by upregulation of PDAP1 expression. Exogenous PDAP1 stimulation accelerates cellular senescence while the deficiency of PDAP1 attenuates replicative senescence. This study facilitates the discovery of potential drug targets and provides a broader understanding of the biological processes of longevity, where PDAP1 emerged as a star for modifying human lifespan.