Hou Tianzhichao, Sha Zimo, Wang Qi, Zhu Yuanyue, Zhu Zheng, Dai Huajie, Zhu Yijie, Wang Tiange, Li Mian, Zhao Zhiyun, Xu Yu, Lu Jieli, Zheng Jie, Ye Jing, Wang Weiqing, Ning Guang, Bi Yufang, Hu Weiguo, Xu Min
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Geriatric Medical Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Aging Cell. 2025 Jul;24(7):e70065. doi: 10.1111/acel.70065. Epub 2025 Apr 10.
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.
识别影响寿命的因素，包括基因或蛋白质，能够实现有效的干预。我们通过整合孟德尔随机化、队列研究和实验研究，确定了潜在的药物靶点，并深入了解了健康长寿的生物学途径。我们利用孟德尔随机化和多性状共定位，结合基因表达（eQTLGen和GTEx）和蛋白质组学（来自五项研究的4746种蛋白质）的最新遗传学数据，确定了组织特异性基因转录本和血清蛋白水平对三种长寿结果的因果效应：父母寿命、前1%和10%的极端长寿。然后，我们在英国生物银行队列中评估了这些潜在遗传靶点与死亡风险和预期寿命的关联。我们进行了体外细胞衰老实验以证实其作用。14种血浆蛋白和9种全血转录本对寿命有独立的因果效应，其中LPA、PDAP1、DNAJA4和TMEM106B的组织特异性转录本和血浆蛋白的级联效应均对寿命有负面影响。具有最强遗传证据的PDAP1（血小板衍生生长因子A相关蛋白1）可能通过改变性激素、肥胖和表观遗传衰老加速来缩短寿命。在前瞻性队列中，血液中PDAP1水平与全因死亡率升高和更多年的寿命损失显著相关。在体外，细胞衰老伴随着PDAP1表达的上调。外源性PDAP1刺激加速细胞衰老，而PDAP1缺陷则减弱复制性衰老。这项研究有助于发现潜在的药物靶点，并更广泛地理解长寿的生物学过程，其中PDAP1成为影响人类寿命的关键因素。
