Section on Clinical Genomics and Experimental Therapeutics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA.
NIH-Oxford-Cambridge Scholars Program, University of Oxford, Oxford, UK.
Nat Commun. 2023 Apr 19;14(1):2236. doi: 10.1038/s41467-023-37729-w.
Biological aging is accompanied by increasing morbidity, mortality, and healthcare costs; however, its molecular mechanisms are poorly understood. Here, we use multi-omic methods to integrate genomic, transcriptomic, and metabolomic data and identify biological associations with four measures of epigenetic age acceleration and a human longevity phenotype comprising healthspan, lifespan, and exceptional longevity (multivariate longevity). Using transcriptomic imputation, fine-mapping, and conditional analysis, we identify 22 high confidence associations with epigenetic age acceleration and seven with multivariate longevity. FLOT1, KPNA4, and TMX2 are novel, high confidence genes associated with epigenetic age acceleration. In parallel, cis-instrument Mendelian randomization of the druggable genome associates TPMT and NHLRC1 with epigenetic aging, supporting transcriptomic imputation findings. Metabolomics Mendelian randomization identifies a negative effect of non-high-density lipoprotein cholesterol and associated lipoproteins on multivariate longevity, but not epigenetic age acceleration. Finally, cell-type enrichment analysis implicates immune cells and precursors in epigenetic age acceleration and, more modestly, multivariate longevity. Follow-up Mendelian randomization of immune cell traits suggests lymphocyte subpopulations and lymphocytic surface molecules affect multivariate longevity and epigenetic age acceleration. Our results highlight druggable targets and biological pathways involved in aging and facilitate multi-omic comparisons of epigenetic clocks and human longevity.
生物衰老伴随着发病率、死亡率和医疗保健成本的增加；然而，其分子机制尚不清楚。在这里，我们使用多组学方法整合基因组、转录组和代谢组数据，并确定与四种表观遗传年龄加速测量值和包含健康跨度、寿命和超长寿命（多变量长寿）的人类长寿表型相关的生物学关联。使用转录组推断、精细映射和条件分析，我们确定了与表观遗传年龄加速有 22 个高可信度关联，与多变量长寿有 7 个关联。FLOT1、KPNA4 和 TMX2 是与表观遗传年龄加速相关的新的、高可信度基因。同时，药物基因组学 cis 工具孟德尔随机化将 TPMT 和 NHLRC1 与表观遗传老化相关联，支持转录组推断结果。代谢组学 Mendelian 随机化确定了非高密度脂蛋白胆固醇和相关脂蛋白对多变量长寿的负面影响，但对表观遗传年龄加速没有影响。最后，细胞类型富集分析表明免疫细胞和前体细胞与表观遗传年龄加速有关，并且在多变量长寿方面的作用更为适度。免疫细胞特征的后续 Mendelian 随机化表明淋巴细胞亚群和淋巴细胞表面分子影响多变量长寿和表观遗传年龄加速。我们的研究结果强调了与衰老相关的可药物靶点和生物学途径，并促进了表观遗传时钟和人类长寿的多组学比较。
