Mitochondrial dysfunction is a well-known contributor to aging and age-related diseases. The precise mechanisms through which mitochondria impact human lifespan, however, remain unclear. We hypothesize that humans with exceptional longevity harbor rare variants in nuclear-encoded mitochondrial genes (mitonuclear genes) that confer resistance against age-related mitochondrial dysfunction. Here we report an integrated functional genomics study to identify rare functional variants in ~ 660 mitonuclear candidate genes discovered by target capture sequencing analysis of 496 centenarians and 572 controls of Ashkenazi Jewish descent. We identify and prioritize longevity-associated variants, genes, and mitochondrial pathways that are enriched with rare variants. We provide functional gene variants such as those in MTOR (Y2396Lfs*29), CPS1 (T1406N), and MFN2 (G548*) as well as LRPPRC (S1378G) that is predicted to affect mitochondrial translation. Taken together, our results suggest a functional role for specific mitonuclear genes and pathways in human longevity.

众所周知，线粒体功能障碍是导致衰老和与年龄相关的疾病的一个因素。然而，线粒体影响人类寿命的确切机制仍不清楚。我们假设，长寿的人类在核编码的线粒体基因（线粒体核基因）中存在罕见的变异，这些变异可以抵抗与年龄相关的线粒体功能障碍。在这里，我们报告了一项综合功能基因组学研究，旨在识别约 660 个线粒体核候选基因中的罕见功能变异，这些基因是通过对 496 名百岁老人和 572 名德系犹太人后裔对照进行目标捕获测序分析而发现的。我们识别并优先考虑富含罕见变异的长寿相关变异、基因和线粒体途径。我们提供功能性基因变体，例如MTOR (Y2396Lfs*29)、CPS1 (T1406N) 和MFN2 (G548*) 以及LRPPRC (S1378G) 中的变体，预计会影响线粒体翻译。综上所述，我们的结果表明特定线粒体核基因和通路在人类长寿中发挥着功能作用。