Department of Genetics, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.
Department of Pharmacology, College of Medicine, Hallym University, Chuncheon, Gangwon, 24252, Republic of Korea.
Geroscience. 2023 Feb;45(1):311-330. doi: 10.1007/s11357-022-00634-z. Epub 2022 Aug 10.
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 (Y2396Lfs29), 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.
线粒体功能障碍是衰老和与年龄相关疾病的已知诱因。然而，线粒体影响人类寿命的确切机制仍不清楚。我们假设，具有超长寿命的人类拥有核编码线粒体基因（mitonuclear genes）中的罕见变异，这些变异赋予了它们对与年龄相关的线粒体功能障碍的抗性。在这里，我们报告了一项综合功能基因组学研究，以鉴定通过对 496 名百岁老人和 572 名阿什肯纳兹犹太血统对照进行靶向捕获测序分析发现的约 660 个 mitonuclear 候选基因中的罕见功能变异。我们鉴定并优先考虑与长寿相关的变异、基因和富含罕见变异的线粒体途径。我们提供了功能性基因变异，例如 MTOR（Y2396Lfs29）、CPS1（T1406N）和 MFN2（G548）中的变异，以及预测会影响线粒体翻译的 LRPPRC（S1378G）中的变异。总之，我们的结果表明特定的 mitonuclear 基因和途径在人类长寿中具有功能作用。
