Department of Biology, University of Rochester, Rochester, NY 14627, USA.
Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY 14642, USA.
Cell. 2019 Apr 18;177(3):622-638.e22. doi: 10.1016/j.cell.2019.03.043.
DNA repair has been hypothesized to be a longevity determinant, but the evidence for it is based largely on accelerated aging phenotypes of DNA repair mutants. Here, using a panel of 18 rodent species with diverse lifespans, we show that more robust DNA double-strand break (DSB) repair, but not nucleotide excision repair (NER), coevolves with longevity. Evolution of NER, unlike DSB, is shaped primarily by sunlight exposure. We further show that the capacity of the SIRT6 protein to promote DSB repair accounts for a major part of the variation in DSB repair efficacy between short- and long-lived species. We dissected the molecular differences between a weak (mouse) and a strong (beaver) SIRT6 protein and identified five amino acid residues that are fully responsible for their differential activities. Our findings demonstrate that DSB repair and SIRT6 have been optimized during the evolution of longevity, which provides new targets for anti-aging interventions.
DNA 修复被假设为长寿的决定因素，但支持这一假设的证据主要基于 DNA 修复突变体的加速衰老表型。在这里，我们使用一组具有不同寿命的 18 种啮齿动物物种，表明更强大的 DNA 双链断裂 (DSB) 修复，但不是核苷酸切除修复 (NER)，与长寿共同进化。与 DSB 不同，NER 的进化主要由阳光暴露塑造。我们进一步表明，SIRT6 蛋白促进 DSB 修复的能力解释了短寿命和长寿命物种之间 DSB 修复效果差异的主要部分。我们剖析了弱（小鼠）和强（海狸）SIRT6 蛋白之间的分子差异，并确定了五个氨基酸残基，它们完全负责它们的差异活性。我们的研究结果表明，DSB 修复和 SIRT6 在长寿进化过程中得到了优化，这为抗衰老干预提供了新的目标。
