Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε and Pol δ replicate DNA during cell division. However, in some cancers, defective proofreading due to acquired POLE/POLD1 exonuclease domain mutations causes markedly elevated somatic mutation burdens with distinctive mutational signatures. Germline POLE/POLD1 mutations cause familial cancer predisposition. Here, we sequenced normal tissue and tumor DNA from individuals with germline POLE/POLD1 mutations. Increased mutation burdens with characteristic mutational signatures were found in normal adult somatic cell types, during early embryogenesis and in sperm. Thus human physiology can tolerate ubiquitously elevated mutation burdens. Except for increased cancer risk, individuals with germline POLE/POLD1 mutations do not exhibit overt features of premature aging. These results do not support a model in which all features of aging are attributable to widespread cell malfunction directly resulting from somatic mutation burdens accrued during life.

体细胞中的突变积累有助于癌症的发展，并被认为是衰老的一个原因。DNA 聚合酶 Pol ε 和 Pol δ 在细胞分裂过程中复制 DNA。然而，在某些癌症中，由于获得性POLE / POLD1核酸外切酶域突变导致的校对缺陷导致具有独特突变特征的体细胞突变负荷显着升高。种系POLE / POLD1突变导致家族性癌症易感性。在这里，我们对来自种系POLE / POLD1个体的正常组织和肿瘤 DNA 进行了测序突变。在正常成人体细胞类型、早期胚胎发生和精子中发现了具有特征性突变特征的突变负荷增加。因此，人类生理学可以容忍普遍升高的突变负担。除了癌症风险增加外，具有种系POLE / POLD1突变的个体不会表现出明显的过早衰老特征。这些结果不支持一个模型，在该模型中，衰老的所有特征都归因于广泛的细胞功能障碍，直接由生命中累积的体细胞突变负担引起。