Institute for Genome Stability in Ageing and Disease, Medical Faculty, University of Cologne, Cologne, Germany.
Cologne Excellence Cluster for Cellular Stress Responses in Aging-Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
Nature. 2021 Apr;592(7856):695-703. doi: 10.1038/s41586-021-03307-7. Epub 2021 Apr 28.
Ageing is a complex, multifaceted process leading to widespread functional decline that affects every organ and tissue, but it remains unknown whether ageing has a unifying causal mechanism or is grounded in multiple sources. Phenotypically, the ageing process is associated with a wide variety of features at the molecular, cellular and physiological level-for example, genomic and epigenomic alterations, loss of proteostasis, declining overall cellular and subcellular function and deregulation of signalling systems. However, the relative importance, mechanistic interrelationships and hierarchical order of these features of ageing have not been clarified. Here we synthesize accumulating evidence that DNA damage affects most, if not all, aspects of the ageing phenotype, making it a potentially unifying cause of ageing. Targeting DNA damage and its mechanistic links with the ageing phenotype will provide a logical rationale for developing unified interventions to counteract age-related dysfunction and disease.
衰老是一个复杂的、多方面的过程，导致广泛的功能下降，影响到每个器官和组织，但目前尚不清楚衰老是有一个统一的因果机制，还是源于多种来源。表型上，衰老过程与分子、细胞和生理水平的多种特征相关，例如基因组和表观基因组改变、蛋白质稳态丧失、整体细胞和亚细胞功能下降以及信号系统失调。然而，这些衰老特征的相对重要性、机制关系和层次顺序尚未阐明。在这里，我们综合了越来越多的证据，表明 DNA 损伤影响衰老表型的大多数（如果不是全部）方面，使其成为衰老的潜在统一原因。针对 DNA 损伤及其与衰老表型的机制联系，将为开发统一的干预措施以对抗与年龄相关的功能障碍和疾病提供合理的依据。
