Zhang Lei, De Cecco Marco, Lee Moonsook, Hao Xiaoxiao, Maslov Alexander Y, Montagna Cristina, Campisi Judith, Dong Xiao, Sedivy John M, Vijg Jan
Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA.
Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA.
Aging Biol. 2023;1(1). doi: 10.59368/agingbio.20230005. Epub 2023 Jun 27.
Somatic mutations accumulate in multiple organs and tissues during aging and are a known cause of cancer. Cellular senescence is a possible cause of functional decline in aging, yet also acts as an anticancer mechanism . Here, we compared somatic mutation burden between early passage and deeply senescent human fibroblasts using single-cell whole-genome sequencing. The results show that single-nucleotide variants (SNVs) and small insertions and deletions (INDELs) are increased in senescent cells by about twofold but have the same mutational signature as early passage cells. The increase in SNVs and INDELs can be explained by increased replication errors due to the increased number of cell divisions senescent cells are likely to have undergone. By contrast, a stark increase of aneuploidies was observed in deeply senescent cells, with about half of all senescent cells affected but none of the early passage cells analyzed. These results indicate that large chromosomal events rather than small base substitutions or insertions and deletions could be mechanistically linked to cellular senescence.
体细胞突变在衰老过程中会在多个器官和组织中积累，是已知的癌症成因。细胞衰老可能是衰老过程中功能衰退的一个原因，但同时也起到抗癌机制的作用。在此，我们使用单细胞全基因组测序比较了早期传代和深度衰老的人类成纤维细胞之间的体细胞突变负担。结果表明，衰老细胞中的单核苷酸变异（SNV）和小插入缺失（INDEL）增加了约两倍，但具有与早期传代细胞相同的突变特征。SNV和INDEL的增加可以用衰老细胞可能经历的细胞分裂次数增加导致的复制错误增加来解释。相比之下，在深度衰老细胞中观察到非整倍体的急剧增加，所有衰老细胞中约有一半受到影响，但分析的早期传代细胞中没有一个受到影响。这些结果表明，大的染色体事件而非小的碱基替换或插入缺失可能在机制上与细胞衰老相关联。
