It is estimated that 10–50 DNA double-strand breaks (DSBs) occur in a nucleated human cell per cell cycle. We reviewed the present state of knowledge and hypothesized that the currently accepted mechanisms cannot explain such high frequency of DSBs occurring daily under normal physiological conditions. We propose an alternative model that implicates illegitimate genomic integration into healthy cells of cell-free chromatin (cfCh) particles released from the billions of cells that die in the body every day. Repeated genomic integration of cfCh may have catastrophic consequences for the cell, such as DSBs, their faulty repair by nonhomologous end joining (NHEJ) followed by apoptosis with release of more cfCh which would integrate into genomes of surrounding cells. This can creates a vicious cycle of cfCh integration, DSBs, NHEJ, and more apoptosis, thereby providing a potential explanation as to why so many billions of cells die in the body on a daily basis. We also recount the recent observation that cfCh integration and the resulting DSBs activate inflammatory cytokines. This leads us to propose that concurrent DSBs and induction of inflammation occurring throughout life may be the underlying cause of ageing, degenerative disorders, and cancer. Finally, we discuss the prospect that agents that can inactivate/degrade cfCh may hold the key to making healthy ageing a realizable goal.

中文翻译：

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DNA双链断裂的起源及其对衰老的影响的新观点

据估计，每个细胞周期在有核人细胞中发生10–50个DNA双链断裂（DSB）。我们回顾了目前的知识状态，并假设当前接受的机制无法解释在正常生理条件下每天如此频繁发生的DSB。我们提出了一种替代模型，该模型隐含着将非法基因组整合到健康细胞中的无细胞染色质（cfCh）颗粒，这些颗粒每天从体内死亡的数十亿细胞中释放出来。cfCh的重复基因组整合可能会对细胞造成灾难性后果，例如DSB，其通过非同源末端连接（NHEJ）的错误修复，然后凋亡并释放出更多的cfCh，从而整合到周围细胞的基因组中。这会造成cfCh整合，DSB，NHEJ和更多细胞凋亡的恶性循环，从而为为什么每天有数十亿个细胞在体内死亡而提供了一种可能的解释。我们还讲述了最近的观察，即cfCh整合和由此产生的DSB激活了炎症细胞因子。这导致我们提出，并发的DSB和一生中发生的炎症诱导可能是衰老，变性疾病和癌症的根本原因。最后，我们讨论了可以使cfCh失活/降解的物质可能成为使健康衰老成为可实现目标的关键。这导致我们提出，并发的DSB和一生中发生的炎症诱导可能是衰老，变性疾病和癌症的根本原因。最后，我们讨论了可以使cfCh失活/降解的物质可能成为使健康衰老成为可实现目标的关键。这导致我们提出，并发的DSB和一生中发生的炎症诱导可能是衰老，变性疾病和癌症的根本原因。最后，我们讨论了可以使cfCh失活/降解的物质可能成为使健康衰老成为可实现目标的关键。