Senescent cell turnover slows with age providing an explanation for the Gompertz law
Senescent cell turnover slows with age providing an explanation for the Gompertz law
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DOI：
10.1038/s41467-019-13192-4
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发表时间：
2019-12-02
影响因子：
16.6
通讯作者：
Alon, Uri
中科院分区：
文献类型：
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作者：
Karin, Omer;Agrawal, Amit;Alon, Uri
哺乳动物衰老的一个原因是衰老细胞（SnC）的积累。SnC会引起慢性炎症，去除SnC会减缓小鼠的衰老。尽管它们的重要性，周转率的SnCs是未知的，其连接到老化动力学是不清楚的。在这里，我们使用纵向SnC测量和诱导实验来表明，SnC在年轻小鼠中迅速翻转，半衰期为几天，但在老年小鼠中将其自身的去除速率减慢至几周的半衰期。这导致临界减速，产生持续的SnC波动。我们进一步证明了一个数学模型，其中死亡发生时，波动的SnCs越过阈值，定量概括了Gompertz定律的死亡率在小鼠和人类。该模型可以超越SnCs来解释果蝇和C.包括生存曲线的缩放和饮食变化对死亡率的快速影响。
A causal factor in mammalian aging is the accumulation of senescent cells (SnCs). SnCs cause chronic inflammation, and removing SnCs decelerates aging in mice. Despite their importance, turnover rates of SnCs are unknown, and their connection to aging dynamics is unclear. Here we use longitudinal SnC measurements and induction experiments to show that SnCs turn over rapidly in young mice, with a half-life of days, but slow their own removal rate to a half-life of weeks in old mice. This leads to a critical-slowing-down that generates persistent SnC fluctuations. We further demonstrate that a mathematical model, in which death occurs when fluctuating SnCs cross a threshold, quantitatively recapitulates the Gompertz law of mortality in mice and humans. The model can go beyond SnCs to explain the effects of lifespan-modulating interventions in Drosophila and C. elegans, including scaling of survival-curves and rapid effects of dietary shifts on mortality.