Patterns of Aging Biomarkers, Mortality, and Damaging Mutations Illuminate the Beginning of Aging and Causes of Early-Life Mortality
Patterns of Aging Biomarkers, Mortality, and Damaging Mutations Illuminate the Beginning of Aging and Causes of Early-Life Mortality
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DOI：
10.1016/j.celrep.2019.11.091
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发表时间：
2019-12-24
期刊：
影响因子：
8.8
通讯作者：
Gladyshev, Vadim N.
中科院分区：
文献类型：
--
作者：
Kinzina, Elvira D.;Podolskiy, Dmitriy I.;Gladyshev, Vadim N.
死亡概率的增加一直是老龄化的一个决定性特征，但人类围产期死亡率一开始很高，并随着年龄的增长而下降。以前的进化模型表明，生物体的衰老是在生殖开始后开始的。然而，我们发现与衰老相关的疾病的死亡率和发病率遵循U型曲线，青春期前最低，而衰老的定量生物标记物，包括体细胞突变和DNA甲基化，则不是这样，这表明衰老开始得很早，但被早期死亡掩盖了。此外，我们的基因分析指出破坏性突变对早期死亡率的贡献。我们认为，死亡率模式在一定程度上是由对早期生命中破坏性突变的负选择所控制的，在相应的基因首次表达后表现出来。死亡模式的反卷积表明，有害的变化而不是死亡是衰老的决定性特征，而且衰老在生命非常早期就开始了。
An increase in the probability of death has been a defining feature of aging, yet human perinatal mortality starts high and decreases with age. Previous evolutionary models suggested that organismal aging begins after the onset of reproduction. However, we find that mortality and incidence of diseases associated with aging follow a U-shaped curve with the minimum before puberty, whereas quantitative biomarkers of aging, including somatic mutations and DNA methylation, do not, revealing that aging starts early but is masked by early-life mortality. Moreover, our genetic analyses point to the contribution of damaging mutations to early mortality. We propose that mortality patterns are governed, in part, by negative selection against damaging mutations in early life, manifesting after the corresponding genes are first expressed. Deconvolution of mortality patterns suggests that deleterious changes rather than mortality are the defining characteristic of aging and that aging begins in very early life.