DNA damage-how and why we age?
DNA damage-how and why we age?
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DOI：
10.7554/elife.62852
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发表时间：
2021-01-29
期刊：
影响因子：
7.7
通讯作者：
Niedernhofer L
中科院分区：
文献类型：
--
作者：
Yousefzadeh M;Henpita C;Vyas R;Soto-Palma C;Robbins P;Niedernhofer L
衰老是一个复杂的过程，导致在压力后失去恢复体内平衡的能力，从而导致发病率和死亡率的增加。许多因素导致衰老，例如大分子损伤的时间依赖性积累，包括DNA损伤。核基因组的完整性对细胞、组织和生物体的健康至关重要。DNA损伤是一个持续的威胁，因为核酸在生理条件下化学不稳定，容易受到内源性和环境因素的攻击。为了解决这个问题，所有生物都具有高度保守的机制来检测和修复DNA损伤。持续的DNA损伤（遗传毒性应激）触发信号级联反应，驱使细胞凋亡或衰老，以避免复制受损的基因组。缺点是这些癌症避免机制会促进衰老。在这里，我们回顾了DNA损伤在衰老中起因果作用的证据。我们还提供了证据表明，遗传毒性应激与其他细胞过程有关，这些细胞过程涉及衰老的驱动因素，包括线粒体和代谢功能障碍，蛋白质稳态改变和炎症。遗传密码受损与衰老的其他支柱之间的这些联系支持了DNA损伤可能是衰老根源的观点。
Aging is a complex process that results in loss of the ability to reattain homeostasis following stress, leading, thereby, to increased risk of morbidity and mortality. Many factors contribute to aging, such as the time-dependent accumulation of macromolecular damage, including DNA damage. The integrity of the nuclear genome is essential for cellular, tissue, and organismal health. DNA damage is a constant threat because nucleic acids are chemically unstable under physiological conditions and vulnerable to attack by endogenous and environmental factors. To combat this, all organisms possess highly conserved mechanisms to detect and repair DNA damage. Persistent DNA damage (genotoxic stress) triggers signaling cascades that drive cells into apoptosis or senescence to avoid replicating a damaged genome. The drawback is that these cancer avoidance mechanisms promote aging. Here, we review evidence that DNA damage plays a causal role in aging. We also provide evidence that genotoxic stress is linked to other cellular processes implicated as drivers of aging, including mitochondrial and metabolic dysfunction, altered proteostasis and inflammation. These links between damage to the genetic code and other pillars of aging support the notion that DNA damage could be the root of aging.