Abstract:
Biological aging results from an accumulation of damage in the face of reduced resilience. One major driver of aging is cell senescence, a state in which cells remain viable but lose their proliferative capacity, undergo metabolic alterations, and become resistant to apoptosis. This is accompanied by complex cellular changes that enable the development of a senescence-associated secretory phenotype (SASP). Mitochondria, organelles involved in energy provision and activities essential for regulating cell survival and death, are negatively impacted by aging. The age-associated decline in mitochondrial function is also accompanied by the development of chronic low-grade sterile inflammation. The latter shares some features and mediators with the SASP. Indeed, the unloading of damage-associated molecular patterns (DAMPs) at the extracellular level can trigger sterile inflammatory responses and mitochondria can contribute to the generation of DAMPs with pro-inflammatory properties. The extrusion of mitochondrial DNA (mtDNA) via mitochondrial outer membrane permeabilization under an apoptotic stress triggers senescence programs. Additional pathways can contribute to sterile inflammation. For instance, pyroptosis is a caspase-dependent inducer of systemic inflammation, which is also elicited by mtDNA release and contributes to aging. Herein, we overview the molecular mechanisms that may link mitochondrial dyshomeostasis, pyroptosis, sterile inflammation, and senescence and discuss how these contribute to aging and could be exploited as molecular targets for alleviating the cell damage burden and achieving healthy longevity.
摘要:
生物老化是由于面对恢复力降低而造成的损伤积累。衰老的一个主要驱动因素是细胞衰老,细胞保持存活但失去增殖能力的状态,经历代谢改变,并对细胞凋亡产生抗性。这伴随着复杂的细胞变化,能够发展衰老相关的分泌表型(SASP)。线粒体,参与能量供应和调节细胞存活和死亡所必需的活动的细胞器,受到衰老的负面影响。与年龄相关的线粒体功能下降也伴随着慢性低度无菌炎症的发展。后者与SASP共享一些功能和中介。的确,损伤相关分子模式(DAMPs)在细胞外水平的卸载可引发无菌性炎症反应,线粒体可有助于产生具有促炎特性的DAMPs.线粒体DNA(mtDNA)在凋亡应激下通过线粒体外膜透化的挤出触发衰老程序。额外的途径可导致无菌炎症。例如,焦亡是全身性炎症的caspase依赖性诱导剂,这也是由mtDNA释放引起的,并有助于衰老。在这里,我们概述了可能与线粒体功能障碍有关的分子机制,焦亡,无菌炎症,和衰老,并讨论这些因素如何导致衰老,并可用作减轻细胞损伤负担和实现健康长寿的分子靶标。