Cytoplasmic chromatin fragments in cell senescence - novel mechanisms and interventions

项目总结 细胞衰老是细胞和组织衰老的原因之一。衰老是由一系列细胞压力引起的。 并以不可逆转的增殖停滞和强大的促炎表型为特征 衰老相关分泌表型(SASP)。衰老相关的增殖抑制与SASP 合作抑制肿瘤，阻止受损的癌前细胞的增殖并促进 免疫清除受损细胞。然而，从长远来看，作为慢性炎症的来源， SASP还促进组织老化和疾病。因此，目前有很多努力致力于 开发消除衰老细胞以促进健康衰老的药理方法。然而， 这些所谓的抗衰老药物往往会显示出不受欢迎的毒性。另一种可能毒性较小的方法是 使用感觉性药物特异性地抑制促衰老的SASP。重要的是，抑制SASP不会 必然损害衰老对肿瘤的抑制作用。相反，消除SASP可以防止 癌症。因此，确定SASP激活的机制很重要，因为它的抑制可能是一种 对抗衰老细胞的延缓衰老作用的方法。 最近，我们发现衰老的细胞将核染色质的碎片脱落到细胞质、细胞质 染色质碎片(CCF)，通过核到细胞质的气泡过程。CCF是非常积极的 DNA损伤标记，磷酸化组蛋白γH2AX。CCF的形成取决于一种新的表现形式 细胞循环过程的自噬，特别是核自噬。胞质DNA传递CCF信号 传感器激活核因子κB，主要的转录激活剂。最近，我们定义了一个 意外的上游触发CCF和SASP，即衰老细胞中功能失调的线粒体。 功能失调的线粒体本身已经与慢性炎症和衰老有关。 我们假设，含有DNA双链断裂的CCF的核排出是一种 DNA修复通路受损的衰老细胞降低毒性DNA双链的核内负荷 休息一下。我们还假设，功能障碍的线粒体触发了自噬依赖的CCF的形成 衰老细胞线粒体到核的逆行信号转导，涉及JNK激酶和转录 低氧诱导因子1a(HIF1a)分别为“JNK-CCF”和“HIF-CCF”途径。 JNK-CCF和HIF-CCF途径的描绘及其相互作用将提供新的机会 干预抑制体内SASP引发的慢性炎症，从而促进健康衰老和 长寿。

PROJECT SUMMARY Cellular senescence is a cause of cell and tissue aging. Senescence is caused by a range of cellular stresses and characterized by an irreversible proliferation arrest and a potent pro-inflammatory phenotype, the senescence-associated secretory phenotype (SASP). Senescence-associated proliferation arrest and SASP cooperate in tumor suppression, by arresting proliferation of damaged pre-malignant cells and promoting immune clearance of the damaged cells. However, over the longer term, as a source of chronic inflammation, SASP also promotes tissue aging and disease. Consequently, there is currently much effort devoted to development of pharmacologic approaches to eliminate senescent cells to promote healthy aging. However, these so-called senolytic drugs tend to show unwanted toxicities. An alternative, perhaps less toxic approach, is to use senomorphic drugs to specifically inhibit the pro-aging SASP. Importantly, inhibition of SASP does not necessarily impair the tumor suppressive role of senescence. On the contrary, elimination of SASP can prevent cancer. Hence, it is important to define the mechanism of SASP activation, because its inhibition may be an approach to combat the pro-aging effects of senescent cells. Recently, we showed that senescent cells shed fragments of nuclear chromatin into the cytoplasm, cytoplasmic chromatin fragments (CCF), via a nucleus-to-cytoplasmic blebbing process. CCF are very strongly positive for a DNA damage marker, phosphorylated histone γH2AX. Formation of CCF depends upon a novel manifestation of the cellular recycling process autophagy, specifically nuclear autophagy. CCF signal through cytoplasmic DNA sensors to activate NFκB, the major transcriptional activator of SASP. Most recently, we have defined an unanticipated upstream trigger of CCF and SASP, namely dysfunctional mitochondria in senescent cells. Dysfunctional mitochondria are themselves already linked to chronic inflammation and aging. We hypothesize that nuclear expulsion of CCF harboring DNA double strand breaks is a mechanism for senescent cells with impaired DNA repair pathways to decrease the intranuclear load of toxic DNA double strand breaks. We also hypothesize that dysfunctional mitochondria trigger autophagy-dependent formation of CCF in senescent cells by retrograde mitochondria-to-nucleus signaling, involving JNK kinase and the transcription factors Hypoxia Inducible Factor 1a (HIF1a), the “JNK-CCF” and “HIF-CCF” pathways, respectively. Delineation of the JNK-CCF and HIF-CCF pathways and their interactions will provide new opportunities to intervene to suppress chronic inflammation driven by SASP in vivo, thereby potentiating healthy aging and longevity.