Cytoplasmic chromatin fragments in cell senescence - novel mechanisms and interventions

细胞衰老中的细胞质染色质片段——新机制和干预措施

• 批准号: 10185176
• 负责人: PETER D. ADAMS
• 金额: $ 62.86万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10185176
• 关键词: Address; Aging; Autophagocytosis; Binding Proteins; Cell Aging; Cell Nucleus; Cells; Cellular Stress; Characteristics; Chromatin; Chronic; Cytoplasm; DNA; DNA Damage; DNA Double Strand Break; DNA Repair Pathway; Data; Development; Disease; Double Strand Break Repair; Event; Excision; Gamma-H2AX; Genomic DNA; Glycolysis; Histones; Human; Hypoxia Inducible Factor; Impairment; Inflammation; Inflammatory; Intervention; Link; Longevity; MAPK8 gene; Malignant Neoplasms; Mediating; Metabolism; Mitochondria; Modeling; Molecular; N-terminal; Nuclear; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphotransferases; Premalignant Cell; Process; Reactive Oxygen Species; Recycling; Role; Signal Transduction; Source; Stains; Testing; Tissues; Toxic effect; Transcription Coactivator; Tumor Suppression; Up-Regulation; age effect; aged; base; cell injury; combat; genome integrity; healthy aging; histone modification; immune clearance; in vivo; inhibitor/antagonist; novel; nuclease; p53-binding protein 1; preservation; prevent; response; senescence; sensor; trafficking; transcription factor; tumor

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.

项目概要 细胞衰老是细胞和组织衰老的原因。衰老是由一系列细胞应激引起的 其特征是不可逆的增殖停滞和有效的促炎表型， 衰老相关的分泌表型（SASP）。衰老相关的增殖停滞和 SASP 通过阻止受损的癌前细胞的增殖并促进 受损细胞的免疫清除。然而，从长远来看，作为慢性炎症的根源， SASP 还会促进组织衰老和疾病。因此，目前正在投入大量精力 开发消除衰老细胞以促进健康老龄化的药理学方法。然而， 这些所谓的抗衰老药物往往会表现出不良的毒性。另一种可能毒性较小的方法是 使用senomorphic药物特异性抑制促衰老的SASP。重要的是，抑制 SASP 并不 必然损害抗衰老的肿瘤抑制作用。相反，消除 SASP 可以防止 癌症。因此，定义 SASP 激活机制很重要，因为它的抑制可能是一种 对抗衰老细胞的促衰老作用的方法。 最近，我们发现衰老细胞将核染色质片段脱落到细胞质中， 染色质片段（CCF），通过细胞核到细胞质的起泡过程。 CCF 对 DNA 损伤标记，磷酸化组蛋白 γH2AX。 CCF 的形成取决于新的表现 细胞回收过程自噬，特别是核自噬。通过细胞质 DNA 发出 CCF 信号 传感器激活 NFκB，SASP 的主要转录激活因子。最近，我们定义了一个 CCF 和 SASP 的意外上游触发因素，即衰老细胞中的线粒体功能障碍。 功能失调的线粒体本身就与慢性炎症和衰老有关。 我们假设含有 DNA 双链断裂的 CCF 的核排出是一种机制 DNA 修复途径受损的衰老细胞可减少有毒 DNA 双链的核内负荷 休息。我们还假设功能失调的线粒体会触发自噬依赖性 CCF 的形成 通过逆行线粒体到细胞核信号传导（涉及 JNK 激酶和转录）来抑制衰老细胞 分别影响缺氧诱导因子 1a (HIF1a)、“JNK-CCF”和“HIF-CCF”途径。 JNK-CCF 和 HIF-CCF 通路及其相互作用的描述将为 干预以抑制体内 SASP 驱动的慢性炎症，从而促进健康衰老和 长寿。