Role of cytosolic DNA-induced sterile inflammation driving cellular and organismal progeria/aging hallmarks

摘要 细胞质DNA的积累已经成为衰老的新标志，它引发无菌性炎症， 会导致组织退化然而，产生胞质DNA或信号传导的机制 它们对衰老的贡献仍然知之甚少。在Hutchinson-Gilford早衰综合征（HGPS）中， 由编码截短核纤层蛋白A的LMNA基因突变引起，该截短核纤层蛋白A称为“早老蛋白”，我们发现 细胞质DNA，伴随着深刻的基因组不稳定性和无菌炎症。这项提案的目的是 是为了确定这种持续的无菌性炎症，其中包括干扰素（IFN）反应和 衰老样分泌表型，驱动早衰症中的代谢功能障碍和组织变性， 定义所涉及的机制。解读控制衰老/早衰症中无菌炎症的机制 将为改善健康老龄化和降低HGPS等疾病的严重程度提供新的策略。 我们的体外和体内数据显示STING和STAT 1驱动早衰样表型。实际上，药理学上， 或STING和STAT 1的遗传抑制了无菌炎症，并改善了 衰老和关键的是，靶向STAT 1增加了早衰小鼠的健康寿命和寿命。然而 早老蛋白参与STING和STAT 1活性的分子机制，以及STING 和STAT 1在早衰症中触发代谢改变和组织变性是未知的。没想到，我们的 数据还显示早老蛋白不触发STING-STAT 1途径的典型cGAMP依赖模式 activation.该提议旨在定义在早老蛋白诱导的细胞凋亡后STING刺激的非规范模式。 细胞质DNA的积累（目的1），STING，STAT 1和下游干扰素刺激的作用 ISG 15等基因驱动细胞代谢改变（Aim 2），STING-STAT 1- ISG 15途径导致组织变性/损失和减少的健康寿命和早衰小鼠的寿命（目的3）。 如果成功，我们的研究将证明，一个基本的机制驱动早衰症是适应不良， 对细胞核/线粒体损伤和胞质DNA积累的反应，这导致持续的和 未解决的无菌炎症/干扰素反应，损害代谢和组织稳态。 证明细胞溶质DNA触发的途径驱动早衰症中的代谢功能障碍和组织损失， 定义所涉及的机制，并表明靶向体内途径中的特定因子， 有益的效果，将有重要的和潜在的变革性的治疗意义，这一毁灭性的 和不可治愈的疾病，这可能与正常衰老过程中的代谢表型有关。

Abstract Accumulation of cytosolic DNAs has emerged as a new hallmark of aging that triggers sterile inflammation and contributes to tissue deterioration. However, the mechanisms that generate cytosolic DNAs or the signaling whereby they contribute to aging remain poorly understood. In Hutchinson-Gilford Progeria Syndrome (HGPS), caused by a LMNA gene mutation that encodes a truncated lamin A named “progerin”, we find build-up of cytosolic DNAs, concomitant with profound genomic instability and sterile inflammation. The goal of this proposal is to determine whether this persistent sterile inflammation, which includes an interferon (IFN) response and a senescence-like secretory phenotype, drives metabolic dysfunction and tissue degeneration in progeria, and to define the mechanisms involved. Deciphering the mechanisms controlling sterile inflammation in aging/progeria will provide novel strategies to improve healthy aging and reduce the severity of diseases like HGPS. Our in vitro and in vivo data show that STING and STAT1 drive progeroid phenotypes. Indeed, pharmacological, or genetic inhibition of STING and STAT1 repressed sterile inflammation and improved cellular hallmarks of aging and, critically, targeting STAT1 increased the healthspan and the lifespan of progeria mice. Yet, the molecular mechanisms whereby progerin engages STING and STAT1 activities, and the roles played by STING and STAT1 triggering metabolic alterations and tissue degeneration in progeria are unknown. Unexpectedly, our data also show that progerin does not trigger the canonical cGAMP-dependent mode of STING-STAT1 pathway activation. This proposal aims to define the non-canonical mode of STING stimulation upon progerin-induced accumulation of cytosolic DNAs (Aim 1), the role that STING, STAT1, and downstream interferon stimulated genes such as ISG15 play driving cellular metabolic alterations (Aim 2), and the contribution of STING-STAT1- ISG15 pathway to tissue degeneration/loss and reduced healthspan and lifespan of progeria mice (Aim 3). If successful, our studies will demonstrate that a fundamental mechanism driving progeria is the maladaptive response to nuclear/mitochondrial damage and accumulation of cytosolic DNAs, which lead to a sustained and unresolved sterile inflammation/IFN response that compromises metabolism and tissue homeostasis. Demonstrating that cytosolic DNA-triggered pathways drive metabolic dysfunction and tissue loss in progeria, defining the mechanisms involved, and showing that targeting specific factors in the pathway in vivo has beneficial effects, will have important and potentially transformative therapeutic implications for this devastating and uncurable disease, which will likely be relevant to metabolic phenotypes during normal aging.