Cancado de Faria Rafael, Silva Lilian, Teodoro-Castro Barbara, McCommis Kyle S, Shashkova Elena V, Gonzalo Susana
bioRxiv. 2025 Apr 4:2025.04.03.645994. doi: 10.1101/2025.04.03.645994.
Accumulation of cytosolic DNA has emerged as a hallmark of aging, inducing sterile inflammation. STING (Stimulator of Interferon Genes) protein translates the sensing of cytosolic DNA by cGAS (cyclic-GMP-AMP synthase) into an inflammatory response. However, the molecular mechanisms whereby cytosolic DNA-induced cGAS-STING pathway leads to aging remain poorly understood. We show that STING does not follow the canonical pathway of activation in human fibroblasts passaged (aging) in culture, senescent fibroblasts, or progeria fibroblasts (from Hutchinson Gilford Progeria Syndrome patients). Despite cytosolic DNA buildup, features of the canonical cGAS-STING pathway like increased cGAMP production, STING phosphorylation, and STING trafficking to perinuclear compartment are not observed in progeria/senescent/aging fibroblasts. Instead, STING localizes at endoplasmic reticulum, nuclear envelope, and chromatin. Despite the non-conventional STING behavior, aging/senescent/progeria cells activate inflammatory programs such as the senescence-associated secretory phenotype (SASP) and the interferon (IFN) response, in a cGAS and STING-dependent manner, revealing a non-canonical pathway in aging. Importantly, progeria/aging/senescent cells are hindered in their ability to activate the canonical cGAS-STING pathway with synthetic DNA, compared to young cells. This deficiency is rescued by activating vitamin D receptor signaling, unveiling new mechanisms regulating the cGAS-STING pathway in aging. Significantly, in HGPS, inhibition of the non-canonical cGAS-STING pathway ameliorates cellular hallmarks of aging, reduces tissue degeneration, and extends the lifespan of progeria mice. Our study reveals that a new feature of aging is the progressively reduced ability to activate the canonical cGAS-STING pathway in response to cytosolic DNA, triggering instead a non-canonical pathway that drives senescence/aging phenotypes.
Our study provides novel insights into the mechanisms driving sterile inflammation in aging and progeria. We reveal a previously unrecognized characteristic of aging cells: the progressive loss of ability to activate the canonical response to foreign or self-DNA at the cytoplasm. Instead, aging, senescent, and progeria cells activate inflammatory programs via a non-conventional pathway driven by cGAS and the adaptor protein STING. Importantly, pharmacological inhibition of the non-canonical cGAS-STING pathway ameliorates cellular, tissue and organismal decline in a devastating accelerated aging disease (Hutchinson Gilford Progeria Syndrome), highlighting it as a promising therapeutic target for age-related pathologies.
胞质DNA的积累已成为衰老的一个标志，可引发无菌性炎症。STING（干扰素基因刺激物）蛋白将cGAS（环鸟苷酸-腺苷酸合成酶）对胞质DNA的感知转化为炎症反应。然而，胞质DNA诱导的cGAS-STING通路导致衰老的分子机制仍知之甚少。我们发现，在体外传代（衰老）的人成纤维细胞、衰老的成纤维细胞或早衰症成纤维细胞（来自哈钦森-吉尔福德早衰症综合征患者）中，STING并不遵循经典的激活途径。尽管存在胞质DNA积累，但在早衰症/衰老/老化的成纤维细胞中未观察到经典cGAS-STING通路的特征，如cGAMP产量增加、STING磷酸化以及STING向核周区室的转运。相反，STING定位于内质网、核膜和染色质。尽管STING表现出非传统行为，但衰老/衰老/早衰症细胞以cGAS和STING依赖的方式激活炎症程序，如衰老相关分泌表型（SASP）和干扰素（IFN）反应，揭示了衰老过程中的一条非经典途径。重要的是，与年轻细胞相比，早衰症/衰老/衰老细胞用合成DNA激活经典cGAS-STING通路的能力受到阻碍。通过激活维生素D受体信号可挽救这种缺陷，揭示了衰老过程中调节cGAS-STING通路的新机制。值得注意的是，在哈钦森-吉尔福德早衰症综合征中，抑制非经典cGAS-STING通路可改善衰老的细胞特征，减少组织退化，并延长早衰症小鼠的寿命。我们的研究表明，衰老的一个新特征是对胞质DNA激活经典cGAS-STING通路的能力逐渐降低，转而触发一条驱动衰老/老化表型的非经典途径。
我们的研究为衰老和早衰症中驱动无菌性炎症的机制提供了新的见解。我们揭示了衰老细胞以前未被认识的一个特征：在细胞质中激活对外源或自身DNA的经典反应的能力逐渐丧失。相反，衰老、衰老和早衰症细胞通过由cGAS和衔接蛋白STING驱动的非传统途径激活炎症程序。重要的是，在一种毁灭性的加速衰老疾病（哈钦森-吉尔福德早衰症综合征）中，对非经典cGAS-STING通路的药理学抑制可改善细胞、组织和机体的衰退，突出了它作为与年龄相关病理的一个有前景的治疗靶点。
