Background Inflammation is a natural part of the aging process. This process is referred to as inflammaging. Inflammaging has been associated with deleterious outcomes in the aging brain in diseases such as Alzheimer's disease and Parkinson's disease. The inflammasome is a multi-protein complex of the innate immune response involved in the activation of caspase-1 and the processing of the inflammatory cytokines interleukin (IL)-1β and IL-18. We have previously shown that the inflammasome plays a role in the aging process in the brain. In this study, we analyzed the brain of young (3 months old) and aged (18 months old) mice for the expression of inflammasome proteins. Results Our findings indicate that the inflammasome proteins NLRC4, caspase-1, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and IL-18 are elevated in the cytosol of cortical lysates in aged mice when compared to young. In addition, in the cytosolic fraction of hippocampal lysates in aged mice, we found an increase in NLRC4, caspase-1, caspase-11, ASC and IL-1β. Moreover, we found higher levels of ASC in the mitochondrial fraction of aged mice when compared to young, consistent with higher levels of the substrate of pyroptosis gasdermin-D (GSDM-D) and increased pyroptosome formation (ASC oligomerization). Importantly, in this study we obtained fibroblasts from a subject that donated his cells at three different ages (49, 52 and 64 years old (y/o)) and found that the protein levels of caspase-1 and ASC were higher at 64 than at 52 y/o. In addition, the 52 y/o cells were more susceptible to oxidative stress as determined by lactose dehydrogenase (LDH) release levels. However, this response was ameliorated by inhibition of the inflammasome with Ac-Tyr-Val-Ala-Asp-Chloromethylketone (Ac-YVAD-CMK). In addition, we found that the protein levels of ASC and IL-18 are elevated in the serum of subjects over the age of 45 y/o when compared to younger subjects, and that ASC was higher in Caucasians than Blacks and Hispanics, whereas IL-18 was higher in Caucasians than in blacks, regardless of age. Conclusions Taken together, our data indicate that the inflammasome contributes to inflammaging and that the inflammasome-mediated cell death mechanism of pyroptosis contributes to cell demise in the aging brain.

中文翻译：

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炎症小体对炎症的贡献。

背景炎症是衰老过程的自然部分。这个过程被称为炎症。在阿尔茨海默病和帕金森病等疾病中，炎症与衰老大脑的有害结果有关。炎性体是先天免疫反应的多蛋白复合物，参与 caspase-1 的激活和炎性细胞因子白介素 (IL)-1β 和 IL-18 的加工。我们之前已经证明炎症小体在大脑的衰老过程中起作用。在这项研究中，我们分析了年轻（3 个月大）和老年（18 个月大）小鼠的大脑中炎症小体蛋白的表达。结果 我们的研究结果表明，炎症小体蛋白 NLRC4、caspase-1、凋亡相关斑点样蛋白含有半胱天冬酶募集结构域 (ASC)、与年轻小鼠相比，老年小鼠皮质裂解物的胞质溶胶中的 IL-18 和 IL-18 升高。此外，在老年小鼠海马裂解物的细胞溶质部分中，我们发现 NLRC4、caspase-1、caspase-11、ASC 和 IL-1β 增加。此外，我们发现与年轻小鼠相比，老年小鼠线粒体部分的 ASC 水平更高，这与更高水平的 pyroptosis gasdermin-D (GSDM-D) 底物和增加的 pyroptosome 形成（ASC 寡聚化）一致。重要的是，在这项研究中，我们从一个在三个不同年龄（49、52 和 64 岁（y/o））捐赠细胞的受试者获得了成纤维细胞，发现 caspase-1 和 ASC 的蛋白质水平在 64 岁时高于52 岁。此外，由乳糖脱氢酶 (LDH) 释放水平确定的 52 岁细胞更容易受到氧化应激的影响。然而，通过用 Ac-Tyr-Val-Ala-Asp-氯甲基酮 (Ac-YVAD-CMK) 抑制炎性体可以改善这种反应。此外，我们发现与年轻受试者相比，45 岁以上受试者的血清中 ASC 和 IL-18 的蛋白质水平升高，并且白种人的 ASC 高于黑人和西班牙裔，而 IL无论年龄大小，高加索人的 -18 比黑人高。结论 综上所述，我们的数据表明炎症小体有助于炎症，炎症小体介导的细胞焦亡机制有助于衰老大脑中的细胞死亡。我们发现，与年轻受试者相比，45 岁以上受试者的血清中 ASC 和 IL-18 的蛋白质水平升高，并且高加索人的 ASC 高于黑人和西班牙裔，而 IL-18 为无论年龄大小，高加索人都高于黑人。结论 综上所述，我们的数据表明炎症小体有助于炎症，炎症小体介导的细胞焦亡机制有助于衰老大脑中的细胞死亡。我们发现，与年轻受试者相比，45 岁以上受试者的血清中 ASC 和 IL-18 的蛋白质水平升高，并且高加索人的 ASC 高于黑人和西班牙裔，而 IL-18 为无论年龄大小，高加索人都高于黑人。结论 综上所述，我们的数据表明炎症小体有助于炎症，炎症小体介导的细胞焦亡机制有助于衰老大脑中的细胞死亡。