Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland.
Biogerontology. 2018 Oct;19(5):325-339. doi: 10.1007/s10522-018-9762-8. Epub 2018 Jun 29.
The aging process is associated with a low-grade chronic inflammation and the accumulation of senescent cells into tissues. Diverse stresses can trigger cellular senescence, a cell fate characterized by cell-cycle arrest and flat morphology. Oncogenic signaling can also induce cellular senescence which has been termed oncogene-induced senescence (OIS). Senescent cells display a pro-inflammatory phenotype which has been called the senescence-associated secretory phenotype (SASP). The secretomes associated with SASP contain colony-stimulating factors and chemokines which stimulate the generation of myeloid-derived suppressor cells (MDSC) by enhancing myelopoiesis in bone marrow and spleen. Enhanced myelopoiesis and increased level of MDSCs have been observed in bone marrow, spleen, and blood in both tumor-bearing and aged mice. Immunosuppressive MDSCs are recruited via chemotaxis into inflamed tissues where they proliferate and consequently suppress acute inflammatory reactions by inhibiting the functions of distinct components of innate and adaptive immunity. For instance, MDSCs stimulate the activity of immunosuppressive regulatory T-cells (Tregs). They also increase the expression of amino acid catabolizing enzymes and the secretion of anti-inflammatory cytokines, e.g. IL-10 and TGF-β, and reactive oxygen species (ROS). On the other hand, the accumulation of MDSCs into tissues exerts harmful effects in chronic pathological disorders, e.g. tumors and many age-related diseases, since the immunosuppression induced by MDSCs impairs the clearance of senescent and cancer cells and also disturbs the maintenance of energy metabolism and tissue proteostasis. The co-operation between senescent cells and immunosuppressive MDSCs regulates not only tumorigenesis and chronic inflammatory disorders but it also might promote inflammaging during the aging process.
衰老过程与低度慢性炎症和衰老细胞在组织中的积累有关。各种应激可以触发细胞衰老，这是一种以细胞周期停滞和扁平形态为特征的细胞命运。致癌信号也可以诱导细胞衰老，这种细胞衰老被称为癌基因诱导的衰老（OIS）。衰老细胞表现出促炎表型，这种表型被称为衰老相关分泌表型（SASP）。SASP 相关的分泌组包含集落刺激因子和趋化因子，通过增强骨髓和脾脏中的骨髓生成，刺激髓系来源的抑制细胞（MDSC）的生成。在荷瘤和老年小鼠的骨髓、脾脏和血液中都观察到增强的骨髓生成和 MDSC 水平增加。通过趋化作用招募具有免疫抑制作用的 MDSC 进入炎症组织，在那里它们增殖，并通过抑制先天和适应性免疫的不同成分的功能来抑制急性炎症反应。例如，MDSC 刺激免疫抑制性调节性 T 细胞（Treg）的活性。它们还增加氨基酸分解代谢酶的表达和抗炎细胞因子（如 IL-10 和 TGF-β）和活性氧物质（ROS）的分泌。另一方面，MDSC 积累到组织中会对慢性病理疾病产生有害影响，例如肿瘤和许多与年龄相关的疾病，因为 MDSC 诱导的免疫抑制会损害衰老和癌细胞的清除，并干扰能量代谢和组织蛋白平衡的维持。衰老细胞与免疫抑制性 MDSC 之间的合作不仅调节肿瘤发生和慢性炎症性疾病，而且可能在衰老过程中促进炎症老化。
