Vida Carmen, de Toda Irene Martínez, Cruces Julia, Garrido Antonio, Gonzalez-Sanchez Mónica, De la Fuente Mónica
Department of Animal Physiology II, Faculty of Biology, Complutense University of Madrid, Madrid, Spain; Institute of Investigation Hospital 12 Octubre (i+12), Madrid, Spain.
Department of Genetics, Faculty of Biology, Complutense University of Madrid, Madrid, Spain.
Redox Biol. 2017 Aug;12:423-437. doi: 10.1016/j.redox.2017.03.005. Epub 2017 Mar 9.
The age-related changes in the immune functions (immunosenescence) may be mediated by an increase of oxidative stress and damage affecting leukocytes. Although the "oxidation-inflammation" theory of aging proposes that phagocytes are the main immune cells contributing to "oxi-inflamm-aging", this idea has not been corroborated. The aim of this work was to characterize the age-related changes in several parameters of oxidative stress and immune function, as well as in lipofuscin accumulation ("a hallmark of aging"), in both total peritoneal leukocyte population and isolated peritoneal macrophages. Adult, mature, old and long-lived mice (7, 13, 18 and 30 months of age, respectively) were used. The xanthine oxidase (XO) activity-expression, basal levels of superoxide anion and ROS, catalase activity, oxidized (GSSG) and reduced (GSH) glutathione content and lipofuscin levels, as well as both phagocytosis and digestion capacity were evaluated. The results showed an age-related increase of oxidative stress and lipofuscin accumulation in murine peritoneal leukocytes, but especially in macrophages. Macrophages from old mice showed lower antioxidant defenses (catalase activity and GSH levels), higher oxidizing compounds (XO activity/expression and superoxide, ROS and GSSG levels) and lipofuscin levels, together with an impaired macrophage functions, in comparison to adults. In contrast, long-lived mice showed in their peritoneal leukocytes, and especially in macrophages, a well-preserved redox state and maintenance of their immune functions, all which could account for their high longevity. Interestingly, macrophages showed higher XO activity and lipofuscin accumulation than lymphocytes in all the ages analyzed. Our results support that macrophages play a central role in the chronic oxidative stress associated with aging, and the fact that phagocytes are key cells contributing to immunosenescence and "oxi-inflamm-aging". Moreover, the determination of oxidative stress and immune function parameters, together with the lipofuscin quantification, in macrophages, can be used as useful markers of the rate of aging and longevity.
免疫功能的年龄相关变化（免疫衰老）可能是由影响白细胞的氧化应激和损伤增加所介导的。尽管衰老的“氧化-炎症”理论提出吞噬细胞是导致“氧化-炎症-衰老”的主要免疫细胞，但这一观点尚未得到证实。本研究的目的是在总的腹膜白细胞群体和分离的腹膜巨噬细胞中，表征氧化应激、免疫功能的几个参数以及脂褐素积累（“衰老的一个标志”）的年龄相关变化。使用了成年、成熟、老年和长寿小鼠（分别为7、13、18和30月龄）。评估了黄嘌呤氧化酶（XO）活性-表达、超氧阴离子和活性氧的基础水平、过氧化氢酶活性、氧化型（GSSG）和还原型（GSH）谷胱甘肽含量以及脂褐素水平，以及吞噬和消化能力。结果显示，小鼠腹膜白细胞中氧化应激和脂褐素积累随年龄增加，但在巨噬细胞中尤为明显。与成年小鼠相比，老年小鼠的巨噬细胞抗氧化防御能力较低（过氧化氢酶活性和GSH水平），氧化化合物水平较高（XO活性/表达、超氧阴离子、活性氧和GSSG水平）以及脂褐素水平较高，同时巨噬细胞功能受损。相比之下，长寿小鼠的腹膜白细胞，尤其是巨噬细胞，显示出保存良好的氧化还原状态和免疫功能的维持，所有这些都可以解释它们的高寿命。有趣的是，在所有分析的年龄段中，巨噬细胞的XO活性和脂褐素积累均高于淋巴细胞。我们的结果支持巨噬细胞在与衰老相关的慢性氧化应激中起核心作用，以及吞噬细胞是导致免疫衰老和“氧化-炎症-衰老”的关键细胞这一事实。此外，测定巨噬细胞中的氧化应激和免疫功能参数以及脂褐素定量，可作为衰老速度和寿命的有用标志物。
