Department of Physiology, Faculty of Biology, Complutense University of Madrid (UCM), Madrid, Spain; Institute of Investigation 12 de Octubre (i+12), Madrid, Spain.
Department of Physiology, Faculty of Biology, Complutense University of Madrid (UCM), Madrid, Spain.
Brain Behav Immun. 2018 Mar;69:440-455. doi: 10.1016/j.bbi.2018.01.003. Epub 2018 Jan 16.
Aging is accompanied by impairment in the nervous, immune, and endocrine systems as well as in neuroimmunoendocrine communication. In this context, there is an age-related alteration of the physiological response to acute stress, which is modulated by catecholamine (CA), final products of the sympathetic-adreno-medullary axis. The involvement of CA in essential functions of the nervous system is consistent with the neuropsychological deficits found in mice with haploinsufficiency (hemizygous; HZ) of tyrosine hydroxylase (TH) enzyme (TH-HZ). However, other possible alterations in regulatory systems have not been studied in these animals. The aim of the present work was to analyze whether adult TH-HZ female mice presented the impairment of behavioral traits and immunological responses that occurs with aging and whether they had affected their mean lifespan. ICR-CD1 female TH-HZ and wild type (WT) mice were used in a longitudinal study. Behavioral tests were performed on adult and old mice in order to evaluate their sensorimotor abilities and exploratory capacity, as well as anxiety-like behaviors. At the ages of 2 ± 1, 4 ± 1, 9 ± 1, 13 ± 1 and 20 ± 1 months, peritoneal leukocytes were extracted and several immune functions were assessed (phagocytic capacity, Natural Killer (NK) cytotoxicity, and lymphoproliferative response to lipopolysaccharide (LPS) and concanavalin A (ConA)). In addition, several oxidative stress parameters (catalase, glutathione reductase and glutathione peroxidase activities, and reduced glutathione (GSH) concentrations as antioxidant compounds as well as xanthine oxidase activity, oxidized glutathione (GSSG) concentrations, and GSSG/GSH ratio as oxidants) were analyzed. As inflammatory stress parameters TNF-alpha and IL-10 concentrations, and TNF-alpha/IL-10 ratios as inflammatory/anti-inflammatory markers, were measured. Animals were maintained in standard conditions until their natural death. The results indicate that adult TH-HZ mice presented worse sensorimotor abilities and exploratory capacity than their WT littermates as well as greater anxiety-like behaviors. With regards to the immune system, adult TH-HZ animals exhibited lower values of phagocytic capacity, NK cytotoxicity, and lymphoproliferative response to LPS and ConA than WT mice. Moreover, immune cells of TH-HZ mice showed higher oxidative and inflammatory stress than those of WT animals. Although these differences between TH-HZ and WT, in general, decreased with aging, this premature immunosenescence and impairment of behavior of TH-HZ mice was accompanied by a shorter mean lifespan in comparison to WT counterparts. In conclusion, haploinsufficiency of th gene in female mice appears to provoke premature aging of the regulatory systems affecting mean lifespan.
衰老是伴随着神经、免疫和内分泌系统的功能障碍以及神经免疫内分泌通讯的紊乱。在这种情况下，机体对急性应激的生理反应会发生与年龄相关的改变，这种改变受儿茶酚胺（CA）调节，CA 是交感肾上腺髓质轴的终产物。CA 参与神经系统的基本功能，这与酪氨酸羟化酶（TH）酶单倍不足（杂合子；HZ）的小鼠中发现的神经心理学缺陷一致。然而，在这些动物中，尚未研究调节系统的其他可能改变。本研究的目的是分析成年 TH-HZ 雌性小鼠是否存在与衰老相关的行为特征和免疫反应的损伤，以及它们的平均寿命是否受到影响。本研究使用 ICR-CD1 雌性 TH-HZ 和野生型（WT）小鼠进行了一项纵向研究。对成年和老年小鼠进行行为测试，以评估它们的感觉运动能力和探索能力，以及焦虑样行为。在 2±1、4±1、9±1、13±1 和 20±1 月龄时，提取腹膜白细胞并评估几种免疫功能（吞噬能力、自然杀伤（NK）细胞毒性、脂多糖（LPS）和刀豆蛋白 A（ConA）刺激的淋巴细胞增殖反应）。此外，还分析了几种氧化应激参数（过氧化氢酶、谷胱甘肽还原酶和谷胱甘肽过氧化物酶活性以及还原型谷胱甘肽（GSH）浓度作为抗氧化化合物，以及黄嘌呤氧化酶活性、氧化型谷胱甘肽（GSSG）浓度和 GSSG/GSH 比值作为氧化剂）。还测量了作为炎症应激标志物的 TNF-α和 IL-10 浓度以及 TNF-α/IL-10 比值。动物在标准条件下维持到自然死亡。结果表明，成年 TH-HZ 小鼠的感觉运动能力和探索能力比 WT 同窝仔鼠差，焦虑样行为更严重。就免疫系统而言，成年 TH-HZ 动物的吞噬能力、NK 细胞毒性以及 LPS 和 ConA 刺激的淋巴细胞增殖反应值低于 WT 小鼠。此外，TH-HZ 动物的免疫细胞的氧化和炎症应激高于 WT 动物。尽管 TH-HZ 和 WT 之间的这些差异通常随着年龄的增长而降低，但 TH-HZ 小鼠的这种过早的免疫衰老和行为损伤伴随着比 WT 对应物更短的平均寿命。总之，雌性小鼠 th 基因的单倍不足似乎会导致影响平均寿命的调节系统的过早衰老。
