CALORIE RESTRICTION AGING AND PROGRAMMED CELL DEATH

程序性细胞死亡(PCD)或细胞凋亡是一种高度调控的 从细胞中去除特定细胞的生理过程 有机体。PCD在胚胎发育过程中起着关键作用 而是贯穿一生的。卡路里限制(CR)延长生命 通过预防免疫等年龄相关疾病在小鼠中的跨度 虚弱、恶性和肾脏疾病。精准的 CR预防年龄相关疾病的免疫学机制 免疫功能的恶化是未知的。CR延缓损失 长期喜爱的C57BL/6xDBA/2F1(BDF1)小鼠的幼稚T细胞和 维持地塞米松诱导的PCD升高。CR也有所下降 转基因MMTV/V-Ha-ras小鼠乳腺癌发病率的研究 P53(促凋亡)肿瘤的高表达 抑制子基因。其他人则表明CR降低了 通过增加肝脏中的PCD而导致肿瘤的发生。 提出的假设是CR增加了负面选择和 胸腺中的PCD通过维持较高的循环水平 肾上腺皮质激素。CR进一步增加CD28共刺激作用 互动。这种相互作用促进T细胞受体(TCR)/CD3- 介导分化和增殖增加，并增强 细胞毒T细胞功能。相比之下，缺乏共刺激 随意(AL)淋巴细胞中的分子可能导致蓄积 激活B细胞的记忆T细胞。日变化和 糖皮质激素的性别差异可能会调节 糖皮质激素受体(GCR)介导淋巴细胞亚群的PCD。 这项建议将研究长寿BDF1免疫细胞中的PCD Al和CR喂养的动物，以确定与性别和年龄相关的变化。 将进行以下研究：1)确定每天是否 CR小鼠GCR改变与地塞米松诱导的GCR增加平行 PCD；2)确定是否有基础和TCR/CD3诱导的减少 联合免疫增强对淋巴细胞亚群PCD的影响 刺激分子3)确定抗PCD基因和前PCD基因 慢性粒细胞白血病患者稳态和活化T淋巴细胞的表达 铝喂养的幼年和老年动物；以及4)确定CR是否增强PCD 并延长bcl2转基因小鼠的寿命。总而言之， 促进我们对衰老过程中免疫功能障碍的理解， 这些研究将确定免疫细胞的PCD是否 受性和卡路里摄入量的影响。

Programmed cell death (PCD) or apoptosis is a highly regulated physiological process which eliminates specific cells from an organism. PCD plays a critical role during embryonic development but is present throughout life. Caloric restriction (CR) prolongs life span in mice by preventing age-associated disorders such as immune deficiency, malignancy, and renal disease. The precise immunological mechanisms by which CR prevents age-related deterioration of immune function are unknown. CR delays the loss of naive T cells in long-loved C57BL/6xDBA/2F1 (BDF1) mice and maintains elevated dexamethasone-induced PCD. CR also decreases breast cancer incidence in transgenic MMTV/V-Ha-ras mice by increasing the expression of p53 (apoptosis promoting) tumor suppressor gene. Others have shown that CR decreases tumorigenesis by increasing PCD in the liver. The proposed hypothesis is that CR increases negative selection and PCD in the thymus by maintaining higher circulating levels of adrenocorticoids. Further CR increases CD28 co-stimulatory interaction. This interaction promotes T cell receptor (TCR)/CD3- mediated increased differentiation and proliferation, and enhances cytotoxic T cell function. In contrast,, deficient co-stimulatory molecules in ad libitum (AL) lymphocytes may lead to accumulation of memory T cells which activate B cells. Diurnal variation and gender based differences in glucocorticoids may modulate glucocorticoid receptor (GCR) mediated PCD in lymphocyte subsets. This proposal will study PCD in immune cells from long-lived BDF1 AL and CR-fed animals to establish gender-and age-related changes. The following studies will be undertaken: 1) determine if diurnally altered GCR in CR mice parallels increased dexamethasone-induced PCD; 2) establish if there is decreased basal and TCR/CD3-induced PCD of lymphocyte subsets due to increased interaction of co- stimulatory molecules 3) determine anti-and pro-PCD gene expression in steady-state and activated T lymphocytes from CR and AL-fed young and old animals; and 4) establish if CR enhances PCD and increases life span in bcl-2 transgenic mice. In summary, to promote our understanding of immune dysfunction during aging, these studies will establish whether or not PCD of immune cells is influenced by sex-and caloric-intake.