CALORIE RESTRICTION AGING AND PROGRAMMED CELL DEATH

程序性细胞死亡（PCD）或凋亡是一种高度调节的细胞凋亡。 一种生理过程，从一个细胞中清除特定的细胞。 有机体 PCD在胚胎发育过程中起着关键作用 而是贯穿一生 热量限制（CR）寿命 通过预防与年龄相关的疾病， 缺乏、恶性肿瘤和肾脏疾病。 的精确 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延迟损失 长期喜爱的C57 BL/6xDBA/2F 1（BDF 1）小鼠中的幼稚T细胞， 维持升高的地塞米松诱导的PCD。 CR也下降 转基因MMTV/V-Ha-ras小鼠乳腺癌发病率 增加p53（促凋亡）肿瘤的表达 抑制基因 其他研究表明， 通过增加肝脏中的PCD来抑制肿瘤发生。 提出的假设是，CR增加了阴性选择， 通过维持较高的循环水平， 肾上腺皮质激素 进一步CR增加CD 28共刺激 互动 这种相互作用促进T细胞受体（TCR）/CD 3- 介导的分化和增殖增加，并增强 细胞毒性T细胞功能。 与此相反，缺乏共刺激 随意（AL）淋巴细胞中的分子可能导致蓄积 记忆T细胞激活B细胞。 日变化和 糖皮质激素的性别差异可能调节 糖皮质激素受体（GCR）介导的淋巴细胞亚群的PCD。 该提案将研究长寿BDF 1免疫细胞中的PCD AL和CR喂养的动物，以确定性别和年龄相关的变化。 将进行以下研究：1）确定是否每日 CR小鼠中GCR的改变与地塞米松诱导的GCR增加平行。 PCD; 2）确定是否存在降低的基础和TCR/CD 3诱导的 淋巴细胞亚群的PCD，由于增加的相互作用， 刺激分子3）决定抗和前PCD基因 在CR的稳态和活化T淋巴细胞中的表达， AL喂养的幼龄和老龄动物;以及4）确定CR是否增强PCD 并延长bcl-2转基因小鼠的寿命。 总之， 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 受到性别和热量摄入的影响。

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.