LIFE EXTENSION EFFECT OF CALORIC RESTRICTION

热量限制的延长寿命效果

• 批准号: 2048125
• 负责人: ROY L. WALFORD
• 金额: $ 34.37万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-06-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2048125
• 关键词: B lymphocyte; T lymphocyte; aging; antigen presentation; caloric dietary content; cancer risk; cellular immunity; cytokine; histopathology; hormone regulation /control mechanism; hybridomas; immunoregulation; laboratory mouse; macrophage; malnutrition; northern blottings; nutrition related tag; radioimmunoassay; radiotracer; tissue /cell culture; transforming growth factors; tumor necrosis factor alpha

Dietary caloric restriction (CR) is the most effective known strategy for lifespan prolongation and cancer prevention in laboratory animals. Our project's aim is to explore several possible mechanisms responsible for these effects. The First Hypothesis relates to nutritional parameters: we suggest that the usual regimen of CR, which consists of intermittent feeding/starvation, may contribute to some of the reported immunologic and endocrine effects, though certainly not to the lifespan extension. Any differences due chiefly to the feeding/starvation schedule itself may not be fundamental to CR effects on aging, and should largely be eliminated from consideration in the search for mechanisms. We will investigate this aspect of CR by comparing selected immunologic and endocrine parameters in mice fed small amounts 6 x/day with an automated feeder to those fed by the traditional intermittent schedule. Second Hypothesis: we suggest that many immunosenescence phenomena correctable by CR are not primarily T and B cell defects, but secondary to age related macrophage (MO) dysfunction, i.e. that the MO is primary in much of immunosenescence. The effect of age and CR will be assessed for MO antigen presentation of influenza and hen egg lysozyme, using T cell hybridomas as well as memory T cells in the assays. Extending this, we will determine whether correcting MO dysfunction by non-CR methods will ameliorate those aspects of immunosenescence which are corrected by CR. Determining the effects of age and CR in relation to several MO cytokines, 1L1, 1L6, TNF and TGF Beta, will further enlarge these perspectives. For TNF, in vivo production and response to the cytokine will be measured in several organs following BCG inoculation. Finally, as a Third Hypothesis: the role of gene expression and of DNA binding proteins as regulatory targets for CR will be explored in a subcontract project. This hypothesis is based on previous collaborative CR data showing a paradoxical change in glucose-regulated protein (GRP gene expression. The study may provide the first insight into a genetic process modifiable by CR.

饮食热量限制（CR）是最有效的策略 用于实验动物的寿命延长和预防癌症。 我们项目的目的是探索几种可能的机制 这些效果。第一个假设与营养有关 参数：我们建议CR的常规方案，包括 间歇性喂养/饥饿可能有助于一些报告的 免疫学和内分泌作用，尽管肯定不是寿命 扩大。主要由于喂养/饥饿而导致的任何差异 时间表本身可能对CR对衰老的影响并不重要，并且 应在很大程度上被审查中的考虑 机制。我们将通过比较选定的CR调查CR的这一方面 小鼠的免疫学和内分泌参数少量少量6 x/天 带有自动喂食器，向传统间歇性喂养的喂食器 日程。第二个假设：我们建议许多免疫衰老 CR可更正的现象不是主要的T和B细胞缺陷，而是 继发于年龄相关的巨噬细胞（MO）功能障碍，即MO 在大部分免疫衰老中都是主要的。年龄和CR的影响将是 评估了流感和鸡蛋溶菌酶的mo抗原表现， 在测定中使用T细胞杂交瘤以及记忆T细胞。 扩展这一点，我们将确定是否通过 非CR方法将改善免疫衰老的那些方面 通过CR纠正。确定年龄和CR的影响 对于几种Mo细胞因子，1L1、1L6，TNF和TGF Beta将进一步 扩大这些观点。对于TNF，体内生产和对 BCG后将在几个器官中测量细胞因子 接种。最后，作为第三个假设：基因表达的作用 DNA结合蛋白作为CR的调节靶标的是 在分包项目中探索。该假设基于以前的 协作CR数据显示了葡萄糖调节的矛盾变化 蛋白质（GRP基因表达。研究可能提供第一个见解 通过CR修改的遗传过程。