What is the target of anti-aging action of calorie restriction?

限制热量的抗衰老作用的目标是什么？

• 批准号: 12670206
• 负责人: HIGAMI Yoshikazu
• 金额: $ 2.3万
• 依托单位: Nagasaki University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670206/
• 关键词: aging; calorie restriction(CR); growth hormonef(GH)IGF-1; Forkhead transcription factor; transgenic rat; lipid metabolism; DNA array; liver; 脂質代謝; 老化; 食餌制限

Growth hormone(GH)/insulin/IGF-1 axis and their subsequent targets, forkhead transcriptional factors, are likely to be an important regulator of lifespan from C. elegans to mammals. Calorie restriction(CR) is a robust, reproducible and simple experimental manipulation known to extend lifespan and retard aging process in several species, but the underlying mechanism is still debatable. However, CR reduces serum level of GH, insulin and IGF-1. Therefore, GH/insulin/IGF-1 and their signal cascade might be involved in the anti-aging action of CR. To understand the mechanism of CR, particularly on a role of GH/IGF-1 axis, we examined lifespan, hepatic gane expression profile and serum and plasma biochemical analysis from wild(-/-), transgenic homozygous mini rats bearing anti-sense GH transgene(severe suppression of GH/IGF-1, tg/tg), and their F1 heterozygous rats(moderate suppression, tg/-) fed ad libitum and 70 % CR.Regardless severity of GH/IGF-1 suppression, CR extended survival markedl … More y on three rat lines, suggesting that the anti-aging action of CR dose not merely depend on GH/IGF-1 axis. The gene expressions modulated by CR were likely to be regulated with GH/IGF-1-dependent and -independent manners. The former up-regulated stress response and xenobiotics metabolism-related gene expressions and the latter modulated lipid metabolism-related gene expressions predominantly. Our data on lipid metabolism of CR rats showed effective lipid utilization including the enhanced lipid anabolism after feeding and lipid catabolism with mitochondrial beta-oxidation more predominantly than peroxisomal beta-oxidation under food shortage possibly through ADD1/SREBP1 and PPARalpha activation. The accelerated efficiency of energy utilization prevents excess energy supplied by feeding from wasting and subsequent cellular damage, suggesting that CR stimulates the intrinsic adaptive system against food shortage through the modulation of lipid metabolism and probably maximizes survival and retards aging process. Less

生长激素（GH）/胰岛素/IGF-1轴及其后续靶点叉头转录因子可能是C.到哺乳动物。热量限制（CR）是一种稳健的，可重复的和简单的实验操作，已知在几个物种中延长寿命和延缓衰老过程，但其潜在的机制仍然存在争议。CR降低血清GH、胰岛素和IGF-1水平。因此，GH/胰岛素/IGF-1及其信号级联反应可能参与了CR的抗衰老作用。为了了解CR的机制，特别是GH/IGF-1轴的作用，我们检测了携带反义GH转基因的野生型（-/-）、转基因纯合小型大鼠的寿命、肝细胞基因表达谱以及血清和血浆生化分析。（GH/IGF-1、tg/tg严重抑制）及其F1杂合子大鼠（中度抑制，tg/-）自由进食，70% CR。无论GH/IGF-1抑制的严重程度如何，CR延长生存期的显著性差异（P <0.05）。 ...更多信息 提示CR的抗衰老作用不仅依赖于GH/IGF-1轴。CR可能通过GH/IGF-1依赖性和非依赖性方式调节基因表达。前者上调应激反应和外源物质代谢相关基因的表达，后者主要调控脂代谢相关基因的表达。CR大鼠的脂质代谢数据显示有效的脂质利用，包括进食后增强的脂质抵抗力和在食物短缺下线粒体β氧化比过氧化物酶体β氧化更显著的脂质代谢，可能通过ADD 1/SREBP 1和PPARalpha激活。能量利用效率的提高防止了进食提供的多余能量的浪费和随后的细胞损伤，这表明CR通过调节脂质代谢来刺激针对食物短缺的内在适应系统，并可能最大限度地提高存活率和延缓衰老过程。少

项目成果

Higami, Y., et al.: "Dietary restriction reduces hepatocyte proliferation and enhances p53 expression but does not increase apoptosis in normal rats during development"Cell Tissue Res.. 299. 363-369 (2000)

Higami, Y., et al.：“饮食限制会减少正常大鼠在发育过程中的肝细胞增殖并增强 p53 表达，但不会增加细胞凋亡”Cell Tissue Res.. 299. 363-369 (2000)

Chiba, T., 他: "Neuroendocrine adaptation by peripheral signals : anti-aging effects by caloric restriction"Microsc Res Techniq. (in press).

Chiba, T. 等人：“外周信号的神经内分泌适应：热量限制的抗衰老作用”Microsc Res Techniq。

Higami, Y.他: "Apoptosis in the aging process"Cell Tissue Res. 301. 125-132 (2000)

Higami，Y.等：“衰老过程中的细胞凋亡”Cell Tissue Res. 301. 125-132 (2000)

Higami, Y., 他: "Apoptosis in the aging process"Cell Tissue Res. 301. 125-132 (2000)

Higami，Y.等人：“衰老过程中的细胞凋亡”Cell Tissue Res. 301. 125-132 (2000)

Ando, K., 他: "Impact of aging and life-long calorie restriction on expression of apoptosis-related genes in male F344 rat liver"Microsc Res Techniq. (in press).

Ando, K. 等人：“衰老和终生热量限制对雄性 F344 大鼠肝脏中细胞凋亡相关基因表达的影响”Microsc Res Techniq（出版中）。