Development of calorie restriction mimetics as a prolongevity strategy
Development of calorie restriction mimetics as a prolongevity strategy
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DOI：
10.1196/annals.1297.074
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Roth, GS
中科院分区：
文献类型：
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作者：
Ingram, DK;Anson, RM;Roth, GS
通过将卡路里限制 (CR) 限制在低于随意水平 30-50% 的水平，对许多物种的研究报告显示，它们的寿命延长、年龄相关疾病的发病率降低和延迟发作、抗应激能力提高并减缓功能衰退。这种营养干预是否与人类衰老有关仍有待确定；然而，来自非人类灵长类动物 CR 研究的证据表明，灵长类动物对 CR 的反应与啮齿类动物中观察到的相似。为了评估人类 CR 效果，临床试验已经启动。即使证据可以证实 CR 是人类有效的抗衰老策略，但由于所需限制的程度和长度，这种干预措施的应用也会存在问题。为了应对 CR 潜在应用的挑战，创建“卡路里限制模拟物”的新研究已经出现。该策略的重点是通过针对受 CR 影响的代谢和应激反应途径来识别模拟 CR 效应的化合物，但实际上并不限制热量摄入。微阵列研究表明，CR 可以改变葡萄糖（能量）处理途径中关键酶的基因表达谱。抑制糖酵解（2-脱氧葡萄糖）或增强胰岛素作用（二甲双胍）的药物正在被评估为 CR 模拟物。关于 CR（降低体温和血浆胰岛素）的生理反应以及针对神经毒性的保护、增强多巴胺作用和上调脑源性神经营养因子的初步研究已经出现了有希望的结果。除了扩大毒性研究之外，还必须完成进一步的寿命分析，以评估任何 CR 模拟物的潜力，但这种策略现在似乎提供了一个非常有前途和不断扩大的研究领域。
By applying calorie restriction (CR) at 30-50% below ad libitum levels, studies in numerous species have reported increased life span, reduced incidence and delayed onset of age-related diseases, improved stress resistance, and decelerated functional decline. Whether this nutritional intervention is relevant to human aging remains to be determined; however, evidence emerging from CR studies in nonhuman primates suggests that response to CR in primates parallels that observed in rodents. To evaluate CR effects in humans, clinical trials have been initiated. Even if evidence could substantiate CR as an effective antiaging strategy for humans, application of this intervention would be problematic due to the degree and length of restriction required. To meet this challenge for potential application of CR, new research to create "calorie restriction mimetics" has emerged. This strategy focuses on identifying compounds that mimic CR effects by targeting metabolic and stress response pathways affected by CR, but without actually restricting caloric intake. Microarray studies show that gene expression profiles of key enzymes in glucose (energy) handling pathways are modified by CR. Drugs that inhibit glycolysis (2-deoxyglucose) or enhance insulin action (metformin) are being assessed as CR mimetics. Promising results have emerged from initial studies regarding physiological responses indicative of CR (reduced body temperature and plasma insulin) as well as protection against neurotoxicity, enhanced dopamine action, and upregulated brain-derived neurotrophic factor. Further life span analyses in addition to expanded toxicity studies must be completed to assess the potential of any CR mimetic, but this strategy now appears to offer a very promising and expanding research field.