Do hunger neuropeptides mediate the link between caloric restriction and lifespan extension?

饥饿神经肽是否介导热量限制和寿命延长之间的联系？

• 批准号: BB/G009953/1
• 负责人: John Speakman
• 金额: $ 78.01万
• 依托单位: University of Aberdeen
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2009
• 资助国家: 英国
• 起止时间: 2009 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FG009953%2F1
• 关键词: Do; hunger; neuropeptides; mediate; link

Seventy years ago it was discovered that if rats are fed less than their normal ration of food they live longer. This treatment has since been found to extend the lives of many different species, including non-human primates. It is known that this process of restricting calorie intake (called caloric restriction - or CR) reduces the risk of developing age related diseases like cancer and it improves levels of many markers that alter with age - such as damage to DNA, fats and proteins, and circulating glucose and insulin levels. Exactly how CR exerts its effects remains uncertain. As a method for extending human life it is recognised that it would be extraordinarily difficult for people in modern society to restrict their intake of food voluntarily. A search has started therefore for drugs that will mimic the effects of CR, but without the need to eat less food. Another uncertainty concerns the mechanism that translates eating less food into switching on the cellular responses that ultimately lead to extended lifespan. There are two ideas about how this might work. When animals and people undergo CR they tend to lose body fat. The response to CR might be switched on by eating less food, alternatively it might be switched on by the reduction in body fatness. Normally these two things change together so it is difficult to separate which is of most importance. I have previously shown that when animals are taken off CR they over-eat until their fat stores are repleted. This suggests that it is probably signals from the fat that are important in signalling to the brain to switch on the 'CR programme' that ultimately extends life. The first part of this proposal aims to explore the roles of reduced fatness and fat signals (called adipokines) as opposed to simply eating less food in initiating the CR programme. To do this I will perform an experiment which dissociates the changes in food intake from the changes in body fatness using mice as a model organism. This can be achieved by exposing mice to different temperatures. For example if the temperature is made warm mice eat less food because their energy demands decrease, but they don't lose body fat because they remain in energy balance. Perhaps mice kept in the warm switch on the CR programme and live longer because they are eating less food. Alternatively if it is fat loss that is important as I suspect from my previous work I predict this manipulation will not switch on the CR programme. To further test the role of adipokines in switching on the CR programme I will perform another experiment where I place animals at normal room temperature under CR so that they lose weight and switch the programme on. I will then implant them with small devices that continuously deliver some of the compounds produced by fat so see if the CR programme can be switched off. Clearly whether reduced body fat, or eating less food switches, on the CR programme it is controlled by events in the animal's brains. My recent work has suggested that some neuropeptides in the hypothalamus are an important part of this process. These neuropeptides are known to interact with some of the signals generated by fat tissue. To experimentally test if they are indeed important I will place animals under CR and then interfere with these pathways by introducing compounds into their brains which disrupt the signalling. These compounds are commercially available and have very specific effects on receptor populations that the neuropeptides of interest interact with. If the neuropeptides that I suspect are important really do switch on the CR programme then interfering with them should switch the CR programme off. If this experiment works the final experiment I will perform is to do the opposite. Introduce compounds that have the opposite effects into the same brain regions. These should in theory turn on the CR programme but without the need for the animals concerned to eat less food.

70年前，人们发现，如果老鼠吃的食物少于它们正常的食物配给，它们的寿命会更长。自那以后，这种治疗方法被发现可以延长许多不同物种的寿命，包括非人类灵长类动物。众所周知，这种限制卡路里摄入的过程(称为卡路里限制-或CR)可以降低患癌症等与年龄相关的疾病的风险，并提高许多随年龄变化的标记物的水平--例如对DNA、脂肪和蛋白质的损害，以及循环中的葡萄糖和胰岛素水平。CR究竟是如何发挥作用的，目前还不确定。作为延长人类寿命的一种方法，人们认识到，在现代社会中，人们很难自愿限制自己的食物摄入量。因此，已经开始寻找与CR效果相似的药物，但不需要减少食物摄入量。另一个不确定性涉及将少吃食物转化为开启细胞反应的机制，最终导致寿命延长。关于这可能如何运作，有两种想法。当动物和人类接受CR时，他们往往会失去身体脂肪。对CR的反应可能是通过少吃食物来启动的，或者可能是通过减少身体脂肪来启动的。通常情况下，这两件事是一起改变的，所以很难分开，这是最重要的。我之前已经证明，当动物不再接受CR时，它们会暴饮暴食，直到它们的脂肪储备得到补充。这表明，很可能是来自脂肪的信号在向大脑发出信号以开启最终延长寿命的“CR程序”时起着重要作用。这项建议的第一部分旨在探索减少肥胖和脂肪信号(称为脂肪激素)的作用，而不是在启动CR计划时简单地减少食物摄入。为了做到这一点，我将进行一项实验，将食物摄入量的变化与身体脂肪的变化分开，以小鼠为模型生物。这可以通过将小鼠暴露在不同的温度下来实现。例如，如果温度变暖，小鼠吃的食物就会减少，因为它们的能量需求减少了，但它们不会失去身体脂肪，因为它们保持能量平衡。也许小鼠在CR节目中保持温暖的开关，活得更长，因为它们吃的东西更少了。或者，如果减脂很重要，就像我之前的工作所怀疑的那样，我预测这种操纵不会开启CR计划。为了进一步测试脂肪因子在启动CR程序中的作用，我将进行另一个实验，将动物置于常温CR下，使它们减肥并打开程序。然后，我会给它们植入小型设备，持续提供一些由FAT产生的化合物，看看CR计划是否可以关闭。显然，无论是减少身体脂肪，还是减少食物摄入量，在CR计划中，它都是由动物大脑中的事件控制的。我最近的工作表明，下丘脑中的一些神经肽是这一过程的重要组成部分。众所周知，这些神经肽与脂肪组织产生的一些信号相互作用。为了从实验上测试它们是否真的重要，我会将动物置于CR下，然后通过向它们的大脑中引入化合物来干扰这些通路，从而扰乱信号传递。这些化合物在商业上是可用的，并且对与感兴趣的神经肽相互作用的受体群体具有非常特定的影响。如果我怀疑是重要的神经肽真的开启了CR程序，那么干扰它们应该会关闭CR程序。如果这个实验成功，我要做的最后一个实验就是做相反的事情。将具有相反作用的化合物引入相同的大脑区域。从理论上讲，这些措施应该会启动CR计划，但不需要相关动物吃得更少。

项目成果

The effects of graded levels of calorie restriction: VI. Impact of short-term graded calorie restriction on transcriptomic responses of the hypothalamic hunger and circadian signaling pathways.

卡路里限制的分级水平的影响：vi。短期渐变卡路里限制对下丘脑饥饿和昼夜节律信号通路的转录组反应的影响。

• DOI: 10.18632/aging.100895
• 发表时间: 2016-04
• 期刊: Aging
• 作者: Derous D;Mitchell SE;Green CL;Chen L;Han JD;Wang Y;Promislow DE;Lusseau D;Speakman JR;Douglas A
• 通讯作者: Douglas A

The Effects of Graded Levels of Calorie Restriction: X. Transcriptomic Responses of Epididymal Adipose Tissue.

• DOI: 10.1093/gerona/glx101
• 发表时间: 2018-03-02
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Derous D;Mitchell SE;Green CL;Wang Y;Han JDJ;Chen L;Promislow DEL;Lusseau D;Douglas A;Speakman JR
• 通讯作者: Speakman JR

The effects of graded levels of calorie restriction: XI. Evaluation of the main hypotheses underpinning the life extension effects of CR using the hepatic transcriptome.

• DOI: 10.18632/aging.101269
• 发表时间: 2017-07-31
• 期刊: Aging
• 作者: Derous D;Mitchell SE;Wang L;Green CL;Wang Y;Chen L;Han JJ;Promislow DEL;Lusseau D;Douglas A;Speakman JR
• 通讯作者: Speakman JR

The effects of graded caloric restriction: XII. Comparison of mouse to human impact on cellular senescence in the colon.

• DOI: 10.1111/acel.12746
• 发表时间: 2018-06
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Fontana L;Mitchell SE;Wang B;Tosti V;van Vliet T;Veronese N;Bertozzi B;Early DS;Maissan P;Speakman JR;Demaria M
• 通讯作者: Demaria M

The effects of graded levels of calorie restriction: IX. Global metabolomic screen reveals modulation of carnitines, sphingolipids and bile acids in the liver of C57BL/6 mice.

• DOI: 10.1111/acel.12570
• 发表时间: 2017-06
• 期刊: Aging cell
• 影响因子: 7.8
• 作者: Green CL;Mitchell SE;Derous D;Wang Y;Chen L;Han JJ;Promislow DEL;Lusseau D;Douglas A;Speakman JR
• 通讯作者: Speakman JR