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

七十年前，人们发现，如果给老鼠喂食少于正常食量的食物，它们会活得更长。此后，人们发现这种治疗方法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（称为热量限制或CR）可以降低患与年龄相关的疾病（如癌症）的风险，并改善许多随着年龄而改变的标志物的水平，如对DNA、脂肪和蛋白质的损害，以及循环葡萄糖和胰岛素水平。CR究竟如何发挥其作用仍不确定。作为延长人类寿命的一种方法，人们认识到，在现代社会，人们自愿限制食物的摄入量是非常困难的。因此，研究人员已经开始寻找一种药物，可以模仿CR的效果，但不需要少吃食物。另一个不确定性涉及到将少吃食物转化为细胞反应的机制，这种反应最终导致寿命延长。关于这是如何工作的，有两种想法。当动物和人接受CR时，它们往往会减掉体内脂肪。对CR的反应可能是通过少吃食物来启动的，也可能是通过减少身体脂肪来启动的。通常这两件事是同时变化的，所以很难区分哪个更重要。我之前已经证明，当动物停止CR时，它们会过度进食，直到脂肪储存耗尽。这表明，可能是来自脂肪的信号在向大脑发送信号以启动“CR程序”方面发挥了重要作用，从而最终延长了寿命。该提案的第一部分旨在探索减少脂肪和脂肪信号（称为脂肪因子）在启动CR计划中的作用，而不是简单地少吃食物。为了做到这一点，我将做一个实验，将食物摄入量的变化与身体脂肪的变化分离开来，用老鼠作为模型生物。这可以通过将老鼠暴露在不同的温度下来实现。例如，如果温度变暖，老鼠吃的食物会减少，因为它们的能量需求会减少，但它们不会减掉体内脂肪，因为它们保持了能量平衡。也许被关在温暖的CR程序里的老鼠会活得更久，因为它们吃得更少。或者，如果减肥很重要，正如我从以前的工作中猜测的那样，我预测这种操纵不会开启CR程序。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，我将动物置于正常室温下的CR下，以便它们减肥并打开程序。然后，我将给它们植入一些小装置，这些装置会不断地输送一些由脂肪产生的化合物，看看CR程序能否被关闭。很明显，无论是减少体脂，还是少吃食物，在CR计划中，它都是由动物大脑中的活动控制的。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。已知这些神经肽与脂肪组织产生的一些信号相互作用。为了实验测试它们是否确实重要，我将把动物置于CR下，然后通过向它们的大脑中引入破坏信号的化合物来干扰这些通路。这些化合物是市售的，对感兴趣的神经肽相互作用的受体群体有非常具体的影响。如果我认为重要的神经肽确实开启了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是反其道而行之。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，这些措施应该启动CR计划，但不需要相关动物少吃食物。

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.