Aging and hypothalamic temparature

描述（申请人提供）：降低核心体温（CBT）具有抗衰老作用，延长变温动物的寿命。在恒温动物中，CBT降低与卡路里限制（CR）有关，这是一种受控的饮食方案，可延长啮齿动物和猴子的寿命，并延缓各种疾病的进展。有人提出，减少CBT本身可能有助于CR的抗衰老作用。为了验证这一假设，我们产生了CBT降低的小鼠。通过在外侧下丘脑（LH）的下丘脑泌素神经元中过表达解偶联蛋白2（UCP 2）产生这样的小鼠（Hcrt-UCP 2小鼠）。UCP 2是一种内部线粒体！使氧化磷酸化与呼吸作用解偶联的膜蛋白，以热的形式耗散质子梯度能量。下丘脑泌素是下丘脑神经肽，参与自主神经功能的调节，在外侧下丘脑的约3，000个神经元中独特表达。局部产热导致LH和POA的温度升高，模仿CBT的增加并激活体温调节补偿机制，最终导致CBT的减少。因此，Hcrt-UCP 2小鼠的寿命增加了17-19%，与其卡路里摄入量无关。此外，与CR小鼠类似，Hcrt-UCP 2小鼠显示氧化应激标志物的年龄依赖性降低，表明CBT的长期降低可能影响自由基形成。因此，Hcrt-UCP 2小鼠代表了研究CBT对衰老影响的新模型。我们提出的实验旨在表征的机制，可能是负责降低核心体温和延长寿命的Hcrt-UCP 2小鼠。

DESCRIPTION (provided by applicant): Reduction of core body temperature (CBT) has anti-aging effects and prolongs life span in poikilotherms. In homeotherms, a lowered CBT is associated with calorie restriction (CR), a controlled dietary regimen demonstrated to prolong lifespan in rodents and monkeys and to delay the progression of a variety of diseases. It has been proposed that reduction of CBT per se could contribute to the anti-aging effects of CR. To test this hypothesis we generated mice with a reduced CBT. Such mice were generated by overexpressing the uncoupling protein 2 (UCP2) in hypocretin neurons of the lateral hypothalamus (LH) (Hcrt-UCP2 mice). UCP2 is an inner mitochondria! membrane protein that uncouples oxidative phosphorylation from respiration, dissipating the proton gradient energy in the form of heat. Hypocretins are hypothalamic neuropeptides that participate in the regulation of autonomic functions uniquely expressed in ca 3,000 neurons in the lateral hypothalamus. Local heat production resulted in temperature elevation in the LH and the POA mimicking an increase of CBT and activating thermoregulatory compensatory mechanisms that ultimately result in a reduction of CBT. As a result, Hcrt-UCP2 mice have 17-19% increases in their life span independently of their calorie intake. In addition, similarly to CR mice, Hcrt-UCP2 mice show age- dependent reduction of markers of oxidative stress suggesting that long term reduction of CBT may influence free radicals formation. Thus, Hcrt-UCP2 mice represent a novel model to investigate the effects of CBT on aging. We propose experiments designed to characterize the mechanisms that may be responsible for the reduction of core body temperature and the prolonged life-span in Hcrt-UCP2 mice.