Aging and hypothalamic temparature

描述(申请人提供)：降低核心体温(CBT)在常温下具有抗衰老和延长寿命的作用。在恒温动物中，CBT降低与卡路里限制(CR)有关，CR是一种被证明可以延长啮齿动物和猴子的寿命并延缓各种疾病进展的受控饮食方案。有人提出，降低CBT本身可能有助于CR的抗衰老作用。为了验证这一假设，我们培育了CBT降低的小鼠。这种小鼠是通过在下丘脑外侧区(LHCRT-UCP2小鼠)的下丘脑下丘脑神经元中过度表达解偶联蛋白2(UCP2)而产生的。UCP2是一种内部线粒体！膜蛋白，使氧化磷酸化与呼吸作用解偶联，以热的形式分散质子梯度能量。下丘脑神经肽参与自主神经功能的调节，在下丘脑外侧约3,000个神经元中有独特的表达。局部产热导致黄体和POA的温度升高，模拟CBT的增加，并激活温度调节补偿机制，最终导致CBT的降低。结果，与卡路里摄入量无关，Hcrt-UCP2小鼠的寿命增加了17%-19%。此外，与CR小鼠相似，Hcrt-UCP2小鼠表现出氧化应激标志物随年龄的减少，这表明CBT的长期减少可能会影响自由基的形成。因此，Hcrt-UCP2小鼠代表了一种研究CBT对衰老影响的新模型。我们建议进行实验，以确定可能导致Hcrt-UCP2小鼠核心体温降低和寿命延长的机制。

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.