Aging and hypothalamic temparature

描述（由申请人提供）：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，较低的CBT与卡路里限制（CR）有关，一种受控的饮食方案被证明可以延长啮齿动物和猴子的寿命，并延缓多种疾病的进展。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，我们制造了CBT减少的小鼠。这种小鼠是通过在外侧下丘脑（LH）下丘脑分泌素神经元中过表达解偶联蛋白2 （UCP2）而产生的（Hcrt-UCP2小鼠）。UCP2是一个内线粒体！一种膜蛋白，它使氧化磷酸化从呼吸中分离出来，以热的形式消散质子梯度能。下丘脑分泌素是参与调节自主神经功能的下丘脑神经肽，在下丘脑外侧约3000个神经元中独特表达。局部产热导致LH和POA的温度升高，模拟CBT的增加，并激活热调节补偿机制，最终导致CBT的减少。结果，Hcrt-UCP2小鼠的寿命增加了17-19%，与卡路里摄入量无关。此外，与CR小鼠相似，Hcrt-UCP2小鼠显示出氧化应激标志物的年龄依赖性减少，这表明长期减少CBT可能影响自由基的形成。因此，Hcrt-UCP2小鼠为研究CBT对衰老的影响提供了一种新的模型。我们提出了一些实验，旨在描述可能导致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.