Aging and hypothalamic temparature

衰老与下丘脑温度

• 批准号: 8037079
• 负责人: BRUNO CONTI
• 金额: $ 31.81万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-15 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8037079
• 关键词: Aging; Body Temperature; Caloric Restriction; Disease; Free Radical Formation; Generations; Heating; Hypothalamic structure; Intake; Lateral; Longevity; Membrane Proteins; Mitochondria; Modeling; Monkeys; Mus; Neurons; Neuropeptides; Oxidative Phosphorylation; Oxidative Stress; Peripheral; Poikilotherms; Protons; Regimen; Regulation; Research Personnel; Respiration; Rodent; Temperature; Testing; Thermogenesis; UCP2 protein; age effect; age related; aged; anti aging; design; dietary control; hypocretin; novel; overexpression; oxidative damage; programs; research study; young adult

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.

描述（由申请人提供）：降低核心体温（CBT）具有抗衰老作用并延长变温动物的寿命。在恒温动物中，较低的 CBT 与热量限制 (CR) 相关，热量限制是一种受控饮食方案，已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，我们培育了 CBT 减少的小鼠。这种小鼠是通过在外侧下丘脑 (LH) 的下丘脑分泌素神经元中过度表达解偶联蛋白 2 (UCP2) 产生的（Hcrt-UCP2 小鼠）。 UCP2是内部线粒体！膜蛋白将氧化磷酸化与呼吸作用解偶联，以热量的形式耗散质子梯度能量。下丘脑分泌素是参与自主神经功能调节的下丘脑神经肽，在下丘脑外侧约 3,000 个神经元中独特表达。局部产热导致 LH 和 POA 温度升高，模拟 CBT 的增加并激活体温调节补偿机制，最终导致 CBT 的减少。结果，Hcrt-UCP2 小鼠的寿命延长了 17-19%，与卡路里摄入量无关。此外，与 CR 小鼠类似，Hcrt-UCP2 小鼠表现出年龄依赖性氧化应激标志物的减少，表明长期减少 CBT 可能会影响自由基的形成。因此，Hcrt-UCP2 小鼠代表了研究 CBT 对衰老影响的新模型。我们提出了一些旨在表征 Hcrt-UCP2 小鼠核心体温降低和寿命延长机制的实验。

项目成果

Metabolic characterization of a mouse deficient in all known leptin receptor isoforms.

• DOI: 10.1007/s10571-009-9427-x
• 发表时间: 2010-01
• 期刊: CELLULAR AND MOLECULAR NEUROBIOLOGY
• 影响因子: 4
• 作者: Osborn, Olivia;Sanchez-Alavez, Manuel;Brownell, Sara E.;Ross, Brendon;Klaus, Joe;Dubins, Jeffrey;Beutler, Bruce;Conti, Bruno;Bartfai, Tamas
• 通讯作者: Bartfai, Tamas

Corrigendum to "Chronic restraint stress triggers dopaminergic and noradrenergic neurodegeneration: Possible role of chronic stress in the onset of Parkinson's disease" [Brain Behav. Immun. 51 (2016) 39-46].

• DOI: 10.1016/j.bbi.2016.12.009
• 发表时间: 2017-03
• 期刊: Brain, behavior, and immunity
• 作者: Sugama S;Sekiyama K;Kodama T;Takamatsu Y;Takenouchi T;Hashimoto M;Conti B;Kakinuma Y
• 通讯作者: Kakinuma Y

Single cell transcriptomics of hypothalamic warm sensitive neurons that control core body temperature and fever response Signaling asymmetry and an extension of chemical neuroanatomy.

• DOI: 10.1016/j.pharmthera.2010.09.010
• 发表时间: 2011-03
• 期刊: PHARMACOLOGY & THERAPEUTICS
• 影响因子: 13.5
• 作者: Eberwine, James;Bartfai, Tamas
• 通讯作者: Bartfai, Tamas

Downregulation of GPR83 in the hypothalamic preoptic area reduces core body temperature and elevates circulating levels of adiponectin.

• DOI: 10.1016/j.metabol.2012.03.015
• 发表时间: 2012-10
• 期刊: METABOLISM-CLINICAL AND EXPERIMENTAL
• 影响因子: 9.8
• 作者: Dubins, Jeffrey S.;Sanchez-Alavez, Manuel;Zhukov, Victor;Sanchez-Gonzalez, Alejandro;Moroncini, Gianluca;Carvajal-Gonzalez, Santos;Hadcock, John R.;Bartfai, Tamas;Conti, Bruno
• 通讯作者: Conti, Bruno

Hypothalamic and dietary control of temperature-mediated longevity.

• DOI: 10.1016/j.arr.2009.07.004
• 发表时间: 2010-01
• 期刊: AGEING RESEARCH REVIEWS
• 影响因子: 13.1
• 作者: Tabarean, Iustin;Morrison, Brad;Marcondes, Maria Cecilia;Bartfai, Tamas;Conti, Bruno
• 通讯作者: Conti, Bruno