Scripps Center for Metabolomics, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Sci Signal. 2020 Sep 8;13(648):eabb2490. doi: 10.1126/scisignal.abb2490.
Calorie restriction (CR) enhances health span (the length of time that an organism remains healthy) and increases longevity across species. In mice, these beneficial effects are partly mediated by the lowering of core body temperature that occurs during CR. Conversely, the favorable effects of CR on health span are mitigated by elevating ambient temperature to thermoneutrality (30°C), a condition in which hypothermia is blunted. In this study, we compared the global metabolic response to CR of mice housed at 22°C (the standard housing temperature) or at 30°C and found that thermoneutrality reverted 39 and 78% of total systemic or hypothalamic metabolic variations caused by CR, respectively. Systemic changes included pathways that control fuel use and energy expenditure during CR. Cognitive computing-assisted analysis of these metabolomics results helped to prioritize potential active metabolites that modulated the hypothermic response to CR. Last, we demonstrated with pharmacological approaches that nitric oxide (NO) produced through the citrulline-NO pathway promotes CR-triggered hypothermia and that leucine enkephalin directly controls core body temperature when exogenously injected into the hypothalamus. Because thermoneutrality counteracts CR-enhanced health span, the multiple metabolites and pathways altered by thermoneutrality may represent targets for mimicking CR-associated effects.
热量限制（CR）可延长多种生物的健康寿命（生物体保持健康的时间长度）并延长其寿命。在小鼠中，这些有益作用部分是通过 CR 期间核心体温降低介导的。相反，通过将环境温度升高到热中性（30°C）来减轻 CR 对健康寿命的有利影响，在这种情况下，体温过低会减弱。在这项研究中，我们比较了在 22°C（标准饲养温度）或 30°C 下饲养的小鼠对 CR 的全球代谢反应，发现热中性分别逆转了 CR 引起的总全身或下丘脑代谢变化的 39%和 78%。全身变化包括在 CR 期间控制燃料利用和能量消耗的途径。对这些代谢组学结果进行认知计算辅助分析有助于确定调节 CR 引起的体温过低反应的潜在活性代谢物。最后，我们通过药理学方法证明，通过瓜氨酸-NO 途径产生的一氧化氮（NO）促进 CR 引发的体温过低，而亮氨酸脑啡肽在体外注射到下丘脑时直接控制核心体温。由于热中性抵消了 CR 增强的健康寿命，因此被热中性改变的多种代谢物和途径可能代表模仿 CR 相关作用的靶标。
