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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Wise, Bradley C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
Sugama, Shuei; Sekiyama, Kazunari; Kodama, Tohru et al. (2017) 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]. Brain Behav Immun 61:389
Zorrilla, Eric P; Conti, Bruno (2014) Interleukin-18 null mutation increases weight and food intake and reduces energy expenditure and lipid substrate utilization in high-fat diet fed mice. Brain Behav Immun 37:45-53
Conti, Bruno; Hansen, Malene (2013) A cool way to live long. Cell 152:671-2
Bartfai, Tamas; Conti, Bruno (2012) Molecules affecting hypothalamic control of core body temperature in response to calorie intake. Front Genet 3:184
Dubins, Jeffrey S; Sanchez-Alavez, Manuel; Zhukov, Victor et al. (2012) Downregulation of GPR83 in the hypothalamic preoptic area reduces core body temperature and elevates circulating levels of adiponectin. Metabolism 61:1486-93
Morrison, Brad E; Marcondes, Maria Cecilia Garibaldi; Nomura, Daniel K et al. (2012) Cutting edge: IL-13R?1 expression in dopaminergic neurons contributes to their oxidative stress-mediated loss following chronic peripheral treatment with lipopolysaccharide. J Immunol 189:5498-502
Eberwine, James; Bartfai, Tamas (2011) Single cell transcriptomics of hypothalamic warm sensitive neurons that control core body temperature and fever response Signaling asymmetry and an extension of chemical neuroanatomy. Pharmacol Ther 129:241-59
Nomura, Daniel K; Morrison, Bradley E; Blankman, Jacqueline L et al. (2011) Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334:809-13
Klein, Izabella; Sanchez-Alavez, Manuel; Tabarean, Iustin et al. (2011) AdipoR1 and 2 are expressed on warm sensitive neurons of the hypothalamic preoptic area and contribute to central hyperthermic effects of adiponectin. Brain Res 1423:1-9
Sanchez-Alavez, Manuel; Alboni, Silvia; Conti, Bruno (2011) Sex- and age-specific differences in core body temperature of C57Bl/6 mice. Age (Dordr) 33:89-99

Showing the most recent 10 out of 22 publications