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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG028040-04
Application #
7796674
Study Section
Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
Program Officer
Wise, Bradley C
Project Start
2007-03-15
Project End
2012-02-29
Budget Start
2010-03-15
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$330,935
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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