Cooler mice live longer

Transgenic mice with lower core body temperatures have markedly longer lifespans

By | November 2, 2006

Genetically reducing the core body temperature of mice by a half-degree Celsius helped them live 15 percent longer, a finding that could shed light on how calorie restriction helps prolong life, researchers report in Science. "Calorie restriction was already known to be associated with reduction of core body temperature in rodents and in primates," co-author Bruno Conti, from the Scripps Research Institute in La Jolla, California, told The Scientist. "What was not known was if the reduction was simply a consequence of calorie restriction or if it also contributed to its beneficial effects. Our studies demonstrate that the latter may be true." Past research showed lowering core body temperature slowed aging and prolonged life in poikilotherms such as fish. Whether this was also true for homeotherms had not been demonstrated. Conti and his colleagues engineered mice that had an overheated hypothalamus. The preoptic area of the hypothalamus serves as the central thermostat for the brain, so heating it up turns down the core body temperature. Specifically, the researchers focused on the hypocretin gene. Hypocretins are appetite-promoting neuropeptides expressed in just 3,000 or so neurons in the lateral hypothalamus, near the preoptic area. The researchers generated transgenic mice using plasmids linking the hypocretin gene to uncoupling protein 2 (UCP2). UCP2 is found in the inner mitochondrial membrane and uncouples electron transport from ATP production, dissipating the proton gradient energy as heat. Over-expressing UCP2 therefore elevated the hypothalamus temperature in the mice. The result was that core body temperatures were lowered by 0.3 degrees to 0.5 degrees C. Experimental female mice lived an average of 20 percent longer than controls, while experimental males had a 12 percent greater life expectancy. Douglas Osei-Hyiaman at the National Institute on Alcohol Abuse and Alcoholism in Bethesda, Maryland, who did not participate in the study, noted in an email to The Scientist that the greater increase in life expectancy in the female mice might suggest that "sex hormones may help some mice attain a lower core temperature faster than others." "What I find interesting about [the study] is that you can isolate one of the seemingly small aspects of the many physiological effects of caloric restriction and still get an effect on lifespan, although not as much as with real caloric restriction. This suggests each of the effects caloric restriction has may contribute incrementally," said Leonard Guarente, of the Massachusetts Institute of Technology in Cambridge, who did not participate in the study. Future longevity studies or research into mutations that increase lifespan "should also see whether or not there's a reduction in the core body temperature, which should be easy to do," Matt Kaeberlein, from the University of Washington in Seattle, told The Scientist. "The question now is what mechanisms are responsible here?" said Kaeberlein, who was not involved in the study. "You should see if all the other biomarkers that correlate with increased lifespan change. Is there reduced oxidative damage, for instance? You should also see if these mice have reduced pathologies of aging, or if these mice, when bred with others that reflect disease models such as Huntington's or Alzheimer's, have offspring with a reduced onset of pathology." The experimental mice indirectly appeared to have increased metabolic efficiency, Conti said. When starved for about a day, they lost significantly less weight than controls, and while the transgenics consumed the same amount of food and water as controls, experimental males weighed 10 percent more, suggesting they required fewer calories to live, most likely reflecting the reduced energy required to maintain a lower core body temperature, he suggested. Conti noted that the research team next plans to determine whether the effects of lowered core temperature are additive to the effects of calorie restriction by placing the transgenic mice on calorie-restricted diets. "You can try these mice out on exercise regimens, or [try] giving them high-fat diets and seeing what effects those have on their longevity," USDA scientist James Joseph at Tufts University in Boston, who did not participate in the study, told The Scientist. Another avenue of research could be to see if mitochondrial function throughout the bodies of the experimental mice matches up "with the same changes observed in calorie restriction, Pere Puigserver at Johns Hopkins University in Baltimore, who was not a coauthor, told The Scientist via email. Charles Q. Choi Links within this article: M.W. Anderson. "Sir2: Scrambling for Answers," The Scientist, Dec. 6, 2004 B. Conti et al. "Transgenic Mice with a Reduced Core Body Temperature Have an Increased Life Span," Science 314: 825-8, Nov. 3, 2006. Bruno Conti R.K. Liu and R.L Walford. "Increased Growth and Life-span with Lowered Ambient Temperature in the Annual Fish, Cynolebias adloffi," Nature 212:1277-8, Dec. 10, 1966 doi:10.1038/2121277a0 Douglas Osei-Hyiaman L. Guarente, Forestalling the Great Beyond with the Help of SIR2, The Scientist, April 26, 2004 Matt Kaeberlein James Joseph G. Flores, "Fast track to longevity,"The Scientist, March 7, 2005

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