"Our study shows it is possible to increase lifespan in mice by modest but prolonged lowering of core body temperature," said Bruno Conti, an associate professor at Scripps Research who led the study. "This longer lifespan was attained independent of calorie restriction."
Prior to this study, researchers had known that core body temperature and aging were related in cold-blooded animals. Scientists had also known that lifespan could be extended in warm-blooded animals by reducing the number of calories they consumed, which also lowered core body temperature. But the degree of calorie restriction needed to extend lifespan is not easy to achieve, even in mice.
Prior to the current study, critical questions about the relation between calorie restriction, core body temperature, and lifespan remained unanswered. Was calorie restriction itself responsible for longer lifespan, with reduced body temperature simply a consequence? Or was the reduction of core body temperature a key contributor to the beneficial effects of calorie restriction? Conti and colleagues wanted to find out.
To tackle the problem, the scientists decided to try to lower core body temperature directly, without restricting food intake. In cold-blooded animals, such as roundworms (C. elegans) and fruitflies (Drosophila), this task is straight-forward--core body temperature can be lowered simply by changing the temperature of the environment. But for warm-blooded animals, the task is much more challenging.
Conti and colleagues decided to focus their efforts on the preoptic area of the hypothalamus, a structure in the brain that acts as the body's thermostat and is crucial to temperature regulation. Just as holding something warm near the thermostat in a room can fool it into thinking that the entire room is hotter so that the air conditioning turns on, the Scripps Research team reasoned that they could reset the brain's thermostat by producing heat nearby.
To do so, they created a mouse model that produced large quantities of uncoupling protein 2 in hypocretin neurons in the lateral hypothalamus, which is near the preoptic area. The action of uncoupling protein 2 produced heat, which diffused to other brain structures, including the preoptic area. And, indeed, the extra heat worked to induce a continuous reduction of the core body temperature of the mice, lowering it from 0.3 to 0.5 degrees Celsius.
The scientists were then able to measure the effect of lowered core body temperature on lifespan, finding that the mice with lowered core body temperature had significantly longer median lifespan than those that didn't. While this effect was observed in both males and females, in this study the change was more pronounced in females-median lifespan was extended about 20 percent in females and about 12 percent in males.
The researchers performed several experiments to make sure that other factors were not contributing to the lowered core body temperature. They confirmed that the experimental mice were normal in their ability to generate fever, and that these mice moved around about the same amount as normal mice. In addition, the researchers verified that the hypocretin neurons producing uncoupling protein 2 were not involved in temperature regulation.
Importantly, the mice in this study were allowed to eat as much food as they wished, and the experimental and control mice ate the same amount. The weight of the female experimental and control mice did not differ significantly. However, experimental male mice weighed about 10 percent more than the control group, most likely reflecting the reduced energy required to maintain a lower core body temperature, according to the paper.
"Our model addresses something more basic than the amount of food," said Tamas Bartfai, who is chair of the Molecular and Integrative Neurosciences Department, director of the Harold L. Dorris Neurological Research Center at Scripps Research, and an author of the paper. "It works at the level of the thermoregulatory set point that is governed by intra-brain temperature and neurotransmitters. This mechanism, we believe, will be a good target for pharmacological manipulation or heating."
The idea to manipulate the temperature set-point came when Conti and Bartfai joined Scripps Research in the year 2000. Both scientists share common interests in neuroimmunology and the mechanisms of fever. It took over five years of work to conclude this study.
The researchers are now working to identify the precise mechanisms that are responsible for the beneficial effects of reduced core body temperature. They are also investigating whether their findings can be applied to research on obesity.
The findings appear in a paper in the journal Science on November 3.
Other authors on the study include Manuel Sanchez-Alavez, Raphaelle Winsky-Sommerer, Maria Concetta Morale, Jacinta Lucero, Sara Brownell, Veronique Fabre, Salvador Huitron-Resendiz, Steven Henriksen, Eric P. Zorilla, and Luis de Lecea, all of Scripps Research.
The study was supported by The Harold Dorris Neurological Research Institute, The Ellison Medical Foundation, and the National Institutes of Health.
About The Scripps Research Institute
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.