Researchers watched two groups of mice, both nearing the end of a two-day fast. One group was quietly huddled together, but the other group was active and alert. The difference? The second set of mice had been engineered so their brains produced more SIRT1, a protein known to play a role in aging and longevity.
"This result surprised us," says the study's senior author Shin-ichiro Imai, MD, PhD, an expert in aging research at Washington University School of Medicine in St. Louis. "It demonstrates that SIRT1 in the brain is tied into a mechanism that allows animals to survive when food is scarce. And this might be involved with the lifespan-increasing effect of low-calorie diets."
Imai explains that the mice with increased brain SIRT1 have internal mechanisms that make them use energy more efficiently, which helps them move around in search of food even after a long fast. This increased energy-efficiency could help delay aging and extend lifespan.
The research findings are published in the July 28 issue of the Journal of Neuroscience.
Imai's past research demonstrated that SIRT1 is at the center of a network that connects metabolism and aging. A form of the gene is found in every organism on earth. The gene coordinates metabolic reactions throughout the body and manages the body's response to nutrition. SIRT1 is activated under low-calorie conditions, which have been shown to extend the life spans of laboratory animals.
The researchers found that the key to the mice's extra activity lies in a small region of the brain called the hypothalamus, which controls basic life functions such as hunger, body temperature, stress response and sleep-wake cycles.
At the start of the research project, the study's lead author Akiko Satoh, PhD, a postdoctoral research associate in developmental biology, saw that mice on low-calorie diets had increased amounts of SIRT1 in specific regions of the hypothalamus and that neurons in the same regions were activated.
So the research team developed mice that continually produced higher amounts of SIRT1 in their brains to see what the effect would be. That's when Satoh observed the mice's unusual level of activity under fasting conditions.
"This is the first time that it has been demonstrated that SIRT1 is a central mediator for behavior adaptation to low-calorie conditions," Satoh says.
Interestingly, these mice, called BRASTO (brain-specific SIRT1-overexpressing) mice, also maintained higher body temperatures after a 48-hour fast than ordinary mice, which experience a drop in body temperature during fasting.
"The BRASTO mice have a better capability to come up with energy to achieve a higher body temperature and increased activity level when food is restricted," says Imai, associate professor of developmental biology and of medicine.