New TSRI Research Reveals Pathway for Anti-Aging Therapies

By Madeline McCurry-Schmidt

Photo of Rigo Cintron-Colon, Manuel Sanchez-Alavez, M.D., Ph.D. and Bruno Conti, Ph.D.

Two new studies led by scientists at The Scripps Research Institute (TSRI) could guide future therapies to improve health and lifespan. Together, the studies in animal models shed light on how reducing calorie intake directly influences lifespan by also reducing body temperature. Importantly, the researchers also identified a molecule that responds to lower body temperatures to regulate lifespan in fruit flies, giving scientists a target for future pharmaceuticals that may increase longevity.

“This exciting discovery demonstrated that the main biochemical pathway that regulates aging acts by lowering body temperature. ,” said TSRI Professor Bruno Conti, who led the first study.

“Flies also live longer in the cold and the mechanisms that regulate this response overlap with key aging pathways,” said TSRI Associate Professor William Ja, who led the second study on TSRI’s Florida campus.

The new research was published in the journal Proceedings of the National Academy of Sciences.

Study Sheds Light on How Calorie Restriction Extends Lifespan

Scientists have long known that reducing calories—without causing malnutrition—can extend lifespan in animals.

“Researchers had found that mice that eat 40 percent less than normal live much longer—and they actually look younger,” said Conti.

Calorie restriction can also lead to a lower core body temperature. This just makes sense, Conti explained. “If there’s no food, it’s smart to reduce body temperature. You’re reducing your energy expenditure,” he said. “It’s fundamental for the survival of the organism.”

The new study finally shows how these two observations are related. Conti and his colleagues found that it all comes down to how the body uses a molecule called the IGF1 receptor. Previous studies had shown that lowering the activity of the IGF1 receptor can extend lifespan.

Using genetically engineered mouse models, Conti’s team found that calorie restriction provides the signal to lower body temperature, and that this occurs by reducing the activity of the IGF1 receptor in the brain.

“For the first time, we showed that calorie restriction, body temperature and the IGF1 receptor are part of the same pathway,” said study first author Rigo Cintron-Colon, a graduate student in the Conti Lab.

TSRI Assistant Professor Manuel Sanchez-Alavez, who is a co-first author on the publication, emphasized that the research should not encourage people to try extreme diets or cool their body temperatures in the hope of living longer. “My advice is: Do not try this at home,” he said. He explained that the study is significant because a better understanding of the full pathway between calorie restriction and lifespan gives scientists several points where they could attempt to intervene with a pharmaceutical.

Inspired by observations that female mice seem more sensitive to calorie restriction, the researchers said their next step is to investigate whether male and female sex hormones affect the pathway.

Photo of Sany Hoxha, Ilaria Drago, Ph.D. and William Ja, Ph.D.

Researchers Identify Potential Target for Anti-Aging Therapies

The second study, led by Ja, drilled even deeper into the relationship between temperature and lifespan.

Using fruit flies as a model, Ja and his colleagues found that colder ambient temperatures result in a “metabolic brake” to slow down the production of new proteins in the cell. A molecule called 4E-BP responds to cold by sparing select proteins and regulating longevity.

Although the Conti and Ja studies were conducted independently, they reveal another intriguing parallel. The biochemical pathways implicated by the two publications are related and interact extensively. “Surprisingly, even though flies don’t maintain their body temperature like mammals do, organisms may use similar mechanisms to regulate lifespan in response to changes in temperature,” said Ja.

“Our results not only shed light on the temperature effect, but they also establish a parallel between temperature and diet, because 4E-BP is thought to play a role in diet-related life extension as well,” added Dr. Gil Carvalho who, along with Dr. Ilaria Drago, was a co-first author on the publication.

“We also show that the effects of diet on aging are cumulative,” Ja said. “Environmental factors such as temperature and diet seem to affect our health gradually over the years, so the sooner we implement healthy changes, the better off we're likely to be.” If the work in fruit flies holds true in humans, he noted, the research emphasizes the need to make healthy decisions from a young age. Ja hopes further studies into 4E-BP help scientists find pharmaceuticals that “tune” the body’s response to diet and temperature to regulate healthy aging.

The study led by Conti, titled “The insulin-like growth factor 1 regulates hypothermia during calorie restriction,” included William Nguyen and Simone Mori from TSRI, Ruben Gonzalez Rivera from the National Autonomous University of Mexico; Tiffany Lien from the University of California, San Diego; Tamas Bartfai from Stockholm University; and Saba Aïd, Jean-Christophe François and Martin Holzenberger from INSERM and Sorbonne Universities. The research was supported by the National Institutes of Health (grant GM113894), INSERM and The National Council of Science and Technology (CONACYT), Mexico (Postdoctoral Scholarship Award No. 37548).

The study led by Ja, titled “The 4E-BP growth pathway regulates the effect of ambient temperature on Drosophila metabolism and lifespan,” included Gil Carvalho, Ilaria Drago, Sany Hoxha, Ryuichi Yamada, Kimberley Bruce, Alina Soto Obando and Bruno Conti from TSRI, and Olena Mahneva from Florida Atlantic University. The research was supported by the National Institutes of Health (grants R01GM113894, R01AG045036, and R21DK092735), the Glenn Foundation for Medical Research/American Federation for Aging Research and The Ellison Medical Foundation.

Send comments to: press[at]scripps.edu

(High-res image)
Two new studies suggest that, despite differences in thermoregulation, conserved genetic pathways connect energy metabolism, temperature, and lifespan in both mice and flies. In mice, calorie restriction lowers body temperature and decreases energy expenditure. This adaptive response is regulated by the IGF-1 receptor to prolong survival. In flies, the nutrient-sensing 4E-BP pathway controls metabolism and lifespan in the context of ambient temperature changes. Digital design by Juan J. Lobos.

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