A drug commonly used to prevent rejection of organ transplants appears to reduce body fat and appetite in older rats. The findings have intriguing implications for humans, researchers say.
Aging can cause many changes to the body, including obesity and a loss of lean mass. With an elderly population that is expected to reach 73 million in the United States by 2030, developing anti-obesity treatments is critical.
While the current findings are limited to rats, the drug rapamycin has potential as a treatment for age-related obesity because it is already used to treat other conditions in people.
“We need to be able to intervene with treatments for older adults,” says Christy Carter, assistant professor of aging and geriatric research at University of Florida. “They’re going to have health care issues, and not everyone can get up and exercise. So if you can give them a jump-start or combine rapamycin with other therapies, you could have better health outcomes.”
Old rat, young body
Obesity among older adults has increased dramatically in the United States during the last 20 years. More than one-third of people over age 65 are obese, according to a study published in 2012 by the Centers for Disease Control and Prevention.
In the first of two studies, published in the Journals of Gerontology, researchers show rapamycin reduces food consumption and body weight. After being treated with the drug, the body weight of 25-month-old rats—about the equivalent of 65-year-old people—dropped by approximately 13 percent.
The drug works by targeting how the body makes leptin, a hormone produced by fat cells that affects hunger and metabolism. The researchers hypothesize that the reduction in eating is due to normalizing the typical age-related spike in leptin.
Rapamycin’s ability to stabilize the rats’ leptin level made them lighter. Overall, there was a dramatic body metamorphosis: rapamycin selectively targeted the fat, allowing the animals to retain lean mass. It worked so well that the older rats ultimately developed a lean-to-fat ratio similar to that of their younger counterparts.
“In this case, we feel like we restored the body composition to that of a young animal,” Carter says.
Dose sweet spot
In the second paper, researchers found that small, intermittent amounts of rapamycin produced the desired slimming effect in both young and old rats. While rapamycin works best in older, obese rats, researchers were encouraged that it also had an effect on certain younger animals.
“One point that is common is that it seems to work better in animals, old or young, that have more fat,” says lead author Philip J. Scarpace, professor of pharmacology.
Getting the correct dose was crucial: Too little of the drug did not reduce obesity, but too much of it caused elevated glucose and fat levels in the blood.
Carter hit the sweet spot in the rats, picking just the right intermittent dose of rapamycin to deliver all of the benefits and none of the unwanted side effects.
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The drug works by inhibiting a signaling mechanism known as mTORC1, a protein complex that is an energy and nutrient sensor. This in turn triggers a response in the brain that curbs eating, effectively reducing age-related fat until the older animals resemble much younger ones.
While rapamycin has yet to be tested in people, the rats were chosen carefully to resemble the aging and obesity pattern of humans, Carter says.
“We’re looking at similarities in longevity, changing body composition and declining physical function—and we’re looking at the same trajectory of age-related obesity.”
Researchers remain unsure whether rapamycin is working in the brain or another part of the body. Next, Carter says she plans to study whether factors released by muscles play a role in fat metabolism.
The National Institutes of Health and the Medical Research Service of the Department of Veterans Affairs funded the work.
Source: University of Florida
