Florida: Aging can cause many changes to the body, including obesity and a loss of lean mass. Now, a group of University of Florida Health researchers has discovered that an existing drug reduces body fat and appetite in older rats, which has intriguing implications for aging humans. Rapamycin, a pharmaceutical used to coat coronary stents and prevent transplant rejection, reduces obesity and preserves lean body mass when given intermittently to older rats. The two rapamycin-related studies were published recently in the Journals of Gerontology as a joint effort of two research teams.
With an elderly population that is expected to reach 73 million in
the United States by 2030, developing anti-obesity treatments is
critical, said Christy S. Carter, Ph.D., an assistant professor in the
department of aging and geriatric research in the UF College of Medicine
and co-lead author of one of the studies. While the current findings
are limited to rats, rapamycin has potential as a treatment for
age-related obesity because it is already used to treat other conditions
“We need to be able to intervene with treatments for older adults.
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,” Carter
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.
Carter and Drake Morgan, Ph.D., an assistant professor in the
department of psychiatry, are the co-lead authors of a paper that shows
rapamycin reduced food consumption and body weight. Using 25-month-old
rats, which are about equivalent to 65-year-old people, researchers
found that body weight dropped by approximately 13 percent after the
rats were treated with rapamycin.
The drug targets 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, researchers found. 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, researchers found.
“In this case, we feel like we restored the body composition to that of a young animal,” Carter said.
In the second paper, researchers found that small, intermittent
amounts of rapamycin produced the desired slimming effect in both young
and old rats. That team included lead authors Philip J. Scarpace, Ph.D.,
a professor in the department of pharmacology, and Nihal Tümer, a
professor in the department of pharmacology and a pharmacologist in the
geriatric center at the Malcom Randall Veterans Affairs Medical Center
in Gainesville. While rapamycin works best in older, obese rats,
researchers were encouraged that it also had an effect on certain
“One point that is common is that it seems to work better in animals, old or young, that have more fat,” Scarpace said.
Getting the correct dose was crucial: Too little of the drug did not
reduce obesity, but too much of it causes 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, Scarpace said. The second paper determined
that the drug works by inhibiting a signaling mechanism known as
mTORC1, a protein complex that is an energy and nutrient sensor. This
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
“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,” she said.
Researchers remain unsure whether rapamycin is working in the brain
or another part of the body. Next, Carter said she would like to study
whether factors released by muscles play a role in fat metabolism.
The studies were supported by grants from the National Institutes of
Health (DK091710 and P30AG028740) and the Medical Research Service of
the Department of Veterans Affairs.