[tt] Another healthy lonegevity protein: uncoupling protein-1

[Hughes, James J.]

http://www.eurekalert.org/pub_releases/2007-12/wuso-ape120307.php

Activating protein enhances average lifespan, limits age-related disease
in mice

St. Louis, Dec. 5, 2007 - Metabolism researchers at Washington
University School of Medicine in St. Louis have found that although it
does not extend maximum lifespan in mice, activating a protein in muscle
tissue increases average lifespan and prevents some age-related
diseases. The researchers believe a similar approach may someday help
people avoid age-related problems such as atherosclerosis, diabetes,
hypertension and even some cancers.

In a series of experiments, the research team bred large numbers of
mice, fed them a normal chow diet and followed each mouse until its
natural death. Half were genetically engineered to make more of a
protein in their muscle tissue called uncoupling protein-1. Their
littermates did not make excess uncoupling protein. In muscle tissue,
uncoupling protein-1 converts the energy from food into heat and mimics
the effects of exercise.

Past research conducted in the laboratory of Clay F. Semenkovich, M.D.,
the Herbert S. Gasser Professor and chief of the Division of
Endocrinology, Metabolism and Lipid Research, had found that mice with
extra uncoupling protein-1 in muscle tissue are protected from diabetes
and obesity.

Because the experiments took so long for this study and involved the
breeding and following of so many mice, Semenkovich was joined on the
paper by three first authors: Alison C. Gates, Ph.D., a former
postdoctoral fellow in the lab now studying at Southern Illinois
University Edwardsville; Carlos Bernal-Mazrachi, M.D., assistant
professor of medicine and of cell biology and physiology; and Sharon L.
Chinault, Ph.D., former postdoctoral fellow and now assistant professor
of biology at MacMurray College in Illinois. The findings are published
in the December issue of the journal Cell Metabolism.

"Uncoupling basically means generating inefficient metabolism," says
Semenkovich. "We knew years ago that when mice manufactured uncoupling
protein in muscle, they didn't become obese. The next challenge was to
see whether the protein would be relevant to some of the major problems
that affect humans, namely aging and age-related disease."

The longest-lived animals in each group lived for 39 months and died
within two weeks of one another. What was different was the median
lifespan for the mice. Median survival in the uncoupled mice was 30
months, compared to 27 months for their wild-type littermates.

"We were a little bit disappointed because we had hoped uncoupling in
muscle would slow aging, but maximum lifespan didn't increase,"
Semenkovich says. "However, the odds of reaching that maximum lifespan
did improve in the uncoupled mice."

Semenkovich says the mice with the genetic alteration were more likely
to live longer, presumably because they were able to avoid age-related
diseases. One result appeared in all of the experiments: Decreasing body
fat and inflammation in the animals by accelerating muscle metabolism
with uncoupling protein delayed death and diseases, including
atherosclerosis, diabetes, hypertension and even cancer.

The researchers examined the mice after each animal died. They were
surprised to find that female mice with the uncoupling protein mutation
were less likely to develop a type of cancer called lymphoma. None of
the genetically engineered females did. No differences in lymphoma rates
were found in male mice. Increased uncoupling protein-1 in muscle also
reduced markers of chronic inflammation.

In a second set of experiments, the researchers found that the uncoupled
mice were less likely to have vascular disease. That was the opposite of
what Semenkovich and his colleagues previously had found in mice
engineered to overproduce uncoupling protein-1 in the wall of the aorta,
the body's primary artery. Rather than being protected from damage,
those mice were prone to develop high blood pressure and
atherosclerosis.

"Where the uncoupling occurs has a big impact," he says. "If this
principle someday becomes a therapy, it will be very important to target
the proper tissues to produce the desired effects."

The team also generated a line of mice that made extra uncoupling
protein only after the animals received drug therapy. They genetically
modified a line of mice that already were prone to become obese. When
the researchers gave these animals an antibiotic drug called
doxycycline, they manufactured more uncoupling protein in muscle tissue
and reversed their problems with glucose metabolism and hypertension
related to their obesity.

Prior to these experiments, the researchers hypothesized that uncoupled
mice might experience the type of increased survival seen in animals on
calorie restriction. "Here at Washington University, we have Dr. John
Holloszy, one of the world's leaders in aging research," Semenkovich
says. "Calorie restriction prolongs lifespan in animals, and Dr.
Holloszy has elegantly begun to translate caloric restriction studies to
humans."

In landmark studies in the 1980s, Holloszy's team also had shown that
rodents getting a great deal of exercise tended to live longer, but
unlike calorie-restricted rodents, their maximum lifespan did not
change. Uncoupled mice, Semenkovich says, resemble the animals that
exercised.

"Uncoupling in muscle may be a substitute for exercise," he says. "If
that's true in humans, and if uncoupling can be done safely, this could
be an important therapy because it's sometimes very difficult to get
people to exercise."

###

Gates AC, Bernal-Mizrachi C, Chinault SL, Feng C, Schneider JG, Coleman
T, Malone JP, Townsend RR, Chakravarthy MV, Semenkovich CF. Respiratory
uncoupling in skeletal muscle delays death and diminishes age-related
disease. Cell Metabolism, vol. 6:6, Dec. 5, 2007.