This Hormone Makes Old Mice Run Like Youngsters

The Rio Olympics do not begin until August, but we already know one thing about the winners—their average age will be around 26, at least for endurance athletes like swimmers and runners^*.  As people reach their 30s and 40s, muscle strength and endurance inexorably decline, pushing them past their peak athletic performance.

Changes in a hormone from an unlikely source—your bones—may be at least partly responsible, according to a new study from the lab of Gerard Karsenty, MD, PhD, chair and the Paul A. Marks Professor of Genetics & Development and professor of medicine .

The researchers found that injections of the hormone—produced most abundantly by the bones of young mice—doubles the distance old mice can run on an exercise wheel.

If the idea of a muscle-enhancing substance secreted from your bones sounds weird, Dr. Karsenty says it makes perfect sense. Muscles work together with bones to produce motion, and it is well known that muscular activity from lifting weights, jumping, or playing tennis strengthens bones.

“If muscle is talking to bone, everything we know about physiology tells us that bone is also talking to muscle,” Dr. Karsenty says.

How could bone communicate with muscle? His lab focused in on osteocalcin, a protein that is produced by bone cells in both mice and humans. Osteocalcin makes up 1 percent to 2 percent of the bone’s mineralized matrix, but several years ago Dr. Karsenty’s lab discovered that osteocalcin present in the bloodstream is delivered to other organs where it acts as a hormone.

One thing about osteocalcin piqued the lab’s interest: in young mice, but not in older ones, the amount of the bone protein found in the bloodstream doubles during exercise.

This observation raised the possibility that osteocalcin affects exercise capacity, so the lab looked for a link between circulating osteocalcin level and athletic performance in mice running on an exercise wheel.

What they found was startling. A normal, young mouse typically runs the equivalent of 1,200 meters (about ¾ of a mile) on an exercise wheel before reaching the point of exhaustion after an hour or so. Older mice exhaust themselves earlier and only run about half that distance.

But when young, normal mice were given extra osteocalcin, their distances increased as much as 20 percent. Conversely, young mice incapable of producing osteocalcin only managed to run 700 to 800 meters, about 20 percent to 30 percent less than their normal counterparts.

More remarkably, old, normal mice injected with osteocalcin just before exercising ran just as far and fast as young, normal mice.

“It’s an astonishing result,” Dr. Karsenty says. “I expected a 10 to 20 percent improvement in the older mice, not 100 percent. We have completely rejuvenated the muscles of old mice, at least in terms of function.”

Osteocalcin, the researchers then found, does this by increasing the amount of glucose and fatty acids that skeletal muscle can take in and consume during exercise.

In people, osteocalcin is probably acting the same way, Dr. Karsenty says. The lab measured osteocalcin levels in young women and older adults, and the results mirrored those in mice. Osteocalcin levels spiked during exercise in young women but not older adults; levels of the hormone dropped precipitously in midlife (around age 30 in women and age 50 in men).

“Exercise is very beneficial to us, so it’s important to try to find things to help older people get more of it,” he says. “Increasing osteocalcin—or mimicking its effects—may be one way to do that.”

Tweaking osteocalcin also may have other therapeutic uses: Dr. Karsenty’s lab has previously found that osteocalcin keeps blood sugar in check and improves male fertility, mood, and memory.

“Bone is not just a victim of aging through osteoporosis, but it may be an active determinant in preventing many deleterious manifestations of aging as long as osteocalcin is being produced.