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To Be Young Again

Stem cell research offers clues -- but don't hold your breath

By the time Tom Rando crosses the finish line of the Boston Marathon,

he will have burned several pounds of fat for energy and lost more than two pints of water. Think of him on the afternoon of April 21. Blisters will likely be flourishing on his feet or might have already lived out their short, painful life spans. Some toenails might be starting the slow process of bidding adieu to their respective toes.

Underneath the sweat and blisters, Rando’s muscles will have taken a less visible beating. Individual muscle fibers, like so many strands of microscopic hair making up the bulky muscle, will have burst and leaked their contents into the surrounding tissue. A certain trepidation in the face of stairs over the next few days will be the outer sign of this internal damage.

That damage will repair itself in a seemingly miraculous process throughout the next month. Stem cells huddled quietly in the various tissues will heed the call of the injured cells, dividing to form two new cells: One will become a replacement stem cell and one will repair the tissue. In the case of muscle, those stem cells are known as satellite cells for their position frozen in orbit around bundles of muscle fibers.

The problem for Rando is that, at 50, his satellite cells aren’t what they used to be.

Or, to be more precise, the satellite cells might be OK, but the old muscle is less able to prod the satellite cells to divide or to guide the replacement cell to form muscle. That communication failure between the muscle and the satellite cell is one reason Rando and all the other runners of a certain age heal more slowly than their youthful competitors.

Rando knows this problem better than anyone, as an athlete experiencing lingering muscle pain and as a scientist who studies muscle satellite cells.

What Rando, MD, PhD, an associate professor of neurology and neurological sciences, has learned is that, at least in mice, older animals’ satellite cells are less likely to repair damaged muscles. When those cells do rise to the occasion, they have a tendency to replace the injured muscle not with a functional new muscle fiber but with fibrous connective tissue instead. Given that data, it’s not surprising that older people tend to have muscles filled with fibrous connective tissue rather than useful muscle. That’s one reason people get weaker with age.

In fact, many maladies of aging beyond muscle weakness might reflect older stem cells’ failure to respond as they did in their prime. In the blood, for example, older stem cells produce more of one type of blood cell and less of another, predisposing older people to reduced immune function, leukemia and anemia. The cells still divide in response to damage; they just get confused about what to do next.

Rando thinks that if researchers learn how to keep stem cells spry, the cells could treat or prevent some diseases of aging or speed healing. New research at Stanford and elsewhere points to ways of winding back the clock in older stem cells for short periods of time.

What’s key here is the word short. Although there’s some debate over the exact role of stem cells in aging, where researchers agree is that returning stem cells to their prime en masse would prove counterproductive for seekers of eternal youth.

“Anything that delays aging is going to come at a cost,” Rando says. That’s because factors that aid stem cells in one tissue may prod cancer or other diseases in another. What’s more, because the stem cells could all age through different mechanisms, there might not be a single treatment that props up aging stem cells bodywide. Instead, he and others envision short-term, stem-cell-based treatments: speeding healing of the skin after surgery or rebuilding the blood system after a transplant.

Of mice, men and their muscles

Rando says the worlds of aging and stem cell research began intersecting in his lab a few years ago, when it became clear that aging is in part due to impaired tissue repair and that stem cells are responsible for that repair. “We were interested in why muscle atrophies with age, but it wasn’t until we began studying tissue repair that we put the aging work in context with the stem cell work going on in the lab,” he says.

Those two lines of research converged in a 2005 Nature paper describing his group’s finding that older satellite cells were perfectly capable of repairing muscle, but only in the presence of a younger animal’s blood. Those satellite cells are victims of their residence in older tissue.

In fact, a small controversy whirls around whether it’s the stem cell that’s aging or if it’s the tissue. Very likely, the answer depends on the location, says Rando. In the muscle, the stem cells behave differently depending on the age of the blood that bathes them. However, others say that in some parts of the body, the bone marrow for instance, the cells themselves might be getting old. That’s why Derrick Rossi, PhD, thinks that, to some extent, an old stem cell is an old stem cell, regardless of the environment. “However, it would be naïve to assume that the older tissue doesn’t influence the stem cells as well,” says Rossi, who was a postdoctoral fellow at Stanford and is now setting up his own lab at Harvard.

For Rando’s work, the group took advantage of a research trick developed by colleagues in the lab of Irving Weissman, MD, who directs Stanford’s stem cell institute. They surgically connected the blood supply of an older mouse and a younger mouse, then damaged the muscle of the older mouse. Those older satellite cells bathed in blood from the younger mouse were able to repair the muscle injury. The muscles of old mice with no access to young blood didn’t heal as quickly.

But don’t go looking for a hit of young blood to complement your next Botox injection. Not only is the blood unavailable, Rando doubts a single transfusion would do much good. [See “Pints from the pint-sized?”]

Nor should those in most urgent need of blood — surgery patients or trauma victims — worry about their blood donor’s age. The red blood cells and platelets that those patients need are equally effective from people of any age, according to Susan Galel, MD, associate professor of pathology at the School of Medicine and associate medical director of the Stanford Blood Center.

Amy Wagers, PhD, a co-author of Rando’s 2005 Nature paper and a former Stanford postdoc, says a hit of some good stuff in that younger blood could beat the blood itself at keeping stem cells spry. “If it is something in the blood serum, you could isolate that and it could be therapeutically useful,” says Wagers, now on Harvard’s faculty.

Wagers and Rando are tackling the issue of aging stem cells from opposite sides. While Wagers teases out what makes young blood so invigorating, Rando seeks what turns older satellite cells into duds. This work led to an interesting discovery. Older muscles contain higher levels than younger muscles do of a well-known protein called Wnt. And it turns out that Wnt blocks normal satellite cell function in muscle. So, block Wnt in older muscles and voila! You’ve made a younger muscle, right?

That’s more or less correct. Thwarting Wnt in older muscles filled their satellite cells with youthful vigor. But there’s more to the story than Wnt. Howard Chang, MD, PhD, assistant professor of dermatology, showed that blocking the effects of a different protein in older skin resulted in cells that appeared more youthful, at least in mice. In fact, researchers at Stanford, Harvard, the University of Michigan and elsewhere have all found proteins present at high levels in older tissues that might regulate how stem cells respond to their environment.

Fountain of youth, or fountain of illness?

Maybe a substance in the blood of young mice (and humans) can limit the amount of age-promoting proteins in stem cells or in the tissues those stem cells call home. Together, the blood and some combination of these proteins might add up to a fountain of stem cell youth. But it would come at a hefty price, according to Rando. In addition to Wnt’s role in aging stem cells, the protein also regulates a variety of vital cellular processes.

That fountain of youth looks a lot less refreshing if disease is the result of imbibing.

Chang said the protein he’s been studying, the one that shows up in abundance in older skin and other tissues, has different roles in different cells. In some cases the protein, NF-kappa-B, prevents cancer, and in other cases it provokes it. It also helps the immune system function properly. In fact, most of the proteins found to be involved in aging seem to have multiple roles throughout the body.

“I think there will be many pathways that will contribute to aging, and reversing any of them will restore normal function,” Rando says. But those benefits will likely come at a cost, including cancer or any number of other maladies that result from tinkering with a protein that’s doing a variety of jobs all over the body.

That’s why “health span” is a catchphrase among scientists studying aging. While drinking from this “fountain of youth” seems inadvisable, a few drops could help people be healthier for the life span they have. “If you can live the same amount of time but spend a greater percent of it healthy, that would be ideal,” says Wagers.

Rando imagines a future five or 10 years from now in which this research leads to ways of healing tissues for short durations of time. The idea is that a short dose of a localized drug would kick the stem cells into gear temporarily, just long enough to heal an injury but not long enough to tempt disease. After a surgery, for example, an injection of something that gives those skin stem cells a boost could help an elderly aunt heal more quickly and get out of the hospital.

This type of treatment would be most likely to succeed in tissues normally maintained by stem cells. So skin and blood, which stem cells constantly regenerate in young people, would make good candidates. But brain and heart would be poor candidates — since not even young people’s stem cells do much to repair these tissues.

As for muscle, although a stem cell-based treatment could eventually work, that day is too far off to help Rando recover from a demanding race. For the foreseeable future, he and other runners will be relying on ice, ibuprofen and time to heal their injuries.

extras headline

Pints from the pint-sized?

Think Again

Tom Rando’s 2005 article in Nature reporting that blood from younger mice helps older muscles caught the attention of men’s magazine writers. They phoned him, asking if blood from young humans was a key to manlier muscles. Rando, an associate professor of neurology and neurological sciences, said no. Nor would it likely return people to their youthful prime.

That’s because in mice, the presence of younger blood simply allowed older stem cells to act like their younger selves. The rejuvenated stem cells repaired damage, but didn’t create new muscle the way bodybuilders might hope. And even if repairing damage were the goal, there’s another hitch. Rando’s older mice received a constant stream of blood from the younger animals. “From what we know, you need continuous exposure for weeks,” Rando says. A one-time transfusion wouldn’t suffice.

But a lack of scientific grounding won’t thwart anti-aging hucksters, says David Magnus, PhD, director of the Stanford Center for Biomedical Ethics. “I can easily imagine a company starting up in another country based on Rando’s findings,” Magnus says. Though the U.S. government prohibits false advertising claims, not all nations do. Setting up shop abroad would also skirt federal restrictions on blood donations from children. Magnus says he is surprised medical scammers haven’t done this already.
— Amy Adams





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