Rolling back the clock on muscle disease, aging

Last week CIRM grantees at University of California Berkeley published a follow-up to some of my favorite stem cell research. I'm speaking personally here as a runner who is getting older and would like to turn my race recovery back to what it was in my youth.

Irina Conboy started investigating the slow response of aging muscle stem cells as a postdoctoral fellow in the lab of Thomas Rando at Stanford University (I've written about that work here). What they found is that older muscles in mice don't respond very effectively to muscle damage. But, and this is a big but, if those older mice have younger blood, the muscle stem cells work just fine. Strange, but true.

Since that discovery, Conboy and her lab at Berkeley has been piecing together the story of how and why the younger blood refreshes those old and tired muscle stem cells. In their latest work, which was published in the journal Chemistry & Biology, they show a way using a short-term dose of chemicals to roll back the clock on mature muscle and return it to an earlier state.

A press release from UC Berkeley says:

Building new muscle to replace old or damaged tissue is the routine job of muscle stem cells, or satellite cells. Stationed along the perimeter of adult muscle tissue, they wait for a signal to grow, divide and fuse into new muscle fibers when there’s damage to repair.

But that repair process gets worn out in people with Duchenne muscular dystrophy, a genetic condition in which muscles degenerate because of a defective structural protein and subsequent exhaustion of muscle stem cells. Muscle repair also becomes incapacitated with advancing age.

The group hopes that by turning back the clock, they can return the muscle to a state where it is better able to repair damage. The press release goes on to say:

The researchers say the next steps include testing the process on human muscle tissue and screening for other molecular compounds that could help de-differentiate mature tissue.

“This approach won’t work for all degenerative diseases,” said Conboy. “It might work for some diseases or conditions where we can start with differentiated tissue, such as neurons or liver cells. But patients with type I diabetes, for instance, lack the pancreatic beta-islet cells to produce insulin, so there is no functional differentiated tissue to start with. Our approach is not a replacement for pluripotent cells, but it’s an additional tool in the arsenal of stem cell therapies.”

The group is a long way from marketing the next race recovery beverage. They still have to show that the technique works in human muscle and that those more youthful cells are better able to repair damage.

CIRM Funding: Irina Conboy (RN1-00532-1)
Chemistry & Biology, September 23, 2011


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On stem cells, aging and hopes for spryer golden years

Last week my three year old scraped up the entire left side of his face. Today, there's barely a trace of the injury. That's the glory of three year old skin, or more precisely, the glory of three year old stem cells.

Erin Allday at the San Francisco Chronicle had a story last week about the issue of aging stem cells featuring several CIRM grantees who are, like me, curious about why stem cells heal damage more slowly as we age. Her story includes Thomas Rando of Stanford University, whose work I wrote about several years ago. What I found fascinating then, and what still isn't understood, is why a stem cell grows less able to repair damage over time. Rando and his former postdoctoral fellow Irina Conboy (now at University of California, Berkeley) have found that in older muscle, the stem cells are still able to respond, but the signals themselves may not be as strong. The stem cells are there, they just don't hear damaged muscle's cry for help.

Allday quotes Rando, who is director of the Glenn Laboratories for the Biology of Aging at Stanford:

“I don’t necessarily see it as a way of reversing Alzheimer’s or making people live to 200 years old, but there’s this dormant potential that can be unleashed that can profoundly affect the way stem cells repair tissues.”

Allday also quotes Irina Conboy, who spoke at last week's annual meeting of the International Society for Stem Cell Research in Toronto:

Like physicists trying to find the unified theory of everything, we’re trying to find the unified theory of all these bad things that happen with aging. I think they all stem from a lack of stem cell responses.

Conboy has a New Faculty Award from CIRM to learn more about how stem cells age.

Nobody is arguing that studying stem cells will uncover the fountain of youth (at least, CIRM scientists aren't). Instead, CIRM President Alan Trounson said that by understanding how and why our body's stem cells age scientists could learn how to keep those stem cells more lively during a person's golden years. We wouldn't live longer, maybe, but as long as we're alive it would be nice to heal more effectively or resist disease. Just having bones heal more quickly could significantly reduce health care costs for the elderly.

“With aging, there are a lot of systems that start to become less efficient or break down or be more inclined to diseases. We may work out ways to provide stem cells that would enable people to remain vigorous.”

Remaining vigorous sounds pretty good to me, even if I don't ever again heal with the speed of a three year old.

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Old muscle stem cells experimentally returned to youth

Researchers at the University of California, Berkeley have found molecular pathways that human muscle stem cells rely on to repair damaged muscle. These pathways are active in younger people but less active in older people, explaining why muscles repair more slowly with age. The group found that younger volunteers had double the number of regenerative muscle stem cells in their thigh muscles compared to older volunteers. After two weeks in a leg cast, both groups began exercise routines to rebuild muscle. During this phase, the older volunteers had four times fewer muscle stem cells and rebuilt muscle more slowly. The researchers said that the poor response wasn’t the fault of the older stem cells. Instead, signals in the aging muscle and blood locked the stem cells in an inactive state. From their work in mice, the researchers knew that proteins present in the muscle surrounding the stem cells helped these cells respond to distress signals from the injured tissue. In the human cells, they found a protein called MAPK that interprets these distress signals and triggers the muscle stem cells to begin the repair process. Young people have high levels of MAPK and older people have low levels of MAPK, providing one explanation for the older volunteers’ poor response to exercise. In a lab dish, the group found that by artificially blocking MAPK in young muscle stem cells they could make young cells respond like older cells in a matter of days. The reverse was also true. Amplifying MAPK in older muscle stem cells in a lab dish rejuvenated the older cells. This work is an important step in verifying results from mouse stem cell aging studies in humans. The researchers hope their work could lead to therapies for muscle diseases and help older people to remain active, build stronger muscles and recover from injury.

EMBO Molecular Medicine: September 30, 2009
CIRM funding: Irina Conboy (RN1-00532-1), Morgan Carlson (T1-00007)

Related Information: Press Release, University of California, Berkeley

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