October 01, 2009
Pathway Suppresses Muscle Repair As We Age

As we age changes in factors excreted by muscle cells suppress stem cells to make them do less repair. So our muscles decay. A change in biochemical signaling can activate stem cells to do more muscle repair.

Berkeley -- A study led by researchers at the University of California, Berkeley, has identified critical biochemical pathways linked to the aging of human muscle. By manipulating these pathways, the researchers were able to turn back the clock on old human muscle, restoring its ability to repair and rebuild itself.

The findings will be reported in the Sept. 30 issue of the journal EMBO Molecular Medicine, a peer-reviewed, scientific publication of the European Molecular Biology Organization.

"Our study shows that the ability of old human muscle to be maintained and repaired by muscle stem cells can be restored to youthful vigor given the right mix of biochemical signals," said Professor Irina Conboy, a faculty member in the graduate bioengineering program that is run jointly by UC Berkeley and UC San Francisco, and head of the research team conducting the study. "This provides promising new targets for forestalling the debilitating muscle atrophy that accompanies aging, and perhaps other tissue degenerative disorders as well."

This builds on work stretching back to when Irina Conboy was at Thomas Rando's lab at Stanford about 6 years ago. This report shows how she and her collaborators are really rolling along progressively putting together more pieces of the puzzle needed to rejuvenate aging muscle. Conboy says she wants to eventually get into human trials with techniques to turn up muscle repair. I fear that getting to human trials will not be easy because the pathways that suppress stem cells in aged bodies do that in order to reduce cancer risk or perhaps other disease risks.

The problem is that aged muscle cells send the wrong mix of signals to neighboring stem cells. This turns down stem cell activity and reduces the amount of repairs that get done.

Previous research in animal models led by Conboy, who is also an investigator at the Berkeley Stem Cell Center and at the California Institute for Quantitative Biosciences (QB3), revealed that the ability of adult stem cells to do their job of repairing and replacing damaged tissue is governed by the molecular signals they get from surrounding muscle tissue, and that those signals change with age in ways that preclude productive tissue repair.

Those studies have also shown that the regenerative function in old stem cells can be revived given the appropriate biochemical signals. What was not clear until this new study was whether similar rules applied for humans. Unlike humans, laboratory animals are bred to have identical genes and are raised in similar environments, noted Conboy, who received a New Faculty Award from the California Institute of Regenerative Medicine (CIRM) that helped fund this research. Moreover, the typical human lifespan lasts seven to eight decades, while lab mice are reaching the end of their lives by age 2.

An enzyme called MAP kinase (and kinases generally hook phosphates onto other proteins - often to regulate them) declines with age and this decline in MAP kinase (MAPK) appears to be key in turning down stem cell activity. The lowered stem cell activity means that muscle damage doesn't get repaired and therefore we accumulate more damage and muscle shrinkage as we age.

The researchers further examined the response of the human muscle to biochemical signals. They learned from previous studies that adult muscle stem cells have a receptor called Notch, which triggers growth when activated. Those stem cells also have a receptor for the protein TGF-beta that, when excessively activated, sets off a chain reaction that ultimately inhibits a cell's ability to divide.

The researchers said that aging in mice is associated in part with the progressive decline of Notch and increased levels of TGF-beta, ultimately blocking the stem cells' capacity to effectively rebuild the body.

This study revealed that the same pathways are at play in human muscle, but also showed for the first time that mitogen-activated protein (MAP) kinase was an important positive regulator of Notch activity essential for human muscle repair, and that it was rendered inactive in old tissue. MAP kinase (MAPK) is familiar to developmental biologists since it is an important enzyme for organ formation in such diverse species as nematodes, fruit flies and mice.

For old human muscle, MAPK levels are low, so the Notch pathway is not activated and the stem cells no longer perform their muscle regeneration jobs properly, the researchers said.

In February 2005 Thomas Rando's group at Stanford showed that blood from young mice helped stimulate regeneration in muscle of old mice. I found that report to be really bad news because it suggests that even if we develop ways to make youthful stem cells programmed to become assorted cell types that by itself won't increase repair by all that much. Our problem is that cells throughout an aging body are either excreting factors into the bloodstream that dampen repairs or the cells are failing to excrete factors that stimulate repairs.

In 2008 Conboy and collaborators found that they could turn up repair capability of mouse stem cells. Now in this latest report they are working with human stem cells.

If the body is turning down MAPK and suppressing stem cells as we age there's probably a constructive reason for this. The most obvious possibility: the repair stem cells are turned down because as they age they become higher risks for turning cancerous. If that is the case (and I think it likely) then efforts to turn up stem cells to do more repair will put us at greater risk of cancer. Therefore we really need effective ways to kill pre-cancerous and cancerous cells as essential capabilities in order to do rejuvenation therapies.

One way to reduce the risk of cancer that likely would come from upregulating aged stem cells would be to replace the aged stem cells with young stem cells. Youthful stem cell lines selected for few mutations would pose less of a cancer risk. But even if suitable stem cell lines could be created for all the types of stem cells in the body getting the replacement stem cells to all the places where they are found is a daunting task. Also, getting existing stem cells to basically all die off to make room for their youthful replacements is similarly daunting.

In spite of the cancer risk for some people the benefits of therapy will outweigh the risks. If, for example, you have a failing heart that is going to kill you in a couple of years then, hey, a stem cell therapy combined with a drug therapy that upregulates stem cells will offer a very favorable ratio of benefits to risks. Stem cell therapies and other therapies to stimulate repair will make the most sense for the most unhealthy first.

Share |      Randall Parker, 2009 October 01 10:29 PM  Biotech Stem Cells

Nick G said at October 2, 2009 4:09 PM:

I'd be a little more optimistic about longevity free of tradeoffs such as cancer.

The fact is that very similar creatures have very different lifespans. Mice live 3 years, and bats live 50 years. Chimps live 50, and humans live 100 (123 max, at the moment). Bats and humans get all diseases, including cancer, much later than mice and chimps.

Rhesus monkeys (and many, many others) on caloric restriction are healthier in every way than their well-fed peers. There's no sign of tradeoffs, besides being a bit grumpy about the food....

Brett Bellmore said at October 4, 2009 8:39 AM:

"But even if suitable stem cell lines could be created for all the types of stem cells in the body getting the replacement stem cells to all the places where they are found is a daunting task."

Save that effort for the CNS; Everything else can just be periodically replaced. Tissue printing will be able to construct whole bodies before we can make Oncosens work.

Post a comment
Name (not anon or anonymous):
Email Address:
Remember info?

Go Read More Posts On FuturePundit
Site Traffic Info
The contents of this site are copyright