August 13, 2007
Wnt Suppresses Stem Cell Repair Work As We Age?

As we age the protein Wnt probably suppresses older stem cells and prevents them from doing needed repair work.

The key to the whole process is Wnt, a protein traditionally thought to help promote maintenance and proliferation of stem cells in many tissues. But in this instance, Wnt appears to block proper communication.

"That was a total surprise," said Thomas Rando, MD, PhD, associate professor of neurology and neurological sciences. "We had no idea that the Wnt signaling pathway would have a negative effect on stem cell function." Rando, who also does research and clinical work at the Veterans Affairs Palo Alto Health Care System, is senior author of the research that will be published in the Aug. 10 issue of Science.

Rando previously discovered (and the link below is to a previous post I did on that report) that old stem cells will act younger if exposed to younger blood. That's very troubling news for efforts to develop rejuvenating cell therapies. If the whole body is full of chemical signals that suppress growth then just replacing older stem cells with younger stem cells won't yield as much increase in healing and repair as our aging bodies need.

Rando had already discovered that old muscle stem cells, if placed in a youthful environment, had just as great a capacity for repairing acutely damaged tissue as do young cells.

It was while the researchers were testing the opposite situation - how the repair capabilities of young muscle stem cells were affected by being placed in an aged environment - that the Wnt pathway came to light. The work was done with live mice whose circulatory systems were joined, and in lab dishes with young cells immersed in serum from old blood.

As expected, the young muscle stem cells were influenced negatively by the aged environment, repairing damaged muscle tissue just as slowly and poorly as old stem cells in the same surroundings. This confirmed their earlier research showing that the ability of muscle stem cells to regenerate tissue depends on the age of the cells' environment (including the age of the blood supplying the tissue), not the age of the stem cell.

The stem cells exposed to too much Wnt failed to produce needed replacement muscle cells. Worse yet, the muscle stem cells formed scar tissue instead.

Rando also found that the misdirected stem cells - the ones that failed to generate new muscle cells in the old environment - were instead differentiating into scar-tissue-producing cells called fibroblasts. The stem cells weren't just failing to respond to the garbled instructions, they were actually giving rise to daughter cells that turned into the wrong thing. The consequence of muscle stem cells producing fewer muscle cells (myoblasts) and more fibroblasts is that the healing muscle had more scar tissue, also known as fibrosis.

"That says something about how cells decide who they're going to be. Even if they start off knowing they're supposed to be a muscle cell, they can change," said Rando. "If you're exposed to the wrong environment, it will change your fate."

Rando said the type of fibrosis that occurs in the aging muscle tissue is the same type seen in muscular dystrophy. He is already exploring how inhibiting Wnt signaling might help provide therapy for that disease.

So as you age your muscles accumulate scar tissue. We need ways to get rid of that scar tissue and replace it with youthful muscle cells produced from youthful and properly instructed stem cells.

Another research group has just discovered that Wnt is able to suppress mouse stem cell activity because as mice age their bodies make less of another protein called klotho. Well, klotho restrains Wnt and the absence of klotho causes Wnt to suppress stem cell division.

Wnt has also popped up unexpectedly in work by researchers at the National Institutes of Health, published in the same issue of Science, who were studying the effects of a deficiency of a hormone called klotho. Klotho deficiency causes a syndrome that resembles extremely rapid aging in mice, which end up dying very young compared with normal mice. In seeking to understand why that happens, the NIH researchers discovered that klotho inhibits Wnt activity. The hypothesis is that klotho production declines with age, and thus its effectiveness against Wnt decreases, allowing Wnt activity to pick up and disrupt the normal signaling to the stem cells in a variety of tissues studied.

You might think hey, why not deliver klotho hormone replacement therapy to slow or reverse cellular aging? Good question. Let me put the question another way: Why does klotho production decline with age? Is it just due to accumulation of damage to klotho-making machinery? My guess: the decline of klotho happens in order to reduce the risk of cancer. As cells age they accumulate mutations that could become cancerous. By slowing cell division by reducing klotho the body reduces healing but on average that reduction in healing becomes a net benefit due to avoided cancer.

Here is the abstract of that NIH study that Rando mentioned. Klotho suppresses Wnt whereas continuous exposure to Wnt causes cells to go into a senescent (old, much lower level of function) state.

The contribution of stem and progenitor cell dysfunction and depletion in normal aging remains incompletely understood. We explored this concept in the Klotho mouse model of accelerated aging. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because klotho is a secreted protein, we postulated that klotho might interact with other soluble mediators of stem cells. We found that klotho bound to various Wnt family members. In a cell culture model, the Wnt-klotho interaction resulted in the suppression of Wnt biological activity. Tissues and organs from klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, klotho appears to be a secreted Wnt antagonist and Wnt proteins have an unexpected role in mammalian aging.

We need to know whether other genes signal klotho's gene to stop expressing itself. We also need to know what upstream event starts the sequence of gene activations and deactivations that lead to too little klotho.

Wnt is an obvious candidate for drug development. A drug that binds to Wnt and blocks its action will probably have the effect of making your stem cells divide more vigorously and to form more types of needed cells. Though such a drug probably would increase your risk of cancer. For someone who is suffering from, say, life threatening cardiovascular disease the trade-off from drug use of getting more repair cell activity with more cancer risk would probably be worth it.

We need much more progress toward the goal of understanding how stem cells interact with aging bodies. In spite of all the news above about Wnt and klotho it seems likely that replacing aged stem cells with more youthful stem cells will yield many therapeutic benefits. The aged stem cells are at greater risk of becoming cancerous. Their replacement by stem cells that have far fewer accumulated genetic defects will reduce the risk of cancer from stem cells as well as provide stem cells that can divide more times. Older stem cells have shortened telomeres that become obstacles in the way of stem cell division.

If we could only find ways to keep stem cells active as the years go by we would develop degenerative diseases of old age much less frequently.

Share |      Randall Parker, 2007 August 13 12:10 AM  Aging Mechanisms

James Bowery said at August 13, 2007 10:33 AM:

"that old stem cells will act younger if exposed to younger blood"

Hey, there may be a use for all those Mexican anchor babies after all: Rejuvenate rich people! All you need is to suck the blood from their veins! Also, powerful politicians running for office could benefit by pulling some of their campaign war chest money out for treatments. I mean, come now, let's be realpolitick here: Don't you think Hillary could do with a few Mexican anchor babies feeding her facial, abdominal and thigh stem cells -- especially if they come with convenient designer carrying pouches and decorator transfusion tubes? Think of the Hispanic vote she'd get carrying little papooses around all the time.:

It Takes a Woman President

And for Wall Street stock analysts on the go, we could have Mexican anchor baby desk ornaments for a "power blood break" during their hectic days. But they'd need to make the desk ornament shells hermetically sealed so the unpleasant sounds and smells from the Mexican anchor babies don't disturb the highly optimized, fine-tuned-like-a-Ferrari work environment.

rsilvetz said at August 13, 2007 6:32 PM:

Response surfaces people. We need response surface profiles for the immune system and for inside the cell pathways. None of this linear thinking is going to cut it in a concentration-based computer system with several thousand inputs and outputs.

AC said at August 13, 2007 11:45 PM:

You've been tagged: The Bayblab is proud to host the first ever blog carnival on cancer research. A blog carnival is an event where a community of bloggers come together to explore a common subject of interest. Not only does it create a tool to exchange ideas, but it is a good way to exchange links and increase readership. The rules are simple, write a post about any aspect of cancer research, for example where you see your field contributing to cancer treatment in the future, and submit a link to your story to the comment section of this post ( by August 24th. Also, please copy and paste this message to the comment sections of as many relevant blogs as you can. Let the fun begin!

JWouters said at August 16, 2007 5:18 AM:

A coupla months ago Wnt was reported to induce hair growth on skin in the mouse model. Seems contradicatory. Maybe the CONTINUOUS exposure to Wnt has something to do with the accelerated senescence; too much of a good thing indeed could trigger cancer and maybe feedback mechanisms kick in at overexposure (of quantity and/or duration). Also, there is not just one Wnt protein but a class of Wnt proteins; check wikipedia and Maybe Wnt pathways/proteins in various tissues exhibit various effects. Anyway, i agree with RSilvetz that the proteomic realm is not to be approached with linear thinking. Mapping it will be required, and a quite tougher challenge (quantity, complexity, dynamics) than that of the genome. Luckily the required technologies (bioinformatics, microarray tech) are advancing aswell.

Alana said at November 7, 2007 12:29 AM:

Watch a short movie to learn how to enhance adult stem cell production.

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