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.
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.
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