SCL Deputy Director Rando’s work with stem cells unravels the mysteries of why people heal less efficiently as they get older
STANFORD – As we age, our bodies’ ability to repair injuries and wounds degrades. Not only does the same type of wound simply take longer to heal in older people than younger people, but the wounds tend to build up more scar tissue and adhesions.
In a novel and exciting series of experiments, Stanford Center on Longevity Deputy Director Thomas Rando and his team are rapidly advancing medicine’s understanding of this phenomenon by deconstructing the complex chemical symphony that orchestrates healing. Publishing in the August 10 issue of Science, Dr. Rando reports that his team has found a misfiring chemical signal that appears to prompt otherwise healthy cells to make the wrong kind of repairs. “The hope is that we may be able to turn those bad instructions off, and help older people heal more efficiently by making sure their cells are receiving the proper instructions,” explains Dr. Rando, professor of neurology and neurological sciences at the Stanford School of Medicine.
Here’s what’s going on: Adult stem cells exist in many kinds of tissues and organs and serve as a sort of building block cell that can develop into the kind of tissue required to repair damage. Stem cells in the skin can develop into healthy skin cells, for example, while stem cells in muscle can become muscle cells. However, in order for the body to repair an injury to a tissue such as occurs from trauma or a surgical incision, the stem cells must receive the appropriate signals from the surrounding damaged tissue. Some of those signals come from cells of the immune system that move into damage to help clear away debris from dying cells. Other signals come from uninjured cells in the tissue. When the stem cells sense these signals, they go through a precise series of processes, including dividing many times in order to generate enough cells that will be necessary to replace the cells that were lost.
Dr. Rando’s research has identified a protein called “Wnt” (pronounced “wint”) that appears to have a profound effect of stem cell function. Wnt is a protein that binds to cells and initiates a chemical signaling system that acts on embryonic stem cells, or cells in a developing fetus, and directs them to become different organs and tissues. Extrapolating from this research, it appears that, in older people, the Wnt pathway in essence shorts out and misdirects stem cells in muscle tissue called satellite cells to become cells called fibroblasts, which make scar tissue. Still unclear is whether the protein is just produced locally in the damaged tissue, or whether it is a hormone-like molecule that circulates in the bloodstream. Although Dr. Rando’s research focused on the repair of acute trauma to muscles, he suspects that the same sort of problem arises on a lesser scale in repairing damage that results from the normal wear and tear of aging.
There is hope that a drug that blocks the misbehaving Wnt pathway could boost the ability of older people to heal faster and better from muscle injuries, Dr. Rando says. There is also reason to believe that the same strategy could help boost the repair of tissues such as skin, gut, bone marrow and epithelium, as well as organs including the liver.
For some time, scientists theorized that stem cells “aged” as we do, and became less potent. However, Dr. Rando made news last year when his team performed a fascinating experiment in which he surgically attached the circulatory system of an old mouse and a young mouse, and showed that the old mouse’s stem cells functioned far better when they were literally exposed to young blood. “By sitting in an ‘old’ environment, the stem cells were in deep hibernation, but when exposed to the young blood they responded very well,” Dr. Rando explains.
“Originally,” he continues, “our excitement was around the question: What’s the great stuff in the young blood?” However, when he attempted to investigate the opposite question of whether the young mice healed less well when they were infused with the older mice’s blood, the next level of experiments showed that the problem was actually a suppressive activity in the older mice’s blood. “The ‘old blood’ environment makes the stem cells turn into fibroblasts, or cells that make connective tissue, rather than healthy muscle cells,” Dr. Rando explains. Further research revealed the connection to the Wnt pathway.
“What we consider minor physical injuries to our bodies when we’re young take on new dimensions as we age,” notes Laura L. Carstensen, PhD, director of the Stanford Center on Longevity. “There was a time when people simply shrugged their shoulders and grouped problems such as reduced healing ability in the category of things that ‘just happen’ as you age. By applying targeted science and technology to understand these mechanisms, we may find that we can impact and enhance, for example, wound healing in older people. Tom Rando’s very exciting work shows the potential of basic research to inform medical strategies that strive to keep older people healthy, independent, strong, and mobile.”
The experiment raises several interesting questions. For example, could blood transfusions be a possible enhancement to wound-healing in the elderly? Dr. Rando doesn’t think so. For one thing, the nature of the experiments he performed would suggest that a patient would have to be exposed to ‘young blood’ for weeks or months to simulate the full exposure to a properly functioning Wnt pathway as the mice received in the experiment. Another concern is that any approach that tinkers with cell differentiation in the body could have the potential to trigger unchecked growth in a particular type of cell, which could cause cancer.
Dr. Rando, who also does research and clinical work at the Veterans Affairs Palo Alto Health Care System, is senior author of the research that was published in the Aug. 10 issue of Science. Dr. Rando’s Stanford co-authors are Andrew Brack, PhD, postdoctoral scholar; Michael Conboy, PhD, postdoctoral scholar; Sudeep Roy, research assistant; Mark Lee, MD, PhD, postdoctoral scholar; and Calvin Kuo, MD, PhD, assistant professor of hematology. The research was funded by the NIH, the Department of Veterans Affairs, the Ellison Medical Foundation and an NIH Director’s Pioneer Award to Dr. Rando.