London, June 16 : Bioengineers at the University of California, Berkeley, say that they have been successful in giving old muscle a shot of youthful vigour during lab experiments.
The researchers say that their work is setting the path for research on new treatments for age-related degenerative conditions like muscle atrophy or Alzheimer's and Parkinson's diseases.
According to them, the study has unveiled two key regulatory pathways that control how well adult stem cells repair and replace damaged tissue.
Irina Conboy, an assistant professor of bioengineering and an investigator at the Berkeley Stem Cell Center and at the California Institute for Quantitative Biosciences (QB3), said that the researchers tweaked how those stem cells reacted to those biochemical signals to revive the ability of muscle tissue in old mice to repair itself nearly as well as the muscle in the mice's much younger counterparts.
The fact that the findings related to adult stem cells that reside in existing tissue, say the researchers, the new approach to rejuvenating degenerating muscle does not involve any ethical and medical complications linked with transplanting tissues grown from embryonic stem cells.
"We are one step closer to having a point of intervention where we can rejuvenate the body's own stem cells so we don't have to suffer from some of the debilitating diseases associated with aging," Nature magazine quoted the study's lead author Morgan Carlson, a recent Ph.D. graduate of Conboy's lab, as saying.
During the course of study, the research team focused on the interplay of two competing molecular pathways that control the stem cells, which sit next to the mature, differentiated cells that make up our working body parts.
The researchers point out that the stem cells are called into action to begin the process of rebuilding as and when the mature cells are damaged or wear out.
"We don't realize it, but as we grow our bodies are constantly being remodelled. We are constantly falling apart, but we don't notice it much when we're young because we're always being restored. As we age, our stem cells are prevented, through chemical signals, from doing their jobs," said Conboy.
The researchers say that one significant observation made during the study was that the stem cells in old tissue were still ready, and able to perform their regenerative function if given the appropriate chemical signals.
According to them, studies have shown that the stem cells start behaving as if they are young when old tissue is placed in an environment of young blood.
"Conversely, we have found in a study published last year that even young stem cells rapidly age when placed among blood and tissue from old mice," said Carlson, who will stay on at UC Berkeley to expand his work on stem cell engineering either as a QB3 fellow or a postdoctoral researcher.
A research article reveals that adult stem cells have a receptor called Notch that tells them that it is time to grow and divide, and a receptor for the protein TGF-beta that sets off a chain reaction activating the molecule pSmad3 and ultimately producing cyclin-dependent kinase (CDK) inhibitors, which regulate the cell's ability to divide.
"Interestingly, activated Notch competes with activated pSmad3 for binding to the regulatory regions of the same CDK inhibitors in the stem cell. We found that Notch is capable of physically kicking off pSmad3 from the promoters for the CDK inhibitors within the stem cell's nucleus, which tells us that a precise manipulation of the balance of these pathways would allow the ability to control stem cell responses," said Conboy.
She claimed that her team was the first to connect Notch and TGF-beta to the process of ageing, and to show that they act in opposition to each other within the nucleus of the adult stem cell.
The researcher revealed that ageing and the inevitable march towards death were partly due to the progressive decline of Notch and the increased levels of TGF-beta, producing a one-two punch to the stem cell's capacity to effectively rebuild the body.
"What we discovered is the interplay between two pathways - one an aging pathway, and the other a youthful pathway," said Conboy.
With a view to determining what would happen if the adult stem cells in old tissues were blocked from reacting to the TGF-beta signals, the researchers compared the muscle regeneration capacity of 2-year-old mice, comparable in age to a 75 to 80-year-old human, with that of 2-month-old mice, similar in age to a 20- to 25-year-old human.
For a group of the old mice, the researchers disabled the "aging pathway" that tells stem cells to stop dividing by using an established method of RNA interference that reduced levels of pSmad3.
The muscle of the different groups of mice were then examined one to five days after injury, in order to compare how well the tissue repaired itself.
It was observed that muscle tissue in the young mice easily replaced damaged cells with new healthy cells, and in contrast, the areas of damaged muscle in the control group of old mice were characterized by fibroblasts and scar tissue.
However, muscles in the old mice whose stem cell "aging pathway" had been dampened showed levels of cellular regeneration that were comparable to their much younger peers, and that were 3 to 4 times greater than those of the group of "untreated" old mice.
Conboy warns that shutting down the TGF-beta/pSmad3 pathway altogether by turning off the gene that controls it might lead to many health problems.
"When we are young, there is an optimal balance between Notch and TGF-beta. We need to find out what the levels of these chemicals are in the young so we can calibrate the system when we're older. If we can do that, we could rejuvenate tissue repair for a very long time," said Conboy
She even cautioned that her team's research should not be interpreted as the cure-all for ageing.
"We're not at a point where we're ready to inject ourselves with TGF-beta antibodies and call it a day. There are multiple mechanisms involved in how our body functions. We know that TGF-beta is involved in one aspect of aging, but we don't know where it fits in the global scheme of aging," said Carlson.