There have recently been scientific articles about using stem cell therapy for “anti-aging” treatments. There has been buzz lately on the internet and in the press about the use of stem cell therapy for “anti-aging purposes”. This is something we have been involved with for some time now.
Even before the days of Ponce de Leon mankind has been intrigued the quest for true age reversal. Recently, there has been some buzz from the University of Miami. A study under the direction of Dr. Joshua Hare. Dr. Hare and his group recently published a study in the Journals of Gerontology. An editorial in the journal stated the following
“MSC transplantation is a promising and innovative approach for the treatment of frailty in older humans" and "stem cells might be the vehicles for youthful regeneration of aged tissues." What the Hare group did was to obtain bone marrow derived mesenchymal stem cells from young healthy volunteers. They then grew the cells in a lab increasing their numbers and gave the cells back to older individuals. So far, the studies have shown significant improvement in some aging perimeters. These cells that are transplanted are called allogenic cells meaning they are from a different patient. We have to commend Dr. Hare and his group for doing this study and advancing the world of stem cell science. Having been involved in the stem cell world for some time now I have seen similar findings.
Although I am not condoning it, mesenchymal stem cells have been used for years as an IV preparation. Typically, these were the patient’s own stem cells usually obtained from the breakdown of fat by an enzyme. Under current standards this practice is not allowed by the FDA. Patients would report improvement in a number of afflictions especially pulmonary problems. However, the evidence was mainly anecdotal. From a scientific point of view this may have occurred from the release of various growth factors. Taking it one step further, giving cells from a younger patient probably is beneficial in that the cells may have better vitality and more growth factors. But there is one big BUT here. We must realize that when we are using allogenic stem cells these are not immune privileged but they are immune evasive. Eventually the body will catch them and destroy them. Will this make a difference? No one can say for sure. I suspect a good arm of the study might be to use the patient’s own stem cells, expand them and give them back to the patient. Will we get the same results as a transfusion from a young patient? Another, intriguing aspect might be to use cells derived from a first or second degree relative. Also, do we want to use some of the plasma from the younger patient?
The next question to ask is if the mesenchymal stem cell is the best cell to reverse frailty? We know that our immune system is intimately related to the hematopoietic stem cell line, mesenchymal stem cells are also very important in immunity. Which cell would be the most important? We don’t know. However, expanding hematopoietic stem cells is a much more difficult task than expanding mesenchymal stem cells. Another question to ask if we have to expand stem cells? I suspect that antiaging treatments may be related to using an increased number of stem cells. One concern of mine is that we know when mesenchymal stem cell populations are expanded they seem to lose some of their immune modulatory aspects. Is this a problem? Perhaps it might be better to expand the number of stem cells while they are in the body. In another word, let the body increase the number of cells. We are aware that there does exist methods to expand cell numbers while they are still in the body. Furthermore, this does not run afoul of the FDA. There are some medications such as Neupogen that can do this. But Neupogen is expensive and can carry serious risks. Some safer methods include laser stimulation, certain supplements, hyperbaric oxygen and its offshoots. Will these techniques work better? Only studies will show. The other question to pose is if it would be better to use bone marrow aspirate intravenously. Bone marrow aspirate can be rich in a type of cell called a T-Reg cell. T Reg cells have a very important control in our immune system. They help to eliminate autoimmune diseases.
About a year or two ago there was some buzz about transfusing blood plasma from young rats to old rats. The results were very promising. The researchers found that the old mice had a reversal of many of the aging processes especially in the brain. The researchers found a protein in the blood of the young mice called GDF11. In this case we are not just slowing down the clock but we are actually turning it backward. There is controversy concerning the GDF11 protein. This is not universally accepted by the scientific community. Some studies showed it very beneficial while other studies showed no benefit or actually a negative benefit. I can confidently say the jury is still out on GDF11.
We have been involved in some antiaging/fragility studies in our office. These studies involve an “early” CD-133 stem cell. This cell is obtained from the patient after stimulation of the marrow with a few different supplements including intravenous CoQ-10. These cells are processed and activated in a propriety fashion and given back to the patient intravenously. We have seen improvements on a number of different levels. This stem cell is sometimes called a V cell or very small embryonic like stem cell. However, a “v cell” is not yet universally accepted in the scientific community. If we think of them as a primitive CD-133 than there is more acceptance.
These very small stem cells are thought to be capable of forming almost any type of tissue. For this reason, these cells are called pluripotent. As I have eluded to in other blogs these cells may be considered the body’s emergency stem cell supply. They also seem to be implicated in acupuncture. These cells are found in something called Bonghan Channels which are intimately related to acupuncture. The problem with the V cells is that they are normally difficult to activate. However, thinking out of the box researchers have devised ways of turning these cells back on. These are the patient’s own cells. The methods of turning them back on are proprietary. We have had the good fortune of working with these unique cells with some excellent results. The tantalizing question is if these cells can be harvested from a son or daughter or grandchild and given back to an older related adult. There is no reason why they cannot be used.
There are some other methods which will slow down aging. We know for sure that starvation will extend life but we are not sure about age reversal but it looks promising. It appears to turn on the surtuin 1 gene. Stimulating this gene may increase stem cell survival and ultimately our own survival. There are many supplements that we know may at least help slow down aging. Some of these include derivatives of beets, broccoli, and a host of other compounds. It appears that these compounds have a distinct effect on stem cells. These supplements can affect the stem cells in many different ways. They may affect the stem cell environment or as it is also called the stem cell niche. If the environment is hostile than the stem cell has a much less chance of success. Those supplements that effect the niche are many times considered antioxidants. The job of the antioxidants is to neutralize the effect of what is commonly called free radicals. These free radicals occur when the body utilizes either oxygen or nitrogen. We are beginning to realize that Nitric Oxide is extremely important to many body functions. Nitric oxide is now known to be a growth, immune, and neuromodulator, as well as a stimulator of stem cell proliferation.
I am certain that stem cells will having an increasing importance in our quest to slow down aging and allow us to age gracefully without the trappings of aging. I think we need to remember that it will not be the stem cells alone but other aspects that will have a direct impact upon them. Hopefully one day we can make the hands of father time’s clock to start running backward or at least more slowly. Dr. P
Lubricin is naturally found in our body as part of the synovial fluid, the viscous substance that cushions and lubricates our joints. The above diagram is a quick synopsis of the effect of Lubricin on osteoarthritis. As we can see a lack of Lubricin will contribute to the formation of osteoarthritis. Lubricin is crucial to allow the two adjacent portions of a joint to glide on one another with minimal friction. It can be called the body’s Teflon system only it works much better than Teflon. Like many good things lubricin is lost over time due to the ravages of aging, injury and exercises. With the loss of lubricin the joint will become painful, stiff and cause the patient discomfort. When the patient reaches this stage, we try to use our tools that are available to us with Regenerative Medicine procedures. A heathier joint will hopefully have Lubricin production back in the mold. We must remember that Lubricin production not only decreases the painful symptoms of degenerative arthritis but also helps control the progression of the disease. Ultimately, this is what we try to accomplish with regenerative procedures. Now if we can combine Lubricin production with a regenerative stem cell procedure we may achieve better overall success.
Let us take a better look at the science of Lubricin. Lubricin is a surface-active glycoprotein secreted in a synovial joint. It plays an important role in cartilage integrity. In healthy joints, Lubricin molecules coat the cartilage surface providing boundary lubrication thus preventing cell and protein adhesion. Lubricin (also known as superficial zone proteoglycan SZP), is a protein expressed by superficial zone chondrocytes and is involved in lubrication of the articular cartilage surface, and also prevents deposits and degeneration of the cartilage and boundaries of the joint. It is the most lubricating and anti-adhesive molecule in the human body. Lubricin biosynthesis and bio distribution are mostly regulated by cytokines and growth factors. These are the same factors produced by stem cells and other cells. Exposure of synoviocytes, chondrocytes and cartilage implants to pro-inflammatory cytokines such as interleukin-1(IL-1) and tumor necrosis factor-alpha (TNF), results in a marked reduction in the expression and/or abundance of secreted lubricin, with corresponding alterations in the amounts of cartilage-associated lubricin. Conversely, exposure to transforming growth factor-beta(TGF-Beta) significantly upregulates lubricin synthesis, secretion and cartilage boundary association. Of course, we must take these results with a grain of salt since they are studies performed in the lab rather than an actual real-life situation. In the field of Regenerative Medicine what happens in the lab does not always translate to real life situations. My suspicions are that these two situations will correlate with each other.
Lubricin plays an important role in joint physiology, and the loss of accumulation of lubricin may be a factor in the pathology of osteoarthritis. There have been some studies in mice where an arthritic condition was created and there were two treatment groups. The conclusion was as follows: supplemental intra-articular Lubricin reduced cartilage damage in the ACL transected rat knee 6 weeks after injury, while treatment with Hyaluronic acid did not. It was found that when the rats were treated with some growth factors which reduce inflammation and increase Lubricin formation than the damage was much lower to the joint in the long run. When people are thinking about joint lubrication they typically think of Hyaluronic acid. These two compounds are not the same. Hyaluronic acid is typically given as a shot to people who have osteoarthritis. It is approved by most insurance companies. It works fairly well in improving symptoms on a temporary basis.
In the case of Lubricin it is the load-bearing and non-load-bearing zones of the joint that give direction and regulation of certain growth factors (cytokines). The effect of certain compounds can have very interesting effects. For example, TGF1(Transforming Growth Factor-1) and heparin will bind and regulate the protein on the load- bearing zone in only 1 out of five times compared to simple saline. In most cases, TGF actually reduces binding of lubricin on the joint and inhibited SZP protein expression compared to saline or to the actual injection of lubricin. Same scenario for heparin. Let us take a better look at this. Heparin is used “to thin out” the blood and in Regenerative Medicine, it is utilized to prevent the coagulation of the platelets in PRP formulations and in Bone Marrow aspirations. So right off the bat if heparin is used than there may be some stimulation of Lubricin. We use heparin in all of our bone marrow aspirates. Now I realize that heparin may stimulate Lubricin production in the joint.
One of the most surprising things I have learned about Lubricin is the effect that saline has on its production. Saline is salt water
(sodium chloride) with the same concentration as our blood. We have found that saline with some other propriety components has a rapid and dramatic effect on the production of Lubricin in the joint. Using saline in a joint, especially a large volume, will stimulate the Superficial Zone Protein (also called Lubricin.) Adding certain cytokines to the mix will help neutralize inflammatory cytokines and further expand the production of lubricin. However, we have found the saline alone has a rather significant effect on the joint. This goes back to something I learned in doing thousands of arthroscopies. When we did arthroscopic surgery on an older person who had arthritis they initially felt better but the improvement did not last. What I realize what we were doing is that we were stimulating the formation of Lubricin. Using saline in a joint, especially a large volume as we do, will stimulate the Superficial Zone Protein (also called Lubricin.) This is a protein that is encoded with proteoglycan 4 (often mistakenly called PRG4) so basically your saline lubricates the joint. At one time, we considered saline a placebo but studies have now shown that saline is a therapeutic agent. Adding AIL-1 and IL-10 in specific ratios will neutralize the inflammatory cytokines and expand our lubricating and preparatory treatment. Joint motion increases the production of lubricin. That's why activity—specifically, exercises for joint mobility is so crucial to maintaining joint health and managing arthritic pain.
A research group from Cornell Univ (Bonassar et al) has discovered that Lubricin helps anchor Hyaluronic acid to the tissue surface. This in turn moves the cartilage in to a low friction regime. A quote from Dr. Bonasser “The implication of this finding is that the efficacy of HA treatment might depend on how much lubricin is in the joint at the time of injection, which could explain why clinical trials of HA have such variable outcomes and may also suggest new formulations of HA that might be even more effective in the clinic,”. Another intriguing twist is the possibility of using the arthrolavage with saline and the growth factors and then treat the patient with Hyaluronic acid. By first increasing Lubricin production we can increase the effectiveness of Hyaluronic acid injections into the joint. There are now studies to produce Lubricin in the lab. This process is called a recombinant DNA product. This means that many time the product is made by bio-engineered bacteria. Lubricin is just one of many new ideas that are arising in the field of Regenerative Medicine as it pertains to joint arthritis. It appears that it may be a good helper to stem cells.
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