Osteoporosis is a disease that weakens bones to the point where they break easily—most often, bones in the hip, spine, and wrist. Osteoporosis is called a “silent disease” because you may not notice any changes until a bone breaks. All the while, though, your bones had been losing strength for many years. Some risk factors for osteoporosis such as being older and female or having a family history of the condition cannot be avoided. But others can, like smoking cigarettes, consuming alcohol, taking certain medications, or being exposed to environmental pollutants. But until now researchers haven't gained a firm picture of how these exposures link up with bone loss. But now the fog is begging to lift. We now know that these environmental hazards seem to affect a very important of genes called the Sirtuin genes which ultimately affect the mitochondria.
Recently, in my reading I discovered some very interesting articles. It now appears the one of the main causes of
Osteoporosis may be damage to mitochondria. The mitochondria are the powerhouses of the cells. They help produce energy of the cell in the form of ATP. We are now aware that many of the diseases of aging are related to mitochondria damage and degeneration. The following is a diagram of the mitochondria and its relationship to the rest of the cell.
It seems that when mitochondria are damaged it will lead to a surge in a cell type called an osteoclast. An Osteoclasts is a cell that nibbles at and breaks down bone and is responsible for bone resorption. Recent animal studies indicate that longevity-associated Sirtuin genes (especially the SIRT1 gene) may serve as an attractive pharmacological target for the treatment of osteoporosis and other bone related disorders. Now let us talk a bit about the Sirtuin genes of which SIRT1 is a very important member.
The Sirtuin genes are also called the longevity genes. There are seven of these genes which are intimately involved in mitochondrial health and numbers. They have a profound effect on many of the different aging pathways in the body. One extremely important fact is that they seem to influence mitochondrial health and numbers. Healthier and increased numbers of mitochondria ultimately lead to more ATP production. Furthermore, we are now aware of the fact that mitochondria do many other tasks other than producing ATP. They may act as signaling beacons directing different cells to different tasks.
A new study led by researchers from Penn's School of Veterinary Medicine reveals a mechanism by which Sirtuin factors and osteoporosis may be linked. Damage to mitochondria—key cellular organelles and energy generators—leads to a surge in the creation of cells called osteoclasts, which are responsible for breaking down bone. The researchers reported these findings in the FASEB journal (Federation of American Societies for Experimental Biology). Here is a quote from the paper “ In a normal individual, the process of bone degradation and rebuilding proceeds in a very balanced way, but in some people they somehow produce a lot more osteoclasts, and this leads to bone loss and osteoporosis," said Narayan Avadhani, a biochemist at Penn Vet and senior author on the work. "We show in this paper that, when mitochondrial function is affected, it not only affects energy production but also triggers a type of stress signaling that induces the overproduction of osteoclasts.”
This is consistent with other findings that mitochondria are involved in much more than energy production. For instance, we know that mitochondria can be involved in neurogenesis signaling. The paper goes on to say that affecting mitochondrial function will trigger a type of stress signaling that induces the overproduction of osteoclasts which are the cells that nibble away on the bone.
It appears that the mitochondria effect a certain type of immune cell called a macrophage. Macrophages are a front line for the immune system, engulfing and digesting foreign invaders to the body. Macrophages are very important cells of the immune system. They have the ability of morph into many different types of cells. Depending upon their environment they can cause tissues to heal or encourage the breakdown of tissue. Macrophages can diversify and transform into osteoclasts when the circumstances are right. This research was performed at Mount Sinai School of Medicine. In this study when the mitochondria were damaged the macrophages underwent stress signaling and transformed into osteoclasts at a much faster rate. We now see that relationship between environmental factors and Osteoporosis may be related to mitochondrial damage.
There are other studies which show a distinct relationship between the Sirtuin genes and Osteoporosis. This makes complete sense given the fact that the Sirtuins and Mitochondria are intimately related. WHAT TIES EVERYTHING TOGETHER? NAD! NAD stands for nicotinamide adenine dinucleotide. It is a potent stimulator of the Sirtuin genes especially SirT1. The diagram below is an excellent illustration of this relationship. We want to block the bone eating osteoclasts and encourage the bone building osteoblasts.
Another good example of this phenomenon is the following illustration of a human thigh bone.
In this diagram we see what seems to cause bone formation by the stimulation of Osteoblasts (CR stands for Calorie Restriction). An agonist is a compound that encourages action. Some of the agonists of the SIRT1 genes include Resveratrol, Pterostilbene, and a host of other phytonutrients. We can also see that calorie restriction and the Keto diet should also have a beneficial effect on osteoporosis. I would like to show an article published this month on just what we are talking about. Here is a picture of the front page of the article
This article is one of many ground-breaking articles. It appears that compounds that target the SIRT1 gene (THINK NAD etc.) may be new SAFE WEAPONS in the war on Osteoporosis. A similar study from the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences confirmed the same findings. Their conclusion “Our findings suggested the potential therapeutic role of resveratrol in osteoporosis treatment and stressed the importance of effective doses when applied”.
We are now aware that NAD+ is a game changer on many different levels but there is good scientific evidence that it can have a profound effect on Osteoporosis. One step we are already doing for osteoporosis is using peripheral blood stem cells and cytokine therapy to help improve osteoporosis.
But wait there is one more aspect in our treatment protocol. This is the aspect of Senescent cells. These are cells that should have died but continue to survive. They cause havoc on the body by their secretion of various “bad growth factors.
In the above diagram SC stands for a senescent cell. A senolytic is a compound that kills the senescent cells. More can be found about these cells at my recent blog https://stemcellorthopedic.com/possible-new-way-treating-osteoarthritis-senolytic-agents/).
Mayo Clinic researchers in Rochester, Minnesota, have found that targeting senescent cells led to an increase in bone mass and strength. The findings, titled “Targeting cellular senescence prevents age-related bone loss in mice” appear online in the August 21, 2017 edition of Nature Medicine. Here is a paragraph from their work:
"While we know from previous work that the accumulation of senescent cells causes tissue dysfunction, the role of cell senescence in osteoporosis up to this point has been unclear," says Sundeep Khosla, M.D., director of the Aging Bone and Muscle program at Mayo Clinic's Robert and Arlene Kogod Center on Aging and a co-author on the study, in the August 21, 2017 news release.
"The novelty of this work for the bone field lies in the fact that, rather than targeting a bone-specific pathway, as is the case for all current treatments for osteoporosis, we targeted a fundamental aging process that has the potential to improve not only bone mass, but also alleviate other age-related conditions”.
I think the above paragraphs are the essence of our approach in targeting Osteoporosis. We are targeting the UPSTREAM AGING EVENTS which lead to Osteoporosis. I believe our approach is totally unique and unlike any other program in the world. Our approach is multi-fold:
Targeting of senescent cells
Using peripheral blood stem cells which have been shown to give improvements in Osteoporosis
Utilizing initially IV loading doses of NAD+ with the NAD Kinase patches and then maintaining NAD levels with oral formulations which are typically higher doses than usually recommended.
Utilizing various supplements which also target the Sirtuin genes.
Proper diet and exercise also are important.
This regimen is unique and at the same time seems to have an excellent safety profile especially when looking at the side effects of various Osteoporosis medicines. Furthermore, this regimen also has significant anti-aging benefits.
- Dr. P
I think we need to look at senescent cells in a bit more depth.I have written about Senescent cells in the past. I have been aware of senolytic agents for a few years now. Actually, I wrote a blog about this back in 2017 which can be found here (https://stemcellorthopedic.com/possible-new-way-treating-osteoarthritis-senolytic-agents/). I am convinced that senolytic agents will help change the face of regenerative medicine and for that matter most of medicine. More importantly they will dramatically increase success in Regenerative procedures. Let us again discuss senescent cells. These are cells that should have died but did not. There are a number of studies in the field of osteoarthritis and its relationship to senescent cells. Eliminating a portion of these cells may produce significant results! Osteoarthritis is but one disease of aging. There seems to be great promise of senolytic agents in combating degenerative conditions. The following diagram gives us an idea of the damage that these cells can cause.
I found an excellent diagram from a site called CellAge
This diagram hits upon the highlights of senescent cells. The essence is that they are producing growth factors that are causing havoc on other neighboring cells.
In the preceding diagram we get a true appreciation of clinical significance of Senescent cells. Once they reach the senescent stage they stop replicating but continue to survive. In the above diagram we see initially the cells have some sort of trigger which causes them to switch to senescence. Once they are in the senescence mode bad things begin to happen. These cells begin to send out signaling molecules called cytokines. These cytokines have far reaching effects. Under normal circumstances the cells of the immune system will attack the senescent cells and destroy them. Actually, these cells will also stimulate a process called Autophagy. Autophagy is an important aging pathway in the body. It is the method that the body will recycle various cellular parts into new cells. Autophagy by itself has significant ramifications in anti-aging and overall health. Eliminating the senescent cells will stimulate autophagy in the right circumstances.
Unfortunately, many times the senescent cells escape detection, they increase in numbers and become like terrorists in our body. They will cause havoc to other cells. Senescent cells look very different from healthy cells. They express different genes, they are prohibited from reproducing or dividing naturally, and they pump out inflammatory “SOS” signals in an attempt to recruit other healthy cells to come to their rescue, usually in vain. These signals include proinflammatory cytokines, chemokines, proteases (enzymes that break down proteins) and other factors that together make up what is called the senescence-associated secretory phenotype (SASP). The inflammation created by senescent cells can lead to tissue dysfunction and even turn healthy cells senescent, like a zombie virus that spreads and eventually causes the zombie apocalypse of late-life frailty and disease. This spreading of cellular senescence may even happen at a distance, with senescent cells in one tissue, like fat, spreading senescence-causing inflammatory signals to cells in another tissue, like muscle. This is why a pendulous belly can be so detrimental to our health.
The agents that go after senescent cells are called a senolytic agents. The breakdown of the word senolytic is as follows: seno refers senescent cells while lytic refers to lysis which means to rupture the cell. So, a senolytic agent is one that kills the senescent cell.
One exciting aspect of our treatment protocols is employing the use of P-53 protein transdermal patch. P-53 in our body is a very potent senolytic agent. unfortunately, it sometimes undergoes a mutation and loses its effectiveness leading to some big problems such as cancers. Another name for the P-53 is “the tumor suppressor gene”. P-53, unlike other agents, can actually repair the cell under the right circumstances. It will analyze the cell and proceed with DNA repair if the damage is not too great. However, if the P-53 determines that the DNA damage is too great it will disable the cell and cause it to go on to death. The P-53 is beneficial in ferreting out senescent cells that may lead to cancers. Unfortunately, as we age the P-53 may undergo mutation and lose its effectiveness. This loss of effectiveness may lead to the development of a cancer. The following diagram shows the P-53 agent in action.
More information on P-53 can be found in a recent blog
The P-53 patch is quite revolutionary. It is definitely part of our armamentarium in our anti-aging. We have had excellent success with the P-53 patches. However, not wanting to rest on our laurels we want to take the treatment of senescent cells down a second road to use in conjunction with the P-53 transdermal patch.
The next diagram shows senolytic agents in action. We can see when the senescent cells accumulate they wreak havoc causing cancer, aging, osteoporosis, osteoarthritis and a host of other degenerative diseases.
We can definitely see the benefits when the senescent cells are cleared away. We also see that the immune system is instrumental in clearing away the senescent cells. It stands to reason that clearing away these cells will lead to anti-aging and most likely better success in Regenerative Medicine which employs stem cells and other regenerative cells. Senescent cells, however, are not all bad, and evidence shows that they play a role in cellular reprogramming and wound healing. Like all things in biology, it is therefore clearly a question of balance: too much clearance of senescent cells would be bad for wound healing and cellular reprogramming, but too many senescent cells lead to damage.
I would like to present a short article that was recently published concerning the use of Senolytic agents, in this case, in pulmonary disease.
Small Pilot Study Points to Feasibility of Larger Trials in Age-Related Diseases
Senolytics target cellular senescence, a process in which damaged cells, rather than dying, persist and become toxic to cells around them. Cellular senescence has been shown to drive multiple age-related diseases, including idiopathic pulmonary fibrosis (IPF), a chronic, irreversible and progressive disease that results in scarring of the lungs. In animal studies, run by Mayo Clinic collaborators James Kirkland, M.D., Ph.D.; Nathan LeBrasseur, Ph.D., M.S., and Tamara Tchkonia, Ph.D., senolytics selectively cleared these toxic cells in mice that model IPF.
A Lethal Disease for Which There are Few Options
"IPF is a devastating and progressive fibrotic lung disease with a median survival of less than five years in newly diagnosed adults usually over 60 years of age," said Anoop M. Nambiar, M.D., M.S., associate professor of medicine at UT Health San Antonio and founding director of the university's Interstitial Lung Disease Program, one of 60 Pulmonary Fibrosis Foundation Care Centers in the United States. Dr. Nambiar is co-first author of the research manuscript and enrolled 12 of the patients at UT Health San Antonio and the South Texas Veterans Health Care System.
Despite the current availability of two U.S. Food and Drug Administration-approved therapies that may slow down disease progression in some IPF patients, the prognosis remains poor and is worse than for many common cancers, Dr. Nambiar said. Lung transplantation may be lifesaving, but often is only an option for younger, healthier patients. "There remains a significant unmet need for safer and better treatments for patients with IPF," Dr. Nambiar said.
Patients Enrolled in Texas, North Carolina
In this first-in-human pilot study, the investigators enrolled 14 older adults diagnosed with stable, primarily mild-to-moderate IPF. Participants were enrolled at both UT Health San Antonio, which served as the primary patient recruitment site, and Wake Forest medical school, which initiated the trial and served as the study coordinating center. "Though small, this pilot study marks a major breakthrough in how we treat age-related diseases such as IPF," said Jamie Justice, Ph.D., assistant professor at Wake Forest medical school, co-lead investigator and corresponding study author. "Here, we've therapeutically targeted a fundamental biological hallmark of aging that is implicated in IPF, and we show early but promising results for the first time in human patients. This small study represents a major paradigm shift in treatment strategy."
Each participant received two senolytic drugs, dasatinib and quercetin (DQ), taken by mouth for three consecutive days each week for three consecutive weeks (nine doses total). All patients were able to comply with this regimen without any discontinuation of the study drugs.
The research team measured clinical laboratory chemistries before and after DQ administration, and performed rigorous symptom questionnaires weekly of health, quality of life and side effects to obtain preliminary evidence of safety and tolerability. The team also evaluated markers of physical function including six-minute walk distance, walking speed, sitting-to-standing repetitions, a frailty index based on clinical laboratory chemistries, and biological assays of senescence-associated proteins secreted by the toxic cells.
The most consistent improvements following senolytic therapy were observed in participants' mobility. The six-minute walk test, timed sitting-to-standing repetitions and other measures were significantly improved after completion of the treatment. The majority of patients exhibited mobility gains of greater than 5 percent. Other physical function markers, including grip strength and pulmonary function testing, did not change.
"No drug therapies, including the available anti-fibrotic drugs, have ever shown to stabilize, let alone improve, an IPF patient's six-minute walk distance," Dr. Nambiar said. "But in this pilot study of DQ, participants' six-minute walk distance improved an average of 21.5 meters.
"We should be cautious about whether this finding is true based upon this small study without a placebo control group," Dr. Nambiar said. "However, this and other results warrant further study in larger randomized, controlled trials."
Preliminary but Encouraging
"Cellular senescence is clearly emerging as a main player in aging," said manuscript co-author Nicolas Musi, M.D., professor of medicine at UT Health San Antonio and director of the university's Sam and Ann Barshop Institute for Longevity and Aging Studies. "Previously, no published data existed to demonstrate that drugs targeting cellular senescence could be safely given to older patients, or that they might be used to treat diseases of aging such as IPF. The pilot research we've reported is preliminary but encouraging."
Dasatinib and quercetin are U.S. FDA-approved for other indications. Moreover, they are effective in eliminating senescent cells originating from different cell types.
"This is the same combination of drugs that was shown to improve pathology in animal models of Alzheimer's disease, which our group, including Dr. Miranda Orr at UT Health San Antonio, demonstrated three months ago for the first time," Dr. Musi said.
Side Effects Did Not Discontinue the Treatment
The most frequent side effects reported after DQ therapy were mild to moderate in severity, including respiratory symptoms such as cough and shortness of breath, and gastrointestinal discomfort or heartburn. Some patients reported skin irritation or bruising related to tissue biopsies obtained for biological measurement purposes.
Limitations and Goals
This pilot study has obvious limitations. First, it was small (14 patients), and substantially larger numbers of research participants are needed to definitively evaluate change in biological markers of cellular senescence. In addition, the study did not enroll a control group of IPF patients who took a placebo rather than the senolytic. "Therefore, any improvements in physical function should be interpreted with caution and require further study," Dr. Nambiar said.
Materials provided by University of Texas Health Science Center at San Antonio. Note: Content may be edited for style and length.
What we gather from this note is that senolytic agents seem to have a very beneficial effect on the senescent cells. Which in turn effects the patient’s health. We should realize that this benefit most likely carries over to all types of senescent cells.
Here is the significance this has on clinical practice. Very few if any doctors, clinics etc are addressing senescent cells. I suspect a good bit of the problem is they are not acutely aware of them and their significance. THIS WILL BE THE NEXT BIG ASPECT OF REGENERATIVE MEDICINE. We are already entrenched in treating senescent cells. We have been utilizing the P-53 patches on some of our patients. Now we are going to take the next step. We have found a source of Quercetin which was fairly easy. The difficult aspect was to find a source of Dasatinib. Luckily, we were successful in this regard. The last piece of the puzzle was figuring out the protocol for dosage regimen. We have now put a very unique protocol together utilizing the P-53 patches, Quercetin and Dasatinib. Typically, the treatment regimen will be one dosage a week for either two or three weeks. Taking senolytic agents for a long period of time can have a detrimental effect on the body. It could actually speed up aging if not done properly. Hence a regimen of only 2 or 3 per year.
Senolytic therapy has not only demonstrated profound rejuvenating properties by itself, but may also help open up opportunities for other rejuvenation strategies to be more effective. It is but one step in our anti-aging protocols. When used with some of our other regimens we feel we have one of the most unique Regenerative and Anti-aging programs around. With time I am sure other progressive clinics will catch on to the topics of senolytic agents.
- Dr. P