The above diagram shows just a portion of the symptoms that some patients who are recovering from Covid-19 infection are manifesting. They present with these symptoms long after they have tested negative for the covid-19 virus. These are a group of patients that are now given the name Covid Long Haulers.
I have written a few articles on some methods that may help prevent patients from becoming infected with the Covid-19 virus. These recommendations include a number of supplements such as Zinc, vitamins C, D, and melatonin . Also, lifestyle changes such as weight loss and exercise may also help. These recommendations are based on science. BUT WE MUST REALIZE THAT THESE ARE JUST RECOMMENDATIONS AND NOT TO BE TAKEN AS THE GOSPEL TRUTH. THEY HAVE NOT BEEN BASED ON RIGOROUS SCEINTIFIC STUDIES. They are based on clinical hunches and observations. The new question is what might we offer those patients who have had a Covid infection and they continue to be symptomatic. We see some of the manifestations below. These seem to be the most common post Covid symptoms.
Patients having long lasting symptoms after a viral infection are not new. This has been seen in the past with Ebola, and the first SARS virus in the early 2000s. Both viruses gave rise to long-lasting symptoms after some people recovered. A 2009 study in Hong Kong found that psychiatric problems and chronic fatigue still plagued SARS-1 survivors up to four years later. People who completely recover from an Ebola infection can still suffer from fatigue, headaches, muscle, joint and stomach pain, eye problems, memory and hearing loss, and mental health issues. The Ebola virus can persist in their bodies, including in the eyes and the central nervous system, even after being cleared from the rest of the body.
Covid Long Haulers, recovering patients whose symptoms persist after their coronavirus infections disappear, are a mix of younger people who never needed hospital care and older people with chronic conditions that predate Covid. Their symptoms trail the infection’s path through their lungs, hearts, muscles, nerves, and brains. Deadening fatigue can dog them for weeks or months. Sometimes their problems wane, then resurface in a stuttering pattern that leaves them wondering if they’ll ever get over the condition. Long-haulers include two groups of people affected by the virus. Those who experience some permanent damage to their lungs, heart, kidneys, or brain that may affect their ability to function. While the second group continue to experience debilitating symptoms despite no detectable damage to these organs. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, has speculated that many in the second group will develop a condition called myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS can be triggered by other infectious illnesses such as mononucleosis, Lyme disease, and severe acute respiratory syndrome (SARS), another coronavirus disease.
WHAT MAY BE THE ETIOLOGY OF THE LONG HAULER SET OF SYMPTOMS?
This may be due to an immune-inflammatory response gone amok, or perhaps to ongoing viral activity that might not be clinically detectable. The etiologies are almost certainly multifactorial, but may involve overzealous immune responses, cardiopulmonary or systemic inflammation, vascular inflammation or clotting disorders, and direct damage from viral replication during acute illness.
COVID-19 often strikes the lungs first, but it is not simply a respiratory disease, and in many people, the lungs are not the worst-affected organ. In part, that’s because cells in many different locations harbor the ACE2 receptor which is the virus’s major target. However, the infection can harm the immune system, which pervades the whole body. ACE2 is a protein on the surface of many cell types. It is an enzyme that generates small proteins by cutting up the larger protein angiotensinogen that then go on to regulate functions in the cell. The following diagram gives an idea of the ACE 2
receptors and their relationship to Covid 19.
Some people who have recovered from COVID-19 could be left with a weakened immune system. Many other viruses are thought to do this. It has been suggested that people who have been infected with measles are immunosuppressed for an extended period and are vulnerable to other infections. This may or may not be case for COVID-19. SARS, for instance, is known to decrease immune-system activity by reducing the production of signaling molecules called interferons. The real problem most long haulers are facing is what is stated earlier by the concept from Dr. Fauci. Many post Covid patients may develop a chronic fatigue syndrome (CFS). CFS, is considered an immune-mediated disorder. It has long been considered a "mystery illness," but that viewpoint is becoming dated. Now it is becoming evident that in CFS there are roles of both of inflammation and autoimmunity. Inflammation is part of a healthy response to problems in the body. When inflammation becomes chronic due to ongoing damage or a misfiring immune system, then you've got a problem. Autoimmunity is when the immune system mistakenly identifies a part of your body as a foreign invader, treating it much like a virus, it needs to get rid of. Your own body triggers its inflammatory process and sends specialized cells to destroy the target and begin the healing process. Only with autoimmunity, the healing process creates more of whatever body part your immune system doesn't like, so it continues to attack and heal and attack in a vicious fashion. The process continues indefinitely. Autoimmunity is a specific type of immune-system dysfunction, but it's important to note that not all immune-system dysfunction is autoimmunity. If we look at the diagram below we see that the symptoms of the Covid Long Haulers and those patients with CFS very much overlap I could substitute the name Covid Long Haulers for CFS.
Thus, one big clue in treating patients with Post Covid syndrome is treat them as we would treat Chronic Fatigue Patients. It seems that patients with the Post Covid syndrome and those who have CFS have many similarities. Both conditions seem to have increased levels of cytokine growth factors such as Interleukin 1 and Tumor Necrosis Factor which cause inflammation. This diagram gives a better picture of the relationship to inflammatory growth factors and the Covid Long Haulers.
Thus, it seems that the evidence is overwhelming as far as inflammatory growth factors being associated with post Covid symptoms. It would seem logical if we diminish inflammation we can diminish many of the symptoms of the Post Covid Long Haulers.
WHAT IS THE ANECDOTAL EVIDENCE WE LOOKED AT FOR COVID LONG HAULERS?
When we looked at the clinical results of some of our post Covid patients it seemed that when attempts were made at reducing inflammation the patients’ health improved. Again, these are anecdotal observations but they are what we observed nevertheless. When we look at the playbook for treating CFS it seems that it might be adaptable to treating the Post Covid Syndrome Long Haulers. We are trying to reduce inflammation in the body
WHAT MIGHT BE OF BENEFIT IN TREATING THESE PATIENTS AND WHAT SEEMED TO WORK?
First off, we think intravenous NAD would be a be a great help. NAD will improve the health of the mitochondria. NAD provides the mitochondria with the necessary tools to produce more ATP which is the cells energy currency. NAD has a significant effect on the Sirtuin pathways in the body. These pathways are intimately involved with longevity and health. There are a number of reports that the body is somewhat depleted of NAD levels after dealing with an infection. The diagram below gives good idea of the importance of the Sirtuin pathway. Influencing the Sirtuin pathway in a positive manner is certainly a step in the right direction in improving the health of the Long Haulers.
NAD certainly has its value but we must remember one important fact. NAD will make senescent cells flourish which is not something we want in a patient who is trying to recover. Remember senescent cells are those cells that should have died but did not. They unfortunately can cause multiple problems in the body such as secreting the inflammatory growth factors. Senescent cells are one of the reasons why Covid-19 seems to be more unforgiving in the elderly. As we age, we accumulate more and more senescent cells. None the less, in the Post Covid long haulers we want to eliminate a portion of the senescent cells. For our general health we still need some senescent cells but we wish to diminish their numbers. This is accomplished by the use of what are called senolytic agents. One of these agents is Quercetin. There are also some other ones which will be of benefit.
INFLAMMATION IN LONG HAULERS
We still have the problem of post infection inflammation. There is no simple solution for turning off inflammation. However, by utilizing and taking advantage of the pathways in the body we are aware of methods to reduce inflammation. The body and its cells are like the hardware of a computer and the pathways are the computer software. In this case we are interested in stimulating the NRF2 pathway software. The Nrf2 pathway is the thermostat of anti-inflammation. Get this pathway activated and inflammation is diminished.
The NRF2 is the software which stimulates the computer hardware namely the genes in the cells which than produce compounds. The above diagram shows the NRF2 pathway in action. What the NRF2 pathway does is produce reduce inflammation in the body. One very good method of doing this is thru the EBO2 protocol. This is a protocol which uses a dialysis filter and blood ozonation at the same time. By using the blood ozonation certain “Ozone Messengers” are created in the body and they appear to have a direct positive effect on the NRF2 pathway. The NRF2 pathway will help stimulate various compounds which will reduce inflammation. Remember that the NRF2 pathway is the computer software, it causes certain genes to turn on and produce certain compounds which dramatically reduce inflammation. We will also be utilizing a supplement that we specifically designed to stimulate the NRF2 pathway.
Another medication that may be of benefit in reducing inflammation in long haulers is a medication called Low Dose Naltrexone (LDN). Naltrexone was approved by the FDA in the USA for the treatment of opioid addiction. For our purposes the dosage we will utilize in long haulers will be much smaller than that used for addiction problems. Naltrexone is an antagonist for the opiate/endorphin receptors. Endorphins are polypeptides made by the pituitary gland and central nervous system to moderate the production of neurotransmitters, such as serotonin and dopamine. Endorphins primarily help to reduce pain and inflammation, promote autophagy, and cellular clean up. For instance, when one gets a high after exercising it is typically from the release of endorphins. In individuals with diagnoses such as depression, fibromyalgia, cognitive degeneration, and autoimmunity we are consistently finding chronically low levels of endorphins. Specifically, low levels of an endorphin called Opioid Growth Factor (OGF). OGF is an endorphin produced in most cells in the body to both influence and regulate cell growth, as well as immunity. When low levels of OGF endorphins exist, it is likely for individuals to develop immune system disorders. Low Dose Naltrexone (LDN) has been shown to increase OGF levels in the body, resulting in positive outcomes for those suffering from a variety of diagnoses.
The following diagram gives an idea of how Naltrexone can accomplish its goals. The diagram shows that reducing certain cytokine growth factors will reduce inflammation. We must be cognizant of the fact that these effects of Naltrexone only occur with the low doses. The lower doses are blocking the activation of certain immune cells. This is accomplished by blocking receptors on the cell surface with low doses.
How does LDN work? LDN first binds to opioid receptors which are found on the surface of the cell. In doing so, it helps to displace the body’s naturally produced OGF. As LDN displaces OGF receptors, affected cells become OGF-deficient and, as a result, three vital processes occur. The first is an increased receptor trying to capture more OGF. Secondly, receptor sensitivity is increased to capture more OGF. Lastly, production of OGF is increased to compensate for the perceived shortage of OGF. Since LDN will only block OGF receptors for three to five hours, the body experiences a rebound effect which greatly increases the production and utilization of OGF. Once the LDN has fallen off the OGF receptors and excreted, the increased number of endorphins bind to the now more-sensitive and more-plentiful receptors. As a result, these new and improved receptors assist in regulating cell growth, promoting healing, reducing inflammation, and increasing immunity and autophagy. This is accomplished by utilizing a low dose of Naltrexone per day.
This is exactly what we are looking for in treating Chronic Inflammation syndrome and Post Covid Syndrome. This is accomplished by utilizing a low dose of Naltrexone per day. We must realize that the Naltrexone must be used only in a low dose. A higher dose will have will not work and will cause the Naltrexone not to work.
One other treatment protocol that seems to have efficacy is the use of a very small embryonic like stem cell, many times referred to as a V cell. V cells are found in each of us. There are some propriety methods of stimulating their numbers and activation. They seem to have some far-ranging effects on various systems in the body. We have utilized these cells for years with great results.
I looked at some of the Post Covid patients that we have treated in our clinic and analyzed what worked well for them. The bottom line is what is our approach in treating Covid Long Hauler patients? THE ANSWER IS REDUCING INFLAMMATION!!
We feel that NAD will be instrumental in treating these patients. This will initially be done with a loading intravenous dose followed by oral doses. We will employ some propriety methods to increase NAD efficiency. The NAD will stimulate the Sirtuin pathways which have multiple desirous effects. We will also treat the patients with senolytic agents to keep senescent cells at bay.
We will also incorporate some other intravenous formulas which will help boost immunity and at the same time help fight inflammation.
The EBO2 protocol will help to stimulate the NRF2 pathway and hopefully diminish inflammation.
Use of some supplements which will help stimulate the NRF2 pathway, the immune system, and well-being.
Utilize low dose Naltrexone. We will utilize a low dose as has been described in the literature. The idea is to again reduce inflammation.
Finally, we will utilize some growth factor transdermal patches. These patches have some potent cytokine growth factors. One is called Interleukin 10 and the other is called Interleukin 1 antagonist. I call Interleukin 10 “cortisone with no baggage”.
V-cell from the patient which will be beneficial on multiple levels.
RIGHT OFF THE BAT, HOWEVER, LET ME GIVE THE DISCLAIMER THAT THIS ARTICLE DOES NOT CONSTITUTE MEDICAL ADVICE -- ONLY MEDICAL HYPOTHESIS. THESE STATEMENTS HAVE NOT BEEN EVALUATED BY THE FDA. They are based on some of our observations and a review of science that is found in the literature. Before embarking on any treatments, one must consult a physician.
The above diagram shows the controversy concerning IGF-1. IGF-1 is both a Dr. Jekyll and Mr. Hyde when it comes to our well-being and longevity. On one hand we see that the IGF-1 axis encourages development, growth, and injury repair. This can give the appearance of vitality and youth. However, appearances can be deceiving. IGF-1 can set the wheels in motion to increase aging by such blocking autophagy and stress resistance and increasing Reactive Oxygen species. These are three of the major hallmarks and causes of aging.
WHAT IS AGING?
Aging is defined as a physiological decline of biological functions in the body with a progressive decline or loss of adaptation to internal and external damage. In humans aging is extremely heterogeneous and can be described as a complex mosaic resulting from the interaction of several random and environmental events. These include both genetic and epigenetic alterations accumulated throughout our lifetime. Despite its enormous complexity, the molecular basis of aging is limited to few highly evolutionarily conserved biological mechanisms responsible for body maintenance and repair.
WHAT IS THE RELATIONSHIP BETWEEN HGH AND IGF-1/INSULIN AXIS?
The above diagram shows the intimate relationship between HGH (Human Growth Hormone) and IGF-1. Typically, Growth Hormone is released by the Pituitary gland. One major role of growth hormone in stimulating body growth is to stimulate the liver and other tissues to secrete IGF-I. IGF-I stimulates proliferation of various tissues including chondrocytes (cartilage cells), muscles cells, and bone cells resulting in bone growth. If one takes an external source of HGH it will have to be converted in the liver to IGF-1.
The metabolic effects of HGH are, in part, mediated through IGF-1 produced in the liver and in the peripheral tissues influenced by HGH. Change in the GH/IGF-1 can possibly be influenced through amino acid supplementation. Specific amino acids—such as arginine, lysine, and ornithine—can stimulate HGH release when infused intravenously or administered orally. It has also been demonstrated that glycine is also one of the stimulatory agents inducing the pituitary gland to secrete HGH. These are all important amino acids utilized in the growth of tissue cause by HGH.
Research shows that one’s metabolism slows down with age. A few reasons for this include less physical activity (exercise), muscle loss (sarcopenia), and the normal aging of the organs. Additionally, loss in lean body mass and muscle tissue can be detrimental when it comes to ill adults. Yet HGH/IGF-1 have major effects on metabolism. It has been shown that HGH’s potential benefits relate to protein metabolism. Many of the functions of HGH are facilitated through IGF-1. Administration of HGH induces a rise in circulating IGF-1 that stimulates glucose and amino acid uptake in muscle, which improves muscle protein synthesis. In catabolic circumstances, the levels of IGF-1 decrease while its binding proteins increase, leading to a lower local IGF-1 activity and contributing to the decreased insulin sensitivity seen in catabolism. Here is another summation of the HGH AND IGF-1 relationship. The bottom line is that IGF-1 will repair and rejuvenate various cells including muscle, bone, and other tissues. The question becomes at what price does IGF-1 accomplish cellular repair and rejuvenation? Also is there a difference between IGF-1 produced naturally and that stimulated by external means?
AND NOW FOR THE CONTROVERSY: DOES IGF-1 DECREASE LONGEVITY?
This illustration is a great one. It shows one of the great risks of IGF-1. We see the many benefits that can be attributed to the IGF-1 but on the other side of the scale we see one big risk namely an increased cancer risk. But this scale is deceptive because if we were to also add the problem of increased cell growth causing decreased longevity the scales would probably be opposite. Remember that IGF-1 causes cell growth. It can act as a gasoline on a fire when it comes to cell growth. This is where the problem lies. Can IGF-1 increase the growth of a few cancer cells to essentially activate them? No one knows the answer to this question. On the other hand, another school of thought professes that the IGF-1 will strengthen the immune system and prevent cancers. Ultimately it is our immune system which prevents us from developing cancer. So which concept is the correct concept??
The question still comes up what is the relationship between IGF-1 and longevity. What is the mechanism? Why does decreasing growth hormone and IGF-1 signaling increase lifespan when it has such an important role in reviving muscle and brain function? One explanation is the thought that curtailing IGF-1 levels increase the expression of other genes that are involved in stress resistance, particularly oxidative damage. Oxidative damage, which is generated everyday through a variety of mechanisms including toxins in the environment, UV radiation, normal metabolism which puts wear and tear on every tissue in our body and on our DNA. If we can boost the activity of anti-oxidant genes that help stave off this damage, then we should be able to delay the deterioration of our tissues and our DNA, thus extending longevity. The very first illustration in this blog shows that IGF-1 will increase oxidative stress. This increased oxidative stress causes increased aging. The chart below also explains this. We can see the intimate relationship growth hormone signals and longevity.
The above chart demonstrates the dichotomy of IGF-1 and longevity. What do we know for sure that will increase longevity? One quick answer is calorie restriction or some form of it. Typically, the faster the cell growth the more various problems will pop up. Calorie restriction will slow down the pace of cell growth. During the last 3 decades one of the most discussed topics in gerontology is the role of the growth hormone (GH)/insulin-like growth factor-1(IGF-1) in the regulation of longevity. Accumulating evidence suggests that this pathway plays an essential role in the pathogenesis of several age-related diseases including cancer, dementia, cardiovascular, and metabolic diseases. More research is needed in this field.
In animal models it was shown that down-regulation of the GH/IGF-1/insulin system significantly prolongs the lifespan. However, in humans the data is contradictory. While it is well known that enhanced insulin sensitivity and low insulin levels are associated with an improved survival, there is evidence showing that attenuation of the growth hormone/IGF-1 axis may have beneficial effects in extending lifespan in humans. However, it is still unknown which are the optimal IGF-1 levels during life to live longer and healthier. How much do these levels change with age? In addition, IGF-1 receptor sensitivity and activation of the post receptor pathway were not evaluated in the majority of the study enrolling long-lived subjects. Therefore, it is not possible to define the real activation status of the IGF-1 receptor signaling through the mere dosage of circulating IGF-1 levels. This renders more difficult the identification of pharmacological or environmental strategies targeting this system for extending lifespan and promoting healthy aging which we call healthspan.
Nonetheless, striking similarities have been described concerning the endocrine profile between centenarians and subjects after a calorie-restricted diet. The following diagrams shows some of these reasons. The endocrine and metabolic adaptation observed in both models may be a strategy to increase life span through a slower cell growing/metabolism, a slower loss of physiologic reserve capacity, a shift of cellular metabolism from cell proliferation to repair activities and a decrease in accumulation of senescent cells. These mechanisms seem to be, at least in part, mediated through the modulation of the GH/IGF-1/insulin system. The following diagram easily explains this phenomenon.
What it boils down to is the fact that IGF-1 will stimulate certain pathways which will stimulate pro-growth and survival but at the same time they will lead to aging due to a variety of effects. IGF-1 activates the Akt pathway, which is a downstream activator of mTOR, both of which are the master regulators of cellular growth and inhibitors of programmed cell death in the body. These are nutrient sensing pathways in the body. These pathways typically oppose longevity.
The IGF-1 pathway will lead to further oxidative stress. While decreased amounts of IGF-1 will lead to the expression of stress resistance genes such as superoxide dismutase. Thus, it stands to reason if we can increase the production of various antioxidant response enzymes than these effects of IGF-1 can be ameliorated. One method of doing this is to increase the stimulation of the NRF2 pathway. Remember that the NRF2 pathway is the thermostat of anti-inflammation in the body.
In the above diagram we see how IGF-1 stimulates the NFkB pathway. NFkB pathway is the major pathway of inflammation. If you stimulate it you stimulate aging. While the antioxidant compounds will force things to go in the opposite direction. These compounds will help put the brakes on aging. They will help to stimulate the NRF2 pathway. This pathway is a gateway to anti-inflammation and health.
WHAT IS THE RIGHT ANSWER? SHOULD WE TAKE ADDITIONAL HGH/IGF-1 AND OTHER PEPTIDES TO LIVE LONGER OR WILL IT SHORTEN OUR LIVES?
It’s a trade-off when it comes to growth hormone/ IGF-1 and the effects they have on the body. We know they enhance muscle, neuronal, and bone growth while simultaneously preventing atrophy. At the same time, they will increase oxidative stress in the body leading to a speeding up of aging. They will also increase telomer shortening leading to potential aging. Which do you prefer, having better muscle and cognitive performance or living longer? Or better yet can we have our cake and eat it too? Are we able to get the absolute benefits of IGF-1 while at the same time not cutting short our lives?
While it is well known that enhanced insulin sensitivity and low insulin levels are associated with an improved survival, there is evidence showing that attenuation of growth hormone/IGF-1 axis may have beneficial effects in extending lifespan in humans. However, tricky question here to which the answer is unknown is what are the optimal IGF-1 levels during life to live longer and healthier. IGF-1 is double-edged when it comes to our health, with the potential to provide much benefit or harm: too little, and we do not develop properly, we lose muscle mass, bone strength diminishes, and our cognition declines as we age; too much, and our cells can grow out of control, leading to cancer and potentially, premature aging. Balancing IGF-1 is a delicate process which is on a delicate scale. What are some of the methods to balance this scale? Is there a difference in the actions of IGF-1 when it is naturally stimulated in the body? It seems that high intensity exercise will increase IGF-1 but at the same time not necessarily diminish longevity. There appear to be some built in mechanism that gives the benefits of IGF-1 without the usual hit on longevity. The following diagram shows this concept.
The question beckons what about those patients who wish to take supplemental peptides of IGF-1 etc to increase its effects?
Why does decreasing growth hormone and IGF-1 signaling increase lifespan when it has such an important role in muscle and brain function. As was mentioned earlier, IGF-1 and its cohorts tend to increase oxidative stress. Thus, it seems like a no brainer if we employ methods which will increase the expression of genes that are involved in oxidative stress resistance, particularly oxidative damage, we may get the benefits of IGF-1 without the fall off in longevity. One of the best methods to accomplish this goal is to utilize the EBO2 protocol. This protocol involves blood filtration and direct ozonation of the blood. Blood ozonation will produce intermediate metabolites which will markedly stimulate the NRF2 pathway. This pathway can put a strangle hold on inflammation in the body. The EBO2 protocol will produce potent anti-oxidants enzymes. THIS IS A VERY IMPORTANT TREATMENT FOR THOSE PATIENTS WHO WILL SUPPLEMENT THEIR IGF-1 LEVELS BY TAKING ADDITIONAL PEPTIDES ETC. EBO2 MAY BE THE SAVING GRACE FOR PATIENTS TAKING SUPPLEMENTAL IGF-1. The next illustration shows a portion of the EBO2 protocol.
There are some other lifestyle factors that can also boost the expression of stress resistant genes without the downsides to low levels of growth hormone and IGF-1. This is called hormesis. Hormesis refers to the beneficial effects of a treatment that at a higher intensity is harmful. In one form of hormesis, sublethal exposure to stressors induces a response that results in stress resistance. The principle of stress-response hormesis is increasingly finding application in studies of aging, where hormetic increases in life span have been seen in several animal models. The “hermetic effect” is actually the mechanism of action of many catechins and polyphenols that are often mislabeled as antioxidants.
Catechins and polyphenols are found in: Green tea, Blueberries and other purple-pigmented fruits/vegetables, Dark Chocolate, Wine, Turmeric. Catechins and polyphenols on their own have no ability to “scavenge “free” radicals like classic anti-oxidants such as vitamins C and E. Rather, they are a little toxic to our cells and thus induce a “hormetic response” by increasing the expression of anti-oxidant genes, and this is why they are put into the category of anti-oxidants. The next illustration shows the benefits of Hormesis. Again, the key here is stress resistance genes.
The IGF-1 pathway is one pathway which will in the future be involved in much research. Manipulating this pathway may lead to many dividends. There is no question of the benefits of IGF-1 etc in increasing our healthspan. There is also no question that these same compounds may diminish our lifespan. We may increase life span through a slower cell growing/metabolism, a slower loss of physiologic reserve capacity, a shift of cellular metabolism from cell proliferation to repair activities and a decrease in accumulation of senescent cells. These mechanisms seem to be, at least in part, mediated through the modulation of the growth hormone/IGF-1/insulin system. We feel that if we modulate the stress resistance genes to produce potent anti-oxidant enzymes we are getting very close to achieving that delicate balance between health span and longevity. If you are taking IGF-1 or a variety of its stimulating peptides and not addressing oxidative stress etc. such as we have mentioned, you are gambling with your longevity.
NF- kB is a central regulator in stress response. The NF- kB signaling pathway can be activated by numerous stimuli as listed in the blue boxes:
In response to these different stimuli NF- kB transcriptionally regulates hundreds of genes, the generalized categories of which are listed in the red circles.
NF-kB is a short name of Nuclear Factor kappa-light-chain-enhancer of activated B cells. It is not a single protein, but a small family of inducible transcription factors that play an important role in almost all mammalian cells. As a common responder to varied stress stimuli, NF-kB is well positioned to play a key role in driving aging. NF-kB has been directly implicated in the aging process. Many biologic pathways implicated in aging, including immune responses, cell senescence, apoptosis, genotoxins (a genotoxin is a chemical or agent that can cause DNA or chromosomal damage), oxidative stresses, cell cycle progression, and inflammation all stimulate the NF-kB family of transcription factors. Transcription factors are proteins that help turn specific genes "on" or "off" by binding to nearby DNA. The function of transcription factors is to regulate or turn on and off genes. It is very important that transcription factors make sure that the genes are expressed in the right cell at the right time and in the right amount throughout the life of the cell and the organism.
NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-kB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-kB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection and improper immune development. For instance, the Covid-19 virus seems to have an affinity for activating the NF-kB causing potentially a cytokine storm and dire consequences.
Damage to cellular macromolecules and organelles is thought to be a driving force behind aging and associated degenerative changes. However, stress response pathways activated by this damage may also contribute to aging. The IKK/NF-κB signaling pathway has been proposed to be one of the key mediators of aging. It is activated by a variety of factors as mentioned above. Transcriptional activity of NF-κB is increased in a variety of tissues with aging and is associated with numerous age-related degenerative diseases including Alzheimer’s, diabetes and osteoporosis.
Pro-growth survival pathways known to promote aging, specifically Insulin/IGF-1 and mTOR are known to stimulate NF-κB. Insulin/IGF-1 act via two mechanisms, AKT and mTOR signaling, to activate NF-κB. However, through AKT, Insulin/IGF-1 signaling also interacts with known longevity processes by inhibiting FOXO. longevity factors such as SIRT and CR, FOXO inhibits NF-κB signaling. Stress/damage pathways known promote age-associated changes including genotoxic stress, ROS, and inflammation also activate NF-κB. NF-κB then acts to promote aging related changes by contributing to cellular senescence, SASP, apoptotic signals and inflammatory responses.
The preceding diagram gives some idea as to the relationship between the NF-kB pathway and aging. One is able to see the relationship between many different pathways in the body and the NF-kB pathway. Interestingly, some of the pathways seem to be opposed to each other. For instance, the pro-growth and survival pathways seem to be opposed to the longevity pathways. The pro-growth pathways are nutrient sensing pathways. They favor cell growth and survival but not necessarily longevity. This is where we start getting some controversy in Anti-Aging medicine. There seems to be a perception that HGH, better known as Human Growth Hormone, is a fountain of youth. This concept is cloaked in controversy. Indeed, HGH can reverse some aspects of aging BUT, AND THIS IS A BIG BUT, this will also stimulate NF-kB which is associated with aging. On the other hand, caloric restriction and the Sirtuin pathways will block NF-kB and thus block aging. For those of you who wish to take a regimen of HGH you may want to think twice about it. However, research shows if HGH is increased naturally (intensive exercise etc.) than NF-kB may not be stimulated in the same manner and aging not encouraged. We also see that stimulation of mTOR will encourage NFkB and possible increased aging. In the above diagram we also see that the AKT pathway (another nutrient sensing pathway) will encourage NFkB activation by disabling the FOXO pathway which is an important longevity pathway. We must remember that not every aspect of the NFkB pathway is negative. It can be important in infections and general stimulation of the immune system.
HOW DOES NF-kB PATHWAY GET ACTIVATED?
The above diagram shows what is called the Canonical NF-kB signaling pathway. NF-kB signaling is initiated when a cytokine growth factor receptor (PRR) recognizes its cytokine, starting a signaling cascade (1) that converges on the phosphorylation of the IKK2 complex. IKK2 then phosphorylates IκBα (2), leading to NF-kB activation and (3) subsequent degradation by the proteasome of some of the NF-kB components. This releases NF-κB (the two green colors) from negative regulation while they are in the cytoplasm. (4) allows the NF-kB dimers to translocate to the nucleus to (5) initiate inflammatory gene transcription. (6) De novo synthesis of IκBα acts as a negative regulator of NF-κB-dependent transcription, limiting inflammation in the absence of further signaling events. (7) Primary response genes include those encoding cytokines such as TNF. (8) Release of these proteins leads to autocrine signaling through cytokine receptors. This, or (9) continued PRR ligation, create a positive feedback loop wherein NF-κB is periodically activated until these signals are eliminated.
This is a somewhat complicated picture of how NF-kB works. The important thing to remember is that when the NF-kB is in the cytoplasm of the cell it is essentially inactive. Remember it is a transcription factor and thus it must move into the nucleus and stimulate the DNA to start its work. When it gets stimulated to move into the nucleus it starts to turn on certain inflammatory genes to produce biological compounds called cytokines etc. The following diagram is complicated yet it is not as complicated as we might think. What we see here is receptors for two master inflammatory growth factors namely IL-1 and TNF. These two growth factors are responsible for a variety of conditions including osteoarthritis, cancer and a host of other diseases. What we need to know on this diagram is that these inflammatory growth factors ultimately stimulate NF-kB. We must also realize that these growth factors can also help to stimulate an immune response in the face of an infection.
Pro-growth survival pathways known to promote aging, specifically Insulin/IGF-1 and mTOR are known to stimulate NF-κB. Insulin/IGF-1 act via two mechanisms, AKT and mTOR signaling, to activate NF-κB. However, through AKT, Insulin/IGF-1 signaling also interacts with known longevity processes by inhibiting FOXO. longevity factors such as SIRT and CR, FOXO inhibits NF-κB signaling.
Stress/damage pathways known promote age-associated changes including genotoxic stress, ROS, and inflammation also activate NF-κB. NF-κB then acts to promote aging related changes by contributing to cellular senescence, SASP, apoptotic signals and inflammatory responses.
In the above diagram we are able to see that two main inflammatory cytokines namely IL-1 and TNF are picked up by the cell surface receptors and stimulate the release of NF-kB from the cytoplasm when it goes into the nucleus stimulating the production of inflammatory agents.
BESIDES CAUSING AGING WHAT ELSE DOES NF-kB DO? SOME GOOD THINGS
The above diagram shows the many faces of NF-kB. Inflammation in cells and tissues has a common pathway: activation of nuclear factor kappa B (NF-kB). “Nuclear” in this case refers to the nucleus of the cell, where chromosomes carry genetic information that influences NF-kB. When NF-kB gene expression signals move into a cell’s nucleus, it activates pro-inflammatory signals called cytokines. These cytokines travel through the circulatory system to trigger inflammatory changes in tissues everywhere in the body.
Inflammation promotes diseases through an array of biochemical pathways. Inflammation has even been shown to shorten telomeres (nucleotide sequences at the ends of chromosomes). When telomeres shorten, cells eventually stop functioning, directly contributing to shortened cellular lifespans. What we also see in the above diagram is the fact that NF-kB will also influence the type of macrophages in the “neighborhood”. It is responsible to produce type 1 macrophages. Type 1 macrophages are very important in fighting infections. While a type 2 macrophages are important in tissue regeneration. It also appears that NF-kB may have a similar effect on the polarization of mesenchymal stem cells (MSCs). Like macrophages, there are two types of MSCs namely type 1 and type 2. Type 1 is very efficient in fighting infections while type 2 is important in tissue regeneration. NF-kB will cause the polarization of MSCs to the type 1.
What is also very important in this diagram is the fact that NF-kB is intimately involved with various aspects of the immune system. NF-κB is a master regulator of innate immune responses, and vital to many of the roles that macrophages and other innate immune cells play in orchestrating the inflammatory response to pathogens. It can help extend the cell life of various cells of the immune system by inhabiting apoptosis. Considered broadly, immune responses can be divided into innate and adaptive responses. The immune response begins with the host recognizing the presence of foreign pathogens, followed by responses at the cellular, tissue and organismal levels, that ultimately lead to the clearance of the pathogen. As such, immune responses can be broken down into individual signal transduction events through which changes in the extracellular environment elicit altered gene expression at the cellular level. In many instances, NF-κB is the transcription factor that mediates these transcriptional changes. The gene products characteristic of early events in immune responses include cytokines and other soluble factors that propagate and elaborate the initial recognition event. The activation and modulation of NF-kB is also a common target of these factors. Thus, in a surprising number of situations NF-kB mediates the critical changes that are characteristic of innate and adaptive immune responses. This has significant implications in the management of the Covid-19 virus.
THE ROLE OF THE NFKB PATHWAY IN MECHANOTRANSDUCTION
Apart from its prominent role in immune response regulation, NF-kB is also identified as a mediator of mechanotransduction in several cell types. Mechanotransduction refers to the processes through which cells sense and respond to mechanical stimuli by converting them to biochemical signals that elicit specific cellular responses. This role is carried out through changes in both its activation, and localization, in response to mechanical signals. Altered cytoskeleton dynamics of a cell, for example, will activate NF-κB. A good example of this is osteoarthritis as is noted above.
WE CAN NOT LIVE WITHOUT NF-kB
Given the enormous number of genes activated by NF-kB and the diverse modes of signaling that impinge upon these transcription factors, there remains much to learn. As can be seen there are a number of roles for the NF-kB pathway. In the past years NF-κB dynamics emerged as key regulators of cell life and death. This family of transcription factors, which in healthy tissues controls tissue homeostasis, responds to external stimuli and coordinates cell growth and differentiation, is often deregulated in cancer cells. Most of these pathways are bad in that they cause inflammation in the body. However, the effects of the NF-kB on our immune system especially in times for a bacterial or viral invader can be lifesaving.
There are a host of supplements that seem to have significant effects of the NF-kB pathway. One which comes to mind is Curcumin. A variety of supplements seem to be the very effective in blocking the stimulation of the NF-kB pathway.