“The Immunity Fix: Strengthen Your Immune System, Fight Off Infections, Reverse Chronic Disease and Live a Healthier Life” is a book by James DiNicolantonio, Pharm.D., with whom Ico wrote “Super Fuel,” and Siim Land, an esteemed biohacker and author of “Metabolic Autophagy.”
Basics of the Immune System
In it, they explore the question of how to improve and regulate immunity – a topic that should be at the top of everyone’s list these days. The catalyst for this collaboration was a series of scientific papers by DiNicolantonio on why some people have poorer COVID-19 scores.
Many who become severely ill produce low levels of type 1 interferon. In addition, their adaptive immune system is weakened. As a result, they cannot clear the virus quickly and must rely instead on a more pro-inflammatory killing of the virus in their cells.
As a refresher, your immune system consists of two primary “arms”:
- The innate immune system, which is your first line of defense and consists of natural killer (NK) cells, macrophages, and white blood cells such as neutrophils
- The adaptive immune system – T cells and B cells that produce antibodies
As DiNicolantonio explains:
We used to think that the adaptive immune system was a system that took a while to work, and that once you were immune through the adaptive immune system, you had longer-term protection, which is true. However, the adaptive immune system also seems to be cross-sensitive, meaning that if you have been exposed to previous coronaviruses, your T cells seem to have some cross-sensitivity to SARS-COV-2.
We used to think that the adaptive immune system was a system that took a while to work, and that once you were immune through the adaptive immune system, you had longer-term protection, which is true. However, the adaptive immune system also seems to be cross-sensitive, so if you’ve been exposed to previous coronaviruses, your T cells seem to have some cross-sensitivity to SARS-COV-2.
So what we see is essentially a decrease in T cells, in the cytotoxicity of these CD8 T killer cells that kill viruses in a nice, apoptotic, controlled way.
When those kinds of immune cells decrease, you have to rely more on the pro-inflammatory innate immune system to clear viruses – so neutrophils, white blood cells and macrophages. They kill in a much more pro-inflammatory, non-specific way and eventually kill healthy, uninvolved cells as well.
We assume that there is essentially a reduction in type 1 interferons, which interfere with the virus. And at the same time, there is a reduction in B and T cells. So the bottom line is that the virus is not cleared as quickly, and there is pro-inflammatory killing.
Siim and I worked together because these things are very complex. We need to make this understandable to the layperson. Our book is about how diet and lifestyle affect these things, and that there are things you can do to support your own immune system.
T-cell function tends to decline with age. It is also decreased in people with chronic diseases. Decreased T-cell function appears to be a major cause of severe COVID-19, because the worst COVID-19 scores are in older people and/or people with comorbidities such as diabetes, hypertension, metabolic syndrome, and cardiovascular disease.
These factors exacerbate the proinflammatory response emanating from SARS-CoV-2, but also weaken immunity in general. “The Immunity Fix” presents lifestyle strategies to help you circumvent and prevent this pro-inflammatory response. “It’s a very holistic approach to looking at the immune system,” Land says.
The two Most Important Nutrient Deficiencies
Diet and supplementation are two important strategies that can help strengthen the immune system. According to Land and DiNicolantonio, vitamin D may be the most important nutrient in this regard. Vitamin D activates more than 2,000 genes, including vitamin K-dependent proteins and repair genes, according to DiNicolantonio. It also helps the body produce potent antimicrobial and antiviral peptides.
People over the age of 60 are nine times more likely to die from COVID-19 than younger people. If you have severe vitamin D deficiency, the risk can be as much as 15-fold higher. So while you can’t change your age, you can certainly change your vitamin D status and potentially minimize your risk.
However, to convert vitamin D to its active form, you need magnesium, so magnesium is probably the second most important nutrient deficiency that should be addressed. Magnesium is also needed for immune cell function. So if your magnesium levels are low, your immune function could be compromised.
People with a genetic magnesium deficiency in their natural killer (NK) cells and their CD8 T killer cells … their immune system is weakened. They have chronic activation of Epstein-Barr, which 95% of us are infected with, and they have a much higher risk of lymphoma, DiNicolantonio says.
And that’s just one nutrient. A deficiency of just one nutrient can essentially cause this immune deficiency. So in the book, we go into how nutrients and the immune system interact and why nutrient deficiencies likely lead to many of these poor COVID-19 results.
Zinc and Selenium are also Important
In terms of importance, zinc would probably rank third. Taking zinc lozenges at the first onset of cold symptoms has been shown to shorten the duration of the cold by six to seven days, but you have to take them properly.
If you use lozenges, you need to take them every two hours,” DiNicolantonio explains. “You have to take it within 24 hours of the onset of symptoms. You have to take about 18 milligrams per dose, and your total daily dose has to be over 75 milligrams.
Fourth on the list is selenium. Selenium deficiency is not only associated with a fivefold higher risk of dying from COVID-19 and a threefold higher risk of having a poor COVID-19 outcome, but also with coxsackievirus-induced cardiomyopathy (Keshan disease).
With selenium deficiency, a non-virulent RNA virus called coxsackievirus, which normally causes hand-foot-and-mouth syndrome only in certain children, can become much more virulent and lead to viral-induced cardiomyopathy. Patients with this cardiomyopathy, called Keshan disease, usually receive selenium. Selenium is also important for the production of glutathione, which appears to play an important role in COVID-19.
The importance of Melatonin
Another factor associated with improved COVID-19 outcomes is melatonin. DiNicolantonio explains:
Melatonin is interesting. I think of it as a kind of molecular hydrogen, but with some added benefits. Melatonin can enter any cell membrane unhindered, so that’s very important. If you want to get at oxidative stress, you have to be able to get at it and get into the mitochondria. Melatonin and molecular hydrogen are two molecules that can do that, and do it really well….
Melatonin is not just a hormone that we secrete in the brain. We synthesize it from serotonin, and it can be produced in many cells. So it’s active throughout the day. Interestingly, it is one of the only molecules that seems to increase transcription of Nrf2.
Most plant polyphenols and all these other Nrf2 boosters only inhibit the Nrf2 inhibitor KEAP1. Essentially, they make the current Nrf2 levels more active. When you add melatonin, it increases the transcription of Nrf2. Very few molecules can actually do that.
And Nrf2 is the means by which we boost our body’s antioxidant enzymes. That’s really the key. If you’re suffering from acute respiratory distress, you should strengthen your entire body’s antioxidant system, and the best way to do that is with Nrf2 activators, especially melatonin.
High-dose Melatonin lowers COVID-19 Mortality
In terms of dosing, a recent case series of 10 patients with COVID-19-related pneumonia administered 36 to 72 mg of oral melatonin per day in four divided doses, well above recommendations for sleep. DiNicolantonio comments:
It’s so safe. Doses of melatonin up to 1,000 mg per day have shown virtually no side effects in humans, except for fatigue and drowsiness … Taking melatonin is associated with an 83% reduction in COVID-19 mortality, a 30-50% reduction in positive tests for SARS-COV-2, and in a case series of 10 COVID pneumonia patients, it shortened the length of hospital stay by five days.
None of the patients who received melatonin needed to be placed on a ventilator or died, whereas in similarly severe COVID-19 cases hospitalized at the same time, 25% to 40% of those patients were placed on a ventilator or died.
As DiNicolantonio explains, melatonin is actively produced throughout the day and is a major antioxidant, meaning it scavenges free radicals. It also binds to melatonin receptors, which upregulate the innate antioxidant defense system.
Melatonin actually seems to concentrate in the bone marrow, and that’s important because our immune system is made up of stem cells that are formed in the bone marrow, DiNicolantonio explains.
These stem cells give rise to immune cells. Some of your immune cells can even produce melatonin. We believe it’s concentrated in the bone marrow to protect immature stem cells and immune cells from oxidative damage, which actually makes a lot of sense.
Nebulized Hydrogen Peroxide
Land and DiNicolantonio hypothesized that inhalation of molecular hydrogen at a concentration of 2% or 3% might be an important strategy in COVID-19 patients requiring hospital ventilation, but it can be very expensive. I think a better alternative would be nebulized hydrogen peroxide that can be used at home. This is my personal strategy, and I have seen many recover from COVID-19 with this strategy. You can watch my video below for a more detailed explanation.
Nebulizing hydrogen peroxide into the sinuses, throat and lungs is a simple, straightforward way to increase the body’s production of hydrogen peroxide to fight infections and support the immune system.
All you need is a tabletop nebulizer, food-grade hydrogen peroxide and some saline solution. That way, you have everything you need and can start treating at home at the first sign of a respiratory infection. Remember that food-grade hydrogen peroxide must be diluted to 0.1% before use.
I believe that the hydrogen peroxide acts like a signaling molecule and may even have a direct virus-killing effect on the cells in the lining of the lungs and sinuses where the virus initially attaches. So you may be killing the virus directly and supporting your immune defenses at the same time.
In addition to addressing nutrient deficiencies, particularly vitamin D, magnesium, zinc and selenium, Land stresses the importance of optimizing the health of your metabolism.
Research has shown that metabolic syndrome, obesity and diabetes, all of these factors, worsen the consequences of COVID-19 and other infections such as influenza. Obesity also increases the length of time you can carry the virus and pass it on. So it’s particularly negative in a society that tends to have poor metabolic health.
An interesting discovery we made while writing the book is that one of the molecules that is activated during infection is called HMGB1, which stands for High Mobility Box-1.
This molecule is activated during infection and is one of the key molecules that balances the cytokine storm by activating NFKB and the NLRP3 inflammasome and ultimately triggering this massive pro-inflammatory cytokine response …
Based on this research, we theorized that hyperglycemia, insulin resistance, and elevated blood glucose make it more likely that HMGB1 will enter the cell and activate NFKB and these other proinflammatory cytokines that eventually lead to the cytokine storm.
The case for a low Linoleic Acid Diet
DiNicolantonio and I discussed the importance of avoiding seed oils in our book Superfuel. In it, we took an in-depth look at the importance of healthy fats for metabolic health and the destructive nature of linoleic acid-rich vegetable oils.
Linoleic acid (LA) is one of the most perishable molecules in food, meaning it is highly susceptible to damage. When it oxidizes, it turns into oxidative metabolites called oxidative linoleic acid metabolites or oxylipids or OXLAMs, which damage proteins, DNA, and cell membranes and are likely the main cause of chronic disease.
OXLAMs also activate signaling pathways that destroy immune defenses. What we didn’t know at the time was that even healthy oils like olive oil can have negative effects thanks to their LA content. LA content is also high in conventionally raised chickens, as these animals are usually fed LA-rich grains.
If you consume more than 10 grams of LA per day, perhaps as little as 5 grams – regardless of the source – you can radically worsen your metabolic health. From a historical perspective, the average consumption of LA 150 years ago was 2 to 3 grams. Today, many consume more than 30 grams per day in their diet. In my opinion, a low-LA diet is perhaps the most important dietary measure of all.
This is an important point, and I think that from the COVID-19 perspective, the most important thing is to increase the resistance of cells to oxidative stress. Unfortunately, the half-life of LA in a high-LA diet is 680 days, and if it is not burned as fuel but stored in tissues, it can lead to oxidation of cell membranes, including immune cells.
When you increase your omega-6 intake, it affects the levels in your immune cells. And when you saturate your immune cells with this oxidized LA, you’re probably at a much higher risk of releasing more pro-inflammatory cytokines in your own cells, and your lungs and arteries are probably much more susceptible to the damage that occurs when our bodies try to kill viruses.
I’m sure if we looked at the blood levels of oxidized LA in severe COVID-19 patients, they would be tremendously high … So yes, it’s probably a major factor in overall inflammation.
Simple Strategies to Improve NAD+ Levels
Another important molecule is nicotinamide adenine dinucleotide (NAD+), which can be increased with the help of precursors such as nicotinamide mononucleotide (NMN) and/or nicotinamide riboside (NR).
Any type of oxidative stress will cause NAD to be depleted. So fix your metabolic disorder first and improve your nutrient deficiencies.
NMN seems to be the better of the two because it activates a utilization pathway. However, you don’t have to take expensive supplements to increase your NAD+ levels. Strategies such as exercise, exposure to heat or cold, and time-released nutrition – which cost you nothing – can get the job done.
Much of the NAD produced by the body is recycled through the utilization pathway. Very little (less than 1%) of it comes from food, particularly tryptophan or niacin.
One of the activators of this NAMPT enzyme that controls the recycling pathway is AMP protein kinase (AMPK), and AMPK is activated primarily by catabolic stressors in the body, such as exercise, sauna, cold, and fasting.
I have come to the conclusion that regular intermittent fasting or time-restricted eating is a very efficient way to keep our energy levels high and prevent the lowering of the other factors that lower NAD, such as inflammation and oxidative stress.
The problem is that NAMPT is controlled by sirtuins and in particular by Sirt1. Sirtuins are longevity genes. Sirtuins also control circadian rhythms. So I think that sirtuins are not expressed when your circadian rhythm is disturbed, when you are doing shift work or suffering from jet lag or something, and then you also inhibit NAMPT, which then shuts down the NAD rescue pathway.
In other words: When sirtuins are suppressed because of an inappropriate circadian rhythm, NAMPT is also suppressed because NAMPT needs sirtuins to function. Sirtuins also consume NAD, and if your NAD levels are low, you will not be able to get the benefits of sirtuins.
I think taking NR and NMN in addition is very useful if you are NAD deficient, because if your NAD level is already low, it’s hard to raise it because it’s already so low and depleted, Land says.
When your NAD level is high, you have fewer negative effects from inflammation and oxidative stress because your body can repair and manage them, whereas when you have a weakened immune system, old age, or nutrient deficiencies with low NAD levels, it’s a vicious cycle. So using an NAD precursor or booster can be a quick fix to get you back on track.
If you use an NAD or NMN supplement, you should buy it in suppository form. Other alternatives include subcutaneous or intranasal administration, all of which are more effective than oral supplements. As DiNicolantonio notes, when NAD levels are low, it’s best to address the underlying cause rather than simply taking supplements.
Ultimately, any kind of oxidative stress leads to a decrease in NAD. So fix your metabolic disorder first and improve your nutrient deficiencies, and your NAD needs will ultimately decrease. Fix the things that are causing you to deplete your NAD.
One of the most common sources of oxidative stress is exposure to electromagnetic fields (EMFs), which is the subject of my book “EMF*D.” Two primary enzymes consume NAD. One is poly-ADP-ribose polymerase (PARP), also known as adenosine ribosyl transferase (ARTD). PARP is used to repair DNA damage, and each time PARP is activated, it consumes 150 molecules of NAD.
The good news is that strategies such as sauna, exercise and fasting not only improve the production of NAD, but also reduce its consumption. These strategies also have an anti-inflammatory effect, which in turn reduces NAD consumption.
Other Benefits of Sauna Bathing
Sauna bathing not only preserves your NAD, but also mimics fever, which is your body’s first line of defense against infection. DiNicolantonio explains:
The reason we get a fever to fight infection is so our cells can then release heat shock proteins. In order for a virus to replicate, it has to infect the cell, hijack the machinery and export its ribonucleoprotein complex out of the cell to replicate. For this complex to be exported, the M1 protein must dock with it.
Heat shock protein 70, which is released during sauna sessions, can bind with the viral ribonucleoprotein complex and prevent the M1 protein from docking. [By inhibiting the export of this viral ribonucleoprotein complex, the heat shock protein essentially inhibits viral replication.
According to Land, regular sauna baths and exercise are among the best measures you can take to boost your immune system and increase your body’s resistance. What’s more, the two actions complement each other.
So, if you exercise before going to the sauna, you will greatly strengthen your body’s ability to deal with infections and other stresses. The heat also promotes recovery from exercise by stimulating growth hormone, repairing damaged proteins and reducing inflammation.