Health & Fitness

Choline is an essential nutrient, but it is not usually classified as a vitamin. According to Biology Online, a vitamin is “a low molecular weight organic compound that is essential for normal growth and metabolic processes and is required in trace amounts.”¹ Since your body can produce some choline in the liver, it is not classified as a vitamin.

Your body needs fat-soluble and water-soluble vitamins to function optimally. Fat-soluble vitamins are stored in fatty tissue and the liver.² They include vitamins A, D, E and K. Water-soluble vitamins are not easily stored and the excess is normally flushed out of your body in the urine. Water-soluble vitamins include vitamin C and all the B vitamins.

Choline is found in fat-soluble and water-soluble compounds in your food.³ Enzymes in your body free the choline from the compounds in your food where it’s absorbed in the small intestines and moved to the liver. Choline is then sent around your body to help make cell membranes.

Your body does not naturally produce enough choline to meet your needs. Therefore, you must get some from the food you eat.⁴ Choline levels are not routinely measured, but most people in the U.S. eat less than the recommended amount of foods containing choline.

While symptoms of a frank deficiency in healthy children and adults are rare, insufficient choline may be linked to health conditions including neurological degeneration and liver disease. Choline functions in the body overlap those of B vitamins, which in part may explain how choline was originally called vitamin B4.

Choline Was Once Considered a Vitamin

The earliest recorded information about choline occurred in 1862 when Adolph Strecker found that when lecithin was heated it generated a new chemical.⁵ He named that chemical choline. Three years later Oscar Liebreich identified a new molecule in the human brain that he named “neurine” and which later turned out to be identical to choline.

Nearly 100 years later in 1954, Eugene Kennedy described a pathway the body uses to incorporate choline into phosphatidylcholine. By this time scientists had identified many of the B complex vitamins.⁶

It wasn't until 1998, though, that the Nutrition Board of the National Academies of Medicine recognized choline as an essential nutrient.⁷ In the fall of 2020, Elena Gagliardi from the ambulatory nutrition services department at Santa Clara Valley Medical Center spoke with a reporter from U.S. News & World Report and explained that choline is not a vitamin.⁸

Instead, it is "a chemical compound vital for its many roles in the body."⁹ Adenine is a chemical constituent of flavin adenine dinucleotide (FAD), which helps convert choline in the mitochondrial matrix.¹⁰

There is a close relationship between adenine and choline — so much so that some also refer to adenine as vitamin B4¹¹ and others use the terms interchangeably.¹² However, it doesn’t matter what term is used, choline is a crucial nutrient for health and wellness.

Choline Is Crucial to Cognitive Function and Liver Health

According to a paper in Nutrition Today, the adequate intake (AI) for choline was calculated when the population levels of it were relatively unknown. Rather than being calculated based on experimental determinations or estimations of intake, it was calculated in part based on a study of adult men who developed liver damage after becoming deficient in it.¹³

The AI levels for others were then extrapolated based on standard reference weights. However, recent analysis has shown nearly 90% of people living in the U.S. do not eat enough choline-rich foods. Added to this, the 2015 to 2020 dietary guidelines for Americans did not recommend sufficient choline-rich foods to meet your needs.

A deficiency in choline can have wide-ranging effects. For example, there are indications that cholinergic dysfunction impacts the development of dementia. Studies and reviews of the literature supported the hypothesis that cholinergic dysfunction contributes to Alzheimer's disease.^14,15

Subsequently, it was discovered acetylcholine plays a central role in the nervous system, which requires an enzyme to synthesize it from acetyl-CoA and choline.¹⁶ The enzyme is called acetyltransferase. This connection likely explains, at least in part, the effect that anticholinergic drugs have on short-term cognitive impairment in the elderly.¹⁷

The medications act on acetylcholine, which sends messages that affect muscle contraction and the part of the brain that handles memory and learning. In one study, 347 participants who had experienced a stroke were given citicoline for 12 months. This is a supplemental combination of choline and cytidine.¹⁸

At the end of 12 months, the researchers found the supplement improved cognitive decline in the participants and “appears to be a promising agent to improve recovery after stroke.” Choline may also be a key factor in nonalcoholic fatty liver disease (NAFLD), which is one of the most common forms of liver disease in the U.S.¹⁹

In part, NAFLD is triggered by obesity and insulin resistance, which scientists find leads to fibrosis and then cirrhosis or liver cancer. There are two forms that are not associated with alcohol consumption. The first is simple fatty liver or nonalcoholic fatty liver (NAFL) and the second is called nonalcoholic steatohepatitis (NASH).

NAFL involves little inflammation or cellular damage, while NASH can lead to fibrosis, cirrhosis or liver cancer. In one study published in the Journal of Nutrition, researchers found women of normal weight who had the highest dietary intake of choline had a lower risk of nonalcoholic fatty liver disease.²⁰

Choline Has a Significant Impact on More Body Systems

According to Chris Masterjohn, Ph.D., choline deficiency may be more significant in the development of NAFLD than consuming too much fructose. His degree is in nutritional science and he believes the rise in fatty liver conditions is largely due to dietary changes.

In his review of the medical literature, Masterjohn found a link between choline and fatty liver, which was initially discovered in research into Type 1 diabetes. He describes the relationship:²¹

"In 1949, however, researchers showed that sucrose and ethanol had equal potential to cause fatty liver and the resulting inflammatory damage, and that increases in dietary protein, extra methionine, and extra choline could all completely protect against this effect.

Conversely, much more recent research has shown that sucrose is a requirement for the development of fatty liver disease in a methionine- and choline-deficient (MCD) model. The MCD model of fatty liver disease is the oldest and most widely used dietary model.

The MCD model produces not only the accumulation of liver fat, but massive inflammation similar to the worst forms of fatty liver disease seen in humans. What no one ever mentions about this diet is that it is primarily composed of sucrose and its fat is composed entirely of corn oil!

The picture that is clearly emerging from all of these studies is that fat, or anything from which fat is made in the liver, such as fructose and ethanol, are required for the development of fatty liver. But in addition to this [same] factor — overwhelmingly, it appears to be choline deficiency — must deprive the liver of its ability to export that fat."

In one study published in the journal Nutrition & Metabolism, researchers enrolled 866 patients with newly diagnosed hepatocellular carcinoma to test survival rates as compared to serum choline levels.²² The data showed patients with higher serum choline levels had better survival rates from liver cancer than those with lower levels.

Choline is a building block of acetylcholine and phosphatidylcholine, a component of very low density lipoproteins.²³ The brain uses phosphatidylcholine to make acetylcholine, which affects cognitive function. Phosphatidylcholine is also used in the treatment of several health conditions, including gallbladder disease, premenstrual syndrome and hepatitis.²⁴

Krill Oil Supports Choline Levels and Physical Performance

Donald Layman, Ph.D., from the department of food science and human nutrition at the University of Illinois, talked about the relationship between exercise performance and choline, saying:²⁵

"Exercise increases energy expenditure, helps maintain body composition, and controls body weight. We all know that routine daily exercise is important, but we often forget that good nutrition choices are essential for optimal muscle performance.

Specifically, choline is part of the neurotransmitter acetylcholine—the signal that stimulates muscle contraction, which supports muscle movement and performance. We also know that choline losses occur after exercise of only an hour, with a long run, cycling or a competitive tennis match."

Choline plays a role in maintaining muscle function. Serum concentrations may be depleted during high-intensity exercise. In one study, researchers engaged 47 triathletes from age 25 to 61 from Ironman distance and Olympic distance triathlons. The group was split into two: 24 received daily krill supplements for five weeks before the race and 23 received a daily placebo of mixed vegetable oils.²⁶

The athletes’ blood was tested before the race, immediately after and the following day. The researchers were analyzing serum choline levels and its metabolites. The data showed serum concentrations decreased significantly in all the races, but those receiving krill oil maintained more of their serum choline than those getting the placebo.

In one lab analysis, researchers found 69 choline-containing phospholipids in krill oil, which confirmed “the complexity of the phospholipid composition of krill oil.”²⁷ The choline composition of krill oil may also be more bioavailable since “It has been suggested that 60% of choline in inorganic salts is lost to conversion to trimethylamine (TMA) by intestinal bacteria.”²⁸

Enzymes may then turn TMA into trimethylamine-N-oxide (TMAO), a potential biomarker for insulin resistance and heart problems. As noted by the researchers, “Choline in the form of PC is considerably less converted to TMA as demonstrated in a single-dose study with krill oil, potentially resulting in more efficient delivery of choline.”²⁹

For example, evidence has shown that 28 days of krill oil supplementation increased choline levels in healthy young adults.³⁰ Additionally, the researchers in this study noted: “no adverse effects on plasma levels of TMAO and carnitine were found.”

How to Get More Choline

In a study comparing phosphatidylcholine, present in krill oil, and choline bitartrate salt, it was found that the krill oil led to higher levels of the important metabolites betaine and dimethylglycine (DMG) along with lower levels of TMAO, which can lead to health issues, compared to the other choline sources.³¹

Krill oil also offers more nutrients, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are beneficial for heart health and have been shown to improve blood pressure,³² reduce overall inflammation, reduce the effects of rheumatoid arthritis³³ and depression³⁴ and help slow the progression of Alzheimer's disease.³⁵

Egg yolks are another excellent choline source. Among egg consumers, approximately 57% met the adequate intake levels for choline, compared to just 2.4% of people who consumed no eggs.³⁶

In fact, the researchers in this same analysis concluded that it’s “extremely difficult” to get enough choline unless you eat eggs or take a dietary supplement, though it’s preferable to get nutrients from dietary sources whenever possible. Other dietary sources of choline include:^37,38

Grass fed beef liver	Organic pasture raised chicken	Wild-caught Alaskan salmon
Roe fish eggs	Atlantic cod	Kidney beans
Quinoa	Brussels sprouts	Broccoli
Shiitake mushroom	Cauliflower	Sunflower seeds

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There’s good news for those of you who have taken the proactive step to make sure your vitamin D level is optimized. Several recent studies demonstrate vitamin D can have a significantly beneficial impact on your cancer risk, both in terms of preventing cancer and in the treatment of cancer.

Vitamin D Reduces Cancer Mortality

In the first of these studies,^1,2 which included 25,871 patients, vitamin D supplementation was found to reduce the risk for metastatic cancer and death by 17%. The risk was reduced by as much as 38% among those who also maintained a healthy weight.

This was a really poorly done study as they only gave participants 2,000 IUs a day and never measured their blood levels. Had there been no improvement, I would not have been surprised, but the fact is it still reduced metastatic cancer and death by 17%, and they found significant benefit among those who were not obese.

This is pretty extraordinary but not as good as epidemiological studies that show a 50% to even 78% reduction in vitamin D sufficient people, as suggested in a study further below. That said, UPI reported the results saying:³

“The benefits of vitamin D3 in limiting metastases — or disease spread to other organs — and severity was seen across all cancers, and was particularly prominent among study participants who maintained a healthy weight …

‘The primary message [of our study] is that vitamin D may reduce the chance of developing metastatic or fatal cancer among adults without a diagnosis of cancer,’ study co-author Dr. Paulette Chandler told UPI.”

The study, published in JAMA Network Open, is a secondary analysis of the VITAL Study⁴ which, in part, sought to determine whether taking 2,000 IUs of vitamin D per day would reduce the risk of cancer, heart disease or stroke in people who did not have a prior history of these diseases.

The VITAL study itself, which followed patients for an average of 5.3 years, found no statistical difference in overall cancer rates among those who took vitamin D3, but there was a reduction in cancer-related deaths, which is what prompted this secondary analysis.

Obesity May Inhibit Vitamin D’s Benefits

The fact that patients with a healthy weight derived a much greater benefit — a 38% reduced risk for metastatic cancer and death compared to 17% overall — suggests your body weight may play a significant role in whether vitamin D supplementation will provide you with the anticancer benefits you seek.

According to study co-author Dr. Paulette Chandler, assistant professor of medicine at Brigham and Women's Hospital in Boston, “Our study highlights that obesity may confer resistance to vitamin D effects.”⁵

There may be something to that. Research⁶ published in 2010 found that dietary fructose inhibits intestinal calcium absorption, thereby inducing vitamin D insufficiency in people with chronic kidney disease.

That said, vitamin D tends to be lower in obese people in general, for the fact that it’s a fat-soluble nutrient and when you’re obese, the vitamin D ends up being “volumetrically diluted.” As explained in the paper “Vitamin D in Obesity,” published in 2017:⁷

“Serum vitamin D is lower in obese people; it is important to understand the mechanism of this effect and whether it indicates clinically significant deficiency … Vitamin D is fat soluble, and distributed into fat, muscle, liver, and serum.

All of these compartments are increased in volume in obesity, so the lower vitamin D likely reflects a volumetric dilution effect and whole body stores of vitamin D may be adequate … Obese people need higher loading doses of vitamin D to achieve the same serum 25-hydroxyvitamin D as normal weight.”

While that particular paper stresses that lower vitamin D in obese individuals might not mean that they’re deficient, others disagree. For example, one study^8,9 found that for every 10% increase in body-mass index, there’s a 4.2% reduction in blood levels of vitamin D. According to the authors of that particular study, obesity may in fact be a causal factor in the development of vitamin D deficiency.¹⁰

Vitamin D Also Improves Colorectal Cancer Outcomes

A scientific review¹¹ published in the September 2020 issue of the British Journal of Cancer noted that having low vitamin D is associated with poor colorectal cancer survival.

To assess whether vitamin D supplementation might improve survival in these patients, they reviewed the findings of seven trials, three of which included patients diagnosed with colorectal cancer from the outset and four population trials that reported survival in incident cases.

Overall, the meta-analysis found supplementation resulted in a 30% reduction in adverse colorectal cancer outcomes. Vitamin D also improved outcomes among patients already diagnosed with colorectal cancer. According to the authors:¹²

“Meta-analysis demonstrates a clinically meaningful benefit of vitamin D supplementation on [colorectal cancer] survival outcomes. Further well-designed, adequately powered RCTs are needed to … [determine] optimal dosing.”

Low Vitamin D Linked to Increased Cancer Incidence

Another review and meta-analysis,¹³ this one published in November 2019 in Bioscience Reports, looked at vitamin D supplementation on cancer incidence and mortality in general. Ten randomized controlled trials with a pool of 81,362 participants were included in the analysis.

While the incidence rate of cancer was very similar between the vitamin D intervention group and the placebo control group (9.16% versus 9.29%), the risk reduction in mortality was deemed “significant.” As reported by the authors:

“The mortality rate of cancer was 2.11% (821 cases) and 2.43% (942 cases) in vitamin D intervention group and placebo group, respectively, resulting in a significant reduction in risk (RR = 0.87).

There was no observable heterogeneity or publication bias … Our findings support a beneficial effect of vitamin D supplement on lowering cancer mortality, especially in subpopulations with no history of cancer, extra use of vitamin D, or calcium supplement.”

Vitamin D Protects Against Breast Cancer

Several studies have highlighted the benefit of vitamin D for breast cancer. For example, an analysis¹⁴ by GrassrootsHealth published June 2018 in PLOS ONE showed women with a vitamin D level at or above 60 ng/mL (150 nmol/L) had an 82% lower risk of breast cancer compared to those with levels below 20 ng/mL (50 nmol/L).

An earlier study,^15,16 which looked at women in the U.K., found having a vitamin D level above 60 ng/mL resulted in an 83% lower breast cancer risk, which is nearly identical to GrassrootsHealth’s 2018 analysis.

One of the most recent meta-analyses^17,18 looking at breast cancer was published December 28, 2019, in the journal Aging. Here, they reviewed 70 observational studies, finding that for each 2 ng/mL (5 nmol/L) increase in vitamin D level there was a corresponding 6% decrease in breast cancer incidence.

Overall, this translates into a 71% reduced risk when you increase your vitamin D level from 20 ng/mL to 60 ng/mL. The following graph, created by GrassrootsHealth,¹⁹ illustrates the dose response between vitamin D levels and breast cancer risk found in this study.

GrassrootsHealth’s 2018 analysis in PLOS ONE also analyzed this dose relationship.²⁰ To do that, they looked at the percentage of breast cancer-free participants in various vitamin D groups, from deficient (below 20 ng/mL) to optimal (at or above 60 ng/mL), over time (four years).

As you might expect, the higher the blood level of vitamin D, the lower the incidence of breast cancer. The graph below illustrates this dose-related protection. At four years, the percentage of women who had been diagnosed with breast cancer in the 60 ng/mL group was 78% lower than among those with blood levels below 20 ng/mL.

How to Optimize Your Vitamin D Level

If you live in the northern hemisphere, which is currently heading toward winter, now is the time to check your vitamin D level and start taking action to raise it if you’re below 40 ng/mL (100 nmol/L). As you can see from the studies above, a vitamin D level of 60 ng/mL (150 nmol/L) or higher is recommended if you want to protect against cancer.

An easy and cost-effective way of measuring your vitamin D level is to order GrassrootsHealth’s vitamin D testing kit. Once you know your current vitamin D level, use the GrassrootsHealth vitamin D calculator²¹ to determine how much vitamin D you might need to reach your target level. To optimize vitamin D absorption and utilization, be sure to take your vitamin D with vitamin K2 and magnesium.

Lastly, remember to retest in three to four months to make sure you’ve reached your target level. If you have, then you know you’re taking the correct dosage. If you’re still low (or have reached a level above 80 ng/mL), you’ll need to adjust your dosage accordingly and retest again in another three to four months.

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As the consumer genetics industry rapidly expands, more and more people are turning to DNA-based services to learn their risk of developing a wide range of diseases. However, the risk scores from these genetic tests are not always as precise as they could be, according to a new study. The scientists examine many approaches to calculating the scores and recommend that personal genomics organizations adopt standards that will raise the bar for accuracy.

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New research has confirmed in laboratory testing that a population of nerve cells near the base of the brain - the RFRP neurons - become active in stressful situations and then suppress the reproductive system.

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Researchers have found that people with sepsis have never-before-seen particles in their blood. The scientists are the first to show that these particles, called elongated neutrophil-derived structures (ENDS), break off of immune cells and change their shape as they course through the body.

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“The Immunity Fix: Strengthen Your Immune System, Fight Off Infections, Reverse Chronic Disease and Live a Healthier Life” is a new book written by James DiNicolantonio, Pharm.D., with whom I co-wrote “Super Fuel,” and Siim Land, an esteemed biohacker and author of “Metabolic Autophagy.”

In it, they review how to improve and regulate your immunity — a topic that should be high on anybody’s list these days. The catalyst for this collaboration was a number of academic papers written by DiNicolantonio on the underlying reasons for why some people suffer worse COVID-19 outcomes.

Many who end up with severe illness produce low amounts of Type 1 interferon. There's also a reduction in their adaptive immune system. As a result, they don't clear the virus quickly and end up having to rely on a more proinflammatory killing of the virus inside their cells instead.

Immune System Basics

As a refresher, your immune system consists of two primary “arms”:

• The innate immune system, which is your first line defense made up of natural killer (NK) cells, macrophages and white blood cells like neutrophils
• The adaptive immune system — T cells, and B cells that produce antibodies

As explained by DiNicolantonio:

“We used to think that the adaptive immune system was this system that takes a while to kick in, and once you have immunity from your adaptive immune system, then you have a longer-term protection, which is true. However, the adaptive immune system also seems to have cross sensitivity, meaning if you've been exposed to previous coronaviruses, your T cells seem to have some cross sensitivity to SARS-COV-2.

So, essentially, what we see is a reduction in T cells, in the cytotoxicity of these CD8 T-killer cells, which kill viruses in a nice, apoptotic, controlled way.

When you have a reduction in those types of immune cells, you have to rely more on your proinflammatory innate immune system for clearing viruses — things like neutrophils, white blood cells, macrophages. They kill in a much more pro-inflammatory, non-specific way, and they end up killing healthy bystander cells.

What we think is going on is, essentially, you have this reduction in Type 1 interferons … which interfere with the virus. And at the same token, you have a reduction in B cells and T cells. So, what ends up happening is you don't clear the virus as quickly, and you end up having this proinflammatory killing.

Siim and I collaborated because these things are complex. We need to get this in layman's terms. What our book boils down to is that your diet and your lifestyle control those types of things, and there's things that you can do to support your own immune system.”

Your T cell function tends to decline with age. It’s also reduced in those with chronic disease. Reduced T cell function appears to be a primary cause of severe COVID-19, seeing how those with the worst COVID-19 outcomes are the elderly and/or those with comorbidities such as diabetes, hypertension, metabolic syndrome and cardiovascular disease.

These factors worsen the proinflammatory response that you get from SARS-CoV-2, but they also weaken your immunity in general. “The Immunity Fix” reviews lifestyle strategies that help you sidestep and prevent this proinflammatory response. “It's a very holistic approach to looking at the immune system,” Land notes.

Top Two Nutrient Deficiencies to Address

Diet and nutritional supplementation are two key strategies that can help boost your immune function. According to Land and DiNicolantonio, vitamin D may be the most important nutrient in this respect.

Vitamin D activates more than 2,000 genes, DiNicolantonio notes, including vitamin K-dependent proteins and repair genes. It also helps your body produce powerful antimicrobial and antiviral peptides.

Those over the age of 60 have a ninefold greater risk of dying from COVID-19 than that of younger individuals. If you’re severely vitamin D deficient, your risk can be 15fold greater. So, while you cannot change your age, you can certainly alter your vitamin D status, thereby potentially minimizing your risk.

However, in order to convert the vitamin D into its active form, you need magnesium, so magnesium would probably be the second-most important nutrient deficiency to address. Magnesium is also required for immune cell function, so if your magnesium level is low, your immune function could be impaired. 

“People who have genetically low magnesium in their natural killer (NK) cells and their CD8 T-killer cells … their immune system is down. They have chronic activation of Epstein-Barr, which 95% of us are infected with, and they're at a much higher risk of lymphoma,” DiNicolantonio says.

“And that's just one nutrient. Being deficient in one nutrient can potentially cause this immunodeficiency essentially. So, in the book, we go through how nutrients and your immune system interact and why nutrient deficiencies are probably leading to a lot of these poor COVID-19 outcomes.”

Zinc and Selenium Are Also Important

In terms of importance, zinc would probably nab the third spot. Taking zinc lozenges at the first onset of cold symptoms has been shown to cut the duration of the common cold by six to seven days, but you have to take it correctly.

“If you're using lozenges, you have to take it every two hours,” DiNicolantonio explains. “You got to take it within 24 hours of symptom onset. You have to take about 18 milligrams per dose, and you have to get the total daily dose over 75 milligrams.”

Fourth on the list would be selenium. Not only is selenium deficiency associated with a fivefold higher risk of dying from COVID-19 and a threefold higher risk of having a poor COVID-19 outcome, but it is also associated with coxsackievirus-induced cardiomyopathy (Keshan disease).

So, if you're deficient in selenium, a nonvirulent RNA virus called coxsackievirus, which typically only causes hand, foot and mouth syndrome in certain children, can become much more virulent, leading to virally induced cardiomyopathy. Patients with this cardiomyopathy, known as Keshan disease, are typically given selenium. Selenium is also important for the production of glutathione, which appears to play a significant role in COVID-19.

The Importance of Melatonin

Another thing that is associated with improved COVID-19 outcomes is melatonin. DiNicolantonio explains:

“Melatonin is interesting. I kind of view it like molecular hydrogen but with some additional advantages. Melatonin can freely pass into any cell membrane, so that's very key. If you want to get to the oxidative stress, you have to be able to access it and get into the mitochondria. Melatonin and molecular hydrogen are two molecules that can do that and really do that well …

Melatonin is not just this hormone we secrete in the brain. We synthesize it from serotonin, and it can be produced in many cells. So, it's active throughout the entire day. What's interesting is that it's one of the only molecules that seems to increase the transcription of Nrf2.

Most plant polyphenols and all these other Nrf2 boosters only inhibit the inhibitor of Nrf2, which is KEAP1. Essentially, they're making the current Nrf2 levels more active. When you add melatonin, that increases the transcription of Nrf2. Very few molecules can actually do that.

And Nrf2 is how we boost our endogenous antioxidant enzymes. Really, that's the key. If you have acute respiratory distress, you want to boost your overall endogenous antioxidant systems, and the best way to do tha is through Nrf2 activators, particularly melatonin.”

High-Dose Melatonin Reduces COVID-19 Mortality

As for dosage, a recent case series involving 10 patients with COVID-19-related pneumonia used 36 to 72 mg of oral melatonin per day in four divided doses, which is far higher than recommended for sleep. DiNicolantonio comments:

“It's so safe. Doses of melatonin up to 1,000 mg per day in humans have shown virtually no side effects besides grogginess and sleepiness … Melatonin use is associated with an 83% reduction in mortality from COVID-19, a 30 to 50% reduction in testing positive for SARS-COV-2, and in a case series of 10 COVID pneumonia patients, it cut the duration of hospital stay by five days.

And none of those patients who got melatonin ended up on a mechanical ventilator or died whereas in similar severe COVID-19 cases that were hospitalized at the same time, 25% to 40% of those individuals ended up on mechanical ventilators or died.”

As explained by DiNicolantonio, melatonin is actively produced throughout the day and is a master antioxidant, meaning it scavenges free radicals. It also binds to melatonin receptors that upregulate your innate antioxidant defense systems.

“Melatonin actually seems to concentrate in the bone marrow and that's important because your immune system comes from stem cells produced from your bone marrow,” DiNicolantonio explains.

“From those stem cells, you get your immune cells. Some of your immune cells can even produce melatonin. We think it's being 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

While Land and DiNicolantonio hypothesized that inhaled molecular hydrogen at 2% or 3% would be a potential important strategy in COVID-19 patients requiring ventilation in a hospital, this can be significantly expensive. A better alternative, in my opinion, would be nebulized hydrogen peroxide, which you can do at home. This is my personal go-to strategy, and I’ve seen many recover from COVID-19 using this strategy. You can review my video below for more detailed in formation.

Nebulizing hydrogen peroxide into your sinuses, throat and lungs is a simple, straightforward way to augment your body’s natural expression of hydrogen peroxide to combat infections and can be used to support the immune system.

All you need is a desktop nebulizer, food-grade hydrogen peroxide and some saline. That way, you have everything you need and can begin treatment at home at the first signs of a respiratory infection. Keep in mind food grade hydrogen peroxide must be diluted down to a 0.1% dilution before use.

I believe the hydrogen peroxide works like a signaling molecule, and may even have some direct viricidal effect on the cells in the lining of the lungs and the sinuses where the virus takes hold initially. So, you're potentially killing it directly, plus supporting your immune responses.

Address Your Metabolic Health

In addition to addressing nutrient deficiencies, in particular vitamin D, magnesium, zinc and selenium, Land stresses the importance of optimizing your metabolic health.

“Research [has found] that metabolic syndrome, obesity and diabetes, all those things, worsen the outcomes of COVID-19 as well as other infections like influenza. Obesity also increases the duration that you can carry the virus and share it for longer. So, it's especially negative in a society that tends to be in poor metabolic health.

One interesting thing that we discovered during the writing of the book is that one of the molecules that gets activated during an infection is called HMGB1, which stands for High Mobility Box-1.

That gets activated during an infection, and it's one of the key molecules that kind of offsets the cytokine storm by activating NFKB and NLRP3 inflammasome and eventually causes this massive pro-inflammatory cytokine response …

What we theorized based on this research, is that hyperglycemia, insulin resistance, elevated blood sugar will make it more likely that HMGB1 is going to get into the cell and turn on NFKB and these other pro-inflammatory cytokines that will 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 dove deep into 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’s highly susceptible to damage. When it oxidizes, it turns into oxidative metabolites called oxidative linoleic acid metabolites or oxylipids or OXLAMs that damage proteins, DNA and cell membranes and are likely the primary culprit of chronic disease.

OXLAMs also activate pathways that destroy your immune response. What we didn’t fully appreciate at the time was that even healthy oils, such as olive oil, can have a negative impact, thanks to their LA content. LA is also high in conventionally raised chicken, as these animals are typically fed LA-rich grains.

If you exceed 10 grams of LA per day, and perhaps as little as 5 grams — regardless of their source — you may radically worsen your metabolic health. From a historical perspective, 150 years ago, the average consumption of LA was 2 to 3 grams. Today, many get more than 30 grams a day from their diet. In my view, an LA-restricted diet may be the single most important dietary intervention available. DiNicolantonio adds:

“That's a great point, and I think from a COVID-19 perspective, the biggest thing you want to do is increase the resilience of your cells to oxidative stress. Unfortunately, if you're consuming a diet high in LA, and if it doesn't get burned for fuel and it gets stored in tissues, the half-life of LA is 680 days, and it can start oxidizing the cellular membranes, including on your immune cells as well.

If you increase your omega-6 intake, that affects the levels in your immune cells. And if you saturate your immune cells with this oxidized LA, you're probably at a much higher risk of secreting more proinflammatory cytokines in your own cells, and your lungs and your arteries are probably much more susceptible to the damage that occurs when our body tries to kill off viruses.

I'm sure if we were to actually look at the blood levels of oxidized LA in severe COVID-19 patients, they would be sky high … So yeah, it's likely a huge driver of overall inflammation.”

Simple Strategies to Improve Your NAD+ Level

Another important molecule is nicotinamide adenine dinucleotide (NAD+), which can be increased using precursors such as nicotinamide mononucleotide (NMN) and/or nicotinamide riboside (NR).

NMN appears to be the superior of the two, as it activates a salvage pathway. However, you don’t need to take an expensive supplement to improve your NAD+ level. Strategies such as exercise, hot or cold exposure and time-restricted eating — which costs you nothing — can get the job done. Land explains:

“A lot of the NAD that your body produces is recycled through the salvage pathway. Very little (less than 1%) of it is going to come from food, especially tryptophan or niacin.

The easiest way to prevent losing your NAD as you get older or as you get immunocompromised is to promote the salvage pathway, and one of the activators of this NAMPT enzyme that governs the salvage pathway is AMP protein kinase (AMPK), and AMPK gets primarily turned on by catabolic stressors in the body, such as exercise, sauna, cold, as well as fasting.

What I've concluded is that doing this regular intermittent fasting or timed eating is a very efficient way of keeping our energy levels high and preventing the lowering of the other things that lower NAD, like inflammation and oxidative stress.

The problem is that NAMPT is controlled by sirtuins and sirt1 especially. Sirtuins are longevity genes. Sirtuins also control your circadian rhythms. So, what I think is that if your circadian rhythms are misaligned, if you’re doing shift work or you're jet lagged or something, then sirtuins are not going to be expressed, and you will also then inhibit NAMPT, which will then shut down the NAD salvage pathway.”

In other words, when sirtuins are suppressed from mismatched circadian rhythms, you also suppress NAMPT, as the NAMPT requires sirtuins to work. Sirtuins also consume NAD, so if your NAD level is low, you’re not going to get the benefits sirtuins provide.

“I think the supplemental NR and NMN are very useful if you're in an NAD-deficient state because the problem is that if you're already low in NAD, then it's hard to raise that bar because you're already so low and depleted,” Land says.

“If your NAD is high, then you experience the less negative side effects from inflammation oxidative stress because your body can repair and deal with it, whereas if you're immunocompromised, you're very old or you are just nutrient deficient and have low NAD, then it's a vicious feedback loop. So, using something like a NAD precursor or a booster can be a quick fix to get yourself back on the right track.”

If you use an NAD or NMN supplement, consider getting it in suppository form. Other alternatives include subcutaneous or intranasal administration, all of which are more effective than oral supplements. That said, as noted by DiNicolantonio, if your NAD is low, your best bet is to address the underlying cause rather than simply adding supplements.

“Ultimately, any type of oxidative stress is going to deplete NAD. So, fix your metabolic dysfunction and improve your nutrient deficiencies first, and ultimately your NAD need is going to go down. Fix the things that are causing you to burn through your NAD.”

One of the most common sources of oxidative stress is electromagnetic field (EMF) exposure, which is the topic of my book “EMF*D.” Two primary enzymes consume NAD. One is poly ADP-ribose polymerases (PARP), which is also known as adenosine ribosyl transferase (ARTD). PARP is used to repair DNA damage, and every time PARP is activated, it uses up 150 molecules of NAD.

The good news is that strategies such as sauna, exercise and fasting not only will improve the production of NAD, but also will reduce the consumption of it. These strategies also lower inflammation, which in and of itself will lower your NAD consumption.

Other Benefits of Sauna Bathing

In addition to preserving your NAD, sauna bathing also mimics a fever, which is your body’s first-line defense against infections. DiNicolantonio explains:

“The reason why we induce a fever to fight an infection is because that allows our cells to secrete heat shock proteins. In order for a virus to replicate, it has to infect your cell, hijack your machinery, and it has to export its ribonucleoprotein complex out of the cell to replicate. In order for that complex to get exported, the M1 protein has to dock onto it.

Heat shock protein 70, which gets released during sauna sessions, can combine to the viral ribonucleoprotein complex preventing M1 protein from docking. [By] inhibiting the export of that viral ribonucleoprotein complex, [heat shock protein] essentially inhibits viral replication.”

According to Land, regular sauna bathing and exercise are among the best things you can do to strengthen your immune system and increase your body’s resilience. The two are also complementary.

Exercise causes preconditioning hormesis, so if you exercise before your sauna, then you significantly bolster your body’s ability to handle infection and other stresses. The heat will also promote recovery from the exercise by boosting growth hormone, repairing damaged proteins and reducing inflammation.

More Information

This interview merely touches on a small number of highlights of the information found in “The Immunity Fix,” so to learn more, be sure to pick up a copy. To connect with DiNicolantonio and Land, see their websites, DrJamesDinic.com and SiimLand.com. Both can also be found on Twitter and Instagram by searching for DrJamesDinic (@drjamesdinic) and Siim Land.

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