How the Nrf2 System Protects Me

How Does the Nrf2 System Protect Me

The Nrf2 system (nuclear factor erythroid 2–related factor 2) is your master switch that turns on some 2,000 genes that help you turn off oxidative stress. The Nrf2 system also activates a whole portfolio of longevity genes. Last week, we learned that oxidative stress is the result of reactive oxygen species, escaping overworked mitochondria and damaging cell membranes. This week, we add the longevity mechanisms.

Nrf2 declines with aging, which appears to be inevitable and its overt causes are elusive. There are a lot of diseases associated with aging. Hence, knowing how Nrf2 interacts with those diseases will give us more tools to get to the root cause and either outright reverse them or soften the blow.

There are 9 standard hallmarks of aging: genomic Instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. An international meeting in Copenhagen just added 5 more. Of those first 9, the Nrf2 system modulates them all dramatically.

For example, Genomic Instability. As we age the lack of DNA repair leads to increased mutations and replication errors, which leads to cancer and cognitive decline. Nrf2 targets genes that lead to improved DNA repair. It's that simple. The key switch to fixing broken DNA is your Nrf2 system.

How about Telomere Attrition? Cells die when their telomeres get too short. Telomeres are the DNA caps on the end of your chromosomes. With each cell cycle, you lose a tiny bit of your telomeres. The Hayflick limit predicts you live only as long as your telomeres. But an enzyme will lengthen your telomeres, cheating the Grim Reaper. It's called TERT or Telomere Reverse Transcriptase. And what does Nrf2 have to do with TERT? Apparently everything. Re-lengthening your telomeres is one of antiageing's "Holy Grails".

Then there are Epigenetic Alterations. Our epigenome is composed of some 20 million markers on our chromosomes that regulate when we turn genes on and off. Those alterations are key to the development of cancers. Again, Nrf2 is key to the whole process of keeping that labeling and marking system stable.

Loss of Proteostasis is basically the accumulation of misfolded proteins. When our proteins are assembled and folded improperly, cells don't function well. Nrf2 actives genes, POMP and the PMSA family in particular, that regulate folding and misfolding. Examples of misfolded proteins include amyloid in Alzheimer's and Alpha-synuclein in Parkinson's.

Get the drift? Virtually every element of our 9 standard "Hallmarks of Aging" are intimately tied to Nrf2 and its appropriate activation. If you want to do a deeper dive: here are just a few of the thousands of research articles detailing that story.

Dysregulated Nutrient Sensing: FASEB, Antiox and Redox,

Mitochondrial Dysfunction: Current Opin Toxic.,

Cellular Senescence: Mol Chem Biochem,

Stem Cell Exhaustion: Frontiers,

Altered Intercellular Communication: Exercise Sport Sci Review, Biochem Pharm.,

It makes sense. If we are to maintain a healthy body, we need a switch that turns on that vitality across the board. Parsing down to the details, that switch, the Nrf2 system, plays a key role in the initiation and promulgation of each of the identified components.

www.What will Work for me? I had no idea about the breadth and depth of the Nrf2 science. In 2010 there were some 400-500 references in Pubmed. Now there are some 10,000 a year and what used to be thought of as a 3 to 4-step process is now much more complex with several hundred interlocking enzymes and interdependent steps. That makes it central to the treatment of just about every disease. Ok, really! Every disease. Next week, the evidence for that and how to treat it.

References: CellCell, Free Radical Biol Med, Nucleic Acid Res, Cell Death Dis, MDPI, Redox Biology, FASEB, Curr Opin Tox, Mol Chem Biochem, Frontiers, Exer Sport Sci Review, Biochem Pharma,

Pop Quiz

1. After 40, it's just patch, patch, patch! Why?                         Answer: Decline in the Nrf2 pathway.

2. Current research focuses on how many hallmarks of aging?                         Answer: The easy answer is 9 well-known ones but there have been recent additions. The story may not be over yet.

3. Can you name a few?                          Answer: genomic Instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. You get an A if you could remember 2.

4. Current research in Nrf2 is dramatically falling off as researchers focus on other things. T or F.               Answer: False. This is just about the hottest topic in town.

5. How many genes are known to be involved with the Nrf2 system?                      Answer: At least 2000 so far.

Nrf2 and Oxidative Stress

Nrf2 System and Oxidative Stress

No, we are not talking about Nerf Balls or Smurfs. The Nrf2 (nuclear factor erythroid 2–related factor 2) system is right up with Nitric Oxide in importance in that it plays a key regulatory role in managing oxidative stress. Oxidative stress is one of the key drivers of getting old and falling apart. That makes understanding it important. Hence, here starts a series to explain it.

First, what is oxidative stress? It is the unbalanced environment where too many oxidizing compounds, "reactive oxygen species", overwhelm your natural antioxidant control systems. Our mitochondria are delicately balanced furnaces and when too many nutrients get shoved in from all directions. extra electrons slip away and glom onto an oxygen molecule, making O2-. It's biochemically impossible to hang onto every electron because of their very nature being a part-time particle and a part-time wave. That O2- is the superoxide anion that is chemically very dangerous. It can degrade membranes and proteins all over the place. If we have enough of the enzyme SOD, superoxide dismutase, we can neutralize it by making H2O2, peroxide. Peroxide is no angel but at least it's not negatively charged. If we have enough glutathione, we can turn peroxide into water. In our brains, our plasmalogen molecules soak up peroxide, becoming the first line of defense in the brain against peroxide. Our plasmalogens decline, synapses disappear, brains shrink and cognitive decline follows.

If we don't have SOD, the O2- molecule may interact with Nitric Oxide and make an ONOO- molecule, peroxynitrite, which is another demon. To round out the BIG 4, peroxide, in the absence of sufficient glutathione or catalase, with react with iron to make OH-, the hydroxyl radical. Glutathione or catalase are two protective "antioxidants" that convert H2O2 to water and oxygen.

There you have it: the Big 4 of oxidative stress, O2-, ONOO-, H2O2, and OH1. They are constantly being made at a low level and being cleaned up. Our immune system uses some of them quite creatively to help kill viruses and invading bugs. It's all in the balance. Too many and you damage just about every pathway that leads to all diseases and aging. Name any disease of aging and you will see oxidative stress as tipping the balance towards having more of it.

Here is the rub. We haven't been very effective at turning oxidative stress off with the oral antioxidant supplement approach. There are foods that help a little, but not at the level needed to dramatically turn on sufficient response.

This is where Nrf2 comes in. Nrf2 is a transcriptional protein that turns on some 2000 genes, all of which combine to turn off oxidative stress. It upregulates the production of more catalase, more glutathione, more superoxide dismutase, the Big 3 internal antioxidants. The Nrf2 system is critical for cell survival in times of oxidative stress.

That's why we need to know about NRF 2 and choose a lifestyle of protecting it. Unfortunately, Nrf2 declines with age. As Hamlet said, "Therein lies the rub". Step one is knowledge. Next week, step two.

www.What will Work for me? I've been pushing anti-oxidants and encouraging all sorts of behaviors to change the course of disease, sometimes to little effect. That has been discouraging to all of us. Gamma, delta tocotrienols, fish oil, turmeric,....on and on and we haven't gotten much return on investment. The Nrf2 system is the controller of your antioxidant response. That's the upstream effect we need to focus on.

References: Wikipedia, MDPI, Science Direct, Wikipedia, Oxid Med Cell Long, Pharnacogn Review, Free Rad Biol Med, Free Radic Bio Med, PlanSponsor, Annual Review Pharm Toxic, Foods,

Pop Quiz

1. What is Nrf2?                                    Answer: nuclear factor erythroid 2–related factor 2 . Stick with Nrf2. It is the primary nexus of your metabolic response to oxidate stress.

2. What is oxidative stress?                           Answer: the imbalance to too many reactive oxygen species driven mostly by loose electrons escaping "overly heated" or damaged mitochondria. "Overheating" of mitochondria is mostly driven by forcing too many carbohydrates and fats into the intake funnel of the mitochondria (Think Thanksgiving Dinner....or even a double burger, fries, and milkshake). They just get overwhelmed and don't have sufficient places to send electrons to. Electrons escape...and you are off to the races. Damage to the lipids of cells sets off more inflammation.


3. Can you name the Four Dark Horsemen of Oxidative Stress?                        Answer: Reactive oxygen species.  O2-, ONOO-, peroxide (H2O2), and OH-. 

4. What does the NRF2 system do to balance that stress?                            Answer: The Nrf2 system is a transcriptional protein that turns on some 2000 genes, all of which shift you to making the BIG 3 internal "anti-oxidants": glutathione, catalase, and superoxide-dismutase. They work mostly by neutralizing the common pathway of oxidate stress, excess hydrogen peroxide.

5. What happens to the Nef-2 system as you age? Answer: it declines. Bummer. But wait, we can help fix that. Tune in next week.

6.  What's a "rub", as per Hamlet?               Answer: a figure of speech from the Elizabethan era using a bump or obstruction on a lawn-bowling fairway that changes the direction of the ball....hence, something that unexpectedly changes your intended course of action. 

Nitric Oxide is Boosted Best by...........Chili Peppers

Nitric Oxide Boosted BEST by.......Chili Peppers

When the august American Heart Association has a paper presented at its annual meeting that the consumption of chili peppers reduces heart disease mortality 26%, cancer 23%, and all-cause mortality 25%, you just have to sit up and take notice. Compare this to the all-cause mortality reduction of statins of 0.49%, and you might be observed rolling your eyes. Which would you opt for? A 25% reduction or a 0.49% reduction? Think long and hard. Then ask, "How is this credible and what is the massive benefit from? How is it mediated?" 

The answer is elegant and simple. It's been missed because it is so hard to measure. Nitric oxide. NO is a gas that doesn't hang around to be measured without very careful clinical research. But you now know that NO plays a key role at the forefront of all the metabolic processes that lead to cardiovascular disease: diabetes, high blood pressure, and inflammation. If we focus on NO, the benefit to heart disease, cancer, and even all-cause mortality makes sense. You want to create a lifestyle that increases your NO production as you age. 

Chilis are grown everywhere and can be purchased for pennies. In fact, since their discovery in the New World by Columbus and dissemination throughout the world, chilis have become intrinsic components of Chinese, Indian, Thai and many other cuisines. Just go to the grocery store and see the "hot sauces" that have proliferated. What used to be a few names now covers hundreds of brands. 

Do we understand the actual pathophysiology of capsaicin on various tissues? Yes. There appear to be several effects on various proteins and enzymes that are affected by capsaicin that is absorbed in the range that humans eating spicy foods would eat. The TRPV1 receptor (Transient receptor potential vanilloid type 1) affects calcium flow across membranes. TRPV1 is widely expressed throughout the whole body, including sensory nerve fibers controlling insulin release from pancreatic beta cells. The increase in Ca acts rapidly to stimulate endothelial nitric oxide synthase (eNOS) activity via binding of the Ca2+/calmodulin complex; in addition, Ca-mediated activation of AMPK and Sirt1 stimulates eNOS activity by modifying its phosphorylation and acetylation status. If you can navigate all that complex language you can simplify it to NO goes up with chilis. There you have it. You want up.

www.What will Work for me? Chilis are an acquired taste. On first exposure, most folks are a bit taken aback. But you become adopted and then you really like it. I have found that a range of products with lots of chilies is easy to add to your cuisine. Spicy Chili Crisp is a Chinese brand with fermented soybeans, chilis and onions that is my current favorite. A dab of that on my deviled eggs and I'm in heaven. I measured my NO level in response 15 minutes after, and didn't see much rise. Perhaps I need more.

References: Biomedicine and Pharm, Am Jr. Prevent Cardiology, Int Jr Vit Nutr Resrch, American Heart Assoc, Br Jr Clin Pharm, New Mexico State Chili Pepper Center, Open Heart, Cell, LegalNomads, Dr Trouble,

Pop Quiz 

1. Chilis were found first where?                            Answer: Probably in Andes/Bolivia and then spread up to Mexico and the Caribbean, where Columbus tasted and liked them, taking them back to Spain. The race was on. 

2. The chili pepper makes the chemical _____________ that has all of its "heat" and biochemical effect.             Answer: Capsaicin. The Carolina Reaper has some 2,000,000 Scoville units and is currently listed as the "hottest" but there are competitors nipping at its rank. You can watch $ 1,000 being won to eat it. A green bell pepper has 0 capsaicin.

3. And what mechanism is going on inside your cells that is beneficial for enduring this insane taste?           Answer: Activate the TRVP1 receptor that puts out calcium. And that activates eNOS, making Nitric Oxide. NO does all the good things we have covered in the last four weeks. 

4. Remember four weeks ago? How much does NO decrease per decade?                          Answer: 12%. If you are 60, you are down 75%. This might be the dominant engine driving aging. 

5. What is a sane way to increase NO?                            Answer: Don't use mouthwash. Don't use fluoride toothpaste. Eat lots of green, leafy vegetables. Infrared saunas help. Exercise helps. Take a NO booster from the N1O1 company. Twice a day. This is the first credible product to market other than the beetroot supplements. There will be more. And eventually cheaper. It's probably a habit you should get in to.

Diabetes is Caused by Low Nitric Oxide

Nitric Oxide Loss Drives Adult-Onset Diabetes

The very first incremental step of developing diabetes is insulin resistance as shown by the increase of fasting blood glucose into the 90s. The Whitehall Study from Great Britain showed that a fasting glucose of 86 determined the absence of cardiovascular risk, with a 6% increased risk for every point above 86. Hence, we need to define a "normal" blood glucose as 86, or A1c as 5.2. That is quite a step lower than our current, supposedly "normal" A1c of 5.6. It's in that gap that diabetes is developing, without our being aware. But awareness starts with knowledge.

That first stage of fasting glucose being in the 90s, or an A1c of 5.6 or higher that identifies over 90% of Americans being slightly insulin resistant, or worse, diabetic.

What is the very first step that starts us down to diabetes? The answer has been around for almost 20 years. It's too high a blood glucose from eating foods that are "too processed", meaning they have pure, white flour and delicious glucose in them in such easily available form that our blood glucose rises too rapidly.

So, we now see that research that identifies the suppression of Nitric Oxide by high glucose, that results in the gradual introduction of insulin resistance. We know that NO is necessary for insulin transport. We also know that persistently elevated glucose, or so-called Adult Onset Diabetes or "insulin resistance" also suppresses NO. There you have it. Both sides of the circle make a self-reinforcing gyre. High glucose makes you put out insulin. Insulin makes you store the calories and becomes fatter, making you more insulting resistant, and making the first, key hormone, NO persistently low.

The use of a continuous glucose monitor is instructive. It will show you exactly how high your glucose goes in response to a meal. A slice of white toast with peanut butter and jelly on it gives me a glucose of 180. Just 6 raisins give me 130. Spinach salad with olive oil.....95. Steak.....90.

Eating the processed food of America with its ultrafine refined white flour is so easily digested that our glucose rises rapidly. Rapid rise of glucose means NO suppression. Do that starting at age two in your highchair, and your body has been doing metabolic battle with lack of NO for decades. No wonder we lose 12% of our NO per decade. The first step, the very first step at NO depletion, is our American, high sugar and flour diet (the foundation of "ultra-processed foods).

www.What will Work for me? I have learned a lot from my continuous glucose monitor. If I embark on a 5-day fast mimicking diet with the CGM on, I can watch my fasting glucose drop from 104 to 92, to 82, 72, and 58 by day 5, all without feeling "hypoglycemic". For most of human history, we ran our metabolism on ketones from eating animal fat, or the green, leafy vegetables that are fermented in our guts to beta-hydroxybutyrate. We also didn't have central heating with natural gas, so we slept in colder places and developed brown fat, that burned off more calories. Neither of those turns on insulin or suppresses NO.

References: Diabetes , Biomedical Reports, Clinical Sci, Frontiers Card Med, Exp Physiology,, KSL, J Biol Chemistry, BBC

Pop Quiz

1. What is the very first step of glucose control?                       Answer: the release of NO that facilitates the secretion of insulin. (Think a trip to a fast-food burger joint, with the milkshake for dessert because you deserve it.). You put out a ton of insulin if you can make the NO to secrete it. But that high glucose will gradually chip away at your NO secretion. That becomes a self-fulfilling positive feedback loop, when you wanted a negative feedback loop.

2. Without sufficient NO, what happens to your arteries?                      Answer: Without NO you have the metabolic table set for sticky white cells and LDLs and you start getting endothelial dysfunction....and then plaque....and then a heart attack.

3. What is a normal A1c, or fasting glucose?                            Answer: Our labs tell us glucose under 100 is normal and A1c below 5.7 is normal. But to have a metabolism that never gets diabetes or heart disease, you need to aim lower: 86 and 5.

4. What is the first step to raise your NO back from the cellar it has been in?                          Answer: When you are in a deep hole, the first step is to stop digging. Stop eating sugar and white flour. More vegetables, more fiber, more exercise, no mouthwash, no Flouride toothpaste, infrared saunas and NO supplements.

5. Does my thermostat at 72 drive down my NO?                            Answer. Ah, Yes.  What a dilemma. It makes us develop less brown fat, that make heat, because we are exposed to less cold stress. Brown fat burns a ton of energy. Instead, we store that energy, and our fat cells get bigger and our waist lines larger.

Nitric Oxide and COVID

Nitric Oxide and COVID

What do all the risk factors for COVID have in common? Heart disease, hypertension, obesity, diabetes, age, male gender. Think for a second. They are a laundry list of Nitric Oxide deficiency syndromes. NO drives your immune system.

The first discovery of NO working was with severe influenza in ICUs with the ARDS syndrome (on ventilators). Those who survived had higher levels. The next discovery was that adding NO to viral cultures of COVID showed that replication of the virus could be stopped in its tracks.

The virus is known to wreak havoc in the endothelium causing localized clotting and catastrophic lowering of your oxygen capacity of your blood. A common observation in the early stages of the COVID pandemic was never-before-seen low levels of oxygen. It was almost surreal as some patients didn't look all that sick. We now know that NO plays a pivotal regulatory role in how well you are oxygenated via a cysteine amino acid on the hemoglobin molecule. No NO, no oxygen carrying, and increased mortality.

SARs, Influenza, and COVID are but three viruses, all that appear to have their severity modulated because of insufficient NO. What about the rest of infections by bacteria? Again, NO is being found to play a virtually central role in response to infections. Macrophages, the garbage trucks of the immune system that gobble up and destroy invading bacteria smother the bacteria with a variety of oxidants, but the cascade is initiated with NO.

There are those who are beginning to refer to COVID as an endothelial disease instead of a respiratory virus. It appears that the spike protein initiates endothelial processes that overwhelm the normal relaxation and smooth blood flow that NO controls.  Clotting of red cells and platelets start, and that slows blood flow, and the normal control mechanisms that guard against that get overwhelmed.  That explains the myriad, bizarre events in COVID like stroke and increased blood clotting in multiple organs.

There are even authors who have suggested that inhaled NO might be a useful strategy but that idea came along too late as the pandemic was winding down and the cost of inhaled NO is considerable. There are also issues with possible toxicity from inhaled NO as too much of a good thing swings things too far and ends up with methemoglobinaemia.

But oral supplementation might be very safe.  In one, as yet unpublished report, 650 severely ill COVID patients were treated with simple oral NO supplementation. Not one died. No side effects were noted. Average oxygen was 14% higher and symptoms lasted one day less than controls. That sounds impressive, but being unpublished means we can't quite depend on it until it is peer-reviewed. But that little note of NO TOXICITY means safety. The lecturer who presented that data stated that he used no masking during the COVID pandemic as he was on NO supplementation for the duration, monitoring his NO daily, eating lots of leafy green vegetables, and never got COVID. Hmm.

www.What will Work for me. What I take away from these ideas is that NO plays a role in controlling respiratory viruses. We lost 12% per decade, making our advanced years somewhat hazardous with a respiratory virus. I've purchased NO boosting lozenges from the N1O1 company and am taking them twice a day. I have also stopped using mouthwash and brushed off my water pick instead. More exercise, more salads, no H2 blockers, and more infrared saunas round out the methods of naturally increasing my own NO. And I think I'll just keep an extra bottle of NO boosting supplements on the shelf to take every couple of hours with my next viral infection. Hope it's a long way away.

References:Jr Virology, European Heart Jr., Med Sci., Signae Vitae, BU. Circulation, JCDR, Jr Virology

Pop Quiz

1. What does NO do to the SARs virus in lab experiments? Answer: Instantly stops it from replicating.

2. What role does NO play in bacterial infections? Answer: More complex but it certainly turns on macrophages to gobble up and work at killing invaders.

3. Do you have enough NO to fight viruses when you are over 50? Answer: All depends on how you view "enough". Certainly, the mortality from influenza and COVID is matched with advancing age.

4. What strategy can you use to increase your NO? Answer: More exercise, more leafy greens, infrared sauna, no mouthwash, no PPIs for GERD, no fluoride toothpaste.

5. Is there any toxicity to taking NO boosters by mouth that work through your natural nitrate/nitrite cycle? Answer: none. Just lowers your blood pressure a little and reduces your risk of stroke a lot.

Nitric Oxide and Your Heart

Nitric Oxide and Your Heart

Half of us will die of cardiovascular disease. Hmm. We are as old as our arteries. What causes our arteries to age? Simple, the lack of nitric oxide. We lose about 12% of our nitric oxide per decade.

We have talked about cholesterol for decades, without really getting anywhere. The question is, what starts the damage to the artery wall that starts the process. The vague term "oxidative stress" is used but doesn't mean much to you. What is that? Essentially it is that very first step of the surface of your artery called the endothelium becoming "dysfunctional". In effect, sticky! And that is driven by lack of sufficient NO. You have too many "reactive oxygen species". You can't clear and get rid of them. You set off inflammatory cytokines (internal signaling messages) that something is amiss. Those three together: oxidative stress, inflammation, and reactive oxygen species are the three elements necessary to start artery damage.

Here is the problem. Nitric oxide declines with aging. By age 40, we are down about 50%. Then, when we exercise we increase blood flow which increases shearing stress on our arteries. In a healthy artery with sufficient NO, that stress is easily withstood. But if your artery is sticky, you get a tiny bit of damage. White cells start to stick, then LDLs and your artery is off to the races

An athlete depends on NO for peak performance. NO increases in robust athletes. If NO drops on exercise, you, by definition will have vascular trouble going on.

Once you have a sticky endothelium, you start getting white blood cells migrating to the injury and LDLs sticking and penetrating the endothelial wall. That's the injury that starts heart disease.

So, can you prevent all that? Well, by all means, yes. You need more NO. We know there are two pathways to make NO. The endogenous pathway goes through L-arginine and two major studies showed that you make people sicker when you give exogenous L-arginine. Oops. Can't do that. That accounts for 50% of our NO production but we can't front-end load until we understand that pathway better.

But the dietary pathway that provides the other 50% of our NO supply, does that work? Well, yes. In a groundbreaking study by Stokes published in 2009 showed that people on an atherogenic diet will have demonstrated white blood cells sticking to their arteries, and when NO is supplied, suddenly the blood flow is fully restored and there is much less sticking, despite the lousy diet.

What is the core of the lousy diet that makes trouble? Simply put, the American Fast Food Diet. Saturated animal fat, sugar, and refined carbohydrates. A trip to whatever burger joint, pizza palace, or ice cream parlor of your choice. Bummer, we like that stuff.

Can we protect ourselves with more NO? Animal studies show that you can occlude an artery for a full hour and show minimal damage to the heart if the animal has sufficient NO. Not only that, there was little damage to the liver either. The study was done in animals that had NO production genetically knocked out proving NO to have a distal endocrine effect in addition to its local chemical effect.

www.What will Work for me. This is mind-boggling. I hear quotes like, "Repairing your NO is the most important health action you can take". I've been flailing around with various beetroot supplements and making teeny, tiny changes from D- all the way up to D+. Hardly a passing grade. But I bought NO supplement from the N1O1 company with 220 mg of NaNitrite per lozenge. My spit test shows I'm up to a C+, B- after the second dose. Ten minutes after it, it showed A-. I'm going to stick with this.

References:Cardiovas Res, Frontiers in Phys, Redox Biology, Circulation, J SportsMed Phys FitPNAS, Jr Heart and Circ Physiology, PNAS, PNAS

Pop Quiz

1. The first step in vascular injury, that kills 50% of us is high cholesterol. T or F. Answer: False. That is way down the road. The first step is endothelial dysfunction.

2. What does endothelial dysfunction mean?                               Answer: You have overwhelmed your body's ability to protect you from oxidative stress/inflammation/reactive oxygen species....all driven by insufficient NO. What then happens is your arteries can't relax when they are meant to relax. So you get high blood pressure.

3. Does endothelial dysfunction (ED) have an effect on the other ED?                        Answer: Yes, in fact, the link between male ED and artery disease is very powerful. Repair of NO gives ED some hope for men and women. (Did you get that?)

4. Are you telling me that the treatment of my NO insufficiency may be more important than my taking my statin?                              Answer: Yup. This is the upstream real cause of heart disease. Cholesterol is a simple money-making adjunct.

5. And last week we talked about mouthwash and PPI drugs both wiping out my ability to make NO? Is that right?                              Answer: Yup. Stop washing your mouth with germ-killing mouthwashes. Brush, floss, water bacteria-killing chemicals. They kill the bacteria in the crypts of your tongue that make nitrite.

Nitric Oxide, The Fulcrum of Life

Nitric Oxide - The Fulcrum of Life

A fulcrum is something on which a process pivots. Ah! That's how important NO is. All three theories of aging, stem cell collapse, oxidation, telomere shortening all pivot on the fulcrum of NO and are actuated and prevented with sufficient NO. NO is so important, that mother's breast milk has more Nitrites and Nitrates (the precursors for NO) in it than any other food, and supplies way over WHO recommendations of consumption for safe health. That's how misunderstood Nitric oxide is. Hence this series on NO. First, we need to debunk its "danger". So, today we just learn what it is. I want to know this.

First of all, what is it? NO is a gas. It is an unstable molecule with an extra electron to give away. That make's it a free radical. But this is the definition of a good free radical. Don't confuse NO with nitrous oxide (N2O, an anesthetic gas) or nitrogen dioxide (NO2, a major dangerous environmental poison). It was named "Molecule of the Year" in 1992 and provided the reason for the Nobel Prize in Medicine in 1998 for the role it plays in vascular health.

Nitric oxide plays a huge role in blood flow. In fact, it has been argued that the delivery of oxygen to tissue is more dependent on nitric oxide levels and blood flow than on oxygen concentration. Levels of nitric oxide predict an athlete's ability to perform more accurately than any other indicator (presuming the same amount of training and hard work!). Levels of nitric oxide predict recovery from a heart attack, blood pressure, stroke, Alzheimer's.

And that's the conundrum. Our ability to make NO declines with aging by about 12% a decade. Hence if you are 60 years old, you only have 30% of the capacity you had as an infant. Without the soothing effect of NO on your vascular tree, you are going to have coronary artery disease. Guess what else won't work? Correct. There is a very high degree of correlation between erectile difficulty and coronary artery disease..... and low nitric oxide.

Here is the nugget of how we make it. There is a nitrogen cycle in nature with atmospheric nitrogen that is oxidized by lightning into nitrates that plants can then use. There is also a nitrogen cycle in humans. It goes as follows. First, we eat nitrates and nitrites from vegetables, mostly green leafy ones. The bacteria in the crypts at the back of our tongues reduce it to nitrites. In our acidic stomach, at least below pH 4, nitrite gets changed into the gas NO. The remaining nitrates are absorbed by the gut into the blood and return, in large quantities to our salivary glands. With our salivary as the main repository of nitrates, we then make saliva and the bacteria in the back of our tongues do their job, reducing nitrate to nitrite. We swallow and our saliva proceeds to our stomach where we make the final end product, NO.

Then, there is a second pathway that makes NO through the breakdown of arginine. That pathway feeds into the nitrogen cycle as well. Curiously, the effort to make more NO through arginine supplementation has not been a resounding success.

Guess what happens when you take mouthwash? Yup. You kill the bacteria in your crypts and your NO goes down and within a week, your blood pressure rises.

Guess what happens when you take PPIs, the most prescribed medication in the world, and make the pH of your stomach neutral with no acid? Yup. In the next three years, your risk of heart attack rises some 20%. Makes sense to be on a PPI and a statin all at the same time, huh!

www.What will Work for me. I'm just learning this. I've seen the pathways for aging that all have NO and the various enzymes that are activated by in cellular oxidation or telomere shortening. But this ideas is boots on the ground in everyday life. I ordered an NO test kit for myself and sure enough, my level was modestly low. So, I ordered Beet Root extract, took two pills and two hours later, sure enough, my level was much higher. My mouthwash just got pitched. I suspect NO and its levels will become one of the most important markers of good health we can follow. And you can test yours at home, cheaply. One minute. And now I understand why the DASH diet and the Mediterranean diet work. They both emphasize lots of leafy, green vegetables, the type that makes more NO. And it has been measured and proven to be the case with both.

References: Wikipedia, The Nitric Oxide Solution, Blood Pressure, PLOS One, Nutrition & Metabolism, Nature Reports,

Pop Quiz

1. What is Nitric Oxide?                 Answer: A gas containing one Nitrogen and one Oxygen.

2. What does it do chemically?                   Answer: It is an electron donor.

3. What role does NO play in aging?                 Answer: All three processes of aging have NO as the key instigator/modulator. (Oxidation, telomere shortening, stem cell fatigue)

4. What happens to our NO levels as we progress through the decades?                    Answer: We lose about 12% per decade. By age 40, we are down 50%.

5. What happens when you carefully rinse your mouth with bacteria killing wash after you floss?      Answer: You successfully kill all the bacteria on your tongue that are helping you make NO. Your blood pressure will rise over the course of the next week. We suspect that same effect happens everytime you take antibiotics for anything. And did you catch that last paragraph above about PPIs?

One Type of Exercise Helps Your Brain the Most

One Type of Exercise Protects Your Brain the Best

In the era of FitBits and ultrasensitive measuring devices, we can now monitor just about exactly whatever you do, all day long. Using that for a useful purpose becomes the next stage of lifestyle research. Wouldn't you like to know if there is any benefit to taking the stairs instead of the elevator? How about walking the dog briskly, or slowly. How about jogging, or folding laundry? Is there a benefit to emptying the dishwasher? Ah! We can now tell you. 

This week's study from the BMJ was all over CNN because it was designed to answer just that question. Movement measuring devices were attached to the thighs of 4,500 mid-life British subjects in the longitudinal cohort study starting in 1970. At age 46, they were offered the opportunity to participate and did. They were studied for 7 days around the clock. They were also tested for verbal memory and executive function. 

Here is the "good news". Moderate activity, of just 6-9 minutes a day, could be shown to assist in better memory, problem-solving and executive function. Moderate activity is something that gets your heart rate up. Biking on the flat doesn't count. Uphill does. Stairs do too....6-9 minutes worth. Aerobic dancing, running, jogging, and swimming all work. Just plain standing, walking around, making the bed, cooking dinner,... those don't do it. It takes a threshold of getting your heart rate up. Now, that explains why 6 minutes of High-Intensity Interval Training works too.

Now, it we can talk you into 20 minutes, that's better yet. But the bottom line, the take-home message, is that your brain will function better with just 6-9 minutes of anything that gets your heart rate up and makes you a bit breathless. (No, that wasn't mentioned.).  And you can tell the difference in just a week.

www.What will Work for me. This is the first study that I've seen that measures mid-life exercise and its effect on "executive function"...decision making. Your brain needs something that exercise provides, and likes a bit more than most of us get. Osteocalcin, the protein that binds calcium and binds it into bone also is known to turn on muscle growth and brain growth. I suspect that is an important link. If you want to go down that rabbit hole, you might be intrigued to understand that osteocalcin is activated by Vitamin K2 (Not K1!). If you can do 40 pushups (men), walk a brisk 3 minute mile (either gender), get up from the ground without touching the floor with your hands, you will live longer. Being fit matters for your longevity, and for a brain to accompany you on the way. My experience is that 25 deep knee bends really gets me winded. I can't do 30 quite yet, but I'm working on it.

References : BMJ,, Women's Health, Cell Metabolism, Nat Rev Endocrin, Jr Bone Miner Res.,

Pop Quiz  

1. You can prove your memory is better with how many minutes of moderate exercise?                       Answer: 6-9 minutes 

2. And that can be measured in normal 46 year olds in how long a period of time?                      Answer: Just 7 days will show a measurable difference 

3. Watching TV and cheering for the Packers counts, doesn't it.                         Answer: No 

(at least not this season). Sedentary couch time, sleeping, standing, folding laundry, may all be noble deeds and worthy of being done...but don't help your brain like exercise 

4. How do I know my exercise is good enough?                                     Answer: Gets your heart rate up and may get you sweaty if the weather isn't too chilly. 

5. Do weights and heavy lifting help?                                         Answer: Indeed it does, just work it enough to get sweaty. Cross Fit can be designed for anyone where ever they are on life's path. Repeated exercise, enough to get you winded and your heart rate up. Your brain will benefit from it.

Vitamin K2 Might be the Holy Grail for Your Heart

Vitamin K2 Might Just be the Holy Grail for Your Heart

The two scourges of modern civilization, osteoporosis, and coronary artery disease. They seem to have skyrocketed together over the last 100 years, concurrently with our remarkable extension of life span. Are we getting more of these two wicked demons just because we are living longer, or has something changed in our environment? Maybe a little bit of both?

Or maybe our world changed. After World War II, virtually every meat producer in America moved their animals off of pastures onto feedlots. Animals that eat grass make Vitamin K2 in their gut from the K1 found in green leaves. There is no K1 in corn and beans. We don't have any measurements from before, but the resultant change is likely hugely significant, probably in part because even with grass-raised animals in our food chain, our prior K2 intake was just barely sufficient, and not enough to be "therapeutic". There is a vast difference between recommended minimum daily requirement and optimal therapeutic requirement.

One of the most common questions I get is "How can I reverse my coronary artery calcium score?" or "How can I fix my osteoporosis?" So, when I come across a story in which an inventive engineer with severe left main calcification completely reversed his calcification with Vitamin K2, I have to pay attention.

Pat Theut, a paper engineer from Up-North, Wisconsin, found severe coronary calcium on an executive physical at the Mayo Clinic. He tried the traditional role of statins and AHA-type advice to no avail. So, he struck out on his own and started reading. Over the next few years, he came up with his own program, centered around much higher doses of K2 (and including regular K1 as well) and reversed his coronary artery disease. Reversed. Gone. Nada. Fixed. And in the process, gave the high dose of Vitamin K2 to his aunt only to see her osteoporosis go away.

K2 activates matrix GLA protein in your arteries. It also activates osteocalcin, the key calcium binder in your bones. Matrix GLA protein binds calcium and pulls it out of your arteries. In fact, there are now emerging studies from Europe showing the more K vitamins you consume, the lower your rate of coronary calcium and coronary artery disease.

The literature is extensive. Even the obverse now seems clear. Take warfarin to prevent blood clots, (a Vitamin K2 antagonist) and observe your arteries turning into rigid, calcified stone.

The implied effect is that the amount of calcium in your arteries predicts the risk of coronary artery disease. And that is true. You don't need an expensive catheterization and its potential risks. You just need a 64-slice CT scanner and 5 minutes. A score of 0 has "0" risk for heart attacks. A score of 400 is dangerous. Getting rid of the calcium starts with Vitamin K2, at least 5 times what is currently available by standard supplement providers. With that in hand, Pat Theut started a company called Koncentrated K at and will sell you just that: 500 mcg of MK7 and 25 mg of MK4 in addition of 5000 mcg of K1. You can't take warfarin with that as the K1 will promptly reverse the blood thinning effect. Read his "Story" and his "Cardiac Manifesto". It's more than just K2. Weight loss, exercise, stress management, and sleep all matter too.

www.What will Work for me? I have been touting the benefit of K2 for 10 years now and feel vindicated by this remarkable anecdote. He is just one person but he emboldens me to push this harder. We have not been successful at reliably reversing osteoporosis or coronary calcium with Super K. It has just 100 mcg of MK7. Not enough. I've even made my own natto so that I can get the benefit of K2 from natural sources (natto is the highest food source of K2) but its flavor is tough to enjoy unless you are born and bred Japanese. But I'm now officially changing my advice for anyone on K2. You are not getting enough with 100 mcg a day. That may meet RDA-type standards, but it is not therapeutic. We are all in a deep, physiologic mess and need MORE. Thank you, Pat Theut.

References: Japanese Natto Association, AJCN, Eur Jr Nutrition,, Cells, J Am Coll Card. ,

Pop Quiz

1. Vitamin K1 and K2 are really, just the same. T or F?                             Answer: Related to some degree but with a completely different side chain, have completely different physiological targets. That is how nature works. Once it finds a working vitamin or hormone, it builds on that base and branches out over time with different effects.

2. If you block K1 with warfarin, what is your chest X-ray likely to look like after about 5 years?               Answer: That's easy. You can see every artery in your entire chest outlined in calcium. I've been in the ER for 25 years and have seen it 100s of times.

3. Where is our food source of K2?                          Answer: It is made in the gut of animals that eat grass.

4. How much of the normal American diet is based on grass-raised meat?                            Answer: It must be in the low single digits.

5. This column suggests we need more K2. How much?                        Answer: Probably 500% more. 5 times. Right. You read it here. Give Pat Theut a high-five after you have read every word of his personal story. Consider that your informed consent.

Create More Happiness for Yourself - Channel Your Inner Finn

Create More Happiness - Channel Your Inner Finn

Ok, ok, not everyone in Wisconsin came from Germany...there have been boatloads of Swedes, Italians, Ukrainians, Poles, Norwegians, and Finns too. But when we hear that Finland just landed "the happiest country in the world" for the fifth year in a row, you might be tempted to ask just what it is that they do. Is our "Finnish" heritage part of why Wisconsin is considered such a welcoming place? Add to their internal happiness, their immigrants end up being the happiest of any immigrants. Something is working right in Finland.

In pursuit of that answer, ask Finland's premier happiness researcher, Frank Martela, just what it is that Finns do to make their country and themselves happy. Here is the list recently published on CNBC.

1. “Kell’ onni on, se onnen kätkeköön.” In English, it means: Don’t compare or brag about your happiness. What that translates into in everyday life in Finland is less showy displays of possessions. You can't tell a millionaire by their clothes or their car. They might be on the bus with you. They certainly won't brag about the neighborhood they live in. Finland has enough lakes and shorelines for just about everyone to live close to water and next to nature. So, you don't have to boast about your place "up north". Finland, after all, is up north.

What that really means is to set your own standards of happiness that you can achieve and be content with who you are. Don't compare yourself to others. You are good enough. And can you help your friends feel the same way? Encourage them to be enough just as they are. Make it infectious.

2. Get close to nature and savor it. Surveys show that 87% of Finns think nature is particularly important. Getting outdoors and taking the 4 weeks of summer holiday that most Finns get away from cities is highly prized. But a walk will do in the park, even in January. Grow a plant indoors. If you can't grow anything, get a bird feeder.  Just notice and enjoy the natural world we live in.

3. Do what you can to increase public trust. Research shows the higher the level of public trust in a society, the happier everyone is. Practice absolute honesty in everything you do. Consider courtesy as your operating system. Drive with kindness and tolerance in your heart. Don't judge the people around you with your first impressions. Practice trusting their goodwill. Let the other guy into your lane. Let the other person go through the door first. Wait your turn in line with patience. Notice how it makes you feel part of the larger whole.

Do you know what happens when you lose a wallet in Finland? You get it back over 90% of the time, with the money in it (11 of 12). (Best of 16 cities studied). Mumbai, India came in at 9/12. New York was only 8/12. Presume goodwill when you speak to the beleaguered customer service person on the phone. Go ahead, be kind, and see if you don't get what you wanted more often. And mostly what you want is a sense of trust and relationship with everyone you meet. Public trust. Nurture it. It's good for all of us.

www.What will Work for me. I've had a lost computer returned to me at Chicago's train station. I remember that as acutely as the time I was mugged in college (The mugger returned my wallet, empty but for my student ID). You know what happened me when I found myself late at night on the train station in St Louis, with only two large, obvious maintenance men there with me, and I didn't have the change to get the train ticket? One of the men gave me a dollar in change. How I wish I had his name. Opportunities to create public trust come up all the time. Be prepared in your heart to give a minute, give a dollar, speak up in kindness, show will be happier.

References: Finland's Characteristics, Wisconsin Historical Society, World Happiness Report, NBER, Reader's Digest, CNBC,

Pop Quiz

1. The happiest countries in the world have the lowest taxes? T or F. Answer: Not asked and not studied, but it could be noted that the highest-taxed countries in Europe are all in the top happiest places to live.

2. Can you think of three ways you can participate in increasing public trust?

3. Can you think of ways that you can feel ok about the choices you make to spend time with your family or friends?

4. What can you do to enjoy nature as we roll through the coldest and darkest days of the year?

5. Will you really be happier in an expensive car?