Scaling the Alzheimer’s Cure

This edition of Aging Matters is stolen from Rhonda Patrick’s interview of Dale Bredesen. That hour is so packed with actionable information and theoretical background that I found myself going through it slowly to understand and digest it. The result was an appreciation for the breadth of vision embodied in Bredesen’s comprehensive program to combat Alzheimer’s Disease, and also discovery of some gaps in which the story appears incoherent.

For my own health and to learn more, I’ve personally signed up for the RECODE program as a patient. After the video analysis I talk about my experience.


The RECODE program in a nutshell
from Deborah Gordon video

  1. Diet
  2. Lifestyle
  3. Hormone re-balancing
  4. Supplements
  1. Diet: Low grains, low glycemic, high fats, quasi-ketogenic, anti-inflammatory. Intermittent fasting (e.g., 13 hours overnight fast every day). Eggs are good. Cilanthro is detoxifying. Ketones are good for the brain. Medium-chain triglycerides (MCTs) are a good shortcut to ketogenesis.
  2. Lifestyle: Exercise 30-60 min each day, the more the better. Weights and interval training are particularly good. Sleep 8 hours each night. Challenge the mind with active learning and problem-solving.
  3. Hormones: Estradiol, testosterone (DHEA), Pregnenolone, Thyroid hormones, Progesterone (but not progestins)
  4. Anti-diabetic supplements: Magnesium, Chromium, Berberine, Vinegar, Cinnamon
    Nootropic supplements: Ashwagandha, Gotu kola, Curcumin, Bacopa, NR, Mg Threonate
    Lion’s Mane, ALCAR=Carnitine, Citicoline, DHA=Omega 3, PQQ,

Blood targets:

  • Homocysteine <7 (!)
  • Vit B12 >500
  • CRP <1
  • HbA1C <5.5
  • Insulin < 5
  • Vit D >50, up to 100
  • Zn/Cu >1 and Zn >100

Also from the Deborah Gordon video: The APOε4 allele is the biggest genetic risk factor for AD. It was the ancestral form of the gene, from early hominid history. In European populations, only 15% of genes are ε4, but there are tribes in Nigeria where the APOε4 gene still predominates and, paradoxically, they have low rates of AD, even lower than Nigerians who don’t have the APOε4 allele. (Maybe it’s something they ate.)

A simple blood test or 23andMe can tell you if you have the APOε4 risk factor, but many people don’t want to know. Bredesen’s program offers differential treatment for APOε4 patients, and can greatly reduce the excess risk if started early.


Notes from Rhonda Patrick’s interview with Dale Bredesen

AD is the 3rd leading cause of death in America, after cardiovascular disease and cancer, and it is rising as the population ages and as better treatments become available for the other two. 5.2 million Americans have been diagnosed with AD, and a substantial fraction remains undiagnosed.

Diagnostic markers of AD are tau tangles and amyloid-β placques in the brain. Amyloid-β is a protein byproduct that aggregates into clumps about the size of a nerve cell. Tau is another protein that clogs microtubules, preventing chemical transmissions. Curiously, most AD patients have these markers, but some people have the markers without dementia symptoms, and others have dementia without the markers.

Plaques are pink, Tau tangles black

Spinal fluid taps can be assayed for presence of Amyloid-β, and this is the most sensitive test we have for AD, with an accuracy of 90%

A-β is both a neurotoxin and a neuro-protector, in different contexts. So the theory is that A-β is produced by the brain in response to insults. A-β can neutralize toxic metals and can kill invading microbes. Some people’s brains produce A-β and it successfully protects them, while others are producing A-β though their brains are overwhelmed. One difference seems to be inflammation. Inflammation in combination with A-β creates a strong dementia risk.

Sirtuins and NFκB are mutually inhibitory. The body flips between a pro-inflammatory state (NFκB) and anti-inflammatory (sirtuins), and age almost always tips the balance toward more inflammation (NFκB).

Microglia are environmental brain cells, not neurons, but important to brain function. They are activated in two forms, called M1 and M2

There’s an ideal ratio of M1:M2 = inflammation:resolution = 2.5 

The amount of A-β in the brain comes from a balance between A-β production during glial metabolism and A-β elimination through phagocytosis. That is to say, A-β is constantly being consumed and eliminated by a class of white blood cells. A blood test by George Bernard has shown that almost everyone diagnosed with AD is not eliminating enough A-β via phagocytosis.

Maresins and resolvins are members of a group of cell signaling molecules called SPMs or “specialized pro-resolving mediators.” Many SPMs are metabolites of omega-3 fatty acids and have been proposed to be responsible for the anti-inflammatory benefits of omega-3 in the diet. Patrick says that in her own research she has found that people who are APOε4 positive benefit from fish in the diet, but not from omega-3 supplements. Bredesen speculates that this might be true generally, and that there are anti-oxidants in fish flesh that we haven’t yet catalogued.

How RECODE Works

Bredesen has identified 36 risk factors for AD, and different patients suffer from different combinations of these. The factors break down into just six categories:

Type 1 AD is primarily caused by Inflammation.

The inflammation may come from a variety of causes, for example

  • leaky gut (which also contributes to arthritis)
  • P gingivalis (a periodontal infection that can spread to the brain)
  • Borrelia burgdorferi is the Lyme bacillus
  • Mold and other fungi in the environment

Type 2 AD is atrophic

Some of the nutrients or hormones necessary for nerve growth and synaptic connection are missing. Examples include

  • Estradiol
  • Vitamin D
  • Progesterone
  • Testosterone
  • Pregnenolone
  • Thyroid hormones

In a healthy brain, there is a balance between learning and forgetting, of growing new synapses and recycling old ones. We can think of Type 1 as too much destruction of synapses, and Type 2 as failure to grow new synapses.

Type 1.5 AD is glycotoxicity=too much sugar

Diabetes has two components: depressed response to insulin (insulin resistance) and excess sugar in the blood (because the insulin signal is not being heeded). The excess blood sugar causes Type 1 symptoms, while the insulin resistance causes Type 2 symptoms. There is both too little creation of new neural connections and also too much loss of existing neural connections. Type 1.5 really means a combination of Type 1 and Type 2, and it is associated with metabolic syndrome or diabetes.

Edward Goetzl of UCSF has shown that AD is characterized by insulin resistance in brain neurons even when the rest of the body is not insulin resistant.

Sugars can bind to proteins, gumming them up, creating Advanced Glycation Endproducts, or AGEs. When this happens because of sugar levels that are too high, it’s called glycotoxicity. Hemoglobin A1c is glycated hemoglobin, and it is commonly measured blood tests to assess the extent to which glycation is a problem more generally.

Note: Symptoms for all Types 1, 1.5, and 2 are memory loss, particularly short-term memory.

If your fasting insulin is >4.5 or your A1c >5.5 or your fasting glucose >93, you have insulin resistance, which is the most common, most important, and most treatable condition leading to AD.

“Ketoflex 12/3” is a mnemonic for Bredesen’s basic diet program: (1) mild ketosis, ongoing (2) flexible vegetarian diet, treating meat as a condiment (3) 12 hours of fasting every night, beginning 3 hours before bedtime.

Vegetarian is fine. If adding meat, it should be grass-fed beef or free-range fowl. If fish, the best fish are Salmon, Mackerel, Anchovies, Sardines, Herring (mnemonic: “SMASH”) to maximize omega-3s and minimize mercury.

Beta hydroxybutyrate (BHB) When the body is fasting or deprived of carbohydrates, it switches over to ketones for fuel. BHB is one of the ketones the body burns, and it also signals the body to alter gene expression in a beneficial way.

Bredesen recommends 70% of calories from fat. This is really on the edge of an extreme keto diet, best achieved with a nut-based diet supplemented by salad oil.

% calories from fat
Walnuts 83%
Sesame Tahini 77%
Avocado 77%
Chocolate unsweetened 74%
Peanuts 72%
Almonds 72%
Sunflower seeds 72%
Egg 64%
Tofu 57%
Chicken drumstick 53%
Salmon 49%
Milk, whole 47%
Ground Beef 44%
High-fat yoghurt 31%
Kale 30%
Brown Rice 15%
Broccoli 8%
Whole Wheat 5%
Oranges 4%
Lentils 3%
Apples 0%

The chart gives you a rough idea of what Keto-flex looks like in practice.  Salads with oily dressing are a good staple, since the greens provide fiber and phytonutrients but few calories, and most of the calories are from the oil in the dressing. Nuts are a tasty protein source that keeps the fat intake high. Fruits are bad news. If you eat an apple (0% of calories from fat), you have to expiate the sin with 1½ Tablespoons of salad oil.

It takes a few weeks to switch over from a sugar-burning metabolism to a ketone-burning metabolism. If you try to do it too quickly, you end up with the “keto flu”, headaches, nausea and low energy.

MCT=Medium-chain triglycerides, such as coconut oil, are the best oils for inducing ketosis. They are good for APOε4 negative people, but with APOε4 positive they pose a long-term risk of “bad cholesterol” in the blood. APOε4 positive people should jump-start a ketogenic diet with MCTs, then switch to olive, sunflower, or walnut oil.

During fasting, the body clears out waste outside cells (glymphatic system) and digests waste within cells (autophagy). For people who are APOε4 negative, 12-14 hours fasting each day is sufficient, APOε4 positive 15-16 hours is better.

Type 3 AD is cortical/toxicity

Derives from toxic build-up, heavy metals, pesticides, environmental toxins. Type 3 tends to present with high ratio of copper to zinc in the blood (generally a bad thing) and low triglycerides (generally a good thing).

Copper and zinc compete in the body, and many factors contribute to an excess of copper in modern Western environments (copper water pipes, low stomach acidity). This is one more reason not to take PPIs for common gastric distress or GERD*.

* PPIs include Prilosec and Nexium. Never take PPIs. If you must take PPIs, get off them after a few weeks.  This advice is from Mitteldorf, not from Bredesen.

Zinc is a component of many enzymes and hormones in the body, and contributes to neurogenesis and to a healthy immune system. Low zinc is also a risk factor for type 2 diabetes. High copper:zinc ratio increases inflammation. There are many good reasons to keep your zinc levels high, from male sexual function to enhanced immune response.

Note: Presenting symptoms for Type 3 are more often problems with disorientation, calculations, visual perception, reasoning and word-finding. Type 3 is more common in younger patients, in females, and in people without the APOε4 allele.

Look up more information about Type 3 under Posterior Cortical Atrophy (PCA).

Damp or water-damaged buildings can lead to toxic mold exposure. Aflatoxin is common in our diet.  It comes from grains or nuts that have been improperly stored, and especially from peanuts. Different people can have very different sensititivies to aflatoxin.

Mold contributes to both inflammation and toxicity. You can test your home for mold spores, or test your urine for mold toxins in the body.

Type 4 AD is vascular

The causes and risk factors are the same as for cardiovascular disease, but arterial blockage can affect the brain as well as the heart.  Multiple small strokes lead to loss of function in specific brain areas, inducing idiopathic forms of dementia.

Type 5 AD Traumatic

The same kinds of cognitive symptoms can derive from trauma to the brain, most often from a car accident or sports injury.

 

From the Discussion between Patrick and Bredesen

Herpes virus is a risk factor for AD, possibly because of its inflammatory effect.

Saunas are protective against AD. This is because of heat shock protein, but also because sweating helps the body to eliminate heavy metals. Wash immediately after sweating with a non-oily soap to assure that the toxins are not re-absorbed.

Homocysteine is a risk factor for faster brain atrophy and worsening cognitive decline. The old standard was <13, but Bredesen likes to see <7. How to lower your homocysteine? Eat raw vegetables, take folate supplements = vitamin B9. Caffeine, metformin, and niacin=vitamin B3 can all raise homocysteine levels. The MTHFR gene variant increases homocysteine levels. The amino acid methionine tends to raise homocysteine, but (the chemical relationship) there is no evidence that supplementing with SAMe increases homocysteine.  Betaine is a supplement that decreases homocysteine directly.  (Betaine also increases stomach acid, so it’s appropriate for some stomachs and not others.)

 

RECODE in My Experience

For a new drug or a specific diagnostic test, translation from the laboratory to the field is straightforward. What Bredesen has is something else.  It is a program of diagnostics, leading (through expert analysis and personal counseling) to an individualized program tailored to the patient. Though in principle it should be scalable, it’s a system that resists mass production. This year, Bredesen has partnered with Apollo Health to train a diaspora of specialized doctors, and begin to offer his program for Alzheimer’s nationwide. The program is called RECODE, for REversal of COgnitive DEcline.

Last fall, I enrolled in the RECODE program to learn more about it, and to help formulate an Alzheimer’s prevention program for myself (age then=69). I was frustrated by the unresponsiveness of the Apollo team. They seemed well-intentioned, but overwhelmed by expansion that was faster than they could keep up with. This summer, I tried again, and I also enrolled Ben (85), a relative who has recently moved with his wife to a Continuing Care facility because of early stage AD.

I found that the dysfunctional system had become functional, and that there is now a network of doctors trained in RECODE, including several near my home in Philadelphia. My personal experience has been good. Dr Reina Marino, who worked with me, was attentive and knowledgable and patient with the technical details that I imagine I was the only patient to ask about. In the months that she has been practicing RECODE, she has already seen some patients significantly improved, though no dramatic recoveries to report yet. She hinted that some patients didn’t follow through with the multi-faceted protocols for changes in life syle, diet, and environment. Indeed, I was disappointed to learn that Ben decided that his memory was “not that bad”, and he couldn’t be bothered with the program. On the other end, Dr Marino has been too busy to follow through with me.  My sample of one may or may not indicate that individualized medicine is time-consuming and expensive. On the subject of “expensive”, Medicare won’t pay for RECODE treatment, and my Medicare Advantage plan only covers a small part of the cost.

The RECODE web site for patients is not as friendly as it ought to be. I’m a computer professional, and I still had to get a RECODE staff person on the phone to tell me what needed to be filled out before I could download my test results and find a practitioner. The interface should be re-designed as soon as is practical to be navigated easily by older people who may be uncomfortable with computer systems.

Two more causes for concern

Ben scored 11 out of 30 on the standard MOCA paper-and-pencil test for cognitive impairment. That’s low even for an Alzheimer’s patient (though, to speak with him, one might have the impression that he was functioning at a high level). I was surprised to see that Ben’s blood test scores were better than mine in most areas. Comparing our two test results, it was not at all obvious why Ben should be impaired while I am not. If these tests are designed to pinpoint an individual cause for individual symptoms, then it seemed to me that they did not distinguish well between Ben’s condition and mine.

Link to my personal RECODE report

The initial report scores patients in five areas:

  • Toxicity–mercury, lead, arsenic, mold, pesticides, toxins that build up in the body
  • Glycotoxicity–accumulated damage from too much sugar in the blood
  • Trophic loss–micronutrients and minerals insufficient in the bloodstream
  • Inflammation–from leaky gut or chornic disease burden or autoimmunity or just aging
  • Vasculature–stiff or clogged arteries depriving the brain of sufficient oxygen

In four of these areas, Ben’s score was better than mine (meaning lower risk); only in glycotoxicity did I do a bit better than Ben. The risks are individually ranked for each patient, and both Ben and I were found to be at highest risk for toxicity, associated with Type 3 AD. But Ben’s toxicity was well below my own.

“This is not a one-size-fits-all program. Everyone’s version of RECODE is personalized, based on their test results.”

This has been a hallmark of the Bredesen protocol from the beginning, based on the premise that AD has very different causes in different individuals. It is, of course, the most difficult thing to achieve while the program is moving from the laboratory into the health care system. Differential diagnosis depends on, first, a computer algorithm, and then, the human intelligence of a doctor or other practitioner who has been trained by the RECODE core team.

Despite our very different profiles and different diagnoses (Type 3 for me, Type 1.5 for Ben), the first three steps in our computer-generated recommendations were identical. The section labeled “Your Suggested Plan” was identical for Ben and myself. The greatest risk factor identified for both of us was toxicity, yet the #1 recommendation for both of us was the keto-flex diet. This is congruent with the paradigm promoted by Mayo Clinic and elsewhere that AD is a kind of “type 3 diabetes”. Bredesen endorses this as one piece of a more complex story, so I had hoped for a more nuanced prescription from RECODE.

Reducing homocysteine was the #2 recommendation for both Ben and myself. The medical establishment recommends keeping homocysteine levels under 15, but Bredesen wants us to cut that in half. I have read the section on homocysteine from Bredesen’s book, and it is not clear whether homocysteine is important because of its direct neurotoxicity or because it is a marker of inflammation. After my RECODE interview, I left the Marcus Institute for Integrative Health with a bottle of a supplement formula designed to lower my homocysteine levels by direct and indirect action. Principal ingredients are B vitamins, N-Acetyl Cysteine (NAC) and (this one was new to me) betaine-HCl=trimethyl glycine (TMG). TMG reacts directly with homocysteine, pulling it out of the bloodstream. Are we fooling ourselves if we pull homocysteine out of the blood without reducing inflammation? David Quig says that betaine works great in the liver, but it doesn’t affect homocysteine levels on the other side of the blood-brain barrier. A better alternative for the brain is 5-methyl tetrahydrofolate, a fancier folate supplement than the common and cheap synthetic folic acid. (Note also that folic acid is toxic to people with the MTHFR allele.)

The bottom line

Last year, Bredesen published an account of replicated success in 100 patients that was, if anything, more impressive than the original. Under his close supervision, the Bredesen lab is able to reverse AD with a rate of success well beyond any treatments in the past. The Bredesen system depends on individualized diagnosis and individualized treatment plans, so scaling his methodology for wide application presents daunting challenges.

59 thoughts on “Scaling the Alzheimer’s Cure

  1. Josh.
    “Sugars” can chemically generate AGEs yes.
    But not glucose itself. It has been selected during evolution as the main single carb monomer (summit source of metabolism in us vertebrates) because its CLOSED circular chemical configuration avoids any free carbonyl group reanting with free amino groups in proteins (generating AGEs) and also DNA (scarcely studies but I suspect most inportant. nuclear DNA is strongly crosslinked in old indi iduals, both with other DNAs an nuclear proteins E.g. MDA and NHNEnal , lipid peroxidation products, are stable enough to difuse e.g from membrane and ROS rich mitochondria to the nucleus. Once inside there BIFUNCTIONAL MDA can crosslink DNA and prots.
    But other “sugars” commming from glucose in glycilysis do have free carbonyl geoups e g.the trioses and can generate AGEs. Same for methylglyoxal etc

  2. Great writeup of the Bredesen protocol. I can highly recommend it. I am treating patients with this protocol with good success. If diagnosed early (when first symptoms occur), stopping AD in its tracks is definitely possible. Have seen minor reversions of symptoms as well, if patients ar not too old (usually under 70).

    Holy grail is prevention. This program is not only good for AD but also good for general well being and desiease prevention.

    • I regularly read about the importance of Melatonin but I am surprised by a post today at https://microwavenews.com/news-center/ntp-turns-search-mechanisms, about the implications it may have on Effects of oxidative and DNA damage.

      There is a lot of emphasis on damage from the inside but there is not so much diffusion about causes outside the human being of extreme danger, such as radiofrequency electromagnetic radiation what induced DNA strand breaks https://onlinelibrary.wiley.com/doi/abs/10.1002 /bem. 2250160309

      As I read today, the NTP plans to investigate on gene expression, oxidative stress and DNA damage and repair, as well as on the possible role played by heat.

      The NTP has already reported finding more DNA breaks —as detected with the comet assay— among the RF – exposed animals, including in the brain where rats later developed tumors

      Those results, presented at a conference two years ago, have been submitted for publication. The paper is currently under peer review, according to Sheena Scruggs in NIEHS ’Office of Communications and Public Information.

      A recent review of some 100 journal articles found that more than 90 percent “confirmed that [low-level] RF radiation induces oxidative effects in biological systems.” It was published in Electromagnetic Biology and Medicine in 2016 https: //www.tandfonline. com / doi / abs / 10.3109 / 15368378.2015.1043557.
      In your Microwave News Louis Slesin posting: When they (Lay H. and Shingh N.) treated the rats with melatonin – a natural hormone that neutralizes free radicals – before RF exposure there were no more DNA breaks.
      If the radiation could indeed generate free radicals, they pointed out, the risks would go beyond cancer to include premature aging as well as Alzheimer’s, ALS and other neurological diseases, https://microwavenews.com/news-center/ntp-turns- search-mechanisms

      • Can you present even an iota of data that reveals reduced lifespan due to normal cell phone radiation levels? The oft-cited paper that found weird cardiac cancers in mice after ridiculously high bombardment with such rf also found that the irradiated mice lived longer than the controls. Notably, this unpopular finding was buried in the fine print. While it might be a secondary contributor, we won’t see lines at the emergency room caused by the current generation of phones, despite ubiquitous chronic usage and close contact.

  3. I just want to say that was such a great and very detailed article. I enjoyed reading about your vs. Ben’s experiences and am now considering doing some AD prevention myself.

  4. Alzheimer’s is just one (five? six?) on a terrible list of diseases the elderly face, and the solutions rendered here are complicated, intrusive, arduous, expensive, time-consuming, and somewhat dubious. It is no wonder that Uncle Ben waved it off! Add to this the countless creeping cardiovascular, pulmonary, hepatic, (etc.) diseases, plus other neural diseases, that likely demand different but similarly difficult regimens. Just staying alive in a wrinkled sack for a few more years appears to be a full time job that you pay dearly to hold. It is a little late for you and me, but starting early with approaches that enhance inborn restorative mechanisms seem like a better use of resources.

    • I agree, Walter. There’s an outstanding question whether Bredesen’s protocol is more than AD prevention, a multi-benefit anti-aging program. I suspect that it is, and I’m encouraging Bredesen to collect methylation data to see if it pans out.

  5. From all the anecdotal evidence ketogenic diet seems to work, at least short term anyway. However, the reason why ketogenic diet works might not be due to the high fat/ low carb composition. It might be due to the avoidance of toxicity of glyphosate in seed crops and arsenic in US grown rice. Practically all seed crops have been sprayed with glyphosate as desiccate before harvest in the US and Canada. Glyphosate upsets gut flora, hence all the health issues resulted from it. Another reason why ketogenic diet works might be due to the fact it’s low protein. Low protein content means less antigens entering blood stream, therefore less inflammation. I have tried a 30 day white rice and blueberry only diet (with Thai or Indian rice cooked in a way to minimize arsenic content). It’s amazing how fast the low-grade pain disappeared. I noticed dramatic improvement by day 5. Of course it’s not only low protein, but also low fat, low calorie (800 calorie, 90/2/8 carb/fat/protein). People in Blue Zones don’t eat ketogenic diet. So I would think it’s fair to say that long term (30+ years) effects of ketogenic diet is still unknown.

    • Thank you, Cassia. A lot of good ideas here. I know that low protein, carb-based diets work for some people and can be (paradoxically) anti-diabetic. I am interested in toxicity of glyphosate, which has become ubiquitous in recent years. It’s easy to believe that glyphosate studies are being actively suppressed.

    • Cassia,

      I’m wondering about the diet.

      Why white as opposed to brown rice?

      Why just blueberries? Wouldn’t other fruits and vegetables (broccoli for example) do just as well?

      Wouldn’t organic rice – like Lundberg – be better?

      • The purpose of the 30 day trial was to eliminate poison rather than uptake nutrition. Brown rice, especially US grown, regardless organically or not, contains high arsenic. Also brown rice contains higher protein, especially lectin, which is a potential allergen. I was trying to see if I can lessen my allergies without doing an actual water fast. Unfortunately allergies are the last symptoms to improve. Why blueberry? I did it in July in Canada, so fresh blueberry was abundant. If I have access to pomegranate, I would probably pick pomegranate over blueberry. Broccoli is too high in protein. I tried to keep protein under 10%.

      • The diet is inspired by Dr. Walter Kempner‘s rice diet. It’s designed as a cure rather than a long term food intake. Basically every day for 30 days, I ate 200 g of white rice and 200 g of fresh blueberries. In my case, it lowered my blood pressure. I had a low grade pain/stiffness on my upper left body from neck to shoulder to left arm. By day 5 on this diet, the pain practically disappeared. When it comes to allergies, my morning sneezing is less frequent and I haven’t had a breakdown that I must take an antihistamine pill. But allergic symptoms haven’t disappeared.

        • I too suffer from allergies and looked at the rice diet a while ago but never tried it. Maybe I should take another look at it. I’m pretty much normal weight so the allergy and inflammation results would be more significant for me.

          Thanks.

    • One point about arsenic in US grown rice that you correctly mentioned: it is a worldwide issue. I live in Cambodia and there is the same, if not higher, level of arsenic in brown rice here and the rest of Asia, if the rice is wet-grown instead of dry grown, which it rarely has been since the changeover to wet field grown rice going back over one thousand years in Asia. Arsenic comes from the soil and it seeps into the water, then the rice, as the rice is growing in the water flooded rice field. Milled white rice has lost some nutrients and bran when it is de-husked, but also has lost nearly all the arsenic. Eat the boring white rice folks- arsenic accumulates in the body and the brown rice is just NOT safe.

      • and what if we don’t eat rice? as in the Palaeolithic diet, without grains, remain green leafy vegetables, sweet potatoes, potatoes, nuts and a little meat, fish.

        • After my 30 day white rice & blueberry diet, I started to add back foods one by one. I was shocked to find out that I couldn’t tolerate well to sweet potato and all the very sweet fruits (grapes, banana, mango etc.). Fortunately all leafy vegetables are OK with me, so is seafood. Maybe only those like me who suffer from autoimmune problems have more food intolerances.

  6. The link to the Bredesden video was a fail for me. Try this:
    https://www.youtube.com/watch?v=Sq7uVZ_0D3U

    I’ve seen what seems to be some valid criticisms of his work.
    I’m a lay person trying to make sense of all the divergent views. Keto does not appeal to me for many reasons. And it seems like naturally we would not follow any protocol 365 days a year. And seasons change and resources would vary.

    I’m also not keen on all the supplements. And “super foods” mentality.

    Is there a middle of the road path that an individual might be able to follow without the personalized medical approach/

  7. ‘This is really on the edge of an extreme keto diet, best achieved with a nut-based diet supplemented by salad oil…’

    I’ve done keto and this particular recipe looks …difficult. In fact it looks like starvation!

  8. Men shoud be careful taking estradiol as it keeps rising after age 50 and I beleive it is a pro-aging hormone in men. Life extension foudnation wrote some article after researching it and suggested increasing estradiol levels in men was a big risk factor for triggering prostate cancer.
    Also how did they leave melatonin out of this mix of hormones??? That seems like extreme negligence to me>>Josh any reasoning behind this? and as I recall the first version of the Bredsen protocol had mealtonin in it. Melatonin has been found to revese menopause in women just entering it. It sdrops dramtically around age 50 which is the likely trigger for menopause. And there was that Brazilian twin study where two identical twins got AD at the same time. one took 6 mg of melatonin per night for sleep , the other did not. After 3 years the melatonin taking twin had not progressed while the non-melatonin taking twin had become a total invalid. Also are you ignoring the mouse model of AD study where melatonin + excercise halted the progression of AD?
    It was shown and confirmed by the NIH that increasing levels of LH (which occur after menopause) drive AD, and guess what melatonin does? it suppresses LH by at least 40% if you take a high enough dose. I wrote a book on melatonin and one on Alzheimers they are mostly the same book…if you are curious you can find them on amazon.

    • Oh I forgot to add-if one had read my book on melatonin or Alzheimer’s they would have learned that eating 3 tablespoons of coconut oil per day for a month in a young man, boosted his pregnenolone levels by 100%!! I never bought the medium chain fatty acid hypothesis of why coconut oil was good for Alzheimer’s I figured it had to be a hormonal effect=that is why I did the experiment. FYI pregnenolone is known to be the “memory hormone” and led to aged mice improving their abilty for memory tasks to the equivalent of young rats.

  9. Great article as always. Thank you. I only regret those ads all around the page. They greatly lower the credibility of your site, Josh. If I send a link to someone who doesn’t know you, he will immediately point out that you write this for profit. Please consider implementing some easy to use donation system instead (if possible).

  10. I searched but couldn’t find methylene blue on this site.

    Have you seen this https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3265679/?log$=activity

    “After more than a century, Ehrlich’s key observation of the high affinity of MB for nervous tissue has been rediscovered in investigations revealing significant effects of MB as a memory-enhancing and neuroprotective agent. Specifically, MB has been reintroduced as a potential pharmacotherapy in mild cognitive impairment (MCI), early Alzheimer’s disease (AD), Parkinson’s disease, Leber’s optic neuropathy and other neurodegenerative disorders bearing in common fundamental deficits in mitochondrial function. MB not only has great affinity for nervous tissue, it has also been recognized as one of the most potent chain-breaking antioxidants (Ohlow and Moosmann, 2011). Recent evidence supports that MB effectively improves memory in healthy animals and humans. “

  11. Hi M, the Chinese parsley “cilantro or coriander” was used in China by miners to not suffer so much damage when breathing metal dust of all kinds.
    The wives prepared the food to the husbands with this herb (it is a chelator). Look for the protocol of use – it has its contraindications – and make simple what some pretend to complicate.
    In the book The Ancient Indian System of Rejuvention and Longevity, we explain how to use all the herbs that have been prescribed to our esteemed researcher but with the mode of ingestion. For example, to rejuvenate with a diet of Ashwagandha you should take 3 mashas -3 gr.- in the morning and evening with warm milk and can mix it with honey. But you should do it every day, at least for a year. For every Chinese or Indian herb there is a mode of administration. In the West the powder is taken as if it were medicine but it is incorrect. I would also recommend taking Ganoderma lucidum. Cordiceps sinensis is very expensive but worth a try. Obviously Shilajit replaces more than a dozen supplements but it must be pure -care- and has its own taking protocol.
    Good luck.

  12. Apples are bad, yet they contain Fisetin. Brown rice has been found to have high levels of arsenic, yet it is recommended. Coffee contains liw level carcinagens, yet the American Alzheimers Association recommends up to 6 cups a day for the prevention of this very disease discussed today. Sorry, but this is yet another solid study chalk full of contradictions to previous rock solid studies. As always, confusion reigns and many recommendations from Doc B will no doubt change. The weight training is always good, safe advice, but running is missing.

  13. I am 67yo and have one APOE4 allele. I am open to drastic changes in lifestyle but I have seen what happened with peers who went low carb. They succeeded in losing weight but their skin turned grey and their hair lackluster. Having seen this happen I am not surprised by the arguments put forward only yesterday by dr. Greger about muscle loss by keto diets. Dr. B.’s approach might be good for alzheimer’s but probably not for muscle loss and methylgloxyl.

  14. From my personal experience I feel PQQ anti-imflamating action only when taking it together with astaxanthin (4mg daily is sufficient). In cold and flu it’s stronger than paracetamol + phenylephrine in Coldrex MaxGrip (in flu twice daily 20mg of PQQ and once daily 4mg astaxanthin). What is your experience with this supplement mix?

  15. Hey Josh, could you do a commentary on Sinclair’s new book? I was horrified by some of the basic errors (he thinks that somatic cells can grow for “40 to 60 doublings” in culture… I’ve taken BJ cells up over 105 cell divisions myself with no genetic meddling). And of course he does a commercial for NMN because he hopes to end-run the NR patents… but I was intrigued by the idea of inducible Yamanaka vectors, he sees that as able to really reverse aging.

    • How did you take the doublings that high? I’ve generally only seen such results when including certain ‘cheats’ in the culture, such as feeder cells, ROCK inhibitors, nicotinamide, or using low O2 perhaps.

      It’s interesting that Sinclair has pivoted to reprogramming as a ‘real’ treatment for aging (as opposed to Sirtuin stuff, which at best can probably only slow it down).

          • There are 46 human clinical trials completed and ongoing on NR, so we’ll have a pretty definitive answer as to whether you need it in addition to NAM soon. It does raise NAD+ more… that’s why there are all those trials 😉

  16. I’m having trouble reconciling recommendations for plant based diets and recommendations for keto diets. High fat vs low fat. In theory, you could do keto with plants based by using a lot of seeds and oils (like this approach) but I’m not sure how practical that is for a long term.

    It seems obvious that the worse possible diet would be high fat and high carb.

    High protein is probably not good except a little more protein for older people is probably a good idea.

    I’m about ready to throw up my hands and go back to a simple balanced diet watching the calories and going for organic and whole foods with smaller amounts of meat and fish.

  17. What benefits can be expected from ignoring AGE evidence?
    For examples, the types of fish and 70% calories from fats recommendations start at AGE Medium levels and go up, depending on the methods of food preparation. A healthy human body’s capability to eliminate the resultant AGEs is easily overwhelmed, and the overflow AGEs are subsequently stored to the detriment of several of the cited health markers.

  18. I think Keto is just another hype. For 25 years I’m committed to a diet that has stood the test of time – Paleo diet. It has just done good to me.

  19. Hello everyone. A couple of quick questions to any/all who care to respond. Recently I started taking “Nutricost Betaine Anhydrous Trimethylglycine (TMG) along with Nutricost N-Acetyl L-Cysteine (NAC) 600mg, 180 Capsules – Veggie Caps, Non-GMO, Gluten Free. My understanding that you need to take B-vitamins with this to get the best effect; I am concerned that most of the products containing both seem to go over-board on the B-vitamins. I already take one a day for men with B-vitamins wonder if that is sufficient? Secondly I also recently started taking Berberine (I am not diabetic so I likely can’t get prescription Metformin) Would it be advisable to take Fisetin with this also?

  20. This is a fresh paper from Nature Communications

    Ageing affects DNA methylation drift and transcriptional cell-to-cell variability in mouse muscle stem cells

    They look at epigenetic drift at single cell level.
    I havent yet read it through but seems very interesting.

    • Most important finding

      While old stem cells show a slight increase in their DNA methylation age, this lags far behind their chronological age. DNA methylation-based age predictors are built with data from bulk tissues that represent a mix of different cell types. It is plausible that small changes in cell composition during ageing could affect the epigenetic age of a tissue2. Stem cells, which generally decrease in number during ageing might be one of these cell populations. Consequently, the epigenetic clock might be a measure of the different proportions of stem and differentiated cells in a tissue.

        • Another interesting finding, that resonates well with earlier some papers, is that ECM related gene expression varies most significantly between cells as the mice age.
          There was a paper earlier on in which old muscle stem cells could profilerate well in young ECM. In my view totally in line with this new paper.
          Also most age related pathologies are related to ECM like atherosclerosis, skin wrinkles, spinal disc problems, myopia, etc.
          My intuition is that ECM related gene expression has weaker feedback control processes than cell internal gene expression, so this is the first thing to go astray.
          Similarly to epigenetic pattern which might not have a clear template so it is hard to repair.

          • It makes you realise how un realistic it is to grow cells in a dish and call it ‘aging’. Clearly cells grow in an environment that is quite different. I expect ECM degradation and cell function are linked, possibly through cell shape and the cytoskeleton.

      • Thanks for sharing Gabor. This is something that I’ve been wondering in relation to non proliferating tissue and the DNAm clock. Particularly muscle and nervous tissue. They show a similar rate of advance of epigenetic age despite their limited proliferation.

        I’ve always wondered if that’s because they’ve sampled proliferative cells present in the tissue as well, particularly white blood cells. I’ve looked into the methods of some of the papers but haven’t found a clear answer.

        To my mind, there’s still an open question as to what makes the clock tick, and whether cell proliferation is one or THE mechanism that causes it to move forward. The Ake Lu paper on the GWAS and hTERT last year seemed to connect the two in vitro. Curiously with non-immortalized cells stopping their epigenetic age after they exhausted their proliferative potential, hTERT inmortilized cells continuing to increse it, and quiescent cells standing still and at a very young age. Perhaps pointing to proliferation and not metabolism as the central driver of DNAm age advance.

        And if quiescent cells retain a very young eAge it may follow that dormant stem cells may also have a younger eAge. So the evolutionary purpose of stem cells may be the preservation of epigenetic state. So indeed, a relative depletion of stem cells may result in an increase of the eAge of a tissue.

        Then again, I believe stem cells are relative rarer in for example nervous tissue. So why does the clock not capture this as an older eAge in those tissues? In fact the cerebellum appears to be relative younger in epigenetic terms.

        • Maybe eAge captures both growing to an adult and growing old. Because both take time and eAge is a linear regression of some markers to age. But at the cellular level the two are different.
          Division can drive the growth clock, metabolism the age clock.
          We should take a deep dive into the data ourselves if we really are to understand it.

          I think the imporant finding here is that stem cells remain much younger than the surrounding tissue.
          Also that the first thing where age related changes start to take effect is the extracellular matrix.
          Maybe if we could clear out the “old” molecules from ECM, we could get an easy way to healthy until 100 or 120 when stem cell aging and exhaustion can really take effect.

          • Hi Gabor. I may be reading too much into that particular study. But looking at the rate of eAge advance it seems strongly coupled with cell doublings and hTERT immortalization. Non immortalized cells slowed down and stopped proliferating and concurrently stopped their eAge flat. Quiescent cells did not increase their Age at all.

            Also, this was an in-vitro study which managed to make the eAge progress way faster than in vivo. Conditions on a dish are of course much different than in live tissue, but I don’t think the metabolic rate alone can be that different (estimated epigenetic age of 50 after 159 days), more than a hundred times fold.

            This leads me to believe that proliferation and moving through cell cycles is what makes the clock tick.

            I agree that the ECM is a major driver of the ageing phenotype. At least at it relates to skin and bone. But maybe not so clear in muscle waster and inmuno-senescence. To my mind though, the process starts at the cellular disregulation level. Reduced ECM protein turnover and maintenance leads to damage accumulation.

          • Interesting Adrian.
            But why Extracelular Matrix (your “ECM” means that?) should strongly drive aging in skin and bone but not in sk. muscle (or heart)?

            THAT “sounds” incompatible with notion that in Biology (as in everything else), Diversity (of tissues in this case) only on the surface looks different, whereas on the deep, in essence, everything is the same” (Parmenides, “sic”).

            E..g. Men frogs insects and jellyfish can be considered different manifestations of the same thing: BACTERIA.

          • Hi Gustavo, rather than a driver, I was thinking of ECM deterioration as a direct cause of some of the ‘cosmetic’ ageing phenotype. Some of the most visible one in humans.

            The ECM makes a larger part of skin or bone than other tissues such as muscle. The loss of bone mass, skin thinning, loss of collagen, flattening of the dermis-epidermis contact layer, all can be associated (partly) to ECM deterioration. That’s not to say that ECM disregulation does not result in pathologies in other tissues, just that the association is perhaps less immediate.

            But I don’t think ECM damage accumulation initiates this process. I believe damage is allowed to build up through reduced tissue turn-over after a change in gene expression.

            I agree that we are just a highly derived uni-cellular colony. But the ECM is precisely one of the things that differentiates us from uni-cellular organisms (most of them at least).

            Since we have already established that uni-cellular lines can propagate indefinitely, one could argue that ageing in multi-cellular organisms results from a failure to repair the ECM over long periods of time. This seems to be one of the positions of the ‘wear and tear’ theory. I don’t believe this, but one can make the case. Think of AGE’s accumulation for example.

          • Hi Adrian,
            Quiescent cells might remain young epigenetically in vitro, but we know they don’t in vivo. Therefore they must ‘age’ because of their environment, perhaps other proliferating cells that they are dependent on, for example. For example, if we replaced all the old and senescent astrocytes in the brain with young replacements, to what extent would we rejuvenate aged neurons?

            I guess it all depends on how you define ‘quiescence’ too. A fibroblast that no longer divides but sits there for a lifetime churning out collagen is quite an active cell and I would expect it’s epigenetic age to advance as a consequence.

  21. Cinnamon has very weak evidence for keeping blood sugar low. I’d not bother with it, though it does have a chemical in it that increases PINK1 which is important for marking dysfunctional mitochondria as part of the cleanup process I think. I’ll have to double check though.

    My main issue here is keeping my blood sugar down, it’s so hard to avoid the tasty things like ice cream and brownies, which is basically my favorite. I try to stay mostly keto in my diet tho but my love for sugary desserts really hurts my efforts.

    • Have you tried Comarum palustre and/or Gymnema sylvestre? The first makes body sensitive to insulin again (thus significantly lowers sugar), the second lowers sugar (but less than comarum) and allegedly regenerates pancreas.

  22. Interesting the comments on NAC. I increased supplementation for other reasons and it is the only time I could get my homocysteine at 10, yes, still too high, maybe giving a try with TMG and of course the B vitamins. I am ApoEe3. Even with TMG I never succeed over 13 years to bring it lower than 10, maybe not too aggressive?

    • B6 is what helps convert homocysteine to cysteine. Interesting that having higher cysteine levels made your homocysteine goes down – maybe it increases the conversion back to methionine?

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