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
Walnuts83%
Sesame Tahini77%
Avocado77%
Chocolate unsweetened74%
Peanuts72%
Almonds72%
Sunflower seeds72%
Egg64%
Tofu57%
Chicken drumstick53%
Salmon49%
Milk, whole47%
Ground Beef44%
High-fat yoghurt31%
Kale30%
Brown Rice15%
Broccoli8%
Whole Wheat5%
Oranges4%
Lentils3%
Apples0%

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.

1st Age Reversal Results—Is it HGH or Something Else?

Yesterday, the TRIIM study was described in science news headlines around the world, though, through a glitch, the original research paper is not yet on the Aging Cell web site. (You saw it first here.) I refer you to the writeup in Nature’s News section for a full summary of the paper, and in this column I will add my personal framing, and what I know about the study from private connection to its authors and one of the subjects. The big news is setback of the epigenetic clock, by several methylation measures. Instead of getting a year older during the trial, nine subjects got a year younger, on average, based on the version of the Horvath methylation clock that best predicts lifespan. The study had been originally designed to regrow the thymus. (Loss of thymus function has been linked to the collapse of the immune system that occurs typically before age 70.)  Imaging showed that the functional part of the thymus expanded over the course of the trial, and blood tests confirmed improved immune function. The treatment included 

  • human growth hormone (HGH)
  • Metformin
  • Vitamin D
  • Zinc
  • DHEA

It is my belief that the age of our bodies is controlled by several biological clocks. (Greg Fahy, who conceived and conducted the TRIIM study, shares this perspective.) Candidates for clocks include 

  1. Thymic involution
  2. Methylation profile
  3. Timekeeper in the hypothalamus
  4. Telomere length
  5. Perhaps some changing homeostatic state of signal molecules and transcription factors circulating in the blood

This story is about #1 and #2.  To be explicit, I’m saying that the body doesn’t wear out with age, but rather aging is a continuation of the timed growth and development program into a phase of late-life self-destruction. Just as growth and development are under epigenetic control. 

Thymic involution

The thymus is a thumb-sized organ just above the sternum where our immune cells are trained to recognize self from other. It is fully developed by the time we are 10 years old, but after that it begins gradually to shrink, simultaneously losing its functional tissue and filling with useless fat. By age 25, it has already lost 30% of its mass, and by age 60 it is less than half its peak size. There is evidence that this is related to the immune decline that contributes so much to growing mortality risk with age, and that reversing that decline might lead to longer, healthier lives. A healthy immune system is important for fighting infection and for eliminating cancer cells before they become tumors. Immune aging may be related to systemic aging in other ways. (Of course, aging affects the immune system, but it also seems that the immune system may be a driving force in other aspects of aging.)

The thymus shrinks and degrades throughout adult life.

Thus, a rejuvenated thymus might have generalized anti-aging benefits. I first learned this story from Greg Fahy, PhD, chief scientific officer at 21st Century Medicine. and, indeed, he was the first to think of thymic involution as an aging clock, and remains the most enthusiastic and most knowledgable expert on the relationship of the thymus to aging.  Twenty years ago, Fahy experimented on himself, and found evidence that he was able to reverse decline of his thymus with HGH=human growth hormone. Ever since, he has wanted to conduct a clinical trial to see if his N=1 result could be replicated.

Methylation aging

Already seven years ago, several of us were speculating [Johnson; Mitteldorf; Rando] that aging is controlled by an epigenetic clock. Epigenetics is gene expression, which changes from moment to moment, from tissue to tissue, and also from young age to old. There are many modes of epigentic control, but the one best studied and easiest to measure is methylation of the cytosine C’s that appear in repetitive islands (C-G-C-G-C-G-C) in our DNA. (Cytosine is the C in ATCG, the four nucleic acids that form the DNA backbone.) Also at this time, Steve Horvath published the first paper using methylation to measure age; Horvath has led in this fast-moving field ever since. I’ve written [here, here, here, and here] about aging clocks based on methylation. The most important things to know are 

  • The methylation state of a person’s DNA is the most accurate known measure of his biological age. The latest methylation clocks can predict morbidity and mortality even better than chronolotical age.
  • I am among the biologists (still a minority but growing in acceptance) that believe methylation is a prime driver of aging. In other words, changing the methylation state of the body’s cells to a more youthful profile will actually make the body younger.

The TRIIM Study

In 2015, Fahy finally had funding and regulatory approval to replicate his one-man trial in a still-tiny sample of ten men, aged 51-65. That it took so long is an indictment of everything about the way aging research is funded in this country; and not just agingall medical research is prioritized according to projected profits rather than projected health benefits. The protocol included frequent and extensive testing of many aspects of age-related health.  Treatment consisted of

  • Human growth hormone (HGH), 0.015mg/Kg body weight, adjusted individually according to metabolic response. HGH doesn’t survive digestion, so it is self-injected with a tiny needle in the belly 
  • Metformin, 500mg daily
  • Vitamin D, 3000 IU daily (5 times RDA)
  • Zinc, 50mg daily (5 times RDA)
  • DHEA, 50mg

The hypothesis was that HGH would stimulate regrowth in the thymus.  Zinc and vitamin D were added because they are known to enhance immune function.  Metformin, a standard diabetes drug, was added because HGH can cause insulin resistance, a pro-diabetic effect.  DHEA is a proto-hormone from which all sex hormones and steroid hormones can be made in the body; and blood levels of DHEA decline steadily with age. DHEA is linked to both better immune function and expression of IGF1. The TRIIM paper says that DHEA was added to help counteract any tendency toward insulin resistance, but according to Examine.com, DHEA does not affect the insulin metabolism.

DHEA levels decline with age. (figure fr Spice Williams-Crosby)

As the study was planned, the primary endpoint was to be thymus size, and so, at considerable expense, MRI images of the thymus were planned up to 5 times during the 12-month study period. Various blood tests were planned to track other metabolic changes, especially to assure that subjects were not being exposed to increased risk of cancer or diabetes. HGH is weakly linked to cancer risk and more strongly to insulin resistance.

Results

Subjects felt a kick from the daily HGH and some reported temporary weight loss and endurance improvement; but the increase in energy was associated with anxiety and insomnia for some. There was no sustained effect on youthful feeling or appearance.

MRI imaging confirmed that, though the thymus wasnt increasing in size, the functional matrix of the thymus was indeed regrowing at the expense of the fatty, atrophied portion in 8 of the 9 subjects. Several blood tests indicated better immune function.

  • C-reactive protein, a marker of inflammation, decreased.
  • The ratio of lymphocytes to moncytes is an emerging measure of resistance to cancer, and TRIIM subjects showed a decrease in monocytes.
  • Portion of the T cells that wer PD-1 positive went down. PD-1 is a means by which cancer cells shield themselves from the immune system.

This level of success might have led to a modestly encouraging publication, but fortuitously, Fahy made contact with Horvath toward the end of the study, and Horvath volunteered to analyze changes in the subjects’ methylation. (TRIIM had preserved some blood samples from each of the patients at each time point, so this could be done retrospectively.) The result demonstrated a decrease in methylation age, consistent enough to be visible in a sample of only 9 subjects. This was the first time that a treatment in humans led to a setback of the epigenetic clock.

There was no reason a priori to  imagine that HGH would affect methylation age, either directly or through its effect on the thymus. If anything, theorists (including Fahy) imagined that the thymus and DNA methylation functioned as indepdent aging clocks.

Fahy reached out to Steve Horvath, who responded with enthusiasm.  Horvath did the methylation analysis and the careful statistics that could draw significant conclusions from a marginal effect in a small sample.

Methylation testing procedure: white blood cells are run through a kit that measures methylation at 850,000 sites in the DNA. Then computer programs are used to extract an age from some small subset of a few hundred sites. Once you have done the lab work, the difficult and expensive part is over. Calculating several different methylation ages is as simple as running the appropriate software package.

  • At the start of the test, the average epigenetic age of the group was already well below average chronological age. This is presumably because the subjects tended to be highly-motivated anti-aging enthusiasts. Whatever they were doing before the TRIIM study was already working well. By the Levine Clock, they were 17 years (!) younger than their chronological age, and by the GrimAge clock they were 2 years younger.
  • A year of extra chronological age would be expected to add one year to the methylation ages, but instead all methylation clocks registered an average decrease in age.
  • The so-called Grim Age clock, new this year from the Horvath lab, is the best available measure of life expectancy. By the Grim Age clock, subjects became a year younger while their chronological age was a year older.
  • For most of the clocks, the big drop in epigenetic age came during the last three months of the trial (months 9 to 12), raising the possibility that there is a latency period, and a longer trial might produce a bigger drop in epigenetic age.
  • After the trial was over, months 12-18, there was a marginal tendency for epigenetic age to “catch up” with chronological age, a loss of the benefit during the test period. The Grim Age clock, arguably the best indicator, did not regress, but held firm at 18 months.

Summary of methylation data from the Aging Cell article. Click to enlarge.

The Bottom Line

There is no known mechanism whereby HGH is expected to affect the methylation profile. This is not to say that it does not do so, but it is just as viable to think that the combination of vitamin D and Zn is affecting methylation age.

High blood levels of vitamin D and zinc are known to be correlated with lower all-cause mortality and longer life expectancy. Metformin is being investigated in its own right as an anti-aging drug. DHEA has been promoted as an anti-aging supplement for decades, though existing studies indicate DHEA does not increase lifespan in mice. The principal effect of HGH is to increase the hormone IGF1, and DHEA also does this, far more cheaply and over-the-counter, but to a much smaller extent.

HGH is both expensive and theoretically suspect for long-term use. Elevated levels of IGF1 are known to decrease lifespan in rodents; dwarf mice and dwarf humans without IGF1 receptors live longer, healthier lives [ref].  Readers looking to make immediate changes to their personal stack based on the results of this experiment might try the four cheap and proven ingredients, leaving out the HGH for now.

The results are tantalizing, and will certainly motivate follow-up studies, despite the fact that there is no patentable element to the TRIIM protocol. There are five ingredients in the cocktail, all credible, and the interactions among the five are completely unstudied. This first TRIIM study presents good reason to believe that there are anti-aging synergies among some of these ingredients, and it should be an immediate priority to study which among the five are synergizing.



Important, though unrelated news:

Cell phone carriers the world over have plans to roll out 5G technology in the next few years. There is growing evidence that existing 4G technology increases cancer risk, and can cause acute symptoms in sensitive individuals. Lab tests indicate that higher frequency radio waves are a more serious threat. 5G operates in a frequency range ~10 times higher than 4G, and because of absorption in the environment, signals have to be stronger.

(This is not ionizing radiation that can directly break chemical bonds. The biological activity of radio waves is not well understood, but there is a theory that it acts by opening calcium gates in cell membranes, which are a primary mechanism of nerve firing, among other ubiquitous metabolic functions.)

There has been no health testing of 5G frequencies, or if the telecomm companies have performed tests, they haven’t published results. We should be demanding extensive animal and human tests before the technology goes into service.

This weekend, a series of videos about health effects of 5G has been opened at The 5G Summit.