A cure for Alzheimer’s? Yes, a cure for Alzheimer’s!

This is the most important column I’ve ever written.  The message is quite complex–dozens of new health parameters to test for and to optimize, all of them interacting in ways that will require new training for MDs.  The message is also as simple as it can be: There is a cure for Alzheimer’s disease. You can stop reading right here, and buy two copies of Dale Bredesen’s book, one for you and one for your doctor:  The End of Alzheimer’s.


Dr Bredesen’s spectacular success is easily lost in a flood of overly-optimistic, early hype about any number of magic cures.  This is an excuse for the New York Times, the Nobel Prize committee, and the mainstream of medical research, but it’s no excuse for me.  I’ve known Bredesen for 14 years, and I’ve written about his work in the past.  His book has been out for a year, and I should have written this column earlier.

I suspect you’re waiting for the punch line: what is Bredesen’s cure?  That’s exactly what I felt when I read about his work three years ago. But there isn’t a short answer.  That’s part of the frustration, but it’s also a reason that Bredesen’s paradigm may be a template for novel research approaches cancer, heart disease, and aging itself.

The Bredesen protocol consists of a battery of dozens of lab tests, combined with interviews, consideration of life style, home environment, social factors, dentistry, leaky gut, mineral imbalances, hormone imbalances, sleep and more.  This leads to an individual diagnosis: Which of 36 factors known to affect APP cleavage are most important in this particular case? How can they be addressed for this individual patient?

Brain cells have on their surface a protein called APP, which is a dependence receptor.  It is like a self-destruct switch whose default is in the ON position.  The protein that binds to the receptor is a neurotrophin ligand, and in the absence of the neurotrophin ligand,  the receptor signals the cell to die.

APP cleavage is the core process that led Bredesen down a path to his understanding of the etiology of AD 16 years ago.  APP is Amyloid Precursor Protein, and it is sensitive to dozens of kinds of signals, adding up the pros and the cons to make a decision, to go down one of two paths.  It can be cleaved in two, creating signal molecules that cause formation of new synapses and formation of new brain cells; or it can be cleaved in four, creating signal molecules that lead to trimming back of existing synapses, and eventually, to apoptosis, cell suicide of neurons.

In a healthy brain, these two processes are balanced so we can learn new things and we can forget what is unimportant.  But in the Alzheimer’s brain, destruction (synaptoclastic) dominates creation (synaptoblastic), and the brain withers away.

On the right, one of the fragments is beta amyloid.  Beta amyloid blocks the dependence receptor, so the receptor cannot receive the neurotrophin ligand that gives it permission to go on living.  Beta amyloid is one of the 4 pieces, when the APP molecule goes down the branch where it is split in 4.

One of the signals that determines whether APP splits in 2 or in 4 is beta amyloid itself.  This implies a positive feedback loop; beta amyloid leads to even more beta amyloid, and in the Alzhyeimer’s patient, this is a runaway process.  But positive feedback loops work in both directions–a boon to Bredesen’s clinical approach. If the balance in signaling can be tipped from the right to the left pathway in the diagram above, this can lead to self-reinforcing progress in the healing direction.  In the cases where Bredesen’s approach has led to stunning reversals of cognitive loss, this is the underlying mechanism that explains the success.

Amyloid has been identified with AD for decades, and for most of that time the mainstream hypothesis was that beta-amyloid plaques cause the disease.  (Adherents to this view have been referred to jokingly as BAPtists.) But success in dissolving the plaques has not led to restored cognitive function.  In Bredesen’s narrative, generation of large quantities of beta amyloid are a symptom of the body’s attempts to triage a dying brain.

 

To tip the balance back toward growing new synapses

Having identified the focal point that leads to AD, Bredesen went to work first in the lab, then in the clinic, to identify processes that tend to tip the balance one way or the other.  He has compiled quite a list.

  • Reduce APPβ-cleavage
  • Reduce γ-cleavage
  • Reduce caspase-6 cleavage
  • Reduce caspase-3 cleavage
    (All the above are cleavage in 4)
  • Increase α-cleavage (cleavage in 2)
  • Prevent amyloid-beta oligomerization
  • Increase neprilysin
  • Increase IDE (insulin-degrading enzyme)
  • Increase microglial clearance of Aβ
  • Increase autophagy
  • Increase BDNF (brain-derived neurotropliic factor)
  • Increase NGF (nerve growth factor)
  • Increase netrin-1
  • Increase ADNP (activity-dependent neuroprotective protein)
  • Increase VIP (vasoactive intestinal peptide)
  • Reduce homocysteine
  • Increase PPZA (protein phosphatase 2A) activity
  • Reduce phospho-tau
  • Increase phagocytosis index
  • Increase insulin sensitivity
  • Enhance leptin sensitixity
  • improve axoplasmic transport
  • Enhance mitochondnal function and biogenesis
  • Reduce oxidative damage and optimize ROS (reactive oxygen species) production
  • Enhance cholinergic neurotransmission
  • Increase synaptoblastic signaling
  • Reduce synaptoclastic signaling
  • Improve LTP (long-term potentiation)
  • Optimize estradiol
  • Optimize progesterone
  • Optimize E2:P (estradiol to progesterone) ratio
  • Optimize free T3
  • Optimize free T4
  • Optimize TSH (thyroid-stimulating llormone)
  • Optimize piegnenolone
  • Optimize testosterone
  • Optimize cortisol
  • Optimize DHEA (deliydroepiandrosterone)
  • Optimize insulin secretion and signaling
  • Activate PPAR-γ (peroxisome proliferator-activated receptor gamma)
  • Reduce inflammation
  • Increase resolvins
  • Enhance detoxification
  • Improve vascularization
  • Increase cAMP (cyclic adenosine monophosphate)
  • Increase glutathione
  • Provide synaptic components
  • Optimize all metals
  • Increase GABA (gamma-aminobutyric acid)
  • Increase vitamin D signaling
  • Increase SirT1 (silent information regulator T1)
  • Reduce NF-κB (nuclear factor kappa-ligllt-chain-enhancer of activated B cells)
  • Increase telomere length
  • Reduce glial scarring
  • Enhance stein-cell-mediated brain repair

This explains why no single drug can have much effect on AD; it’s because the primary decision point depends on a balance among so many pro-AD (synaptoclastic) and anti-AD (synaptoblastic) signals.  Addressing them all may be impractical in any given patient, so the Bredesen protocol is built around a detailed diagnostic process that identifies the factors that are most important in each individual case.

Three primary types of AD

Bredesen’s diagnosis begins with classifying each case of AD into one of three broad constellations of symptoms, with associated causes.

 

Type I is inflammatory. It is found more often in people with carry one or two ApoE4 alleles (a gene long associated with Alzheimer’s) and runs in families. Laboratory testing will often demonstrate an increase in C- reactive protein, in interleukin-2, tumor necrosis factor, insulin resistance and a decrease in the albumin:globulin ratio.

Type II is atrophic. It also occurs more often those who carry one or two copies of Apoε4, but occurs about a decade later. Here we do not see evidence of inflammatory markers (they may be decreased), but rather deficiencies of support for our brain synapses. These include decreased hormonal levels of thyroid, adrenal, testosterone, progesterone and/or estrogen, low levels of vitamin D and elevated homocysteine.

Type III is toxic.  This occurs more often in those who carry the Apoε3 allele rather than Apoε4 so it does not tend to run in families. This type tends to affect more brain areas, which may show neuroinflammation and vascular leaks on a type of MRI called FLAIR, and associated with low zinc levels, high copper, low cortisol, high Reverse T3, elevated levels of mercury or mycotoxins or infections such as Lyme disease with  its associated coinfections.  

(This box quoted from Dr Neil Nathan’s book review)

There’s also a Type 1.5, associated with diabetes and sugar toxicity, a Type IV, which is vascular dementia, and a Type V which is traumatic damage to the brain.
These categories are just a start.  The patient will work closely with an expert physician to determine, first, where are the most important imbalances to address, and, second, which of the changes that cna address them are most accessible for the life style of this particular patient.

 

Success

Bredesen wrote a paper in 2014 about successes in reversing cognitive decline with his first ten patients.  As of this writing, he has treated over 3,000 patients with the protocol called RECODE (for REversal of COgnitive DEcline), and he claims success with all of them, in the sense of measurable improvement in cognitive performance.  This contrasts with the utter failure of all previous methods, which claim, at best, to slow cognitive decline.

Translation to the millions of Alzheimer’s patients will require training of local practitioners all across the country.  A few doctors have already learned parts of the Bredesen protocol, and Bredesen’s website can help you find someone to guide your program, but you will probably have to travel.  The first training for doctors is being organized now through the Institute for Functional Medicine.

 

Implications

This is a new paradigm for how to study chronic, debilitating diseases.  Type 2 diabetes comes to mind as the next obvious candidate for reversal through an individualized, comprehensive program.  Terry Wahls has pioneered a similar approach with MS.  Cancer and heart disease may be in the future.

I’ll go out on a limb and say I think Bredesen’s protocol is the most credible generalized anti-aging program we have.  (Blame me for the hyperbole, not Dr Bredesen — he has never made any such claim.) Could we adopt Bredesen’s research method to accelerate research in anti-aging medicine?  Perhaps biomarkers for aging (especially methylation age) are approaching a point where they could be used as feedback for an individualized program, but Horvath’s PhenoAge clock will probably have to be 10 times more accurate to be used for individuals.  Averaging over ~100 individuals can give this factor of 10 in a clinical trial.  Still, we don’t have the kind of mechanistic understanding of aging that Bredesen himself developed for AD before bringing his findings to the clinic; and this is probably because causes of aging are more complex and varied than AD.

Disclaimers:  I’m pre-disposed to think highly of Dale Bredesen and his ideas for 3 reasons.  He was a friend to me, and gave me a platform when I was new to the field of aging.  He believes that aging is programmed. And his multi-factorial approach parallels the research I have advocated for researching other aspects of aging.

Rhonda Patrick interviews Dale Bredesen on FoundMyFitness

100 thoughts on “A cure for Alzheimer’s? Yes, a cure for Alzheimer’s!

  1. Hello there
    I saw the protocol when it was first published on the Buck Institute website…
    Which has been removed, I think to drive patient traffic to Bredsen and co.
    That protocol included MELATONIN which I do not see in the protocol above. Melatonin will cause changes in many other hormones such as suppressing Lutenizing Hormone which has been implicated in Alzheimer\s disease buynis not mentikoned above. Melatonin also causes an increase in progesterone which is very neuroprotective adn declines with age. Years before this protocol Brazilian doctors were stopping Alzheimner\s form progressing with just melatonin supplemenbtation at night. Recently there was a study showing that melatonin and exercise reversed dementia in a mouse model of Alzheimer’s. Whhy don’t you ask Bredsen what happened to the melatonin in te original protocol? And why he has not identified :LH incrteases plus progesterone decreases after age 50 as a prime driver of Alzheimers?? If he truly has identified various subtypes of Alzheimers that’s great . It just looks a bit complicated to me and the removal of melatonin from the protocol does not make sense to me as I am ujnder the impression that melatonin is the active hormone doing all the heavy lifitng in Alzheimer\s reversal.If they are hiding the melatonin I am guessing they might want to make the protocol hard to follow without a physician. Possibly the melatonin is hidden behind the “optimize progesterone” part of the plan. I wrote a book all about it and here is the link>>>>

    https://www.amazon.com/dp/B007SHFRSS

    ALZHEIMER’S TREATMENTS THAT ACTUALLY WORKED IN SMALL STUDIES! (BASED ON NEW, CUTTING-EDGE, CORRECT THEORY!) THAT WILL NEVER BE TESTED & YOU WILL NEVER HEAR ABOUT FROM YOUR MD OR BIG PHARMA !

    • Melatonin is part of the treatment for some patients — I don’t know if it’s just a few or almost all. Read the book. The protocol is evolving as Bredesen gains more field experience and learning from it. But it’s already the only game in town — real cures for people who have been given only palliatives in the past.

      • Josh, While Melatonin may not be an AD cure, the studies you link to actually note some significant benefits. Moreover, the doses given were relatively low (3mg – 9mg). Jeff recommends much larger dosages. In any case, if I understand Jeff’s logic correctly, much of benefit of Melatonin comes from the downstream increase in other hormones (eg progesterone, etc), and decrease in others (i.e. LH, FSH). It would be interesting to see how Bredesen’s protocol modulates those factors. In the end, we may be talking about many of the same bio markers being affected.

        • Hello Amando

          My book will be free for the next 5 days you can find it on amazon..

          in it you will learn that

          -melatonin can be used as birth control in women at 5 mg per night..so I reccomend 120 mg per night for men just to adjust for weight differences

          -melatonin peaks at night but the peaks almost dissappear by the time we hit 60 years old

          -fasting/starvation boosts melatonin levels which explains how CR slows the agng process and prevents reproduction, it does this through dramically boosting melatonin levels

          -Suppressing LH in women stops AD progression, while boostng progesterone in men will halt the progression this explains how coconut oil might be benficial for AD-

          -A docotor wrote a book about coconut oll curing her husbands dementia, she clamied it was the ketogenic and short chain fatty acid aspects that were important. I did not believe it, had a 30 yearold guy measure his pregnenolone levels before and after a month of eating 3 tablespoons of cocnut oil per day>>>>his pregnenolone levels doubled! Pregenenolo e is know as the memory hormone and is the direct precursor to progesteorne, the most neuroprotective substance known to man!

          -Much Much more in the book get it!! free

  2. Sounds enormously expensive. To what extent is AD reversed? Do people come back functional? Why would you think, given the proposed mechanism, that this is in any way, anti-aging (truthfully we use some of the same reasoning in some of our approaches), but what other evidence is there of rejuvenation, rather than the ‘cure’ (to be seen, how long does it last, does it take life-long ‘adjustments’? And the little things, like activating PPR-gamma and TERT, how are they effected, not to mention changing the concentrations of the all the hormones, peptides, cytokines etc. In ways this seems a bit like the ‘bio-similar’ approach to duplicating the blood composition of a young person, which seems to have some effect. Gratitude is not a good reason for accepting evidence. Everyone wants to cure AD (us too), but I can’t see how this will translate to tens of millions of people. I believe there are better ways- even here, which of the components are unnecessary to produce the desired effects, just going through them combinatorially to see which could be eliminated would take a lifetime, maintaining the levels of expensive biologicals in the blood over long periods of time would be extremely labor-intensive and expensive.

    • It’s too early to have any idea how much it will cost. It’s still being done as an extension of a research project. The treatments themselves are not expensive, even in aggregate. Lab tests are just a few thousand dollars–less than a week in a nursing home. The big cost is the expert guidance. Within a few years, we will have a national corps of professionals trained in this specialty. After that, maybe an AI system that makes individualized diagnosis both cheaper and more accurate.

    • As to my claim that the Bredesen protocol is anti-aging and not just anti-Alzheimer’s, I am out on a limb here, trusting my intuition. The intuition is based on the fact that so many of the components overlap with other anti-aging regimens (e.g., glutathione, vitamin D, low-sugar, sleep hygiene, immune health), and also to my belief that the brain plays a role in regulating the rate of aging.

  3. I believe the issue of Alzheimer’s and neurodegeneration to be far more simple from a pathophysiological perspective. Alzheimer’s is fundamentally caused by aldehyde toxicity stemming from one or a combination of alcohol intake, diet (i.e. high carb/low fat), candida infection, tobacco, and diminished capacity to weather oxidative stress due to ageing. Bizarrely enough, I believe a physiologically sound hangover cure is the only way to halt its progression. The problem is, from a capitalistic perspective, that the same ‘aldehyde detoxification protocol’ (combining ALA, NAC, nicotinic acid, vitamin C, zinc, sulforaphane etc.), would be integral in so many other NDCs (autoimmune disorders, degenerative disorders, even, I expect, cancers), that industry does not want to acknowledge such a basic principle. I’ve written about it in my less than scientific blog.

    • @Joshua
      “Alzheimer’s is fundamentally caused by aldehyde toxicity stemming from one or a combination of alcohol intake, diet (i.e. high carb/low fat) ”
      How do you explain the low rates of dementia in the well studied “Blue Zone centenarians”

      High complex carb/low fat and protein is a proven longevity diet.

      • Complex carb yes, but the vast majority of people consume their carbohydrates in the form of sugars and other less healthy carbohydrate sources (we know this). I was not familiar with the concept of blue zone centenarians, but after looking it up it is clear that all of these places are islands (Sardinia, Okinawa etc) where it is safe to assume that the prevailing diets incorporate fish (high fat/protein) on a regular basis. Similarly, ‘the Okinawan diet has only 30% of the sugar and 15% of the grains of the average Japanese dietary intake.’ I do believe a diet high in fat, high in protein, and high in micronutrients (i.e. a ketogenic diet) to be the most restorative diet in individuals who have been chronically undernourished and have become immunocompromised. For everyone else, a balanced diet void of simple carbs. I’m just stating what we know already.

  4. Alzheimer’s is fundamentally speaking caused by aldehyde toxicity, whether from diet (high carb), alcohol, smoking, candida, unhealthy vegetable oils etc… An aldehyde detoxification protocol mirroring that of a physiologically sound hangover cure is the most obvious approach to halt it’s progression. ALA, NAC, nicotinic acid, zinc, selenium, molybdenum, vitamin C, glutamine, glycine, taurine, beta alanine. The same protocol would be invaluable in almost every NDC in the developed world.

    • The problem with ALA and NAC seems to be dosing. These anti-oxidants are very helpful at therapeutic dosages. However, larger dosages over long term are counterproductive and my cause more harm than good.

      • Yes, this is true. I don’t think massive doses need to be given for there to be a therapeutic benefit. And I suppose the whole point of a protocol combining multiple antioxidants is that it is complementary and therefore minimises the risk of anti oxidative stress. You still need sufficient quantity for there to be a therapeutic benefit. NAC is a tricky one. It’s an amino acid, and you get much larger quantities of cysteine from a protein-based food source anyway. It seems dosing in the case of supplements has merely been dictated by how much can fit into a capsule, rather than any actual scientific rationale. I assume taken in isolation it exerts something of a therapeutic benefit over a natural food source. ALA I’m not sure about either. Again, with any supplementation protocol you have to be weary as to whether or not by supplementing you diminish the body’s own capacity to produce things itself. But that logic can also be used to assume that certain diets and ageing itself weaken the body’s capacity to produce these antioxidants endogenously, and therefore it becomes necessary to supplement in these scenarios. That is the case for any disease caused by aldehyde toxicity (autism, autoimmune disorders, alzheimer’s etc…).

        • If something works, you can be sure about it. If on the other hand, half of the ingredients are superfluous you can get the same benefits at half the cost, but which ones are superfluous is the problem. What I’m wondering is whether this is a life-long program requiring continuous treatment or not? Changing the blood composition is what this is all about, changing it to ‘ideal’ concentrations of components, which I assume (‘assume’ makes a ‘ass’ out of ‘u’ and ‘me’) are the concentrations present in the blood of healthy young people. But, as Steve Hill once wrote to me, “Blood plasma is weak tea.”, and so it is. The real solution is to reverse aging.

          • All these compounds contribute in some way to the apparatus by which we protect ourselves from the damaging effects of aldehydes. I don’t think it should be a lifelong protocol at all. Obviously there are times in life when we succumb to higher levels of oxidative stress than others, and its about being able to recognise that and act accordingly.

            It’s about ageing better for me, not so much about reversing ageing. A lot of people continue to drink alcohol in old age in what is likely a subconscious effort to speed up their own demise. But then a lot of people simply succumb to misinformation and are let down by the system. If you truly want to reverse ageing (by that I mean tap into the body’s restorative mechanisms) then it would require, I believe, a combination of a simple ketogenic diet (high in eggs, meat, fish, aged cheese and green vegetables), aldehyde detox supplements (as and when detox is required), regular cold exposure/cryotherapy, saunas and exercise (some high intensity, some low intensity).

          • If that diet reversed aging, everyone would know about it. Ketogenic diet makes sense but it does not produce miracles. No, I’m talking real youth again, everything else is just slowing the decline and has the untoward effect of extending senescence. Do I think it is possible? Yes.

          • That all depends on your definition of youth. It is metaphysically impossible to reverse the ageing process unless you are referencing the philosophical view of eternal return?

          • Metaphysically impossible? In your metaphysics, perhaps. What are the laws of metaphysics? Rejuvenation has occurred in the ‘real world’.

          • Let’s not get into metaphysics at this time in the morning (in the UK).

            Clearly complete rejuvenation is possible on the cellular level as many papers have shown (Yamanaka factors, RNA splicing factors, immortalization through telomerase). It ‘only’ remains to demonstrate this in a vastly more complex organism fully of nested levels and feedback loops.

          • It’s effectively a choice between a lifetime of anti-oxidative stress or a lifetime of oxidative stress. Or something in the middle. It’s really that simple. I liken anti-oxidative stress to being a superhero, and a lifetime of oxidative stress to being something more akin to a villain, except to each individual the other person has an alternative view of what is good, and what is bad. Philosophy teaches us that the right path is, invariably, something in the middle. But if you truly want to ‘reverse’ the ageing process (i.e. achieve something close to immortality), if such a thing exists, I assume you would need to follow a path of anti-oxidative stress.

          • Cells can die of oxidative stress or of reductive stress, look it up. The cell daily cycles between extremes of reduction and oxidation (of its cytosol) in what is called the circadian cycle. Although most believe this to be a TTFL mechanism (Transcription Translation Feedback Loop), that Rube Goldberg contraption lies atop a more primitive mechanism, measured by the oxidation state of the hugely abundant cytoplasmic protein, peroxiredoxin. This alternation between oxidation and reduction of peroxiredoxin occurs in the complete absence of DNA (in red blood cells) and appears in all kingdoms from Archaea to Animal.

          • Okay then, rejuvenation on the organismic level? Remember that experiment where there was a time-limited, sequential expression of Yamanaka factors in old rats (or mice?,engineered, of course) that reset the ages of these animals? I’m sure some readers do. How about the work of Cai, Dongsheng in injecting stem cells into the hypothalmus to rejuvenate animals and extend their lives? And the work of the Conboys showing how parabiosis rejuvenated stem and progenitor cells of many types – work added to by Amy Wagers and Saul Villeda. Even McCay in the 50’s showed evidence for organismic rejuvenation by parabiosis, and Ludwig, in the 80s demonstrated lifespan extension by these means.

      • You are certainly right that there is a requirement for both oxidative stress and a more reduced state. For example oxidative stress (via fractured mitochondria) is required to signal differentiation requirements to stem cells, but in time this can exhaust them. On the flip side, a reduced state with enlarged (fused) mitochondria is the signal for stem cells to divide symmetrically and recover their numbers. A vastly longer and healthier life is possible if one can balance these two requirements – but I suspect one will always run out of functional cells eventually without having these supplemented from time to time, for example with exogenous stem cell injections, or in vivo rejuvenation of old cells. I honestly don’t think we’re that far away from these treatments being possible and efficacious.

        • Yes. It becomes a self-perpetuating cycle. The notion that to gain immortality you have to drink the poison essentially. This logic can be applied to many aspects of life, and humanity. And it is frankly absurd.

        • Yes, the important parameter to look at is redox potential – the redox potential of the cytoplasm and nucleus become more positive (more oxidizing) with age,while the ER, which requires a more oxidizing environment to work properly in its job of proper protein folding, becomes more negative, or reduced with age. This is a biomarker few use but it seems very dependable, can be approximated by the amount of GSH in tissues and/or the GSH/GSSG ratio, and I think points to the causes of cell-autonomous cell death in aging organisms. Of course, aging is not cell autonomous

          • I like the notion of reductive stress. Which is why, I assume, it is important to engage in physical activities that cause oxidative stress when following a protocol that increases the body’s anti-oxidant capacity…effectively, doing the same things a younger person might do, triggering the signals that require the body to adapt to environmental stresses (as mark suggested). You can’t just swallow a pill and expect to stay young. Its a lifestyle choice encompassing diet/supplementation, physical activity, breathing techniques, heat/cold exposure, as well as avoidance of toxicity (principally, sources of aldehydes/heavy metals). And equally important is mental stimuli of course. There is no such thing as a magic pill.

          • I don’t, however, agree with the use of exogenous stem cells as part of any protocol unless ethically bioengineered

          • I’m afraid I don’t understand your objection to exogenous stem cells unless engineered, is your fear that they might be a ‘black market’ in these tissues?

          • We can now make pluripotent stem cells out of any somatic cell in your body Joshua – so no need to worry about using embryos to keep us young!

  5. Wow! This is the reason I am a regular reader of Josh’s blog. What a gem. I was completely unaware of Bredesen’s work and without Josh’s brilliantly short explanation I would have missed the importance. I agree with Josh this seems to be the best current approach and success in anti aging. I am personally even more thrilled because one of the strategies of our team of scientists is based on exactly this: multifactorial action to rebalance back to levels as seen in youth. I will be buying and devouring this book asap.

  6. Josh is right in my opinion.
    I am treating patients very similarly to the Bredesen protocol (in Germany) and I see more or less the same results.
    Patients ARE getting better, typical symtoms can be halted and in many cases reversed. I don’ think the significance of this has been appreciated. Big Pharma will hate this.

  7. Increasing telomeres, reducing oxidative stress and NF-kB, increasing insulin sensitivity, increasing glutathione, increasing stem cell mediated repair, etc., etc…..

    This IS pretty much a recipe for addressing every cause and symptom of aging.

    • That’s very interesting. What biomarkers in particular have you found to be instructive and what treatments to bring those biomarkers back into range have you found to work?

      I also have an autistic son.

      I’d be grateful if you’d drop me an email:

      [email protected]

  8. I had a thought….
    when you find something that is unpatentable that can cure a particular condition and you want to make money off of your discovery, you have to hide it in a confusing mix. I have a freind who runs a biopharma plant and figured out that Lactoferrin was a sugar that when taken every day clings to the inner walls of one’s bladder and makes it harder for bacteria to attach and cause a UTI. He added a bunch of othe substances to it and is now selling it to doctors a an alternative to antibiotics. Of course he gets a great price for the product because it works in most cases. BUt it really has only one active ingredient, and the rest ot the ingredients cold be considered a smoke screen, Just some food for thought. If I had to guess , I would say melatonin is the active ingredient in the Bredsen protocol.

      • NO!! Josh !!!
        you are misinterpeting this abstract..they are only talking about how mletonin helps people with alzheimers sleep/// In the last sentence they add>> Melatonin treatment seems to constitute a selection therapy to ameliorate sundowning and to slow evolution of cognitive impairment in AD patients.

        And the one identical twin study they mention is one of the cases studies I use to MAKE the case that melatonin STOPS the progression of Alzheimers…it was about 2 identical twins who got alzhiemers at the same time one took 6 mg of melatonin per night for sleep the other did not…the melatonin taking twin remained at his starting point (FAST scale 5) where he just needed help picking out his clothes. The control twin who took no melatonin declined to the point fast (7B)where he could not contol his bladder/bowel..could not lift his head could only speak in a few grunts about a 7 word vocabulry….So you obvioulsly just breezed the abstract If you want a full translation of the original study it is reprinted iin my book on AD !!! And I always thought you were a careful researcher!!

      • who is this oboxious hyena kirk? is this someone hiding behind a troll name? take alook at my last posts…or why dont you send me your email address and ill send yo a fsree copy of the book you schmuck

      • Yewah Kirk the Jerk…

        I make a fortuine off of selling the ebook for 2.99 at amazon yeah that must be my motive…..

        ok everybody my melatonin/alzheimers ebook (EDITED by the Dr Ward Dean) will be free at amazo for the next 5 days and you dont even need a kindle to read it amazon wil.l just give you a free reading ap

        here is the link>>>>
        https://www.amazon.com/dp/B007SHFRSS

        ALZHEIMER’S TREATMENTS THAT ACTUALLY WORKED IN SMALL STUDIES! THAT WILL NEVER BE TESTED & YOU WILL NEVER HEAR ABOUT FROM YOUR MD OR BIG PHARMA !

        • I started taking melatonin only because of Jeff Bowles research. From night one felt good next day. Even if I miss a night sleep is normal so it is not causing dependency. I am at 10 mg only because when I tried 20 mg the next day felt quite sleepy. I know I have benefited due his research – thank you Jeff.

      • Melatonin is a hormone that controls many other hormones so could it affect all 55 things that Bredsen has identified? Absolutely and much more….And if you just accept all 55 items tha t he identified as crucial and necessary you must be quite naive…He is just throwing everythinjg and the kitchen sink at the problem…It sounds more lije a smoke screen to me to hide the active ingredient melatonin.(and maybe excercise) . did you notice he promotes fasting also? What does fasting do? Boosts melatonin. He suggests one make sure progesterone levels are correct>> What does melatonin do? It causes you to make more progesterone…etc etc.. I f he did not make it complicated and require docotors to come pay for training in the protocol how could he make a nickel off of it??? I beleiv he has treated more than 3,000 patients so far….HMMM let me see 3,000 x $2,000 =- 6 million! There is a reason doctors all drive fancy cars.

        • Jeff, what a cynic you are! That’s pretty hard training physicians, really labor intensive, not the best way to make money – selling e-books is easier, (no offense). So I’m not saying, and don’t believe that it’s being done for the money, but getting money for doing a technically difficult and laborious process is not wrong or unusual. The human body is a complex machine with trillion, trillion moving parts that’s way beyond our understanding. Pressing a button here, turning a knob there produces interesting results, like savages fooling with the controls on a TV, and your ‘technique’ of pushing a button has hard as you can for as long as you can, might sometimes produce good results. I think though we’re beginning to understand the underlying machinery however – and there will be more ‘focused’ approaches, I believe that’s happening now. We may present at the A4M meeting in Vegas, mid-Dec. then maybe I can give an example or two. As you say, there are many factors which control wide varieties of genes – transcription factors, mTOR and other kinases (ATM, Akt etc.), histone modifiers, and modified histones as well the miRNA families. Picking the proper subset to target is the trick.

          • HAHA HArold yes you are right I am a cynic..As I have been ripped off before…By a Dr Richard Bowen and the editor of rthe journal who published my first paper on aging. You can see right in the abstract I made the prediction that suppressing LH would be a good treatemnt for Alzhedimers Disease….It was accepted for publication in november of 97 after being in review for 1 year or so…Oddly 3 months befoe the paper was accepted a Family Practie MD in Florida who had been treating overweight people in his 10 Phen Fen diet pill clinics suddenly had an inspiration. He figured out that giving Lupron to peple with Alzaheimers would stop it in its tracks and he filed a use patent on the idea! This was the beginning of Voyager Pharmaceuticals that raised 50 million to do a phase II study about suppressing LH with Lupron to stop Alzheimers. It worked in women but not in men so the compabny went under just when it was filing its IPO to raise another 100 million. i was able to find the link between my editor David Horrobin and Dr Bowen…..a one Goran Jamal (Horrobins assistant) and nanacy Rossman, Richard Bwen’s neighbor.the funny thing is that Bowen claimed a man with AD who got Lupron shits for his prostate cancer had a miraculsous recovery..noone could ever find this patient, and it turns out it does not work in men! HAHAHA. So could I see another doctor doing something unethical? Easy for me to see

          • Jeff, you know a bit about my history, you know I was ripped off too. But, there’s no use complaining about the way world is, the best thing to do is to try to make the world a better place, at least that’s the way I look at it. I found people to work with in India (and I seem to have been destined to live in India my entire life), and it’s been amazing – I hope to give you (everyone), results soon (and I have them) that will knock your socks off. I believe I have proven everything I’ve said about aging, in the best possible way. I’ll end it the way ‘The Count of Monte Cristo’ ends “Attendre et esperer.” “Wait and hope.” The answer is so simple and obvious, it’s given as a hint in the Bible, I’m not religious (not an atheist either), but the hints are so obvious in retrospect, remind me to tell you them in a decade (or better, in a hundred years); the hint is the Tree of Life in the garden of Eden is guarded by a fiery Angel.

  9. I see a number of items on the list are optimize something. I assume optimize means not too low, not too high.

    One caught my attention in particular: Optimize all metals.

    What kind of metals are talking about? This can be quite a long list. Are some more important than others?

  10. @Jeff Bowles,

    Jeff, you are married to Melatonin. No doubt, melatonin is useful and part of the tool box. BUT: No single substance will work in Alzheimer. I have read your book but it is a misguided idea to hunt for the “wonder drug”, negating the complexity of the disease.
    I am seeing patients every day, treating them by and large with the Bredesen protocol and they ARE getting better. No other approach comes even close, imho.
    Werner

    • I thought Jeff was ‘married’ to vit D3, or maybe LH? This melatonin obsession is new. Melatonin is good, and maybe melatonin is a preventative for brain degeneration – as sleep itself may prevent many disorders. The differences as I see them between this Josh-vaunted treatment (the translation from ten patients to three thousand may not be so seamless) is that (and I agree with this) this treatment recognizes the non-cell autonomous nature of aging, recognizing that aging is to an extent controlled by the body (through hormones, cytokines, etc. not the cells, and agrees with aging as a ‘programmed’ process, a process of post-adult ‘development’. What I wonder is how substantial the benefits of this treatment are, have these people been tested in an objective way? Are there other age-biomarkers indicating changes towards as youthful phenotype?

    • ok werner look into the history if a company called Voyager Pharamceuticals…they [atented the (my) idea of using Lupron to treat alzheimers by suppressingf luteinizing homrone..they spent 50 million on phase II studies and found this single magic bullet prevented the progression of Alzheimers in a grou[ pf women

      Unfortunately it did not work in men, so the project went belly up. I know why it didnt work in men, Alzheimers has different hormonal drivers in m,en and women…..melatonin addresses both of these hormone changes. Alzheimers in men is driven by progesterone decline…not LH increase

    • and why will a single substance not work on alzheimers? a single molecule cured Hep C….a single vaccine [revents polio….whaty you mean to say i think is that you believe that single substance has not been found yet and might be difficult to find….I disagree

      • And Werner how can you call melatonin a single substance? That might be true for say a vitamin like vitamin C..but melatonin is a hormone what do hormones do ? Control genes many many genes clock genes, apoptosis genes, dna damage repair genes, mitosis genes, etc,,,AND it also controls the levels of many other hormones like progesterone tetsoterone estrogen LH FSH etc and each of these hormones control lots of genes…So to say melatonin cant work because it is a “single substance” is nonsense. Just look at vitamin D3 it has been found to control or affect 2,700+ genes!!!! And yes , like melatonin d3 is a hormone not a vitamin!

  11. “What kind of metals are talking about? This can be quite a long list. Are some more important than others?”

    Copper is neurotoxic, so this is important. Often zinc is low and copper high. Then the heavy metals like mercury, cadmium etc.
    A chelation protocol is useful for flushing out the heavy metals.

  12. When does one have Alzheimer’s Condition?
    When we hit our forties, memory declines. For instance, I have always been good at memorizing what other people make lists for by tagging it in my mind. I can no longer do this. Is this Alzheimer’s? Would this protocol help?

    • Bredesen is recommending testing for everyone around age 45. Metabolic tests can detect the beginnings of AD decades before the first symptom, and changing life habits early can mean that the symptoms never materialize.

    • Laura:

      If your are only in your 40s and experiencing obvious memory deficits, it could be due to nutritional deficits or blood sugar issues (both low or high)

      Have you had your blood sugar evaluated by a nutritionally savvy doctor?

      If not, it is a good idea to do so. Make sure they check for long term blood-sugar parameters and short term. Both hypogylcemia and hyperglycemia.

      Memory loss is not always Alzheimers.

      Josh’s article has helpful suggestions as do some of the comments.

      Also smoking, of course, is detrimental because of toxic additives, although pure nicotine from gum may help memory.

      A small amount of alcohol may be helpful, while too much alcohol is detrimental to cognition.

      Exercise is helpful to prevent cognitive decline because obesity is a major inflammatory factor and inflammation hastens disease as was stated in Josh’s article.

      Healthy fats including EPA DHA Gla helps cognition, as do other nutrients that reduce inflammation.

      IMO, nutrients are most beneficial as a preventive approach. So the sooner you start the better.

      There may be a few nutrients that can reverse disease processes, but most work best as a preventive.

      Also head or brain injuries can cause memory deficits, even if they occur early in your life.

    • guess happens in your 40 s and 50s

      dramatic declines in the memory hormone pregnenolone.
      a decline of the neuropprotective hormone progesterone to about 0 in women at menopause, and
      a huge crash in your master control/ anti aging hormone melatonin and a crash in the neurosteroid DHEA just google any one of these hormones and the word aging then click on images and you will see what I am talking about

  13. This is an email I received from Dr Bredesen last night:
    — JJM

    1) We have a paper in press, due to appear 10.22.18 (open access, JADP, I’ll send a copy as soon as available), showing 100 patients with documented improvement—some with MRI volumetrics improved, others with quantitative EEG improvements, others with evoked response improvements, and all with quantitative cognitive assessment improvement. Some are very striking—12 point improvements in MoCA, for example—others less so, but all also have subjective improvement. Hopefully this will address some of the criticisms that we haven’t documented improvement in enough people.

    2) We were just turned down again for a randomized, controlled clinical trial, so on the one hand, we are told repeatedly that no one will believe that this approach works until we publish a randomized, controlled study, and on the other hand, we’ve been turned down (first in 2011/12, and now in 2018), with the complaint that we are trying to address more than one variable in the trial (as if AD is a single-variable disease!). Something of a catch-22. We are now resubmitting (unfortunately, the IRBs are not populated by functional medicine physicians, so they are used to seeing old-fashioned drug studies), and we’ll see what happens.

    3) I’ve been extending the studies to other neurodegenerative diseases, and it has been impressive how much of a programmatic response there seems to be in these “diseases.”

    4) I agree with you that there are many features in common with aging itself.

    5) You made a good point that APP is a dependence receptor, and in fact it functions as an integrating dependence receptor, responding to numerous inputs (Kurakin and Bredesen, 2015).

    6) In the book and the publications, we don’t claim it is a “cure” since we don’t have pathological evidence that the disease process is gone. What we claim is “reversal of cognitive decline” since that is what we document.

    7) As I mentioned in the book, AD is turning out to be a protective response to multiple insults, and this fits well with the finding that Abeta has an antimicrobial effect (Moir and Tanzi’s work). It is a network-downsizing, protective response, which is quite effective—some people live with the ongoing degenerative process for decades.

    8) We have seen several cases now in which a clinical trial of an anti-amyloid antibody made the person much worse in a time-dependent manner (each time there was an injection, the person would get much worse for 5-10 days, then begin to improve back toward where he/she was, but over time, marked decline occurred), and this makes sense for the idea that the amyloid is actually protecting against pathogens or toxins or some other insult.

    9) It is important to note that we’ve never claimed that all people get better—this is not what we’ve seen. People very late in the process, or who don’t follow the protocol, or who don’t address the various insults, do not improve. It is also turning out to be practitioner dependent—some are getting the vast majority of people to improve, others very few, so this is more like surgery than old-fashioned prescriptive medicine—you have to do a somewhat complicated therapeutic algorithm and get it right for best results.

    10) I’m very interested in what is needed to take the next step in people who have shown improvement but who started late in the course. For example, we have people now who have increased MoCA from 0 to 9 (or 0 to 3, etc.), with marked subjective improvement but plateauing at less than normal. These people had extensive synaptic and cellular loss prior to the program. So what do we need to raise the plateau? Stem cells? Intranasal trophic support? Something else?

    11) I haven’t yet seen a mono-etiologic theory of AD or a mono-therapeutic approach that has repeatedly positive results, so although I understand that there are many theories and treatments, there doesn’t seem to be one etiology to the disease, nor does there seem to be one simple treatment that works for most. It is much more like a network failure.

    • This is a very interesting post and I’m working my way through the book. I can appreciate Dr. Bredesen’s dilemma with regard to a controlled trial. The medical community at large is very skeptical of anecdotal reports, even with large numbers. The problem here, and with any anti-aging study as well, is that the disease itself has multiple etiologies and the treatments are patient specific and involve multiple interventions according to the individual. This does not lend itself to a well controlled placebo study where one intervention, usually a drug , is placebo matched and there are no intervention changes over the course of the study. So I doubt that one would ever get this past an IRB.

      That being said, we also know that even the best studies are not foolproof and are often not able to be replicated, not to mention the financial biases that are all too often present with pharmaceutical companies.

      It has been my experience that when a physician presents his case studies it is almost always done in good faith, and is an honest reporting, and shouldn’t be rejected out of hand.

      It is my impression that Bredesen has made a major contribution in halting, or even reversing this terrible disease, and I hope that internists, geriatricians and neurologists will sit up and take notice.

      • Dear Paul, I appreciate your efforts and I’m sure your patients do too, but there’s a question I’ve asked a couple of times without response: if the treatment is discontinued for a time, do the patients revert? That is, is this a lifetime treatment or can it be discontinued after a time, or perhaps, what is the length of the time the patients will remain lucid (are they?) after treatment ends? Of concern to me at least is how much this treatment might cost on a monthly basis. It seems very labor-intensive, but of course some of your testing and dosing could be automated… From what I’ve experienced the costs of the tests themselves would be in the thousands even if you buy the reagents and do them yourselves, add to that the costs of reagents for adjusting blood concentrations for all those factors quantified.
        Not that I’m trying to diminish your accomplishment, it does validate much of what many of us believe about aging/AD. I think there’s a better way, but you are perhaps like the Montgolfier brothers who proved the principle of human flight, though it took considerable time to come up with the powered, heavier-than-air planes that made flying practical. Of course, we all want to see the results, and we all want to see this work.

        • Hi Harold

          I would agree with you that his approach may be both costly and labor intensive, but it may be worth it to those physicians willing to put in the work and those patients where the cost may be less than either a senior living facility or a nursing home.

          I don’t know whether his patients must be on treatment forever or face relapse. I strongly suspect that , like most medical interventions , the approach is more of a control than an actual cure. If you think about it, we don’t actually cure much other than certain infectious diseases.

          Despite these obstacles, it’s a great first step, and over time will hopefully get more streamlined and affordable.

        • Harold – Most of the “prescriptions” of the Bredesen protocol are lifestyle changes, not pills. And in the book, he is clear that when people revert to their former habits, their AD comes back. So yes, he’s asking us to give up sugar and avoid mercury in our environment and there doesn’t come a time when everything is OK now so you can eat sugar and get new silver fillings in your teeth.

          We don’t yet have a rejuvenation treatment, so we don’t know whether it will be one-time or something we need to repeat every day. Most of us would be really, really happy with either.

          • Josh, real rejuvenation would be a one time thing, time and again. So if you’re really rejuvenated, and there’s no reason you should age at an accelerated rate, you would simply start normally aging, needing ‘renewals’ every decade or so to regain your youth. Will renewals become less effective with time – probably, but so will our knowledge of how to fix that. “All problems have solutions, all solutions produce problems, but all problems have solutions.” (Part of David Deutsch’s philosophy of ‘optimism’.)

          • I conside lifestyle changes the weak spot in Bredesen’s protocol.

            Changing diet, introducing intermittent fasting, exercise, cold schock, heat schock etc. They are all free or very cheap, but they require strict compliance and discipline. It is well known that people usually fail, if they need to change their lifestyle completely from one day to the other. Look e.g. at the growing obesity epidemic and type II diabetes.

            Perhaps AD is sufficiently scary for most people so they will actually make the necessary changes? We shall see…

          • Exactly. Rejuvenation will restore us to our prime, with normal aging recommencing immediately.

            Perhaps it might be possible to entirely stop any deterioration at all – but doubtful by biologocal means – as just the heat of running a human body has the potential to damage DNA. So we’d need nanobots or something similar, and maybe re engineer the human body so we’d be more machine than man. Nevertheless this isn’t really necessary for rejuvenation.

      • There have now been three studies just in the past year linking AD to several Herpes strains. Mark, you and I have discussed on several occasions the growing evidence for an underlying infectious cause of every age-related illness. As you say, the immune system needs to be functioning optimally and there are quite a few things that can help it along.

  14. For josh and the other skeptics

    Melatonin And Exercise Work Against Alzheimer’s In Mice
    By NutritonReview.org – October 1, 2012 0324
    The combination of two neuroprotective therapies, voluntary physical exercise, and the daily intake of melatonin has been shown to have a synergistic effect against brain deterioration in rodents with three different mutations of Alzheimer’s disease.

    A study carried out by a group of researchers from the Barcelona Biomedical Research Institute (IIBB), in collaboration with the University of Granada and the Autonomous University of Barcelona, shows the combined effect of neuroprotective therapies against Alzheimer’s in mice.
    Daily voluntary exercise and daily intake of melatonin, both of which are known for the effects they have in regulating circadian rhythm, show a synergistic effect against brain deterioration in the 3xTg-AD mouse, which has three mutations of Alzheimer’s disease.

    “For years we have known that the combination of different anti-aging therapies such as physical exercise, a Mediterranean diet, and not smoking adds years to one’s life,” Coral Sanfeliu, from the IIBB, explained. “Now it seems that melatonin, the sleep hormone, also has important anti-aging effects.”

    The experts analysed the combined effect of sport and melatonin in 3xTg-AD mice which were experiencing an initial phase of Alzheimer’s and presented learning difficulties and changes in behaviour such as anxiety and apathy.

    The mice were divided into one control group and three other groups which would undergo different treatments: exercise -unrestricted use of a running wheel-, melatonin -a dose equivalent to 10 mg per kg of body weight-, and a combination of melatonin and voluntary physical exercise. In addition, a reference group of mice were included which presented no mutations of the disease.

    “After six months, the state of the mice undergoing treatment was closer to that of the mice with no mutations than to their own initial pathological state. From this we can say that the disease has significantly regressed,” Sanfeliu states.

    The results, which were published in the journal Neurobiology of Aging, show a general improvement in behaviour, learning, and memory with the three treatments.

    These procedures also protected the brain tissue from oxidative stress and provided good levels of protection from excesses of amyloid beta peptide and hyperphosphorylated TAU protein caused by the mutations. In the case of the mitochondria, the combined effect resulted in an increase in the analysed indicators of improved performance which were not observed independently.

    Treatment not easily transferable to humans

    “Transferring treatments which are effective in animals to human patients is not always consistent, given that in humans the disease develops over several years, so that when memory loss begins to surface, the brain is already very deteriorated,” the IIBB expert points out.

    However, several clinical studies have found signs of physical and mental benefits in sufferers of Alzheimer’s resulting from both treatments. The authors maintain that, until an effective pharmacological treatment is found, adopting healthy living habits is essential for reducing the risk of the disease appearing, as well as reducing the severity of its effects.

    The melatonin debate

    The use of melatonin, a hormone synthesized from the neurotransmitter serotonin, has positive effects which can be used for treating humans. With the approval of melatonin as a medication in the European Union in 2007, clinical testing on this molecule has been increasing. It has advocates as well as detractors, and the scientific evidence has not yet been able to unite the differing views.

    According to the Natural Medicines Comprehensive Database, melatonin is probably effective in sleeping disorders in children with autism and mental retardation and in blind people; and possibly effective in case of jet-lag, sunburns and preoperative anxiety.

    “However, other studies which use melatonin as medication show its high level of effectiveness,” Darío Acuña-Castroviejo explained. He has been studying melatonin for several years at the Health Sciences Technology Park of the University of Granada.

    The expert points out that international consensus already exists, promoted by the British Association for Psychopharmacology -also published in the Journal of Psychopharmacology in 2010-, which has melatonin as the first choice treatment for insomnia in patients above the age of 55. This consensus is now being transferred to cases of insomnia in children.

    Its use in treating neurodegenerative diseases is acquiring increasing scientific support in lateral amyotrophic sclerosis, in Alzheimer’s, and Duchenne muscular dystrophy.

    “Even though many more studies and clinical tests are still required to assess the doses of melatonin which will be effective for a wide range of diseases, the antioxidant and anti-inflammatory properties of melatonin mean that its use is highly recommended for diseases which feature oxidative stress and inflammation,” Acuña-Castroviejo states.

    This is the case for diseases such as epilepsy, chronic fatigue, fibromyalgia, and even the aging process itself, where data is available pointing to the benefits of melatonin, though said data is not definitive.

    • I wonder what the effect of reversing cellular age-phenotype, (which might better be stated as “changing the cellular environment so as to produce a different cellular-age-phenotype-equivalent corresponding to cells derived from a young organism (in terms of all measurable parameters, like mitochondrial efficiency, transcription profiles, SA-foci in chromosomes, SA (senescence associated) beta-galactosidase, etc., is on the AD brain. The experiments of Saul Villeda showed both neoneurogenesis in treated (by heterochronic parabiosis) animals and increased (to near young) cognitive ability (as measured by time to solve a maze), as compared to untreated age-matched controls. Cause and effect?

  15. another one for Josh and the skeptics
    J Pineal Res 1998:25:260-263

    Two twins with Alzheimer’s and one takes melatonin: A case report

    Brusco LL, Marquez M, Cardinali DP. Monozygotic twins with Alzheimer’s disease treated with melatonin: case report. J. Pineal Res. 1998; 25:260-263. @ Munksgaard, Copenhagen
    Departamente of Fisiologie and Cultadde Medicina
    Universidad de Buenos Aires,
    Argentina

    Abstract: Monozygotic twins with Alzheimer’s disease of 3 years duration were studied. The onset of the disease differed by about 6 months between twins and was characterized by a primary impairment of memory function. Clinical evaluation at the time of diagnosis indicated a similar cognitive and neuroimaging alteration in both patients, as well as a similar neuropsychological impairment. A possible genetic origin of the disease was suggested as similar diseases suffered by the mother. Patients were initially treated with vitamin E (800 iu/day|. starting at approximately the same time (about 3 years ago), they received 50 mg/day thioridazine because of the behavioral and sleep disorder. One of the patients was treated with melatonin (6 mg orally) at bed time daily for 36 months. Evolution of the disease in the melatonin-treated patient indicated a milder impairment of memory function, with substantial improvement of sleep quality and reduction of sundowning. This led to discontinuance after 3 months of thioridazine treatment. Present clinical evaluation indicated a difference in functional stage of the disease between the twins (Functional Assessment Tool For Alzheimer’s Disease (FAST), with a score of 5 in the twin who received melatonin and of 7b in the twin who did not receive it. Since experimental data on melatonin in Animals indicated its antioxidant, antiapoptotic, and B-amyloid-decreasing activity, the hypothesis that melatonin has a beneficial effect in Alzheimer’s disease patients should be considered.

  16. in case you dont know level 5 means you just need help picking out your clothes to wear as one puts it
    score 7b means you cannot control your bowles cannot hold your head up and have lost almost all your vocabulary

  17. I’m hoping that it’s a typo and not a ‘Freudian slip’, that Jeff Bowles spells ‘bowels’ as ‘bowles’. Now you may have a good point Jeff, melatonin is not a big money-maker, it can’t be patented, so Big Pharma has no interest in developing it. And perhaps Jeff’s Texan use of several times the recommended dose of a micronutrient which seems (I haven’t seen data) to produce an effect (placebo effect?, are there well-controlled studies? Is there a dose dependency?) Personally I’ve been using melatonin for more than twenty years and at age seventy-something, I haven’t noticed any deterioration, in fact, maybe the opposite.

  18. oops did I do that ? Josh please change that typo!!!
    Hi Harold …melatonin is the caloric retriction hormone
    It peaks at night but that peak can be dooubled or even higher duirng periods of starvation…and that is what triggers the other hormone chages that lead to the anti aging cr effect….like after 5 days of fasting n humans>>> suppressing LH and FSH by 33% doubling dhea cutting testosteorne in half in men….here is an excerpt from my 1998 paper on aging>>>

    During famine conditions or CR one would expect that in addition to the increase in cGMP activity, that an increase in cGMP stimulating hormones would be seen. Also, one would expect a decline in cAMP stimulating hormones. In a study of human males undergoing 5 days of fasting (136) the following hormone level changes were seen, (for hormones not measured in this study other references are noted):

    cAMP stimulating hormones:
    TSH declined by 67%-as expected
    LH decreased by 33%-as expected
    FSH decreased by 33%-as expected
    cortisol increased by 110%-unexpected
    estrogen -increased by 10%-unexpected

    cGMP stimulating hormones
    Melatonin increased +/-100% in rats (137)-as expected
    GH increased 200%-400% in men (138) -as expected
    DHEA-S increased 100%-expected
    Testosterone-decreased 50%- unexpected

    T3 and T4 were relatively unaffected, and prolactin declined 25% but is not listed because it is an “ambidextrous” hormone stimulating both cAMP and cGMP depending on which receptors it influences.

    The above results reasonably conform to expectations based on the prior hypothesis regarding cAMP and cGMP stimulating hormones. However, by examining the exceptions additional important insights can be gained. First, the cortisol increase of 110% is definitely not expected as it is a cAMP hormone and the hormone is widely known to be implicated in accelerating the diseases of aging in persons where it is chronically elevated. What is also known about cortisol

  19. Final comment on melatonin>>>>

    DId you know that it can reverse human menopause if started soon after emnopause starts kicking in?? Yeah google it…

    It can also regrow hair in men by boosting progesterone levels which is the original 5 alpha reductase inhibitor which was ripped off and tweaked by bigpharma to bring you ]atentable proscar and avodart each with some deadly side effects (much moe aggressive cancers) compared to progesterone….

    and yes melatonin given at the first sign of dementia will reverse it….

    here check out this blog post and if you like it you should download my ebook on Alzheimers/ melatonin IT IS FREE FOR THE NEXT 4 DAYS

    here is a short article
    Amazing! Melatonin Secrets That Almost Nobody Knows About!

    https://jefftbowles.com/melatonin-secrets-that-almost-nobody-knows-about-amazing/

    Amazing! Melatonin Secrets That Almost Nobody Knows About!

    And I am still waiting for josh to ADMIT HIS MISTAKE ABOUT CLAIMING STUDIES IN THE 90\s SHOWED MELATONIN DID NOT HELP AD!! THIS WAS A HUGE ERROR!!!

  20. @ Professor Harold Katcher,
    What you are saying about parabiosis and organismic rejuvenation makes complete sense to me.
    But where I’m confused is how can we (I) change cell signalling (for example blood plasma biomarkers) to be youthful again?
    My first overall approach to health & longevity has been what I think of as Tier 1 (as per Michael Rae PhD over at SENS) refers to which is ensuring RDA levels of micronutrients. I practice some time-restricted feeding (eating approx 16-8 hours per day and meals earlier than later to help with autophagy/cellular cleanup).
    Perhaps some more hormonal signalling makes sense such as melatonin and D3 (as per Jeff’s extensive research) however I already take these, but perhaps in not high enough quantities to be useful for rejuvenation.
    I also think that hormesis (via perhaps something strong and well-researched) such as taking sulforaphane intermittently will do many things such as upregulate glutathione (and other exogenous anti-oxidant production), decrease inflamation, improve just above everything from cognitive function to detox, even reduce cancers …
    Can you provide any further hints/advice here??
    I loved your hints about the Tree of Life … I’m left wondering if the hint is to eliminate the ‘Fiery Angel’ which represents ?? inflammation (sorry I’m lame) …

    • I thought the same about the fiery angel Aslan!

      Likely stem cell activation requires inflammation, even though that is what many old people die of (via various diseases). So an antiaging protocol will likely requiring cycling periods of high and low inflammation, high and low ROS, high or low NRF2, Botch or Notch signalling, etc.

      • I think timing of doses is a factor rarely considered in aging, but also believe there’s a strong relationship between aging and the circadian rhythm, especially the deeper more fundamental rhythms behind redox changes. It is, for example, the kinase mTOR that’s behind metabolic/redox switching; that is, from OXYPHOS, to aerobic glycolysis (for growth) through shunting through the oxidative parts of pentose phosphate pathway, for the production of NADPH and its use in reducing glutathione, the glutaredoxins, thioredoxins and peroxyredoxins, among others, and basically restoring (almost) the reduced state of the cytosol and nucleus. It is the “(almost)” that matters and is controlled by the body, I think.
        As for the solution to my hint, well we’ll have to wait. If I’m wrong (but I have evidence that I’m not – but who knows, there’s the expression from the gold mining days, ‘flash in the pan’) then it doesn’t matter, if I’m right (and I’m pretty sure I am – it’s amazing to have spent much the past decade arguing with everyone in the field of aging (of which I was not even a part, originally) and finally to have been proven correct in the best possible way, makes me feel strange, I can’t quite believe it myself. On the other hand, I had the privilege of saving someone’s life two days ago, someone I hold dear, and I’ve been learning a lot about the importance and beauty of life, how even your most profound grief (and fortunately, I was spared that), is as valuable to you as your happiness – both are miracles. So I’m happy to be able to add to its extension – though lately I’m wondering if limiting it’s application, so as not to include dictators for life, and would-be such people, might be doable.

        • Fiery Angels that must be presumably overcome or defeated.
          Fire is oxidation; consuming oxygen, so we need to put out the fire; stop oxidizing? Stop production of or quench the damage from ROS…
          I’m dying as well… only slowly Professor Katcher.
          Give us another hint??

          • Here is the King James version

            Now the serpent was more subtil than any beast of the field which the LORD God had made. And he said unto the woman, Yea, hath God said, Ye shall not eat of every tree of the garden?
            2And the woman said unto the serpent, We may eat of the fruit of the trees of the garden:
            3But of the fruit of the tree which is in the midst of the garden, God hath said, Ye shall not eat of it, neither shall ye touch it, lest ye die.
            4And the serpent said unto the woman, Ye shall not surely die:
            5For God doth know that in the day ye eat thereof, then your eyes shall be opened, and ye shall be as gods, knowing good and evil.
            6And when the woman saw that the tree was good for food, and that it was pleasant to the eyes, and a tree to be desired to make one wise, she took of the fruit thereof, and did eat, and gave also unto her husband with her; and he did eat.
            7And the eyes of them both were opened, and they knew that they were naked; and they sewed fig leaves together, and made themselves aprons.
            8And they heard the voice of the LORD God walking in the garden in the cool of the day: and Adam and his wife hid themselves from the presence of the LORD God amongst the trees of the garden.
            9And the LORD God called unto Adam, and said unto him, Where art thou?
            10And he said, I heard thy voice in the garden, and I was afraid, because I was naked; and I hid myself.
            11And he said, Who told thee that thou wast naked? Hast thou eaten of the tree, whereof I commanded thee that thou shouldest not eat?
            12And the man said, The woman whom thou gavest to be with me, she gave me of the tree, and I did eat.
            13And the LORD God said unto the woman, What is this that thou hast done? And the woman said, The serpent beguiled me, and I did eat.
            14And the LORD God said unto the serpent, Because thou hast done this, thou art cursed above all cattle, and above every beast of the field; upon thy belly shalt thou go, and dust shalt thou eat all the days of thy life:
            15And I will put enmity between thee and the woman, and between thy seed and her seed; it shall bruise thy head, and thou shalt bruise his heel.
            16Unto the woman he said, I will greatly multiply thy sorrow and thy conception; in sorrow thou shalt bring forth children; and thy desire shall be to thy husband, and he shall rule over thee.
            17And unto Adam he said, Because thou hast hearkened unto the voice of thy wife, and hast eaten of the tree, of which I commanded thee, saying, Thou shalt not eat of it: cursed is the ground for thy sake; in sorrow shalt thou eat of it all the days of thy life;
            18Thorns also and thistles shall it bring forth to thee; and thou shalt eat the herb of the field;
            19In the sweat of thy face shalt thou eat bread, till thou return unto the ground; for out of it wast thou taken: for dust thou art, and unto dust shalt thou return.
            20And Adam called his wife’s name Eve; because she was the mother of all living.
            21Unto Adam also and to his wife did the LORD God make coats of skins, and clothed them.
            22And the LORD God said, Behold, the man is become as one of us, to know good and evil: and now, lest he put forth his hand, and take also of the tree of life, and eat, and live for ever:
            23Therefore the LORD God sent him forth from the garden of Eden, to till the ground from whence he was taken.
            24So he drove out the man; and he placed at the east of the garden of Eden Cherubims, and a flaming sword which turned every way, to keep the way of the tree of life.

          • Yes, thanks Jeff, the important parts are:
            22. And the LORD God said, Behold, the man is become as one of us, to know good and evil: and now, lest he put forth his hand, and take also of the tree of life, and eat, and live for ever:
            24. So he drove out the man; and he placed at the east of the garden of Eden Cherubims, and a flaming sword which turned every way, to keep the way of the tree of life. (‘to keep’ means to keep hidden) – yes, cherubim to the east, hadn’t even noticed that before – now it’s getting obvious!

          • Here’s an excerpt from an old article about the Bresden protocol before they emoved the reference to melatonin>>>>

            Memory loss associated with Alzheimer’s reversed for first time
            Small trial by UCLA and Buck Institute succeeds using ‘systems approach’ to memory disorders
            Mark Wheeler | October 02, 2014

            redesen’s approach is personalized to the patient, based on extensive testing to determine what is affecting the brain’s plasticity signaling network. In the case of the patient with the demanding job who was forgetting her way home, her therapy consisted of some, but not all, of the components of Bredesen’s program, including:

            eliminating all simple carbohydrates, gluten and processed food from her diet, and eating more vegetables, fruits and non-farmed fish
            meditating twice a day and beginning yoga to reduce stress
            sleeping seven to eight hours per night, up from four to five
            taking melatonin, methylcobalamin, vitamin D3, fish oil and coenzyme Q10 each day
            optimizing oral hygiene using an electric flosser and electric toothbrush
            reinstating hormone replacement therapy, which had previously been discontinued
            fasting for a minimum of 12 hours between dinner and breakfast, and for a minimum of three hours between dinner and bedtime
            exercising for a minimum of 30 minutes, four to six days per week
            Bredesen said the program’s downsides are its complexity and that the burden falls on patients and caregivers to follow it. In the study, none of the patients was able to stick to the entire protocol. Their most common complaints were the diet and lifestyle changes, and having to take multiple pills each day.

            The good news, though, said Bredesen, are the side effects: “It is noteworthy that the major side effects of this therapeutic system are improved health and an improved body mass index, a stark contrast to the side effects of many drug

          • Akshay, Harold – we are all very excited to see your results, when you can release them. And if you want any draft reviewers please let me know! I’ve read and dissected thousands of papers on aging (I’m really obsessed with this problem, I know!)

            Best Regards, Mark.

          • Thank you Mark for all your support. Yes indeed you do have a passion for aging research and a keen analytical mind. To verify the replicability we are launching some more trials – also in larger mammals. Will keep you posted on publishing and trial highlights.

  21. Jeff,
    How much melatonin do you think I need in my 40’s (healthy, fit male).
    I honeslty (previously) thought 5mg per night was a high dose … you talk about up to 120mg on your blog … I also take 3000-4000IU of D3 on average daily with LEF ‘Super K’ which has K1, K2-MK4 and 100mg of K2-MK7 (daily)
    Sincerely appreciate your input,
    Aslan

    • Hello Aslan
      As far as melatonin goes I figured if you want the maxium life extending benefits of melatonin you need to take a dose high enough to shut down reproduxtion in women. The same thing that occurs with extreme caloric restriction. In women the dose that was used for birth control was 75 mg per night so I just assumed men weigh more and randomly picked 120 mg per night. Read my Alzheimers book which is free for 3 more days on amazon it is mostly about melatonin. As far as D3 goes I took 4000 iu a day for 10 years adn it kept me from getting a cold and eliminated cracking in my shoulders But did nothing else only until I upped my dose to 25,000 to 50,000 to 75,000 a day did I get some major results like repair of my hip click of 26+ years it took 2 years of high dose d3 to completely eliminate my adult onset seasonal allergies..Keep in mind if you sit in the summer sun for 1/ 2 hour at the beach your skin will make 20,000 iu of d3…you should also take k2 and magnesium with high dose d3

  22. @ Jeff Bowles,
    Jeff,
    I skimmed through the majority of your book;
    Absolutely amazing and fantastic … I cross-referenced much as well and I’m a believer in the benefits (and safety) of melatonin – thank you much for your hard work and contribution to health & aging!!
    Sorry for doubting you,
    Sincerely,
    Kirk

    • Well Im glad you saw the light….I really dont care if I sell an ebook at 2.99 or not I am semi retired and have no wants or needs
      .. If you liked the azheimers/melatonin book you will also really like
      what darwin could not see the missing half of the theory

  23. Check out this 1 star review for Bredsen’s book they spent $30,000!! On doctors and things!!! JACKPOT!!!!

    1 star-
    We spent 30,000 to participate in Dr. Bredesen’s immersion program and saw no benefit. We have been unable to get answeres as to how many people are recovering. The other patients that we are in touch with are not recovering. I trusted Dr. Bredesen because of his impressive credentials. However I have been profoundly disappointed at the lack of candor concerning the immersion program and the outcomes. I am sad that I encouraged my aging parents to spend a huge amount of their money on this program. The priority of proprietary concerns over patient outcomes is a huge red flag. We were vulnerable and fell victim to unsubstantiated claims.. The false hope generated is the worst part. I must agree with the reviewer: BEWARE!!!!!!
    Leave a reply

    • Thank you Jeff, but for a spelling mistake, it was a well-written review (by which I mean the writer wasn’t an idiot, so we should pay some attention to his comments. That was my fear, – we still don’t know how many successes they had, but we don’t read a lot of, “Wow Dr. Bredesen has made me young again!” and that would be my criterion for a successful treatment. It’s easy to fool yourself, you can do all the lab tests, adjust all parameters, get measurements telling you it’s working, but if the patient doesn’t tell you it’s working, you are fooling yourself. If indeed what Dr. Bredesen is doing is trying to reproduce young blood plasma in old patients (I suppose young blood is the model for the preferred concentrations for all of the dozens of blood factors that he believes need to be controlled and adjusted.) In that case my published method of HPE (heterochronic plasma exchange) is much better; Dr. Bredesen can only control the concentration of factors he knows about, the importance of any of those factors individually is debatable, but the sum total effect of all of them together seems to be negligible as well. I’m afraid that unless Jesse Karmazin secretly wrote this ‘review’, I’d have to say there was very little or no benefit from all those tests and ‘adjustments’, the game isn’t worth the candle. I’m afraid Josh, you may have been taken in by another of the many parties trying to cash in on the anti-aging research boom that’s occurring, you vouch for his integrity, but people are awfully good at fooling themselves when they want a particular result. What is the theoretical justification for this approach, where is the experimental justification? Where can we read about this, that is, which peer-reviewed publications has Bredesen put out regarding this work?

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