Letter to an Incipient Cancer Survivor

by

This is a letter I wrote to a dear friend from the 1970s who has been diagnosed recently with colon cancer.  She had surgery last summer to remove the primary tumor, and is in the midst of a 12-week course of chemotherapy.  She has, in my opinion, a well-balanced view of the relative merits of traditional vs alternative treatments. One unusual thing about her situation is that she has an extraordinary social support system, having led a community of peer counselors within the disability community for many years, and now benefiting personally from the community of people she has helped.

Dear M—-,

  We would like to be able to derive from the research on controlled clinical trials a “best bet” treatment option, but the data to support this inference don’t exist.  One reason is that only chemotherapy has been tested with controlled clinical trials, and for your particular brand of cancer, the odds that chemo offers don’t look attractive.  For alternative treatment modalities, we have only anecdotes and not controlled trials. Another reason is that cancer is an individual disease, more so than heart disease or infectious diseases.  Different people respond very differently, and the medical community has not yet figured out how to tell in advance which treatments will work for which patients.

   Western medicine profoundly misunderstands the nature of cancer.  The classical understanding is that cancer results from a series of random mutations as the body’s stem cells divide, culminating in some combination of genetic abnormalities that enable a single cell to evade apoptosis and all the body’s defenses against cancer.  In this paradigm, the root of the problem is in the DNA of the cell nucleus. But we know from experiment this is not true. When the DNA-nucleus of a cancer cell is transplanted into a normal cell, the normal cell remains normal, and when the DNA-nucleus of a normal cell is transplanted into a cancer cell, the cell remains cancerous [ref, ref].  I don’t pretend to understand the true cause of cancer, but I suspect it is related to the mitochondria at the cellular level, and to immune and other deficiencies at the system level that make the metabolism as a whole hospitable to cancer.

   When our bodies are healthy, cancer is nipped in the bud, probably as a frequent and routine occurrence.  Cancerous cells are induced to commit suicide (apoptosis) or they are marked out by the immune system and destroyed by white blood cells.  Cancer arises as a clinical reality only when the body fails to do this. Western medicine makes the mistake of focusing exclusively on killing the cancer, without attention to re-balancing the body or strengthening the immune system so cancer cannot recur.  In fact, chemo and radiation both damage the immune system, which you depend on to guard against a recurrence.

   I’ve heard some doctors say, and I believe it’s true, that all cancer treatment modalities rely in the end on your immune system to kill the last few cancer cells and to prevent recurrence.  When cancer recurs, is it because just one cancer cell managed to survive the onslaught of chemo, or is it because the immune system is so weak that the body is highly vulnerable to new instances?  It is an academic question, because in any case we need a healthy immune system to survive.

    At some point, our plan will be to switch over from killing the cancer to healing your body and restoring your immune system.  Maybe we’re already at that point, after surgery + four chemo infusions. Maybe you’re ready now to make the transition. Cancer-killing treatments make you feel bad, accelerate aging, and damage your body.  In contrast, healing and immune support will feel good in the present and will have beneficial side-effects for other aspects of your health.

   There are many credible alternative cancer treatments out there.  None of them is a universal cure, but all of them have worked for some significant percentage of people who tried them.  The plan will be to choose an alternative clinic or a medication or a diet plan and try it for about 6 weeks. The proposal depends critically on having a sensitive and non-harmful test that you can do every 6 weeks for feedback on whether the treatment is working.

       My proposal will take time.  I believe you have time. You’re not going to die this year or next year, and we have time to try at least a dozen treatments.  We don’t expect the first one or the second to work, but there’s a good chance one of them will. There are many, many stories of people who have banished cancer from their bodies.  You’re the next success story, waiting to be told.

   I propose that you tell your oncologist that you want to find out if the 4 doses of chemo have killed the great majority of the cancer, so that you can now strengthen your own system to handle the last few (chemo-resistant) cells.  Tell her that you are open to returning to chemo in the future should it be necessary, but that for the next phase, you want to try a series of alternative treatments that are non-toxic and have only beneficial side-effects. Each of these has worked for some fraction of patients, and your expectation is that one of them will work for you.  Tell her that you would like to ask her to work with you as an expert diagnostician, using blood tests and subjective state of health to tell when a treatment is not working, so you can move to the next option, and to tell you when a treatment is working, so you can stick with it.

    (I believe PET scans are the most informative test for cancer, but your oncologist will know much more than I.  PET scans are expensive, and I imagine that insurers discourage their overuse. More concerning is that the radiation dose is about 100 times a chest x-ray [ref], so we’ll be counting on your oncologist to come up with a less damaging battery of tests that you can do, perhaps as often as every 6 weeks.)

    We have lots of candidate treatments to try, from the Moss Report, from the Polizzi video or a long list of herbal medicines, from your sources and mine.  There are approaches that involve killing cancer cells with medicines that are much less toxic to your non-cancerous cells, for example, intravenous vitamin C, curcumin, cannabis, dichloracetate, and many others.  A complementary approach strengthens the body’s resistance to cancer, especially the immune system. In the end, it must be your own healthy immune system that protects you from cancer. Reishi and other mushroom extracts, Cimetidine=Tagamet, Nigella sativa (kalonji seed), spirulina, and green tea extract are among many nutracuticals that strengthen the body’s resistance to cancer.  I want to remind you especially of the research of Valter Longo, a USC professor who has worked with fasting and diets that discourage cancer.  There are alternative cancer clinics in Canada and Mexico and around the world that have cured some fraction of the people who have sought their help.  

    Almost all of these interventions have been attacked or dismissed as frauds.  Sometimes this is because they really are frauds, and sometimes it is the medical community circling its wagons to avoid infiltration by researchers outside the mainstream.  Until we look in detail at the accusations and the results, it is difficult to tell the difference, and even then we’re often left guessing. Much of the debunking is based on theory–“there is no credible biochemical mechanism by which xyz can cure cancer.”  I take these pronouncements with a grain of salt, and look only at the empirical results. We don’t understand cancer well enough to dismiss anything on theoretical grounds

    Any one of these options has a low probability of providing deliverance from your cancer, but you have time to try 10 or 20 of them, and there is a very good chance that you will respond to one of them.  You are destined to become the next “miracle cure” cancer anecdote — we just don’t know yet which one you will be.

    I’ve mentioned to you a fallback option, in the unlikely event we should find ourselves two or three years from now with a persistent, active threat of cancer.  The last resort would be to replace your immune system with a bone marrow transplant from your niece (or another related donor, preferably younger).  The upside is that the transplanted immune system absolutely will not tolerate your cancer, and will eliminate it promptly.  The downside is that you expose yourself to “graft-vs-host disease”, in which your immune system also treats healthy cells as “foreign” and attacks them.  This is a potentially fatal complication, and would probably consign you to immune suppressants for the rest of your life.

I’m in this with you for as long as it takes.  So are your dear friends and family and the deep community of people who are full of gratitude for the years of love and attention you have offered them.

— Josh

Discover more from Josh Mitteldorf

Subscribe to get the latest posts sent to your email.

156 thoughts on “Letter to an Incipient Cancer Survivor”

    • Today (12/2) I got a call from M. saying that her latest PET scan came through completely clear. She is cancer-free. This isn’t supposed to happen with colon cancer, and especially not so quickly (4 months).

      Miracles are just things that science doesn’t understand yet.

      Reply

      • This is where the alternate interventions are most valuable to remain cancer free acting as preventives – not many prescription meds there. I hope Josh can make use of his talent for research to identify which natural therapies would be helpful for colon cancer.

        Reply

        • It happened so quickly, it’s hard to know what was working. She had the main tumor surgically removed in August, and was mid-way through her first course of chemo. She was undergoing intensive counseling, using visualization exercises, much laughter and much rage. She was fasting before chemo, and on a ketogenic diet in between. Supplements included curcumin, fisetin and reishi mushrooms, and I’ll have to ask her what else.

          I’ll continue to work with her as she passes into the prevention phase.

          Reply

          • Anyway it’s great news because you were so concerned for her you wrote an entire post and got us all invested as well. It’s a kind of vindication for you. Let this be an example of natural adjuvant therapies. Her doctors may stop all conventional therapies but I hope she continues with the natural therapies. It doesn’t matter who achieves it or how it is achieved I know that these days will be looked back in future as disease and aging days like we look back how people died of infections like flies but which are now easily curable. I marvel at us as a species: for all our faults – and there are many – the way we have been able to evolve our intelligence and our technologies is unique in the entire known Universe. We will outgrow Nature’s own biochemical programming and the ultimate prize may be a world without aging and disease. Another mind boggling direction is our ability to manipulate matter. This can lead to building planets and Suns in distant future protected from the violence of the known Universe. If only we don’t destroy ourselves first.

          • That’s great news Josh.

            Ketogenic seems to be a good bet if you have cancer – no glucose and cancer cells have to live off glutamate. Much slower growth, and potentially might shrink enough to be surgically removed without chemo.

            I think Josh you should try and find the best way for your friend to recover from chemo as long term it’s bound to have caused damage to the body.

          • Thank, Mark – Chemo has been hard on her. She had severe neuropathy in hands and feet, which compounded nerve damage she has had all her life from a birth defect. If you have any suggestions, this is a field I know little about.
            – Josh

          • You might want to research Curcumin.

            A recent report indicates that Curcumin prevents tumor growth by interfering with the way the tumor cells handle sugar.

            It does this without having the same effect in healthy cells, apparently.

    • Josh, there is something that has always puzzled me about cancers. How do they evolve?

      When we die our cells die, including any cancerous cells.

      Evolution requires natural selection operating on survival, but cancer does not survive our death… hence, evolution of cancers should be impossible.

      The complex mechanisms cancer uses to defeat our immune system must be the result of evolution… so how does it happen?

      Reply

      • Jim, this is a really good question. There are a lot of misguided articles in the field of evolutionary medicine that make the mistake that you have corrected here.

        There is “somatic evolution”, which is evolution over the course of a cell’s lineage within one human lifetime. Cancer cells do a lot of evolving because they have high mutation rates and fast reproduction, so they learn to evade the body’s immune system and to protect themselves from chemo that is imposed.

        Beyond that, I believe that the long-term evolution of the process by which we get cancer is part of an evolved program that regulates lifespans. I have associated my name with this hypothesis, and it remains controversial (though not rejected as absolutely as it was just 10 years ago).

        Reply

        • I have been impressed at the descriptions from doctors who went out from Europe in the late 19th century to Africa and Asia; the locals had a much lower incidence of cancer; (or zero cancer). Short explanation: the white flour and white sugar that white man brought seems incriminated. Descriptions of the Inuit in the 19th century: essentially no cancers seen. For an insight into cancer, I think Tom Seyfried has been very illuminating; https://www.youtube.com/watch?v=APwnkpD_BfI and for the key point of fasting before chemo: Valter Longo documented that https://www.youtube.com/watch?v=dVArDzYynYc and at 40mins into this https://www.youtube.com/watch?v=t1b08X-GvRs

          Reply

          • Fred:

            It is interesting that the people of Hong Kong eat a Cantonese/Mediterranean style diet and have some of the longest lived people.

            Here is a link to a March 2018 article that describes why they live longer.

            It discusses lifestyle and social connections, public safety, climate and diet as possible life-extending factors.

            https://www.cnn.com/2018/03/02/health/hong-kong-world-longest-life-expectancy-longevity-intl/index.html
            ————–
            A portion of the article:
            “We studied the Chinese diet, and it’s quite similar to the Mediterranean diet,” he said, with meals often consisting of fish, fruits and vegetables, rice, nut oils for cooking and meat chopped up into dishes rather than eaten as whole portions.
            ——————————————

      • Another way of looking at it: Why would evolution only act at the level of the organism? It also acts at the level of the cell. This is in general subordinated for the good of the organism, but in the wrong conditions cellular evolution can run contrary to survival of the organism – and cells expand as much as possible instead of remaining under the control of the organism.

        Reply

        • That theory has been promoted recently by Paul Davies. I think he’s on the wrong track. Sure, evolution makes mistakes, but if it lasts hundreds of millions of years, it’s not a mistake, and we should be looking for purpose. There is broad evidence that the purpose is to limit the life of the individual organism. This is the thesis of my book, Cracking the Aging Code, and I ask you to look at all that evidence before dismissing the idea.

          Reply

  2. If I was facing her diagnosis, I would certainly want you as a friend. Your support, knowledge, and kindness will go a long way in helping her down this road. Kudos, Josh.

    Reply

  3. My mother died of colon cancer, from the time I was 14 until she died when I had just turned 18. They were four years of agony and praying for death. Naturally I’ve spent my adult life under the cloud of familial cancers, with requisite colonoscopies. This is one disease I’d like to vanquish. So, Josh you concluded your proposals with a sure-fire if dangerous way to beat cancer, replace your immune system with a (young) immune system with will fight the cancer and possibly your internal organs as well. Now it’s the ‘(young)’ I want to ask about , is there experimental evidence that replacement with a young immune system is what gives the anti-cancer response, or is it simply the replacement with a ‘new’ immune system (that is dis-regulated, or ‘differently-regulated’ to be pc)? That is, to make myself clear (Akshay?), what if you could rejuvenate the immune system already present, in situ? Do you suppose that might have the same effect and yet not risk autoimmune reactions? For example, newly born macrophage come out as fighters called M1 macrophage, and are often converted to M2 macrophages which are more conciliators, and actually collude to help protect cancer cells (which is no crime, mind you). If those M2 macs could be converted back to M1 macs, then the cancer would suddenly find its bodyguards are out to kill it. I think that’s doable.

    Reply

    • I would agree Harold. Josh too mentioned in his letter how in our prime we have tools that nip cancer in the bud but as we age many of them progressively become dysfunctional. Thymus is the best example. Again for those that do not subscribe to aging as a program – it begins to shrink a few days after we are born – without any accumulated damage or other theory of aging. It seems to never stop shrinking and we depend on it for one our most important immune assassins: T-cells. Dr. Greg Fahy I believe is one of few who has succeeded in inversing the involution of the Thymus and Josh your dear friend must consider his regimen. Another one pointed out in one of my posts is a naturally derived cardiac glycoside which I believe is approved for cardiovascular health. It’s side effect is reversing the methylated silencing of Tumor Suppressor Genes – our 2nd most important if not the most important weapon to prevent cancer. This reversing leads to increase of TSG expression even in the aging. There is a study. Some of herbs and their extracts have studies that have decoded their action against cancer at the molecular level.

      Reply

      • This is interesting/tantalising. I’d be interested to learn more. Can you be more specific a about the cardiac glucoside, study and herbs you are mentioning here?

        Reply

        • The cardiac glycoside is called Procscillaridin A. In a study published in Cancer Research in March 2016 called Targeting Calcium Signalling To Induce Epigenetic Reactivation Of Tumor Suppressor Genes in Cancer, Dr. Issa and his colleagues uncover the mechanism by which Cardiac Glycosides reverse epigenetic Silencing of Tumor Suppressor Genes. Dr. Issa screened 1,100 FDA approved drugs to find the ones that reversed the Tumor Suppressor Gene Silencing. They found 11 out of which Proscillaridin A a Cardiac Glycoside was the most potent. I have recently become a fan of Dr. Jean-Pierre Issa. Besides the above quoted study he has also published ‘Caloric Restriction delays age related methylation drift’ in Nature on 14th September 2017 explains how the rate of changes in our epigenome as we age impacts our lifespan. Caloric Restriction slows that drift and so does rapamycin explaining their life extension benefits in humans. Both were brilliant eye openers for me: latter about methylation drift which then made me make sense of Horvath clock. Former study gives evidence that this drift is reversible! Which is great news for all anti agers like this community. Western medicine seems to be prescribed after a disease is already playing havoc but one could repurposed Proscillaridin A as a powerful preventive that one could take regularly to protect us from cancers caused by aging. This cardiac glycoside is of plant origin.

          Reply

          • Thanks for the links and for your solid analysis. The only thing I want to comment on is “methylation drift”. Some of what happens to methylation with age can be characterized as “drift” because it is loss of order. But more than half of it is directed, by which I mean it is ordered. Some interpret this ordered change as the body trying to rescue itself from damage, but in my view, it is the body destroying itself. For example, expression of genes promoting inflammation is upregulated with age.

          • Here’s a newer study of Proscillaridin A, used to treat lung cancer in mice:
            https://www.nature.com/articles/s41419-018-0733-4

            This is a proof in a live animal of the principle that Issa established. Blocking calcium unexpectedly changes methylation patterns in a way that reactives the Cancer Suppresor Gene (CSG) that the cancer cell had turned off. In this Chinese study (from Macau), the mouse tumors shrank. They shrank less than with a chemotherapy agent, but the Proscillaridin A was not toxic, while the chemo agent was quite toxic.

  4. Thanks again Josh. As one, of no doubt many, Cancer surviving/fighting persons with scientific training I appreciate your thoughtfulness and practicalness. I’m about 14 years out from diagnosis, survived being on dialysis in the mornings, chemo in the early evening, and on & on, and now teach ballroom dance to other 70 year olds. Yes, and still get treatments from time to time and am holistic in my treatment choosing. I practice Dr. Longo’s Fasting Mimicing Diet and that’s help reduce my side effects.
    Appreciatively, John

    Reply

  5. A close relative of mine got colon cancer, with liver metastasis after 6 months. She survived the typical 3 years, being on almost continued chemotherapy for that long time, and suffered 3 surgical interventions, the last one of them only the surgeon to say to the family that nothing could be done but return to the oncologist…..to die withing 0,5 -1 year more.

    Alternative therapies like strongly increasing neutrophiles with granulocyte-colony stimulating factor where strongly discredited by head of Spanish oncologists here, based exclusively on the fact that its main proponent (Prof. Bru, UCM) “was not oncologist but Professor of Mathematics”!. My relative only adhered very slightly to this alternative therapy because of discomfort with too frequent G-CSF injections needed. She increased her neutrophiles only around one tenth of what Prof. Bru recommended to be effective.

    At the beginning of the disease I also suggested to the oncologist about the potential role of methionine restriction (to try to “kill” tumor by famine) to what the oncologist reacted (opposed) strongly stating that high nutritional state was absolutely necessary.

    She also tried (mild to avoid rebound) oral treatment with bicarbonate because many serious scientific paper from a research group in Florida (US) showed that it strongly inhibited metastases (around 90% inhibition) although not at all the growth of the tumor. The result we got was exactly what those papers said. Oncologist was surprised because of the long time (1,5 year) that it took for the secondary cancer cells in the liver to metastatize to lung and peritoneum, 1,5 years after they had “closed” the patient at the 3rd surgical intervention saying that “nothing could be done” to save her. In fact she finally died from the huge liver tumors (“more than 10” tumors counted, and some more than 13 cm in size at 9 months prior to death), fortunately without the strong pain that would have occurred should the cancer have invaded the bones. I am grateful to the Florida scientists for this. They only published their scientific papers but this was very nice for my relative in the end.

    Among the chemotherapies she received one was “Cetuximab” about which discrediting huge studies (based on more than 500.000 people studied) were published after the death of my relative. These “officially adopted” treatments (huge proteins that scarcely can cross huge tumor masses containing lipid membranes), absolutely useless, cost around 100.000 Eur per pateient per 6 months treatment and are draining our public health social security system of resources.

    My general impression was that the oncologists behave as a group of professional interest rather than caring for the patients, in what refers to alternative treatments, and also that a lot of interest on the side of international pharmaceutical companies are dominating the oncologists who simply obey them… Of course the oncologists never recognized their ignorance about cancer. Impossibility to cure colon cancer with metastasis was explained to us only by the surgeons (the ones who save many lives when they catch the cancer “on time”, before it enters the internal medium and metastatizes).

    So, this is my very ugly experience with cancer and the oncology medical establishment. It was clear to me that they know almost nothing about cancer. And it makes me especially angry when they say in TV that 50% of colon cancer cases are nowadays “cured” when this is absolutely false. What they “cure” is cases in which cancer has still not crossed the barrier with the internal medium. When it is inside and creates metastasis, there is no cure at all by any oncologist worldwide. That is for sure. I have experience asking for help with important specialists at CA-USA, Norway, UK, Japan and Taiwan apart form various different ones in Spain.

    Reply

  7. From Josh: I have flagged (but not erased) Jonas’s comment because I’m unsure where he’s coming from. I corresponded with Jonas privately, and he told me he was a cancer researcher, and that Jonas is not his real name. I offered to preserve his anonymity if he would share his credentials with me, but he didn’t answer. I’m just paranoid enough to think that there are people paid by the pharmaceutical industry to monitor social media and tilt the discussions in their direction. I don’t know that this is Jonas’s situation, but I find it suspicious that he is unwilling to use his real name here, or even to share it with me in private. – JJM

    Jonas’s comment follows:
    ——————————————————————-

    I was interested in reading your letter as my family has had its fair share of cancer.

    Your first paragraph is relatively truthful. Many cancers are just difficult to treat and one patient with colon cancer does not have the same cancer as another colon cancer patient. But then you went off track and started misquoting references and making up data.

    “Western medicine profoundly misunderstands the nature of cancer.” Seriously? And you do?

    “But we know from experiment this is not true.” Did you even read the references you provided about cytoplasmic transfer? You got it backwards. The two papers (by the same group) took cytoplasmic material (cytoplasts) from malignant rat liver cells and transferred it into normal rat liver cells which made them malignant. Fusion of cytoplasm from normal cells into tumor cells made them less tumorigenic. How is that the same as taking DNA-nucleus from malignant cells into normal cells? The references provide further support for the idea that the DNA mutations in the cancer cell results in mutated cytoplasmic proteins (or other cellular components) that can increase cell growth of normal cells.

    “I don’t pretend to understand the true cause of cancer, but I suspect it is related to the mitochondria at the cellular level”. You suspect? How about give the second rat reference the credit for suggesting this idea first.

    “There are many credible alternative cancer treatments out there.”. Please name one proven alternative treatment. One. Proven.

    Now let’s talk about the clinical study you cite. It’s a small study published in the Journal of Korean Medical Science. “I like to quote this 2014 study of women with ovarian cancer. The lower the weight, the longer the survival.” Why do the authors of this study state the exact opposite in their Discussion? “Underweight patients in our study showed a significantly poor survival rate than other BMI groups.”

    “There are alternative cancer clinics in Canada and Mexico and around the world that have cured some fraction of the people who have sought their help.” What fraction would that be? Try 0%. Did any of those clinics actually try to monitor and kept track of these patients? No. Did any of those clinics compare their patients responses from their ‘miracle’ treatments to patients receiving no treatment or palliative care? No. Why? Because if they did, the clinics would find that their treatments are useless. They have a vested interest (read profit!) in ‘hype’ not ‘proof’. The only thing these clinics do is separate desperate people with a debilitating disease from their hard earned money.

    What exactly was your goal of this ‘letter’? Satire? Convince readers to buy useless herbal medicines? What?

    Reply

    • Thanks for your comment, Jonas. I am writing my opinion, and there is evidence to support it, and I hope it is clear from context that I don’t claim to represent the consensus of the medical community.

      Yes, I think the dominant view that cancer is caused by somatic mutations is incorrect. The evidence in favor of that position is that most teratogens are also carcinogens. (Incidentally, this is the basis of the Ames test that has been widely used for screening carcinogens for decades.) But in the decades since the Ames test, we’ve learned that cell metabolism is controlled by epigenetics much more so than genetics, and an epigenetic basis for cancer makes more sense to me. I’m not alone, but I grant you that this is still a minority opinion. Here is a link to the Wikipedia article on cancer epigenetics.

      Concerning the experiments in which cell nuclei and cytoplasms were swapped: I would say it makes little difference whether you talk about keeping the nucleus and swapping out the cytoplasm or keeping the cytoplasm and swapping out the nucleus. This experiment has been repeated several times since the original in 1987, and the result is always the same: it is the cytoplasm that determines whether the cell is cancerous, not the DNA.

      Of course, I don’t take credit for the idea that cancer is a mitochondrial disease. I should have credited Otto Warburg, who was the first to put forward the germ of this idea in the 1930s.

      You challenge me to “Please name one proven alternative treatment. One. Proven.” I hope I have made it clear in the article that proof is exactly what we lack. The alternative treatments have not been tested with randomized case-control studies. Only surgery, radiation, and chemotherapy have been subjected to tests with that level of rigor. My point is that that doesn’t mean that these treatments are ineffective–only that we know so much less about them. The reasons that we know less about them have more to do with economics and patent law than they do with the merits of the treatment. It is for this reason that I counsel my friend to try a dozen unproven treatments, with the expectation that there is a good chance one of them will help her, maybe cure her.

      Concerning the relationship between BMI and survival, I thank you for pointing out an error. The graph I included shows just what I said, but it comes from an earlier study, not the one that I linked to. After reading your comment, I have reviewed more evidence on BMI and cancer survival, and I find that there are conflicting claims. As you said, the study that I linked to actually found higher survival for higher BMI. I’ve removed the diagram and the discussion of BMI from the post, with gratitude to you and apologies to my readers.

      Concerning alternative cancer clinics: My point is that some people who go to these clinics come away cured, and many more come away with significant benefit that lasts for years. Typically, these cures occur after patients have exhausted Western medical treatment, and their doctors have given them up to die. In other words, people go there in desperation, and some of them are helped. We don’t know what their success rates would be under standardized conditions. We don’t know how their cure rates might be affected if people went there before they reached the desperation of late-stage cancer. I don’t know of an unbiased survey of alternative cancer centers that could help guide us to those that are more credible, and if any readers can point me to one, I will be grateful to study it.

      Thanks again for your comment, Jonas. The perspective you offer is shared by many cancer professionals, and deserves representation here.

      Reply

      • “it is the cytoplasm that determines whether the cell is cancerous, not the DNA.” Please provide additional references. I’m interested in reading more about this. So where does the ‘stuff’ in the cytoplasm come from? Is there some genetic material floating around in the cytoplasm (not counting the mitochondria which contains DNA for ~14 genes) that encodes for proteins and noncoding RNAs? Not that I’m aware of. Epigenetics definitely plays a role. However, it still affects the nuclear/mitochondrial DNA (shutting down/turning on oncogenes/tumor suppressors). The majority of cancers are due to changes in the DNA (mutations or epigenetics). That’s why the field has had some successes in targeting mutated driver proteins. The immune system recognizes that a cell is cancerous by ‘seeing’ mutated antigens/proteins on the outside of the cell (encoded by the altered DNA) and eliminates the cell. The cancer cells that survive can, in turn, evolve ways to avoid the immune cell attack.

        I’m sure some people might be cured/helped in these clinics. However, we don’t know why. Would they go into remission anyway? We don’t know. Did their last conventional treatment finally work? Possibly. We don’t know. The new immune-targeted drugs actually cause the cancers to get larger (infiltration of immune cells into the tumor) before the drugs start to work. There is no evidence that the treatments these for-profit clinics are providing help the patient. I can understand a patient being so desperate that they will try anything. However, there is no such thing as alternative medicine. There is medicine that works and medicine that doesn’t. There is no magic pill/potion/concoction that some obscure clinic has ‘discovered’ that the rest of the cancer research field ignored. Suggesting that sick patients travel to such clinics and spend a considerable amount of money on useless treatments is giving them false hope (and possibly causing them harm) and in many cases, putting their families at risk of financial ruin. Trying 12 treatments? Based on what? Testimonials from clinic patients that survived? Such evidence is clearly biased and not believable. If all the money spent on such clinics was pooled, we could actually test some of these treatments in a clinical trial (assuming there is some preclinical evidence). But then, these clinics would likely go out of business.

        “We don’t know how their cure rates might be affected if people went there before they reached the desperation of late-stage cancer.” Perhaps not. But that is not a reason to visit these clinics selling snake oil sooner. Perhaps you should tell your readers to take better care of themselves in the first place (exercise, healthy eating, don’t smoke/drink), since that has been proven to reduce cancer risk and improve cancer patient survival.

        Reply

        • Dr. Jonas,
          Newman DJ et al in a review mentioned that 60% of all anti cancer drugs approved in last 30 years were derived from natural sources. Unfortunately they represent the ones that were patentable. As you know there are thousands of good quality pre-clinical trials of natural molecules and compounds which show promising or sometimes remarkable actions against cancers – many of them have examined their molecular paths causing the attacks on cancer. But they do not progress beyond the preclinical stage due to inability to patent them. There have studies in human cancer patients showing significant increase in efficacy of FDA approved cancer drugs when given along with natural adjuvant therapies. So would it be correct to say that only those drugs that have been approved by FDA and can be prescribed by doctors are real and the rest is snake oil?

          Reply

          • Snake oil is one of the few effective, safe, anti-inflammatory drugs. Read the latest Vascepa study from AMRN… and stop calling pharma patent drug failures “snake oil”.

          • I would define ‘snake oil’ as ‘drugs/herbs/potions’ promoted to affect human diseases/conditions without evidence.

            I work in the field of experimental cancer therapeutics. I use plant extracts to try and identify chemicals that may, one day, provide benefit to cancer patients. And I agree, you cannot patent a plant (GMO notwithstanding). However, the inability of extracts to advance to clinical trials has little to do with patenting. Adding plant extracts to cancer cells growing on a plastic dish and watching them die is useless with regard to how this might work in a patient. If an extract works on cells, it should be tested in an animal model or two. If that works, then you ‘might’ be able to advance it to a phase I clinical trial. But you can’t jump from “inhibits cells on a dish” to “let’s give it to patients”. That’s just unethical. Since plants/herbs/extracts are typically consumed orally, the plant chemicals circulating in the body (and ultimately, the tumor) after consumption would be entirely different (following digestion in the stomach, absorption/metabolism through the intestine, and metabolism by the liver) than those chemicals in the extract that you add to the plastic dish of cells. Some of those ‘active’ plant chemicals (in a dish) may not even get absorbed into the body and would never make it to the tumor (conversely, metabolism of the plant chemicals by the body may create active components not present in the plant extract itself). A main problem with natural product extracts is the variability of the plant itself: when was it harvested (Spring or Fall), where was it grown (soil composition), how was it processed, how long was it stored, etc. All of these factors effect the chemical composition of plants. Another problem has to do with the extraction itself. How reproducible is the extraction process? How many times did the researcher make the extract? In most published articles, only once (which, in my opinion, is a big failure by the natural product researchers). Thus, we have no idea if the researcher made a second extraction from a separate batch of plants that they would get the same experimental result. If you can’t reproduce your results, then the first observation was a fluke and invalid. In order to get an herbal product into a clinical trial (assuming you have strong preclinical proof of efficacy), you must be able to show that you can make/buy the product consistently and safely. If not, the chemicals would be different between batches/lots and the effect on the patient would be different. The clinical trial would be inconclusive.

          • Dr. Jonas,
            I would agree with all that you said about plant extracts. As Dr. Barja says replicability is the key. I have read that gaining FDA approval for a synthetic molecule takes $100 million or more. If even a small part of that is invested one could standardize all the issues you mentioned with natural extracts. But if after spending the money one is unable to patent it getting returns on investment becomes very difficult. That is where many good candidates do not get the investment they need to translate into cancer medicine. There are ways to bypass the oral delivery and digestive tract anomalies. My colleagues are working on it. Despite this risk our venture has worked only on natural extracts
            and endogenous molecules as I have a bias against synthetics. Our entire strategy is to use Nature’s own bioengineering which is brilliant to say the least and augment it where it falters with tools give by Nature. This combination seems to show much less side effects than prescription medicine. It also allows one to look at potent preventive medicine not just curative.

        • Hi Jonas:

          (You said: “I’m sure some people might be cured/helped in these clinics. However, we don’t know why. Would they go into remission anyway? We don’t know. Did their last conventional treatment finally work? Possibly. We don’t know.”)

          Jonas:

          Well at least you are open minded enough to acknowledge that some are cured by such treatments.

          There is a book titled:

          Love, Medicine and Miracles: Lessons Learned about Self-Healing from a Surgeon’s Experience with Exceptional Patients Paperback – July 22, 1998
          by Bernie S. Siegel (Author)

          I think you might find it to be an interesting read.

          I believe you are a cancer researcher based on what you have written. You were trained in traditional science.

          I, too, do not wish to divulge my real name, even privately, by email. It is nothing nefarious. Just a privacy issue.

          (Jonas wrote: ” Perhaps you should tell your readers to take better care of themselves in the first place (exercise, healthy eating, don’t smoke/drink), since that has been proven to reduce cancer risk and improve cancer patient survival.” )

          I agree with that advice, IMO, preventive care is the best approach.

          Josh does offer that advice throughout his writing.

          It is true, though, that many traditional medical cancer treatments weaken the host.

          I had a friend who had her breast cancer put into remission by chemo and radiation treatment but died on the train of heart failure, on her way home, after learning that fact.

          The chemo and radiation had weakened her heart, profoundly.

          https://www.health.harvard.edu/heart-health/treatments-for-breast-cancer-may-harm-the-heart

          If life is all an illusion, as the Buddhist say, perhaps it is all snake oil and our mind and the mind’s personal beliefs are the real cure.

          Just sayin’

          Reply

          • Jonas,
            As a researcher of plant extracts in cancer therapeutics have you come across “oleander soup”? Also Jon Barron has a “blood cleanser” that has anti-cancer properties. Hopefully you won’t go off at the mention of his name. The herbs in his formula have a long history of traditional medical use by different people including Native Americans.

  8. Cancer is such a terrible and terribly complicated problem, but we’re certainly making remarkable headway. Most recent successes are based on immunotherapy, most specifically priming the patient’s own immune system to attack and kill the cancer cells. This has been impeded by cancer’s ability to fool the immune system into perceiving them as normal cells and therefore not killing them. The recent Nobel prizes in medicine were awarded to two scientists who figured out a way to bypass this dilemma and inhibit negative immune regulation. This is an enormous step and has been described as the penicillin of cancer therapy.

    To this end, I would say that any method that enhances immunity is almost certainly a good thing, be that hyperthermia as described in the article posted by Mark, rapamycin, cistanche, reishi, puerhh tea, green tea, modified rice bran, or curcumin, it’s worth a shot. Some western oncologists are also starting to employ ldn along with cbd as a complement to chemotherapy.

    I understand the comments expressed by Jonas, but I’m not sure why, when given the equivalent of a death sentence, one wouldn’t try all kinds of options, as well as the standard ones to try to defeat this awful illness.

    Reply

  11. Many of you will have already read this paper but it bears repeating

    http://www.pnas.org/content/115/8/1883

    This model, based on decline of the immune system, shows this, in combination with a smaller number of somatic mutations, shows a better fit to the rise in cancer incidence with age than the traditional accumulation of 6 or 7 required mutations.

    So as far as prevention is concerned, a strong immune system should be our first aim. Once cancer has occurred I’m less confident in immunotherapies than many, but we’ll see.

    Reply

  12. Cancer is a systemic disease. The fact that it appears in certain tissues is because that tissue is the weakest part.
    When a system is heading to a certain state, to stop the evolution to that state is necessary a radical modification of interaction with the environment (in physics this is called a phase transition). For an organism a radical change could be a severe and prolongend calorie restriction.
    For example I read about 12 cancer japanese patients who tried to climb Himalaya. From the 8 that returned, all have the cancer totally curred without chemo.

    The most important to not to recidive is not to return to former way of life.

    Reply

    • Given that an underlying level of mutations will always be occuring, but does not normally result in cancer, makes me realise how important the environment and epigenetics is. For example the standard lifestyle of the cancer victim is sedentary, poor diet (way too many simple carbs), and too many calories through the the day with barely an hour to digest.

      Cancer may be inevitable if we live long enough. But that should not be happening to people in their 40s, 50s, even 60s.

      I regard cancer as a lifestyle disease.

      Reply

    • I’m a great fan of Paul Davies when he writes about physics, and especially the foundations of quantum mechanics, the anthropic priciple, and the nature of consciousness.

      In this case, I think that Davies has his facts right, but perhaps their significance is not as he thinks it is.

      Davies notes that cancer cells invoke an ancient, inherited genetic mechanism that responds to stress by mutating, taking a chance on new genetic combinations when the old ones don’t seem to be working.

      So far, so good. But this is no surprise. Evolution has learned that re-purposing genes that are already developed and available is a lot easier than developing whole new genetic mechanisms from scratch. Biology is overflowing with examples of this phenomenon. Almost every enzyme in the body has multiple functions in multiple systems, in different places at different times.

      Cancers that find this particular mechanism evade the body’s immune system, and hence we notice them more.

      Davies claims, “It has sweeping implications for therapy.” I don’t understand this, but I hope he’s right.

      I might add parenthetically that aging itself coopts existing systems in the body in its campaign to kill us. Inflammation is an important first-line defense, but in old age it turns against us. Apoptosis is essential for ridding the body of damaged and senescent cells, but in old age, healthy muscle and nerve cells start eliminating themselves with apoptosis. And the immune system, in old age, is turned against self in various auto-immune disorders, especially arthritis.

      Reply

      • Almost everything about aging seems to be a result of evolution shifting risk of death from young, child bearing adults, to the old. The ultimate example of this is cellular senescence, which is the last line of defence against a growing cancer.

        Cancer needs to get big enough before it’s arrested by senescence to win the several million to one lottery of a single cell immortalising. So evolution sets the limit in such a place that it will give the young enough cellular divisions to maintain health, but not too many – in case of cancer. Living longer means the limit has to be pushed up, but then you need better front line cancer defences, which evolution won’t develop unless it has to.

        That’s my take on it, anyway, and might explain why cancer incidence levels off and even fall in the very old – none of their cells has enough replications left to grow a cancer big enough to immortalise. It might also explain why cancer in the young is rare, but pretty deadly when it does occur.

        If this is true then a solution to cancer is to keep all our telomeres just long enough to maintain tissues, but no longer.

        Reply

        • Hi Mark,

          You say that ‘The ultimate example of this is cellular senescence, which is the last line of defense against a growing cancer’, and that seems to be the current consensus. But what if most cancers already begin from the ‘get-go’ with a telomerase expressing cell and the failure to move past this state is what gives rise to uncontrolled growth?

          Over at anti-aging firewalls Vince Guiliano has recently posted a lit. review of some of the latest papers on cancer and epigenetics. One of the hypothesis that they put forward is that natural expression of OSKM factors in response to stress, and to allow re-generation, may be the underlying trigger of cancer.

          Somatic cells would be constantly de-differentiating and failure to arrest the cell cycle at the right point due to either point mutations that impair tumour suppressor genes or to epigenetic dis-regulation will result in uncontrolled growth.

          So it would not really matter how many replications that cell line has undergone, because they would be reset by de-differentiation every time. I do suspect that telomere attrition is a growth control mechanism, so this is probably not the whole story.

          Vince goes on to cite a couple of very interesting papers that discuss some types of cancers where mutations are not detectable plus others that seem to be caused mainly by epigenetic disruption.

          From one of the papers: “we propose that particular types of cancer, in which causative mutations are not often detectable, such as pediatric cancers like Wilms’ tumor, may develop mainly through alterations in epigenetic regulation triggered by dedifferentiation”.

          Reply

          • The actual causative factor for the genesis of a cancer cell makes for an interesting discussion,but from a practical point of view, whether epigenetic, mutation, or both, we will probably not be able to stop it and we don’t need to do so.
            The problem arises when cancer cells divide to the point of feeling crowded. That is the signal that triggers metastasis. That’s what kills us. So we can coexist with cancer as long as it doesn’t spread.
            This can be achieved via multiple pathways. One of the most promising is to control inflammation, in particular IL6 and IL8, which are both vital to the metastatic process.
            Another possibility is to stop cancer cell movement and much progress is being made there.
            IP6 actually causes the cancer cells to differentiate into more mature cell types making them much less aggressive.

            If we can prevent metastasis, then we’ve essentially cured cancer regardless of its cause.

          • Actually you are aware of this phenomenon Akshay as I refer you back to your own blog on this subject entitled , Cancer and Aging- A Complete Cure For Aging, where you cite the important work of Jayatilika and Wirtz at JHH for recognizing that tumor density, and not size, accounts for metastasis, and IL6 and 8 are important signalling proteins in this process.

          • Haha you are right! Thank you – glad to know someone as brilliant as you does read my blog 🙂 Dr. Hasini Jayatilaka is my favourite young scientist. The discovery about density being the trigger was eye opening. My fandom was validated recently when she was selected Forbes 30 under 30. Made me very happy.

          • There are certainly parallels between senescent cells and cells undergoing trans or de differentiation Adrian. I am skeptical however that widespread de-differentiation occurs in humans. I would agree that inflammatory signalling is probably attempting to attract stem cells and maybe make somatic cells more plastic. So inflammation is probably trying to help you with aging, in my view.

            As far as I am aware the genesis of cancer begins with a mutation or epi mutation (the latter presumably through signals from other cells). The braking genes, mainly p53, then halts this growth. Only if p53 (or potentially something downstream of it) is mutated can cancer beat this barrier (note there is also a p16 brake for some cells). After this, replicative senescence is the final barrier, which stops every cancer cell, barring less than 1 in a million that manage, through massive genetic rearrangements, to express telomerase.

            Also note that senescence is often temporary, so the immune system is required to clear the arrested cells. It’s all about keeping the numbers of errant cells too low to cause an issue to the organism.

            In addition to what Paul says about blocking metastasis, which is after the cancer is immortalised and rather large, we could of course just aim to lower ROS, the main cause of DNA mutations, to reduce the chance of cancer occuring in the first place. Easier said than done, however, and preventative rather than a cure.

          • Hi Akshay. It would be very beneficial to know if your protocol just dampened inflammation, or removed the cause of the inflammation – which in my view is a requirement foot tissue regeneration, with persistent inflammation a sign that regeneration is not occuring. It’s a case of the body putting it’s foot down on the accelarator peddle harder, but not getting anywhere because the ‘car’ is doesn’t have any tyres.

          • When you speak of ROS, are you referring specifically to mitochondrial ROS, and if so , would the answer be to use the usual suspects to dampen it, or more specifically something like mito-q?

          • Mark this is what I understand and correct me if I am wrong: upon any relevant stimuli M1 macrophages release proinflammatory cytokines Tnf-a and IL6. In the young this is followed by anti inflammatory M2 macrophages that repair tissue and resolve the inflammation. As we age sufficient polarizatiom to M2 does not occur leaving unresolved inflammation – thereby rising levels of Tnf-a and IL6 amongst others. When this dysfunction is resolved due to anti aging interventions the balance between M1 and M2 is restored thereby reducing the levels of IL6. Here is an article on a study that shows a simple way one can restore balance:
            https://www.sciencedaily.com/releases/2018/04/180425093745.htm

          • L Theanine and melatonin both inhibit tnf, IL 6 and IL8. Its interesting that the release of IL 6 from muscle is anti-inflammatory, such as occurs with exercise, whereas the IL6 from immune cells is pro- inflammatory. I fact, IL 6 is a better biomarker of inflammation than is CRP.

      • “I might add parenthetically that aging itself coopts existing systems in the body in its campaign to kill us.”

        That’s one side of the coin. The other is that the life always seeks new better ways to evolve. Too many limitations accumulates after a certain age.
        Josh, frankly now, there will come a time (in 20, ,30 or 50 years) when you’ll be “tired” of life (even in very good health). Ask the healthy very old men and women (over 85) if they want to live 30 years more.
        The aging process could at best be stopped but not reversed (rejuvenation). If it will be found a way to rejuvenate somebody then also the psyche of that person will be so tranformed that he (she) will be another person. This is equivalent with the death of the former (old) person.

        Reply

        • Hardly. There is no 80 or 90 year old in what I’d call good health.

          When (not if) rejuvenation occurs, you are quite right that people will grow and change, perhaps forgetting much of past lives, because that is how the brain adapts. But that is not a bad thing. And I will not be tired of heathy life in mere decades.

          Reply

        • Florentin:

          I agree that rejuvenation would likely transform a person’s psyche (spirit) (soul) and perhaps change them profoundly… and in a healthy way.

          I do not think it will bring the death of the old persons memories, though, as if reborn and needing to learn everything all over again.

          Of course, I could be wrong. No one really knows what the soul is and where it actually resides.

          I think that being very old and weak is likely very damaging to the psyche.

          Very old people often comment on how they feel like a shadow of their former selves.

          Much of depression the elderly feel is associated with all the losses they experience. … loss of strength, health, the ability to think sharply.

          So in that respect, being rejuvenated to a younger stronger healthier phase of life, will be beneficial and transformational, IMO.

          Reply

  15. Don’t know if this is old news to any of you, but to me it is new, and quite exciting.

    Metformin stimulates DICER1:
    https://www.ncbi.nlm.nih.gov/pubmed/26990999

    DICER1: A Key Player in Rheumatoid Arthritis, at the Crossroads of Cellular Stress, Innate Immunity, and Chronic Inflammation in Aging:
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066587/

    A little preview:

    “DICER1 plays an essential role in the maintenance of genome integrity (9), especially through interactions with the DNA damage response (DDR) pathway. It has been shown that in response to double-strand breaks in DNA, DICER1-dependent accumulation of break-specific dsRNAs facilitates the recruitment of reparation factors. Interestingly, this mechanism is also needed for the maintenance of telomeres (10).”

    Thoughts?

    Reply

    • I was sharing this because i got the impression that many of Josh readers was choosing eg. rapamycin instead of metformin. I believe there is room for both agents, but of course there is always the possibility of too much Mtor inhibition.

      But collectively, the anti-cancer, ampk activation, Methylation effects, mtor inhibition, anti AGE (gycation), and new to me the increase in DICER1 expression it is becomming a really interesting molecule.

      Metformin have likewise shown to increase Nampt and Nampt we know is the rate-limiting enzyme in the (NAD+) salvage pathway that converts nicotinamide (niacin) to nicotinamide mononucleotide (NMN) in mammals to enable NAD+ biosynthesis.

      Low dose niacin + metformin = more nad+???

      btw, i read this, and thought you would find this paper interesting Josh: “Transposable elements, placental development, and oocyte activation: Cellular stress and AMPK links jumping genes with the creation of human life.”

      https://www.ncbi.nlm.nih.gov/pubmed/30037614

      Good evening everyone.

      Reply

      • Elkaer thank you sharing the metformin article. Here is another finding: https://www.frontiersin.org/articles/10.3389/fendo.2018.00657/full

        It directly binds and activates Sirtuin1 which was news for me. Relooking metformin and currently switched from rapamycin to metformin. Keeping 2 days holiday in a week.

        From another study on possible synergy:
        Males given Met/Rapa had a 23% increase in median longevity, higher than the 10% effect produced by Rapa alone in C2006 or the 13% effect in C2009 males.
        Female mice given Met/Rapa also had a higher percentage increase in median lifespan (23%) than females that had received rapamycin alone in the previous C2006 and C2009 cohorts (18% and 21%, respectively), but the difference did not reach significance by log-rank testing.

        Reply

      • A few thoughts on metformin.

        It’s a mitochondrial inhibitor, more specifically an electron chain transport inhibitor , which may in part explain its side effect of fatigue.

        It does a decent job of lowering glucose, insulin,a nd IGF-1, which may explain its anti- cancer mechanism in diabetics, but not so much in non- diabetics.

        Not a bad downstream inhibitor of TOR, but rapamycin exerts a more direct hit.

        The longevity data with rapamycin is much more compelling.

        I feel that metformin is a decent drug without much risk, but the benefits in my opinion are fairly modest.

        Reply

        • Thanks to both of you for your replies, i apriciate it.
          On the topic, Blagosklonny is out with a new paper. For the avid reader, nothing new under the sun. Except maybe only the importance of a rapamycin dose in the higher range:

          “In these studies, rapamycin was most effective at high doses [88,89,93–96,100–103]. Its effect and that of everolimus lingers after their discontinuation [104], even after a single dose [105]. What appears to be important is to reach high peak levels using a single high dose [93,94].”

          Any qualified guesses on why this could be? just longer duration of Mtor supression? or total Mtor supression needed for stem cell rejuvantion?

          On another note this might be useful for your friend Josh: “Mannose impairs tumour growth and enhances chemotherapy.”
          https://www.ncbi.nlm.nih.gov/pubmed/30464341/

          D-Mannose is a carbohydrate and easily attainable.

          Lastly, i cant wait to hear more about your project Akshay, i am wondering if GHK-cu and andrographolide plays a part in it. I wish you the best of luck.

          Reply

        • I recently stopped taking Metformin.

          I was meeting a handful of people, taking it for anti-aging claims, who were complaining of side effects after four to five years of use.

          The side effects were a creeping inability to exercise to capacity, fatigue, and serious abdominal bloating.

          These issues all resolved upon quitting the Metformin, according to those people.

          I did not experience major side effects when using Metformin, but I also, did not feel any improvement on it.

          I was taking Metfomin for the anti-aging claims, at a very small dosage, and I took it for only about a year.

          Reply

          • I agree Paul, 15mg per month would be a interesting idea, but I’ve never known anyone to take so much in one go. It might take the best part of 2 weeks to clear rapamycin from your system at that dose.

          • It’s an interesting thought. Essentially one would be on it for 2 weeks and then off for 2 weeks. You could also wait a month for the next dose.

            I wonder above mouth ulcers and is the mTOR 2 hit too great at that dose?

            Blagosklonny seems to think that the dose is safe.

          • Yes, Metformin is a mitochondrial inhibitor.

            Just some speculation:

            Mitochondrial inhibitors may be okay if a person is insulin resistant, or if there is a need for a mitochondrial inhibitor to squelch tumor growth or mitochondrial hyperactivity.

            However, Metformin may not be a good anti-aging drug for a healthy person.

            Here is a link and an article excerpt:

            https://www.sciencedirect.com/science/article/pii/S2211383512000949

            In genetic study, inhibition of mitochondrial function by gene modification leads to protection of insulin sensitivity.

            Several reports suggest mitochondrial hyperactivity and overload as major cause of insulin resistance.

            This point has been demonstrated in Asian Indian immigrants in the United States18 and in animal models of diabetes and obesity

            …..And below is another link & article excerpt regarding tumor growth:

            https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4017650/

            Researchers have proposed two ways that metformin could affect tumors.

            First, insulin is known to prompt cancer cells to divide, so the slower rate of tumor growth could just be a side-effect of the metformin reducing the amount of insulin in the blood.

            Alternatively, metformin could target cancer cells more directly by cutting the energy supply produced by their mitochondria.

            Metformin has been shown to disrupt complex I of the electron transport chain that is used by cells to generate energy.

            However, it is not known if disrupting complex I would actually stop cells dividing because they can generate energy in other ways.

          • Those are excellent points Heather. Metformin probably benefits those whom are insulin resistant and mitochondrial inhibition is a major mechanism. It’s doubtful that non diabetics benefit much if at all. I’m also not sold on a synergy with rapamycin.

            There are those who question the benefits of rapamycin stating that the lifespan and healthspan effects are modest at best. I’m starting to strongly believe that it’s largely a matter of dose and dosage frequency. This is in fact the case with all medications. I think that we’ve only scratched the surface of rapamycin potential.

          • That’s interesting Heather.

            Clearly many in today’s calorie rich world just get too much energy input, hence the insulin resistance – but inhibiting CxI seems an extreme measure. What happens to all the free electrons from the Krebs cycle? Maybe there is sufficient input via CxII to avoid an increase in ROS.

          • Paul & Mark:

            I agree on all counts.

            Paul:

            Regarding both Rapamycin and Metformin, perhaps it is dosage that makes the beneficial difference.

            I am also not personally sold on the synergy between the two drugs, or even the benefit of either drug, in a healthy individual.

            Still, time may prove me wrong.

          • I wonder, if we can actually achieve the same results by simply restricting protein intake and combine this with the use of natural mTOR inhibitors like EGCG, curcurmin etc. Maybe throw in some IF on top of that. Cheaper and probably more appealing to those, who prefer a “natural” approach.

          • I think we need to be careful about jumping on the low protein bandwagon. I personally am a meat eater and I don’t think protein is the main reason for excessive mTOR activation. I think it’s insulin resistance driven by excessive carbohydrate consumption. This leads to a inexorable rise in chronic mTOR activation (always snacking on carbs) as we age. So what if there’s a big mTOR spike with a protein heavy meal? That is what we want. What we don’t want is mTOR turned on all the time.

            So my conclusion is eat protein but eat occasionally. And don’t over eat carbs or snack on them.

          • Any restriction may not be a good approach. Founder of Atkins diet one of the most popular diets of its time died relatively young. As we know our nutrient sensor dysfunctions by over activation as we age. It’s activation is also important for us but not the overactivation. Anything of natural origin that can help us inhibit mTOR just enough to rebalance it safely would work best to ameliorate many dysfunctional complications caused by aging. Restriction at some level will prove harmful. But such hormetics will also only act as boosters and slow down certain aging dysfunctions. We need safe method to fully stop or reverse all dysfunctions caused by aging to get full benefit we are seeking of healthy longevity.

          • This is complicated because it seems that mTOR activation by protein may be tissue specific to some degree. In mice fed a ketogenic diet, the diet affected mTOR signaling in tissue specific ways, with protein having a more profound effect on skeletal muscle. Perhaps carbs affect other tissues to a greater degree. We need a study looking at patterns of mTOR activation in different tissues subjected to different stimuli.

            I don’t want to enter old age as skeletal and flabby so I’ll continue to eat a wide variety of healthful foods including meats. TOR signaling can be modified via other interventions.

          • Well, regarding diet….., the Mediterranean diet seems to always come out on top as the healthiest choice.

            The Mediterranean diet involves eating meat sparingly.

            I agree that the Atkins diet did not appear to enable Dr. Atkins to avoid heart disease, although he did have history heart disease and his father died young. So maybe it did extend his lifespan some.

            My personal observation, though, from people on a high protein, high saturated fat, diet from meat, is that they do lose weight but they look somewhat wizened.

            Perhaps they looked wizened because of bone or muscle mass loss. They think they look great, though, because they have lost weight.

            Some newer studies show that the Atkins diet does not raise LDL (the bad lipoprotein) except in a subset of individuals (likely genetically disposed).

            People with heart disease are often slim because of cardiac Cachexia.

            People with cancer often lose a tremendous amounts of weight.

            So, just being slim, in and of itself, is not an indication of health.

            I had a friend that was on a the Atkins diet and he did lose a lot of weight followed by two heart attacks.

            After his first heart attack I once watched him bunch together about eight slices of bacon and then shove them very quickly into his mouth while chomping down, which resembled a wood chipper to me.

            I thought: he is going to have a second heart attack. Sure enough three weeks later, he did.

            Still, there are people who eat a lot of bacon and live until 98.

            It’s complicated.

          • Against aging diet of any kind would be inadequate except for Calorie Restriction. Rapamycin is considered kind of a mimetic of CR. With regards to diet as Paul said well balanced one should be fine – any extreme one by removing a food group usually leads to more harm than the benefits. Two of my friends on ketogenic diet in the midst of ketosis lost sleep. Couldn’t sleep a wink. We know how harmful that can be.

          • You won’t lose muscle mass on a meat diet, in fact you’re highly likely to gain it. But it does take 2-3 months to get fat adapted and in the interim you’d probably be weaker.

            As for chloresterol, it’s synthesis is set by insulin levels, so low carb will sort that out. Also one thing to bear in mind – you can’t eat high fat with sugar. Any sugar and the body will burn that and store the fat. But if you cut out the carbs below a certain level the fat will be burned instead. Being fat adapted gets most of its benefits from PPAR activation. And indeed this shares many of the benefits of calorie restriction (the body has to burn fat stores with insufficient food intake).

            If high fat and protein really lead to heart disease we’d see it in Innuit and (historical) Mongolian populations. But we don’t. We see it in high carb and sugar societies.

            Problem with the Mediterranean diet is that it is probably inseparable from the lovely climate and lifestyle.

          • Mark:

            The Innuit Eskimos get their fat from whale blubber and that is suppose to be high in EPA/DHA.

            So the type of fat one eats is important.

            As for an excessively high meat diet making one more muscular, that has long ago been proven a myth.

            We only need a certain amount or protein and going beyond that does not build muscle.

            Adequate protein, plus working out builds muscle.

            A person will not build muscle simply by eating a lot of meat or protein.

            Also, there are other sources of protein other than meat.

            Humans have slow rates of growth and relatively low protein requirements compared to other animals .

          • It would be interesting to see a study done on macro nutrient consumption and muscle building in weight lifters.

            I haven’t seen such a study, but I’d bet protein requirements are higher than you think.

          • Mark:

            I am not aware of any definitive studies.

            So you may be right. The jury appears to still be out on this one.

            Still, body builders often die young, particularly those who eat an excessive amounts of red meat to build muscle.

            Too much protein can adversely effect nitrogen balance.

            There are suggestive studies that show that Protein requirements are typically claimed to be based on body weight, varying from 0.8 grams to 1.8 grams per Kg., depending on activity levels, age, climate, and various other health factors.

            There are no studies that state that regularly eating higher levels of protein, than suggested as required for weight, disease, and activity levels, have any benefit for muscle building.

            ——————————–

            This study, linked below, suggests that excessive protein from meat, particularly, may have adverse effects.

            https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4045293/

            [ Despite the fact that short-term high protein diet could be necessary in several pathological conditions (malnutrition, sarcopenia, etc.), it is evident that “too much of a good thing” in diet could be useless or even harmful for healthy individuals [1, 29].

            Many adults or even adolescents (especially athletes or body builders) self-prescribe protein supplements and overlook the risks of using them, mainly due to misguided beliefs in their performance-enhancing abilities [30].

            Individuals who follow these diets are therefore at risk [31]. Extra protein is not used efficiently by the body and may impose a metabolic burden on the bones, kidneys, and liver.

            Moreover, high-protein/high-meat diets may also be associated with increased risk for coronary heart disease due to intakes of saturated fat and cholesterol or even cancer [31].

            Guidelines for diet should adhere closely to what has been clinically proved, and by this standard there is currently no basis to recommend high protein/high meat intake above the recommended dietary allowance for healthy adults [32–35].

            Further investigation with large randomized controlled studies could provide more definitive evidence. ]
            ———————————-

          • “Moreover, high-protein/high-meat diets may also be associated with increased risk for coronary heart disease due to intakes of saturated fat and cholesterol or even cancer.”

            I’m sorry, but I can’t take any study seriously that makes such a statement.

            Saturated fat and chloresterol do not cause heart disease or cancer. Eating a load of processed, sugary carbs does.

            I know that this is not the mainstream view, as yet. But it will be.

          • I agree that too many simple carbohydrates with a high glycemic index are not healthy.

            Complex Carbohydrates with a low glycemic index, are healthier, when eaten in moderation

            In addition, an EXCESS OF PROTEIN, through a process called gluconeogenesis, turns the excess proteins into sugar.

            In addition, too high levels of amino acids will affect BOTH the inflammatory insulin pathway AND the mTOR pathway by stimulating it.

            Too much mTor will stimulate adipogenesis or new fat formation in the body of humans.

            mTor stimulation will also inhibit cellular autophagy.

            Conversely, a high fat diet will cause the hypothalamus to inhibit the mTOR pathway and reduces hunger.

            So it’s complicated to say the least.

            Maybe a good approach is to eat mostly good fats such as those from nuts and fish, unrefined olive and coconut oils, with minimal amounts of beef and other meat proteins.

            Everything in moderation, perhaps.

          • I agree you CAN eat complex carbs, but as you yourself point out via gluconeogenesis, you don’t HAVE to.

            You can’t do without fats or protein however.

            And as for mTOR, I’d worry more about the chronic ratcheting up of insulin caused by carbs turning mTOR on permanently, rather than protein.

            And that’s not even starting on glycation end products and excess LDL production caused by living off carbs (as most people do).

            The problem is that we’re all told to have a balanced diet. But very few people do, as everyone is addicted to carbs.

          • I never advocated that one can do without fats or proteins. I spoke about moderation and balance.

            Also the protein need not be sourced from meat to be negative.

            I said EXCESS PROTEIN, based on a preponderance of studies, has been consistently shown to have a negative effect on health in humans.

            The adverse effect appears to be influenced particularly by meats, and when exceeding the human protein requirement.

            Bear in mind that each individual human has a unique biochemistry, and certain metabolic conditions or diseases or disorders, change dietary requirements. …Sometimes drastically,

            In addition, it is interesting that a recent study appears to suggest what may behind the “French Paradox” by indicating that fermented cheeses and yogurt and other fermented milk products, despite a high fat content, do not increase heart disease. …Whereas meat protein does.

            The blue zone areas of the world, are regions where a high number of people live to be a healthy, sharp minded, active 100 plus, with low rates of heart disease, cancer, diabetes, and obesity.

            If you research those regions you will see that they eat meat and cheese protein sparingly.

            They mainly eat Legumes, grains, fruit, green leafy vegetables, hearth healthy nuts and oils, with some fermented cheeses, but with meat, particularly beef, being eaten sparingly and mainly as a side dish, not the main course.

            The blue zones are in Ikaria, Greece; Okinawa, Japan; the province of Ogliastra in Sardinia, Italy; the community of Seventh-Day Adventists in Loma Linda, California; and Costa Rica’s Nicoya Peninsula.

            Moreover, EXCESS PROTEIN, beyond the human requirement, loads the body with amino acids. And that will affect BOTH the inflammatory insulin pathway AND the mTOR pathway.

            Remember in the blue zones they consume complex carbs with a low glycemic index.

            Protein in excess activates the mTor pathway and that makes new fat cells it also inhibits autophagy, or the cleaning out of cells.

            Eating fat, blocks the ability of leptin to activate the mTOR pathway, via the hypothalmus, AND reduces food intake overall.

            The source of the fat determines it’s health aspects, negative or positive.

            When we eat Carbohydrates, we affect the insulin pathway.When we eat fat, nether. When we eat Protein, we stimulate BOTH insulin and the mTOR pathway.

            The fat is shown to be healthier if it comes from heart healthy vegetable oils and fermented cheeses, as the French favor, or oily fish rather than, excess meat, particularly red meat.

            Also, It was recently learned that pork, beef and lamb all contain a sugar which is naturally produced by other carnivores but NOT humans.

            That study appears to suggest when a human eats meat, the body triggers an immune response to the foreign sugar, producing antibodies which spark inflammation, and eventually cancer.

            So, if you are a dog or a wolf or a lion perhaps meat will extend your life, but most studies in humans do not suggest that it does.

            Dogs and Wolves also have a shorter intestine and therefore the meat does not sit in their digestive track as long, creating toxic waste products.

          • I agree with you on fats, Heather.

            Blue zones are interesting, but hardly convincing. There are too many confounding factors. And too much variation in the so called all important factors. How would you explain long lived areas like Hong Kong, with large meat consumption?

            Show me a real study showing meat causes heart disease. It can’t be epidemiological. And can’t be confounded with carbohydrate consumption.

            Or better still. Try a ketogenic diet like me and see how amazing you feel and look after a few months. Oh and to get back to the subject of this post, have a weapon against cancer built into your lifestyle automatically.

  16. Here is a report for a cure for pancreatic cancer, which is almost always deadly and “incurable” as of conventional medicine. It is in German but many – I guess – can read and understand it. Google translate will help if needed.
    ————————————————————————————-
    Bauchspeicheldrüsenkrebs – wieder einmal besiegt

    Eine der dramatischsten Krebsformen ist das Karzinom der Bauchspeicheldrüse. Fulminanter Verlauf. Nur sehr kurze Lebenserwartung. Der Patient wird quitte-gelb, isst nichts mehr, magert rapide ab, hat grausige Schmerzen. Oft verbunden mit Lebermetastasen, nicht operabel. Bleibt eigentlich nur Morphium.

    Wenn man solch einen Patienten trotz aller Voraussagen am Leben erhält, es ihm gut geht, er also beschwerdefrei ist und wenn der Krebs samt Metastasen Jahr für Jahr kleiner wird… dann berichtet ein Arzt darüber. Auch wenn ihm dieser Bericht um die Ohren gehauen wird aus dem einfachen Grund:

    Das Wunder heißt Vitamin C. Wieder einmal.

    Es genügen wenige Worte. Mann. 68 Jahre. Großer Bauchspeicheldrüsenkrebs, Leber voller Metastasen. Lehnt jegliche Behandlung ab. Operation sowieso nicht möglich, aber eben keine Chemotherapie, keine Bestrahlung.

    Kommt vor. Gibt es. Der Mensch hat mit seinem Leben abgeschlossen. Will die letzten Tage durch Chemotherapie nicht noch unerträglicher machen. Alles verständlich.

    Der Patient bekam zwei bis drei Mal wöchentlich
    Vitamin C 75 -125g als Infusion.

    In der veröffentlichen Arbeit sehen wir ganz anschaulich jährliche Kontroll-PET-CT´s und sehen, wie der Krebs kleiner wird, wie Metastasen verschwinden.

    Entscheidend: der Patient verlor kein Gewicht mehr, hatte keine Schmerzen. Also fast Idealzustand trotz dieser Zeitbombe im Bauch.

    Weshalb er dann nach vier Jahren gestorben ist? Nun ja… Schulmedizin. Man hat ihm auf Verdacht einen Stent, ein Röhrchen in den Gallengang geschoben. Zum besseren Abfluss. Zwei Wochen später septischer Schock. Notfall. Das Röhrchen war gewandert und hat den Darm durchlöchert. Das war´s dann.

    Quelle: ANTI-CANCER DRUGS 2018 Apr; 29 (4): 373

    Das Geheimnis dahinter ist selbstverständlich kein Geheimnis. Wurde uns schon 2005 erklärt von Wissenschaftlern des NIH, also der größten und wichtigsten Forschungseinrichtung dieses Globus.
    Als sie zeigten, dass man mit Wasserstoffperoxid Zellen töten kann. Besser gesagt: Krebszellen. Und dass eine Vitamin C – Infusion genau dieses Wasserstoffperoxid (H₂O₂) produziert, Krebszellen tötet. Umliegende gesunde Zellen aber in Ruhe lässt.

    Schon einmal hatte ich Sie gefragt, wie man es schaffen könnte, genügend Vitamin C genau an die Krebsnester hinzuschaffen. Korinthenkacker und Klugsch… halten das natürlich für nicht möglich. Nun ja, vielleicht haben sie Recht.

    Haben sie natürlich nicht. Siehe oben. Zwei bis drei Mal die Woche jeweils 75 -125g Vitamin C haben gewirkt. Sogar beim unheimlichsten aller Krebse.

    Quelle: PROC Nat Acad Sciences Vol 102 no. 38, 13604. Doi: 10.1073/pnas.0506390102

    Reply

  17. Hi Paul. Almost certainly we are talking about mtROS. That seems to be the main source of nuclear DNA damage and cellular arrest.

    MitoQ might help. As might other electron acceptors like methylene blue. Such long terms studies have never been done on humans and cancer rates, though I have read good things about mitoQ and metastasis prevention.

    https://www.sciencedirect.com/science/article/pii/S2211124714005270

    Thanks for the clarification Akshay. Intriguing about the two edged sword of inflammation.

    Reply

    • Hi Mark,

      Replication, rather than ROS, seems to be the main source of mutation in humans. Men’s germ cells undergo about 400 replications per generation while women’s only about 30. As a result men’s germ cells harbor 10 times as many mutations by the age of 30, with very little increase in total mutations during the fertile lives of women.

      Somatic mutation rate seems to be higher by most accounts. Perhaps female eggs are under a certain state of quiescence that allows them to preserve their genome integrity better than other tissues. But some level of maintenance activity must still go on.

      You can find a nice chart of the mutation rate over at Laurence Moran’s blog ‘the Sandwalk’:
      https://sandwalk.blogspot.com/2017/11/parental-age-and-human-mutation-rate.html

      ROS may be a major cause of DNA damage and a trigger of a DNA damage response that leads to cell arrest, senescence or apoptosis. But metabolism alone seems to be a minor source of mutation.

      Although these levels are appreciable, from 1 to 10 mutations per cell division depending on the source (and the tissue), I am skeptical that mutation alone is the trigger of cancer. Perhaps in fast proliferating tissues is more of a factor, but in most somatic cells the levels seem to be similar to inter-generational mutation rates.

      To me, there clearly needs to be another process underlying it. Most cancers exhibit behaviour we only see in stem cells, so I would say they originate in that state and the failure to control its proliferation. We know that this process is largely driven by epigenetic control so it makes sense something similar is going on in cancer.

      I think that one of the reasons we have traditionally regarded cancer as mainly driven by mutation is because we are assuming they accumulate to disruptive levels as we age. But this does not seem to be the case. Personally, I think it is the down-regulation of the immune system that results in the higher incidence with age.

      I agree that in the short term this does not lead to any practical application, but long term I hope that’s not the case. We have only just discovered iPSC cells and OSKM factors, much is left to research.

      Reply

      • Hi Adrian,

        Yes we discussed this upthread and I posted a paper which modelled cancer incidence based on immune decline with a small number of mutations, rather than the larger number traditionally required. So I agree cancer is not primarily caused by mutations but by the loss of the ability to nip them in the bud that leads to cancer. It may well also be that a young cellular environment also exerts a level of epigenetic control beyond immune signalling.

        As for aging, this is somewhat different as it is not caused by mutations, but by the amount of cellular arrest caused by (primarily) ROS, and the requirement to replace such losses, which ultimately can lead to proliferative exhaustion, if the consequent senescence and inflammation does not get us first.

        Reply

  18. So rapamycin leads to a younger epigenetic age whereas anti-hypertensives are aging, at least according to a recent study showing that all BP meds lead to an older epigenetic profile.

    This presents a real conundrum to a practicing physician such as myself where, over the long term , the cure may be worse than the disease. Even worse, the cutoff for treating hypertension has become even stricter. This is almost a holy grail of the medical community so refusing to treat HBP for almost any reason would be seen as a severe violation of standard of practice.

    My own experience has shown me that very few things actually make me feel younger. These include rapamycin, pine bark extract, exercise, and perhaps melatonin. On the other hand, when I tried the ACE inhibitor lisinopril, I literally felt older, so I think there may be something to this study, but it surprises me that it pertained to all BP interventions.

    Reply

    • I wouldn’t get too hung up on Horvath’s clock Paul.

      Anti hypertensives don’t make you older (your own experience with ACE inhibitors not withstanding). They just make certain cells in the artery wall live longer. Hence they have more time to acquire epigenetic variations.

      This is the same reason those with longer telomeres appear to have an older epigenetic age: they cells need replacing less often from the (epigenetically younger) stem cell pool.

      Incidentally sartans activate telomerase in endothelial cells. Win win as far as I can tell.

      Reply

      • That makes sense, but then I would assume that under the influence of rapamycin, which slows cellular proliferation, that they too would be replaced less often and would have an older epigenetic age, but that is not the case.

        On the other hand, rapamycin tilts the anabolic/ catabolic balance towards the catabolic and that would indeed cause those cells to be replaced with younger ones and a younger epigenetic age would be the result. This effect may actually be real.

        Reply

        • Rapamycin might make cells live longer, I don’t know. But it also suppresses inflammation and probably reduces many growth and metabolic signals. This probably accounts for slower methylation changes.

          Reply

        • Paul

          You wrote: [ “On the other hand, rapamycin tilts the anabolic/ catabolic balance towards the catabolic ” ]

          Well, that is why it may be crucial to get the dosage correct because what if a too high dose pushes one too far toward the catabolic state.

          One issue with older folk is inability to hold onto muscle and weight loss in general.

          Rapamycin does cause weight loss. But the balance may be crucial

          Cigarettes cause weight loss, too.

          Reply

          • Heather

            David Sabatini, an expert in all things mTOR, believes that catabolic breakdown, followed by rejuvenation by younger and healthier tissues, is the reason for the subjective improvements that many of us experience after just a couple of months on rapamycin.

            It would also explain the objective increase in cardiac ejection fractions which is evidenced in the recent dog studies.

          • To me this suggests Paul, that you might only need to take rapamycin for a couple of months every X years.

            Fits with my subjective experiences of being on rapamycin for almost 2 years, then doing it only 1/month, then going back on it weekly, then coming off it for a protracted period. Although I felt the improvements you describe in the first 6 months, it now doesn’t seem to make.any difference whether I’m on or off it (age 40), and I still feel as good.

          • That makes sense in theory, but I think Matt Kaeberlein said that after 6 months off of rapamycin that the dogs returned to baseline function. I’m starting to think that a hefty dose once a month is ideal, but I don’t know what that might mean exactly.

          • Hi Paul:

            I honestly did not feel any subjective improvements on Rapamycin. None.

            Perhaps because I have been for a long time taking natural substances that block the mTORC1 pathway and had no health issues to correct.

            Also, I am tending to think Mark may be on to something in that Rapamycin may only be needed ever X number of years to perform the mentioned effect of catabolic breakdown followed by rejuvenation.

            I am not arguing the effect, only the method of getting there.

            Even the natural mTOR inhibitors may only be needed cyclically. …stopped for two years after being taken for a few months.

            Like Mark, I feel no difference since stopping the Rapamycin, but again, that may be because I had no health issues that needed correcting.

            Perhaps if some one has decreased cardiac injection fraction, either diagnosed or undiagnosed, or a weaker immune system, and the rapamycin is used, then they would feel a difference and it would be measurable.

            What does it do in a healthy person, though?

            Could it throw off balance in a negative way?

          • Only about 15% of rapamycin is absorbed and it varies a great deal among individuals. It has also been my experience that men see better results. Perhaps mTOR levels in women are lower since they generally have less growth and development than men.

            Also remember in the Kaeberlein mouse study that the males responded very robustly to very high doses, whereas the females died of hematologic malignancies.

            I had a 25%drop in my insulin levels, a 15 lb. weight loss, and a 10% drop in my white count. Also had a significant increase in endurance and overall well being.

          • Many people who take an anti aging drug/supplement or lifestyle intervention expect an instantaneous effect. But in my opinion aging is very slow in humans. Yes you can tell the difference between even a 20 and 30 year old, but our interventions are as yet very crude. Almost miraculous results may occur with very old animals (or humans) taking rapamycin. But others (often younger) experience nothing.

            Until we have a real and accurate way to assess the process of aging (which is more accurate than just looking to someone), we will have these difficulties in assessing efficacy. Or until we have such an effective remedy for aging that there is no doubt.

          • Paul:

            You wrote: [ “I had a 25%drop in my insulin levels, a 15 lb. weight loss, and a 10% drop in my white count. Also had a significant increase in endurance and overall well being.” ]

            That is excellent Paul.

            I think perhaps I felt no change because I have been taking nutrients and herbs for years, some of which offer similar benefit to Rapamycin, therefore all of my similar parameters were already in range.

            Also, I was already slim and exercise vigorously daily.

            So, Perhaps Rapamycin does slow aging, but it will not be obvious in a person that has no measurable health issues to address.

            Or, it could be, as the studies show, that women do not respond the same way men respond.

            Mark:

            You wrote: [“Almost miraculous results may occur with very old animals (or humans) taking rapamycin. But others (often younger) experience nothing. “]

            I agree. So then the question of risk vs benefit arises.

            I may revisit Rapamycin at a later date, or even after some of the dog studies are completed.

            But for now, I am taking a break.

            However, if I was seeing the improvements Paul is seeing, I would continue with Rapamycin.

          • Great if it works Josh. From what I’ve seen so far from my reading of Horvath’s papers, and the results at Longecity using related clocks – I think it’s got a way to go.

  20. OT for this thread, but I look forward to Josh and others commenting on the latest senolytic discovery ( Azithromycin, FDA approved and generic) — very selective activity seems promising. Obviously more study will be required.

    https://www.researchgate.net/profile/Bela_Ozsvari/publication/328948748_Azithromycin_and_Roxithromycin_define_a_new_family_of_senolytic_drugs_that_target_senescent_human_fibroblasts/links/5bfd33dea6fdcc35428b7dba/Azithromycin-and-Roxithromycin-define-a-new-family-of-senolytic-drugs-that-target-senescent-human-fibroblasts.pdf?origin=publication_detail

    Reply

  21. Re. the Horvath clock, I wonder if anybody else missed out on this July’18 study that published a new clock, specifically developed to measure DNAm age in skin and blood tissue.

    https://www.aging-us.com/article/101508/text

    They can now detect an increased DNAm age in progeria patients and a wider correlation between cell proliferation (doubling) and DNAm age. They can also better plot fibroblast methylation age to the chronological one whereas the previous pan-tissue clock would make them appear older than other tissues (they still could be, according to other measures).

    Very important insights in my opinion. Previously, we could only link DNAm age to metabolic processes, to account for the apparent constant rate of ageing observed in non proliferating tissues and the fact that some cells in culture didn’t seem to increase their DNAm age with cell doublings.

    So could it be that DNAm age is correlated to cell proliferation after all?

    Reply

  23. Here’s a fascinating study of centenarians, and in particular the very healthiest subgroup, focusing on the importance of T cells, T cell telomerase activity and telomere length, and how these relate to high levels of function in the very old. They also discuss the role of chronic inflammation and IL 10 levels.
    I’m now cycling in four supplements to help with T cell activation.

    https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12859

    Reply

    • Many thanks Paul for bringing it up.

      There’s also a very interesting discussion on the Telomere position effect over long distances. This study and the latest Horvath epi. clock I posted above, which shows a correlation between cell divisions and DNAm age, have rekindled my interest in telomeres.

      This is the case that Michael Fossel has been making for many years. In particular when it came to explain progeria, the effects we see would be the result of excessive cell proliferation, as cells affected by the defective protein that causes the disease commit apoptosis and others proliferate to take their place at a higher rate than in healthy individuals.

      Perhaps we have been a bit too hasty to dismiss telomere attrition as a principal cause of ageing.

      Reply

      • You’re right. Many HAVE been too hasty to dismiss telomere attrition as a primary cause of aging.

        Think of it this way. It’s very simple. Any damage, be that ROS from mitochondria, invasion by viruses, impact damage from sports, mutations from smoking, whatever – cells will die and others will have to divide more to replace them. Hence lifestyle factors and genetic predispositions and plain old luck lead to the exact patten of aging in different tissues in different individuals, but aging will always occur eventually if for no other reason than shortening telomeres and altered (read impaired) gene expression, which makes it more difficult for cells to make further replacements in the face of damage.

        Reply

        • Cancer makes immortal cells. It regenerates telomeres by generating telomerase. So telomere length is not finite. What we lose with aging is our ability maintain it’s length. That makes it an outcome in a cascade wherein it causes loss of cell viability. If one takes another example of thymus one can show it as a cause of aging by the same logic. As it shrinks immune function begins to get affected. Immune dysfunctions lead to chronic inflammation which in turn leads to most of the diseases associated with aging. But that’s not the case. The program that shrinks the thymus from the time we are born also reduces our telomerase. There is a program that dials down our ability to repair and regenerate.

          Reply

          • I never said it was finite. Cells clearly can re-extend their telomeres; this has been demonstrated many times, many different ways in the lab.

            The question is why this doesn’t happen in grown humans.

            I think it is probably built in as a way of shifting cancer risk from the young to the old. Others, yourself and Josh included believe it’s the downstream consequence of a more fundamental program.

            Either way should be amiable to intervention and the reversing of aging. And I don’t care which turns out to be true, so long as the problem is solved!

          • Hi Akshay.

            Just had my mind blown by this paper.

            https://elifesciences.org/articles/17915#abstract

            Its a study profiling gene expression changes in the brain in the mid-twenties being very important to the onset of schizophrenia.

            In my view this strongly supports your assertion of programmed changes in gene expression leading to down regulation of maintenance pathways.

          • Mark thanks for sharing this paper. Completely missed it. I totally share your excitement about this paper. The significance is more for aging rather than schizophrenia. I have been coming across such evidence. One can predict by these selected changes in gene expression. I have shared a few of these evidences on my blog. So the conclusion I came to was that having learnt that aging is a program that deliberately changes gene expressions which results in down regulation of repair and rejuvenation pathways (in such a conserved fashion that one can predict age by a particular trajectory of developing dysfunction) there are 3 interventions one can attempt: Find technology to reverse methylation drift in the epigenome – basically prevent or reverse each negative change in gene expression: Or upregulate repair and rejuvenation pathways – one needs to find and do all otherwise due to the level of interconnection the few remaining can soon affect the others: Or hack the program. Harold and I tested the latter 2 and got mind blowing results. The first one is being done by George Church. Jeff is also through his research reversing some of the key age related changes which is why his readers are getting such great results. Greg Fahy is on to a reversal which evidences is showing may be right on top of the cascade of changes – thymus involution and the progressive dysfunctions arising in our immune system.
            What I find very good about you Mark is that you do not get dogmatically stuck in any one theory. Like me if you find strong evidence you are always ready to reconsider. Paul is another such crusader along with Josh. True researchers at heart get more excited by the solving of the aging puzzle rather than whose theory is correct or incorrect. But right now Harold seems to have found the Holy Grail. Which is fantastic news for passionate anti agers.

          • Of course the paper does not explain what the trigger for such gene changes is, other than it being part of development and possibly related to methylation changes.

            Looking forward to seeing what buttons you and Harold have learned to press to restore youthful gene expression!

            I have recently been experimenting with ways to increase progenitor cells and also the clearance of old cells. I’ve found evidence that the two processes can be synergistic. Will beat this thing!

          • Akshay, it all sounds very encouraging, and I wish you the best of success. I hope the pill won’t be just another antioxidant-pill, ramping up Nrf2, downregulating NF-Kb and so on.

            We have plenty of mitchondrial “renewal-kits” on the market, which do little to nothing.
            What annoys me most about aging is the loss of flexibility in muscles, morning stiffness in tendons/joints and of course decreased ATP production in muscle mitochondria. In my 30’s I could jump right out of bed and run 5miles without warming up. This is long over…..

            IMO, one of the overlooked hurdles in aging is the build up of crosslinked proteins in the extracellular matrix. Currently, we have no way of getting rid of this extracellular garbage. Senolytics is of no use. Epigentic rollback won’t help us either.

            To my knowledge there is no SAFE way to reverse crosslinked proteins. Additonally, a method that would address the destruction of about 20 different types of known crosslinks seems like an overwhelming task.

          • Ole all I can say is you won’t be disappointed. No it’s not a ‘pill’. Besides upregulation of repair systems I would add clean up of cellular and extra cellular debris and restoring the thymus as the 3 interventions that should give long lasting results. There are 3 that can partially clean up the cross-links and lipofuscin, misfolded proteins, mitochondrial aggregates and AGEs.
            You should be able to try them hopefully in 2019.

      • For 3 consecutive days every other week some combination of

        Andrographis
        NK cell activator
        Reishi extract
        Astralagus as TA 65
        Cistanche
        Puerh tea

        Reply

  24. There is much to consider here Adrian.

    First of all, both groups, those with long and those with short telomeres achieved longevity, but the distinction of course was in regards to overall health and functionality. The group with the longest T cell telomere lengths and telomerase activity were clearly healthier. This coincides with the prevalent notion that immune functioning is of enormous importance and immunosenescence is a big problem. But questions remain.

    Does telomerase advance the epigenetic clock? Do long telomeres correlate nicely with a long and highly functional life, but not to advancing maximal longevity?

    Would it be optimal to combine an mTOR inhibitor to a telomerase stimulator, but not continuously, but rather in a pulsed manner, like monthly?

    Maybe add in some T cell activators like modified rice bran, Cistanche, pue-rh tea, Reishi, etc., also cyclically?

    Still much to learn.

    Reply

  25. The “Hasini” protocol to inhibit IL-6 to stop cancer from metastasizing uses a combination of two FDA approved pharmaceuticals.

    The inexpensive and non-toxic polypodium leucotomos extract sold as “Heliocare” has been reported to suppress IL-6 very well in vitro. “Surprisingly, the production of the inflammatory cytokine IL-6 was completely abolished (100% inhibition) by PLE at all doses tested.” Also known as “Fernblock” this fern extract prevents sunburn and inflammation. (perhaps by IL-6 suppression). https://www.ncbi.nlm.nih.gov/pubmed/10928072

    Reply

    • ROCK inhibitors are precisely what I have been researching for rejuvenation (as part of my cyclical statin-sartan protocol). Turns out that they aid in the conditional reprogramming of normal cells into progenitor-like cells when combined with senescent feeder cells. Direct ROCK inhibitors aren’t generally available, but statins have been shown to have this effect over time, which probably explains their benefits on endothelial cells and also their long term side effects (blocking of stem cell differentiation).

      https://www.ncbi.nlm.nih.gov/pubmed/22189618

      Interesting that the combination with mTOR inhibition produces another distinct but no doubt related effect.

      Reply

          • None.
            But I’ve been taking a 1/2 tsp of 100:1 Reishi root extract b.i.d. along with 4mg of candesartan b.i.d. just in case it improves my endothelium. (Not that I know of anything wrong). The reishi extract is a substitute for Fluvastatin which is presumed to work via rho-kinase inhibition in the study below.

            “A Low-Dose Combination of Fluvastatin and Valsartan: A New “Drug” and a New Approach for Decreasing the Arterial Age” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4363554/

          • Good to see someone else has picked up on Janic’s work Robert. I’ve tried his one month protocol and experienced benefits. Any particular reason you don’t want to use a statin?

      • Statins are known to have all sorts of negative effects on muscle in SOME users when a particular gene known as Atrogin 1 turns on and begins muscle breakdown.

        In some users the muscle weakness and muscle breakdown and other issues are quite obvious.

        Rhabdomyolysis can be deadly.

        The heart is a muscle.

        The breakdown of muscle is associated with illnesses such as cancer, sepsis, and AIDS.

        So if that Atrogin 1 gene is activated statins should not be used.

        Reply

        • Well in all the studies by Janic et al. the treatment was at a very low dose (10mg statin) and only for 1 month, so probably no need to worry about side effects. In fact he discovered that a low dose and a limited time protocol was MORE effective for the pleitrophic effects he was after (arterial rejuvenation). And if you are still worried – Q10 can be supplemented at the same time and according to my research should not impact on the effectiveness of the treatment. It is also my view (opinion rather than established fact) that the side effects of Statins are likely down to a bias in stem cell division preventing proper differentiation – which is useful for increasing progenitors, but if continued too long will harm the body because of the constant requirement for differentiated cells.

          https://www.researchgate.net/publication/280496460_Low-dose_fluvastatin_and_valsartan_rejuvenate_the_arterial_wall_through_telomerase_activity_increase_in_the_middle-aged_men

          It’s really quite remarkable work although some more work is required to fully explain the effects – mainly about how the ROCK inhibition either creates or sets free endothelial progenitor cells. For me the only downside is that the arterial rejuvenation (also likely by virtue of the bloodstream to help other organs), which is on the order of 10 years(!), only lasts around 6 months before the aging phenotype reasserts itself. The treatment can be repeated successfully, but still – perhaps Akshay can shed light on the signalling in the bloodstream that has this unfortunate effect?

          Reply

          • Mark my thoughts are that various damage occurs due to deliberate down regulation of repair systems. When we can find a safe agonist of any of the repair systems it will mitigate the damage outcome of that pathway and will continue to do so until at some point it is overwhelmed by interconnected rising cascade of other outcomes of damage. But one must not miss an opportunity to benefit till then. I myself take 5mg atorvastatin 4 times a week even if my cholesterol levels are considered by doctors in safe zone.
            On the over all boost one can get by the hormetics I believe that when it doubt go with Paul. I stopped my brief experiment with metformin 500mg and switched back to rapamycin 3mg once a week. One more study came out concluding that metformin negatively impacted capacity to exercise.

          • Hi Mark
            That’s a fascinating article and pretty amazing actually. Valsartin is hard to get at the moment due to a massive recall due to contaminants ( NMDA) or something. I now think that if your arteries are presently pretty clear that it may be possible to prevent coronary artery disease almost entirely and perhaps indefinitely with

            1. K2 and magnesium
            2. Pine Bark Extract and Goyu Kola
            3. Once every 6-10 months of low dose fluvastatin with valsartin
            4. rapamycin

            It seems that the endothelial benefits of the third approach is linked to significant telomerase activation. This will raise the debate of trade off once again, CAD vs. cancer due to telomerase and longer telomeres. As you know, I believe that critically short telomeres are DNA destabilizing and are much more of a cancer risk than long ones, but the objection will be raised.

          • Thanks Akshay and Paul for your ideas.

            I think that it’s likely some extra endothelial cells are formed because of the statin-sartin combination and this is the source of the extra telomerase and NO, etc. I don’t understand why treating for longer or at a higher dose gives a worse outcome, as ROCK inhibition will be greater with a larger statin dose. There must be some sort of complex, negative feedback loop.

            After treatment has ceased the normal growth signals will probably cause the extra progenitor cells to differentiate and the benefits will gradually be lost. So this is as expected.

            I wonder if a prior senolytics course might change the signalling so that the benefits would last longer? After all young people take a while to get old!

            I agree with you Paul that telomerase is as Michael Fossel’s says, ‘permissive of cancer, but not causal’. But we do know the glitazones (PPAR activation) are linked to bladder cancer – I believe there may be a similar mechanism of action at work here, and increasing the migration ability of progenitor cells might be cancer permissive too in the long run if other things are lined up (such as poor metabolic health).

        • Mark:

          Unfortunately the side effects of pharmacuetical drugs do not rear their ugly heads until it is too late, far too often.

          IMO, even a small intermittent dosages of statins can cause damaging epigenetic gene changes.

          But, if you are happy using statins, go for it.

          I have lowered Cholesterol in many people, totally without drugs, only nutritional and lifestyle changes.

          There is a small subset who may need the statin. Perhaps you are one.

          It that case it’s a risk benefit decision.

          Reply

          • Cholesterol reduction is irrelevant – it’s ROCK inhibition I’m after. Hence the idea of short term, low dose statins. It’s the pleiotropic effects that may prove anti aging.

    • Thank you for the link.

      This validates the self-observed negative affects on exercise capacity reported to me by a handful of people using a similar dosages of Metformin for anti-aging self experimentation.

      Reply

    • “Slowing Aging Using Drug Synergy” Optimum combinations of rifampicin, rapamycin, metformin, allantoin, and psora-4 were investigated to extend the lifespan of C-elegans.
      https://www.biorxiv.org/content/biorxiv/early/2017/06/21/153205.full.pdf

      Best combination was rifampicin 50 uM plus rapamycin 100 uM which nearly doubled lifespan.

      They found metformin was “poisonous” when combined with rifampicin, lowering the lifespan achieved with rifampicin alone.

      They found the optimum dose of metformin combined with rapamycin was only 25 mM (and rapamycin at 50 mM). Higher concentrations of metformin gave lower lifespan.

      Reply

      • Rifampicin appears to be a ROCK inhibitor.

        Kaplan Medical … Termination of transcription sometimes requires a protein called rho (ρ) factor. The prokaryotic RNA polymerase is inhibited by rifampin.

        ROCK inhibition combined with Rapamycin benefits are seen with Balogskonny on using statins with Rapamcyin as well as the study Robert posted showing benefits of Rapamycin, Rifampicin, and Allatonin.

        Reply

Leave a Comment