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Is there a way to exploit the metabolic quirk of cancer?

Is there a way to exploit the metabolic quirk of cancer?
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One night, as I alluded to in this post, Tim and I were having dinner and the topic of cancer came up.  Personally and professionally I have a great interest in cancer, so when Tim asked if I could write something about cancer that was: (i) interesting to a broad audience, (ii) not technically over the top, (iii) not my typical 5,000 word dissertation, (iv) yet nuanced enough for his readers, I agreed to give it a shot, in about 1,000 words.  (The content of this blog went up on Tim’s blog last week, but I’ve reproduced it here, less Tim’s commentary.)

Semantics and basics

Before jumping into this topic I want to be sure all readers — regardless of background — have a pretty good understanding of the ‘basics’ about cancer and metabolism.  In an effort to do this efficiently, I’ll list concepts here, such that folks can skip them if they want to, or refer back as necessary. This way, I don’t need to disrupt the ‘story’ with constant definitions. (Yes, I realize this is sort of cheating on my 1,000 word promise.)

Cancer – a collection of cells in our bodies that grow at roughly normal speeds, but that do not respond appropriately to cell signaling. In other words, while a collection of ‘normal’ cells will grow and stop growing in response to appropriate messages from hormones and signals, cancer cells have lost this property.  Contrary to popular misconception, cancers cells do not grow especially fast relative to non-cancer cells.  The problem is they don’t ‘know’ when to stop growing.

Metabolism – the process of converting the stored energy in food (chemical energy contained mostly within the bonds of carbon and hydrogen atoms) into usable energy for the body to carry out essential and non-essential work (e.g., ion transport, muscle contraction).

ATP – adenosine triphosphate, the ‘currency’ of energy used by the body.  As its name suggests, this molecule has three (tri) phosphates.  Energy is liberated for use when the body converts ATP to ADP (adenosine diphosphate), by cutting off one of the phosphate ions in exchange for energy.

Glucose – a very simple sugar which many carbohydrates ultimately get broken down into via digestion; glucose is a ring of 6-carbon molecules and has the potential to deliver a lot, or a little, ATP, depending on how it is metabolized.

Fatty acid – the breakdown product of fats (either those stored in the body or those ingested directly) which can be of various lengths (number of joined carbon atoms) and structures (doubled bonds between the carbon atoms or single bonds).

Aerobic metabolism – the process of extracting ATP from glucose or fatty acids when the demand for ATP is not too great, which permits the process to take place with sufficient oxygen in the cell.  This process is highly efficient and generates a lot of ATP (about 36 units, for example, from one molecule of glucose) and easy to manage waste products (oxygen and carbon dioxide).

The process of turning glucose and fatty acid into lots of ATP using oxygen is called ‘oxidative phosphorylation.’

Anaerobic metabolism – the process of extracting ATP from glucose (but not fatty acids) when the demand for ATP is so great that the body cannot deliver oxygen to cells quickly enough to accommodate the more efficient aerobic pathway. The good news is that we can do this (otherwise a brief sprint, or very difficult exertion would be impossible).  The bad news is this process generates much less ATP per carbon molecule (about 4 units of ATP per molecule of glucose), and it generates lactate, which is accompanied by hydrogen ions.  (Contrary to popular belief, it’s the latter that causes the burning in your muscles when you ask your body to do something very demanding, not the former).

Mitochondria – the part of the cell where aerobic metabolism takes place.  Think of a cell as a town and the mitochondria as the factory that converts the stored energy into usable energy.  If food is natural gas, and usable energy is electricity, the mitochondria are the power plants. But remember, mitochondria can only work when they have enough oxygen to process glucose or fatty acids. If they don’t, the folks outside of the factory have to make due with suboptimally broken down glucose and suboptimal byproducts.

DNA – deoxyribonucleic acid, to be exact, is the so-called “building block” of life. DNA is a collection of 4 subunits (called nucleotides) that, when strung together, create a code.  Think of nucleotides like letters of the alphabet. The letters can be rearranged to form words, and words can be strung together to make sentences.

Gene – if nucleotides are the letters of the alphabet, and DNA is the words and sentences, genes are the books – a collection of words strung together to tell a story.  Genes tell our body what to build and how to build it, among other things.  In recent years, scientists have come to identify all human genes, though we still have very little idea what most genes ‘code’ for.  It’s sort of like saying we’ve read all of War and Peace, but we don’t yet understand most of it.

FDG-PET – a type of ‘functional’ radiographic study, often called a ‘pet scan’ for short, used to detect cancer in patients with a suspected tumor burden (this test can’t effectively detect small amounts of cancer and only works for ‘established’ cancers). F18 is substituted for -OH on glucose molecules, making something called 2-fluoro-2-deoxy-D-glucose (FDG), an analog of glucose. This molecule is detectable by PET scanners (because of the F18) and shows which parts of the body are most preferentially using glucose.

Phosphoinositide 3-kinase – commonly called PI3K (pronounced “pee-eye-three-kay”), is an enzyme (technically, a family of enzymes) involved in cell growth and proliferation.  Not surprisingly, these enzymes play an important role in cancer growth and survival, and cancer cells often have mutations in the gene encoding PI3K, which render PI3K even more active. PI3Ks are very important in insulin signaling, which may in part explain their role in cancer growth, as you’ll see below.

The story (in about 1,000 words, as promised)

In 1924 a scientist named Otto Warburg happened upon a counterintuitive finding. Cancer cells, even in the presence of sufficient oxygen, underwent a type of metabolism cells reserved for rapid energy demand – anaerobic metabolism.  In fact, even when cancer cells were given additional oxygen, they still almost uniformly defaulted into using only glucose to make ATP via the anaerobic pathway. This is counterintuitive because this way of making ATP is typically a last resort for cells, not a default, due to the very poor yield of ATP.

This observation begs a logical question? Do cancer cells do this because it’s all they can do? Or do they deliberately ‘choose’ to do this?  I’m not sure the answer is entirely clear or even required to answer the macro question I’ve posed in this post. However, being curious people we like answers, right?

The first place to look is at the mitochondria of the cancer cells.  Though not uniformly the case, most cancers do indeed appear to have defects in their mitochondria that prevent them from carrying out oxidative phosphorylation.

Explanation 1

Cancer cells, like any cells undergoing constant proliferation (recall: cancer cells don’t stop proliferating when told to do so), may be optimizing for something other than energy generation.  They may be optimizing for abundant access to cellular building blocks necessary to support near-endless growth.  In this scenario, a cancer would prefer to rapidly shuttle glucose through itself. In the process, it generates the energy it needs, but more importantly, it gains access to lots of carbon, hydrogen, and oxygen atoms (from the breakdown of glucose).  The atoms serve as the necessary input to the rate-limiting step of their survival — growth.  The selection of cancer cells is based on this ability to preferentially grow by accessing as much cellular substrate as possible.

Explanation 2

Cells become cancerous because they undergo some form of genetic insult.  This insult – damage to their DNA – has been shown to result in the turning off of some genes (those that suppress tumor growth) and/or the activation of other genes (those that promote cell growth unresponsive to normal cell-signaling).  Among other things, this damage to their DNA also damages their mitochondria, rendering cancer cells unable to carry out oxidative phosphorylation.  So, to survive they must undergo anaerobic metabolism to make ATP.

Whichever of these is more accurate, the end result appears the same – cancer cells almost exclusively utilize glucose to make ATP without the use of their mitochondria.  A detailed discussion of which explanation is better is beyond the scope of my word allotment, and it’s not really the point I want to make.  The point is, cancer cells have a metabolic quirk.  Regardless of how much oxygen and fatty acid they have access to, they preferentially use glucose to make ATP, and they do it without their mitochondria and oxygen.

So, can this be exploited to treat or even prevent cancer?

One way this quirk has been exploited for many years is in medical imaging.  FDG-PET scans are a useful tool for non-invasively detecting cancer in people.  By exploiting the obligate glucose consumption of cancer cells, the FDG-PET scan is a powerful way to locate cancer (see figure).

FDG-PET

You can probably tell where I’m leading you.  What happens if we reduce the amount of glucose in the body? Could such an intervention ‘starve’ cancer cells?  An insight into this came relatively recently from an unlikely place – the study of patients with type 2 diabetes.

In the past few years, three retrospective studies of patients taking a drug called metformin have shown that diabetic patients who take metformin, even when adjusted for other factors such as body weight and other medications, appear to get less cancer. And when they do get cancer, they appear to survive longer. Why? The answer may lie in what metformin does.  Metformin does many things, to be clear, but chief among them is activating an enzyme called AMP kinase, which is important in suppressing the production of glucose in the liver (the liver manufactures glucose from protein and glycerol and releases it to the rest of the body).  This drug is used in patients with diabetes to reduce glucose levels and thereby reduce insulin requirement.

So, the patients taking metformin may have better cancer outcomes because their glucose levels were lower, or because such patients needed less insulin. Insulin and insulin-like growth factor (IGF-1) also appear to play an integral role in cancer growth as recently demonstrated by the observation that people with defective IGF-1 receptors appear immune to cancer. Or, it may be that activation of AMP kinase in cancer cells harms them in some other way.  We don’t actually know why, but we do know that where there is smoke there is often fire. And the ‘smoke’ in this case is that a relatively innocuous drug that alters glucose levels in the body appears to interfere with cancer.

This may also explain why most animal models show that caloric restriction improves cancer outcomes.  Though historically, this observation has been interpreted through the lens of less ‘food’ for cancer. A more likely explanation is that caloric restriction is often synonymous with glucose reduction, and it may be the glucose restriction per se that is keeping the cancer at bay.

Fortunately this paradigm shift in oncology – exploiting the metabolic abnormality of cancer cells – is gaining traction, and doing so with many leaders in the field.

Over a dozen clinical trials are underway right now investigating this strategy in the cancers that appear most sensitive to this metabolic effect – breast, endometrial, cervical, prostate, pancreatic, colon, and others.  Some of these trials are simply trying to reproduce the metformin effect in a prospective, blinded fashion.  Other trials are looking at sophisticated ways to target cancer by exploiting this metabolic abnormality, such as targeting PI3K directly.

To date, no studies in humans are evaluating the therapeutic efficacy of glucose and/or insulin reduction via diet, though I suspect that will change in the coming year or two, pending outcomes of the metformin trials.

Last point (beyond my 1,000 word allotment)

Check out this blast from the past! Gary Taubes, who is currently working hard on his next book, came across the article the other day from 1887.

1887, NYT, sugar and cancer

Influences

I’ve been absurdly blessed to study this topic at the feet of legends, and to be crystal clear, not one thought represented here is original work emanating from my brain.  I’m simply trying to reconstruct the story and make it more accessible to a broader audience.  Though I trained in oncology, my research at NIH/NCI focused on the role of the immune system in combating cancer. My education in the metabolism of cancer has been formed by the writings of those below, and from frequent discussions with a subset of them who have been more than generous with their time, especially Lewis Cantley (who led the team that discovered PI3K) and Dominic D’Agostino.

  • Otto Warburg
  • Lewis Cantley
  • Dominic D’Agostino
  • Craig Thompson
  • Thomas Seyfried
  • Eugene Fine
  • Richard Feinman (not to be confused with Richard Feynman)
  • Rainer Klement
  • Reuben Shaw
  • Matthew Vander Heiden
  • Valter Longo

Further reading

I do plan to continue exploring this topic, but for those of you who want to know more right now and/or for those of you with an appetite for depth, I recommend the following articles, some technical, some not, but all worth the time to read. This is the short list:

  1. Relatively non-technical review article on the Warburg Effect written by Vander Heiden, Thompson, and Cantley
  2. Science piece written about cancer (for non-technical audience) by Gary Taubes
  3. Non-technical talk by Craig Thompson
  4. Detailed review article by Tom Seyfried
  5. Review article on the role of carb restriction in the treatment and prevention of cancer
  6. Talk given by author of above paper for those who prefer video
  7. Moderately technical review article by Shaw and Cantley
  8. Clinical paper on the role of metformin in breast cancer by Ana Gonzalez-Angulo
  9. Mouse study by Dom D’Agostino’s group examining role of ketogenic diet and hyperbaric oxygen on a very aggressive tumor model
  10. Mechanistic study by Feinman and Fine assessing means by which acetoacetate (a ketone body) suppresses tumor growth in human cancer cell lines
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About the Author:

Peter Attia, M.D., is a physician in private practice in NYC and CA. His practice focuses on longevity and healthspan. His clinical interests are nutrition, lipidology, endocrinology, and a few other cool things.

Discussion

  1. Mark  February 4, 2014

    Regarding your statement: “To date, no studies in humans are evaluating the therapeutic efficacy of glucose and/or insulin reduction via diet….” There have been a couple small (and at least one ongoing) studies of ketogenic diet on glioblastoma. Simply search on “ketogenic glioblastoma.”

    (reply)
    • Peter Attia  February 4, 2014

      Were they efficacy studies or safety/tolerance studies? If true efficacy studies, my bad.

    • Jake R  April 21, 2014

      I don’t know what an “efficacy study” is, but this one from the Barrow Neurological Institute looks like one to me. Here is the purpose of the study:

      “This study aims to see if reducing blood sugar and increasing ketones (a metabolic product that comes from using fats for energy) can increase survival and enhance the the effects of standard radiation and chemotherapy treatments used to treat glioblastoma multiforme (GBM). These changes occur from use of a ketogenic diet. This research has 2 goals:

      1. Show that patients can tolerate the diet and maintain low blood glucose and high blood ketone levels.
      2. Show if this diet enhances the effectiveness of standard treatment by prolonging survival of patients with a GBM.”

      http://clinicaltrials.gov/show/NCT02046187

    • Peter Attia  April 21, 2014

      Will be interesting to see results when they are finished.

  2. Ryon Graf  February 4, 2014

    Nice writeup!

    “To date, no studies in humans are evaluating the therapeutic efficacy of glucose and/or insulin reduction via diet, though I suspect that will change in the coming year or two, pending outcomes of the metformin trials.”

    While a one-arm Phase 1 trial, “Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer: A pilot trial” did monitor and report glucose, % ketosis, triglycerides, cholesterol, and disease progression. See Table 5 and Figure 5.

    (reply)
    • Peter Attia  February 4, 2014

      Thanks, Ryon. Yea, I meant more around efficacy, but these smaller phase I trials are a necessary step to get there. (p.s., Fiesta tomorrow?)

  3. Joe  February 4, 2014

    Great post Peter!

    I find this topic very interesting. There’s no doubt that cancer seems to travel with the so-called “diseases of civilization” such as heart disease, diabetes, and obesity. It wouldn’t be at all surprising to me if the underlying cause of cancer is the same as the rest of these diseases. Wouldn’t it be something if Ketogenic diets turned out to be the primary cancer intervention? Thanks for posting. BTW, I have been eagerly awaiting any news regarding Gary Taubes next book since I enjoyed both “Why We Get Fat” and “Good Calories Bad Calories” so much. Do you have any idea what the topic might be?

    (reply)
    • Peter Attia  February 4, 2014

      Gary’s next book is on sugar — this history of all the science on all sides of the debate. I don’t think I’m allowed to disclose the title, though.

    • Ash Simmonds  February 4, 2014

      “Good Sugar, Bad Sugar”?

      “Why We Get Sweet”?

    • Peter Attia  February 4, 2014

      Ha ha! Here’s a piece of unknown and probably not cared for trivia. Gary wanted GC,BC to be called “The Alternative Hypothesis.” Publishers didn’t like it. Gary and I still like that title more.

  4. jw  February 4, 2014

    So, do loyal readers get the other 4,000 words?

    (reply)
    • Peter Attia  February 4, 2014

      Ha! I should dig up the earlier versions of this before I chopped it down to 1,000. I would actually like to do a talk on this subject to cover it in greater detail. You can definitely get your itch scratched by reading the 10 “further readings” at the bottom. At least to hold you over.

  5. Jeremy Tyler  February 4, 2014

    This was a great read! I read a lot of similar stuff in Taubes work. I posted it to my local low carb group ( https://www.facebook.com/groups/699448060101662/ ), feel free to leave a comment :). I’m going to be sure to check out all the articles. I really appreciate your scientific detail on these subjects. I’m very meticulous and so are you and I appreciate it. I too would like the 4000 word blog. Also, maybe you could share some more excerpts from Taubes new book eh?

    (reply)
    • Peter Attia  February 4, 2014

      Ah, this is all I can share for now… But it will be worth the wait.

  6. Dave  February 4, 2014

    Explanation 3: Oxidative (or other) damage to mitochondria (membrane and/or mtDNA) activate anaerobic pathways and destabilize the genome (see Seyfried). Possibly an ancient adaptive response left over from our single-celled ancestors?

    (reply)
    • Peter Attia  February 4, 2014

      Fair point. This is really a 2B, though. Either, they do this because they need the throughput (1) or the do this because they have no choice due to mitochondrial damage (2); “2A — genetic cause” and “2B — oxidative cause”

  7. Sidney Phillips  February 4, 2014

    Great article. What have you heard about the link between Glioblastoma Multiforme and active CMV infection? Life Extension foundation has published an interesting article about the link between CMV and Glioblastoma Multiforme. For those patients who have GM and CMV, taking the CMV drug Valganciclovir extended life considerably:
    https://www.lef.org/featured-articles/Brain-Tumor-Treatment-Breakthrough.htm

    (reply)
    • Peter Attia  February 4, 2014

      Hmmm, not sure how I missed this in NEJM. Will check out. Seems interesting.

  8. Justin Wilford  February 4, 2014

    Hi Peter, Great work as usual. You really are doing a public service here. As I was reading your post I thought you’d like this recent article (if you haven’t seen it already) on the decline in lactate in the tumor microenvironment in patients on a ketogenic diet. It connects cancer metabolism to cancer immunology. Sounds like your kind of thing. And others here would be interested as well. It’s just one more mechanism by which the KD might have an anticancer effect. http://www.jimmunol.org/content/191/3/1486.full.pdf

    (reply)
    • Peter Attia  February 4, 2014

      This would make sense, if they are “starving” cancer cells of glucose, I guess.

    • Justin Wilford  February 4, 2014

      Oops. Meant to include the money quote: “Depletion of glucose levels using a ketogenic diet to lower lactate production by glycolytic tumors resulted in smaller tumors, decreased MDSC frequency, and improved antitumor immune response. These studies provide evidence for an immunosuppressive role of tumor-derived lactate in inhibiting innate immune response against developing tumors via regulation of MDSC and NK cell activity.”

  9. Chris  February 4, 2014

    Peter, even though this is not in direct relation to what is mentioned above, do you think that anaerobic metabolism can only be done via the breakdown of glucose outside mitochondria?
    If so, does this means that when you’re ketoadapted you can’t actually improve strength training under ketosis?

    I dont know what to attribute this to, but I did increase my gym lifting performances once I got ketoadapted (after a few weeks of ketosis). It would be interesting to know your opinion because you know there’s a great debate in the exercise community.

    (reply)
    • Peter Attia  February 4, 2014

      No, remember anaerobic metabolism is a place on a spectrum, between aerobic and CK. The question is “How fast is the body asking for ATP?” In strength training you will typically hit 2 of these 3 systems, but you’re still using BHB for fuel, it’s just insufficient to meet all of the demands. I have now witnessed enough athletic performance in ketosis to say without hesitation that ketosis does not imply a reduction in athletic performance and activities that demand strength and speed. Perhaps for some people under some conditions, but certainly not universally, and not if a person is adapted. To fully get into my thoughts on this, however, requires a full post, which I can’t do at the moment.

    • Jason  February 4, 2014

      If you ever get time, or maybe a quick “yes” or “no” answer, I would like to hear your thoughts about strength gains on a ketogenic diet. Now that everything is “solid” in ketosis I find myself at a plateau at the gym in regards to strength increases (squats, deadlifts, etc) and was starting to wonder if an insulin spike might be necessary to trigger additional muscle growth (e.g. “carb nite” or cyclical ketogenic diet).

      Have you seen “arbitrary” strength gains on athletes on a ketogenic diet ? My only other theory is that too much running/aerobic activity/catabolic time is interfering with the anabolic side of the coin. If I can figure out a way to gain strength while staying ketogenic (without resorting to carbs) I would be one happy camper.

    • Peter Attia  February 4, 2014

      Addressed in other comments, but I don’t recall which post(s). Short answer: probably more related to training and muscle fiber recruitment than ketosis per se.

  10. Steve Whitaker  February 4, 2014

    Hi Peter,

    another great article, thanks for writing it.

    I was just curious how you thought Dr. Nicholas Gonzalez work fit in with your article, as I seem to recall that his work involves HCLF for some cancers and LCHF for others IIRC?

    Regards

    (reply)
    • Peter Attia  February 4, 2014

      No overlap at all to my understanding.

    • Herb  February 4, 2014

      Here’s Dr Gonzalez’s take on the Ketogenic Diet and Cancer…

      http://www.naturalhealth365.com/ketogenic_diet/cancer_part_1.html

    • Peter Attia  February 4, 2014

      I guess we’ll see.

    • Boundless  February 4, 2014

      > I guess we’ll see.

      And relatively soon, I should think.

      Meanwhile, some key data might already be “out there”, waiting to be harvested.

      If NK has a role in cancer therapy, it could also be expected to be prophylactic.

      A subset of the population have already chosen to be low carb, if not keto, and have been so for a decade or more. If there is some cancer prevention value therein, it might be possible to quantify it. A statistical population may exist, but is anyone studying it?

      The problems, of course, include:

      Healthy people often don’t go to doctors at all, and when they do, MDs usually have zero curiosity about why they aren’t sick, never suspect diet, wouldn’t know what questions to ask if they did, and probably have no means of reporting data in any useful form.

      Epidemiologists may not be studying healthy people either, also probably don’t inquire about diet, again wouldn’t know what questions to ask if they did, and have no template for reporting.

      Oncologists are in no position to report anything, because they never see people who don’t get cancer.

  11. Y. Barney  February 4, 2014

    Thanks for another great article Peter!
    Do you know anything about DCA (Dichloroacetic acid) and Cancer? the early studies (U of Alberta, 2007, 2010) appear promising and further anecdotal testimonials are also interesting. The claim is that DCA somehow activates the cancer cell’s mitochondria to utilize Oxygen again rather then ferment Sugar, thus creating the “natural” Apoptosis of a defected cell.
    It sounds “to good to be true” sort of thing, so I wander what’s your take on it.

    (reply)
    • Peter Attia  February 4, 2014

      I’m not aware of any human clinical data on DCA, but some of the in vitro stuff looked promising, as you note. I guess, much like this, we’ll need to wait and see how it fully pans out in humans. The good news is one can’t act on DCA now. One can, if they choose, act on this metabolic insight.

  12. Alexandra M  February 4, 2014

    Just yesterday I handed this paper to an oncologist and he looked at me as if I’d suggested pixie dust. He was concerned about feeling “hungry and headachey.” However he glanced at the authors, said, “Hey, I know that guy!” and accepted the paper:

    http://download.journals.elsevierhealth.com/pdfs/journals/0899-9007/PIIS0899900712001864.pdf

    (Sorry if this is a duplicate – I haven’t looked at all your links yet.)

    (reply)
    • Peter Attia  February 4, 2014

      Ha, it is, but that’s ok.

    • Alexandra M  February 4, 2014

      He also remarked that these studies are “just biochemistry,” as though biochemistry, biology, and physiology were non-overlapping fields. This is someone with an excellent reputation, highly respected in his field, so it just goes to show the tendency for each specialty to be “driving down the highway looking at the road through a drinking straw.”*

      *From one of Malcolm Gladwell’s books.

  13. Edward  February 4, 2014

    Hi Peter,

    Way back in the early 70’s nine obese men in an VA hospital in SoCal were fasted for two months (yikes!) and then administered an insulin infusion to the point that blood glucose levels were as low as 0.5 mmoles/liter (9 mg/100 ml) yet they failed to exhibit hypoglycemic reactions. It would be interesting to see if that low of a blood glucose would starve cancer cells. This would have to be done in an acute care setting, of course, ideally an ICU.

    Their levels of ketones were remarkable in and of themselves in terms of whether or not we can run almost completely on ketones. I guess this shows that we can, although muscle wasting would probably produce some glucose through gluconeogenesis. Still a FBS of 9 doesn’t lie.

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC332976/pdf/jcinvest00637-0253.pdf

    Regards,

    Edward

    (reply)
    • Eric  February 5, 2014

      Hi Paul,

      I was going to post about the study you reference but luckily you beat me to it!

      Even during complete therapuetic fast, blood sugar is obviously maintained. I belong to Dr. Richard Feinman’s (“the other”) blog in which he points out that cancer cells are great at “pirating” sugar even in low sugar environments. (Do they have an over expression of GLUT transporters on their cell walls?)

      So a complete fast may not be enough to starve the cancer of it’s life giving glucose. But a keto-adapted person can be infused with insulin and achieve EXTREMELY low levels of blood sugar. Maybe that would do the trick.

      It would be great to see this therapy attempted – would a Dr. be risking their license if they tried it?

      -Eric

  14. Jim B.  February 4, 2014

    Great post, really interesting! Been seeing Dr. Warburg’s work refernced a lot lately regarding cancer, fascinating. I read this the other day, similar topic, but with a different twist, talks about sulfate synthesis and sulfate transport, what are your thoughts on that?

    http://www.westonaprice.org/cancer/cancer-to-the-rescue

    (reply)
    • Peter Attia  February 4, 2014

      Once forgotten, now back in focus.

  15. Chris  February 4, 2014

    Peter, thank you very much! I really wanted some expert insight because it didnt seem to make sense. You know all the mumbo jumbo in the industry that you need carbs to perform well in strength training. I will dig more into this because it’s a really interesting topic. I know you love it as well!

    Thanks again Doc!

    (reply)
  16. Boundless  February 4, 2014

    And coincidentally (timed for World Cancer Day, today), WHO has a report this week on the “alarming” increase in cancer world-wide.
    http://www.iarc.fr/

    Being wedded to the somatic theory of cancer, they are in a panic about what to do about it. “Global battle against cancer won’t be won with treatment alone” indeed, since most Standard of Care treatment provides appallingly little return on the huge expenses involved.

    WHO proposes “taxes, advertising restrictions, and other regulations” to restrict consumption of cancer correlates, including tobacco, alcohol and, curiously, sugar-sweetened beverages.

    They don’t seem to be interested in why sugar correlates, of course. Might it be something about the pervasive HFCS used, or perhaps there’s a problem with too much glucose and/or fructose generally, or both. Ordinary citizens are going to figure this out decades before WHO does.

    “Adequate legislation can encourage healthier behaviour, …”
    Rubbish. In the case of tobacco and alcohol, it will just reward organized crime, who will bootleg around the taxes. People who smoke or consume excess booze know the score. If they aren’t deterred by the well-known health and longevity consequences, taxes, and even outright prohibitions aren’t much further disincentive.

    And as with that nanny state initiative in NYC, restricting sugar pop will have near zero effect on the real problem: the full time high glycemic metabolism that most of the world is on. I suspect there’s a direct correlation between the rise in cancer and a shift in macronutrient balance in world diets (plus contributions from the makeup of the carbs and fats consumed).

    (reply)
    • Peter Attia  February 4, 2014

      Agree with your insights. *WHY* is sugar consumption correlated with [fill in the blank disease]?

  17. Anonymous  February 4, 2014

    As an oncology dietitian, I work with patients everyday who have cancer cachexia. Is is well-established that some cancers as they become more advanced, specifically oral, esophageal, gastric, pancreatic, and some lung cancers, result in derangements in metabolism that result in cachexia. Patients with cachexia are also often anorexic at this stage of the disease and eat very little. Despite this, the cancer progresses.

    What’s not making sense to me about this idea of attempting to “starve” cancer through caloric restriction is that cancer cells will demand energy substrate whether it’s endogenous or exogenous. In other words, if cancer patients restrict carbohydrates, the cancer cells will obtain glucose by breaking down body proteins resulting in more rapid decline and malnutrition. In fact, in cancer cachexia, endogenous protein and fat breakdown at higher than normal rates. It may be slowed to a degree by withholding exogenous energy substrate, but even under starvation conditions cancer cells continue to grow by demanding energy substrate from healthy cells.

    Many of my (non-cachectic) patients ask me about the ability to “starve” their cancers by following a low-carb diet. But I use the analogy of pregnancy. We know that a fetus will get its energy and nutrients it requires at the expense of the mother’s body, if necessary, to continue to grow and develop. The fetus will fail to survive only if the mother’s nutrient stores become so depleted that her life, too, is at risk.

    While I think this all very, very fascinating, it seems more plausible to exploit this idea through the development of pharmacological treatments rather than through specific dietary restrictions. I always argue that we cannot tell our food which cells to feed and which to starve. If you attempt to starve the cancer cells through dietary restriction, you will also starve the healthy cells that give the body a fighting chance to sustain itself – not to mention the cancer patient’s quality of life during the time they have left to live it. So until we can find a way to orchestrate this, I question the ability of very low carb diets as a means to slow cancer growth to the point of any meaningful clinical outcome.

    (reply)
    • Peter Attia  February 4, 2014

      You make a lot of great points, and ultimately, I think the best treatment for cancer will first and foremost be avoidance. I believe diet plays a role here, at least as far as what we can control. Second, that is, once cancer is present, “success” will probably be a combination of things — diet, drugs, non-pharma interventions (e.g., hyperbaric oxygen), but all will need to be tailored to metabolic (vs. genetic) markers specific to the tumor itself, not just the histology.

    • Larry Candell  February 6, 2014

      Is it possible that the cachexia is a result of the fact that cancer is a constant drain on the body’s stores of glucose? By inefficiently utilizing glucose for its energy needs, the cancer puts such a drain on blood glucose that the patient feels as though they are on a low carb diet (or that they are constantly doing high intensity intervals…carb burning exercise). If a tumor used 20 kcal/hr of glucose (the equivalent of only 2 kcal/hr aerobic), that would be nearly 500 kcal per day or over 0.25 pounds of glucose per day. This is on top of normal basal metabolic needs.

      Ironically, following this logic, the patient with cachexia would be best served by going on a very high carb diet. Clearly this will not address the underlying problem, but it may well improve appetite and allow for stabilization of weight loss. Have such experiments been tried?

    • XO2062  February 6, 2014

      One thing is missing in the big picture. Yes, tumor cells will try everything to suck the glucose, also those out of gluconeogenesis. However, the cells, even the tumor cells need “door opener” to get the glucose inside the cells and that is insulin. When somebody does ketogenic diet, the insulin is usually at very low level so the energy supply to the tumor cells will be limited and on the long run the chance should be there that the tumor cells get starved.

    • Gabe  February 9, 2014

      (This is directed at XO2062)

      You are mistaken; unfortunately – well, as far as cancer treatment is concerned, at least – cells are, in fact, not dependent on insulin as far as their glucose uptake is concerned – that is nothing more than a widely propagated myth ; see for example http://weightology.net/weightologyweekly/?page_id=571 – , so there goes that line of reasoning.

    • Gerald Berry  March 15, 2015

      I do not pretend to fully understand the arguments of biochemists, astrologers or the other learned people who each explain the causes and cures for cancer in such highly technical terms.

      However this I know, in September 2014 I was diagnosed with metastatic melanoma. The surgeon advised me the best that could be done for me was reduces the suffering by surgically removing tumors as they surfaced.

      I was led to adopt a hi fat lo carb diet at the same time as I developed this deadly cancer. Some four months later I had a PET scan and guess what? There is no further sign of the dreaded disease. To boot, my blood pressure has dropped back to 120/69 and the fat round my waist has gone having lost some 8kgs. My energy levels are those I enjoyed five maybe more years ago.

      My fear is that those who stand on the edge of the pool, telling us how to swim, often fail to appreciate which of the objects of their research are the cause and which are the effect. Would I be in error if I suggested this could represent a fundamental flaw in the subsequent conclusions

      If you are a fellow cancer victim please don’t sit on the edge of the pool discussing the pros and cons of swimming. Jump into the water by adopting a strict way of life like “Banting” and enjoy the results. Please gentlemen and ladies we need to focus on correcting all the contributing causes and then trust that the effects will disappear.

      PS Regarding the issue of caloric restriction and it’s effect on cachexia, I highlight the fact that I get my calories from fat, and suffer no malnutrition or cachexia as a result. I am well nourished.
      A.G.Berry

  18. Norm  February 4, 2014

    Thanks for another great piece Peter.

    Would you please elaborate on this : “PI3Ks are very important in insulin signaling”

    In diabetics how effective/ineffective is it to inject insulin as compared to metphormin to control glucose levels?

    (reply)
  19. Norm  February 4, 2014

    Piece by Gary Taubes has clarified both of my questions. Thanks

    (reply)
    • Peter Attia  February 4, 2014

      Love when that happens.

  20. Bjorn  February 4, 2014

    I’ve been waiting for this post and it was really informative and on a good technical level for me to understand. Thanks!!
    I’ve been eating a lchf diet since I started reading up on this about a year and a half ago when my dad was fighting cancer in the esophagus. What’s your take on other reasons for cancer to develop, like radiation, chemicals etc? My mom was a flight attendant for many years and she died of breast cancer as did many of her colleges. Coincinence or perhaps caused by the radiation on the aircrafts? My parents were both lean, healthy and active but sure they ate carbs like all “normal” people do.
    What about children’s cancer? Can that too have to do with diet or what causes that? How about leukemia where you don’t have a tumour?
    I want cancer to be a metabolic disease 100% cus then I feel I can affect my own destiny so to speak, but I just don’t get these questions into the equation even though I am very exited about this research and hope it will lead to great stuff in cancer care. Sorry about my english (I’m Swedish).

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    • Peter Attia  February 4, 2014

      Beyond the scope of quick response.

    • Bjorn  February 5, 2014

      Ok, let me try something shorter.
      A college of mine has leukemia (not sure which kind) and he has a major sweet tooth, eating mars-bars and cupcakes for breakfast, drinking at least two cokes a day.
      Do you believe the same principles for cancer cell metabolism goes for leukemia cancer cells? If so, do you know where I can read about this with a specific focus on leukemia so I can try and convince him he should think about his sugar intake? Thank you!

    • Peter Attia  February 5, 2014

      It may not be histology specific, but rather tumor specific.

  21. Solomon  February 4, 2014

    “Dr. Freund, who is unknown as an authority, has advanced a theory wholly inconsistent with the results of years of scientific research.” Why are our scientists often so dismissive seeing that a lot of what was thought of as scientific fact have turned out to be false?

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  22. RachelC  February 5, 2014

    Thanks so much for the layman’s lesson in cancer metabolism. This will be great info for those in my family unfortunately currently struggling with type 2 & recurrent breast cancer.

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  23. Jim  February 5, 2014

    The idea of “starving” the cancer by not eating carbohydrates doesn’t really add up for me very well. People on low carb have only slightly lower glucose concentrations in the bloodstream. There should be plenty to feed hungry cancer cells.

    But, as I think you alluded to, what if the low carb diet ALSO causes changes in the hormone milieu that somehow does not allow the cancer cells to import glucose? Now THAT seems reasonable to me. Do cancer cells need insulin to import glucose?

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    • Peter Attia  February 5, 2014

      Well it’s more nuanced than plasma glucose, as you allude to. On the plasma side, it’s probably more about the ratio of BHB to glucose — the closer to 1 (in mM), the better. For example, a BHB of 4 mM and a glucose of 75 mg/dL (about 4 mM) is a VERY different physiologic state that a BHB of 0 and a glucose of 85-100 mg/dL. Secondly, the role of insulin and IGF are much different in these scenarios. Same for other tumor growth factors.

  24. Richard Nikoley  February 5, 2014

    Peter:

    What a coincidence, since we just reconnected a few days and this happened in the interim.

    http://freetheanimal.com/2014/02/medical-insurance-helping.html

    In the meantime, I’ve been sent this:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3312698/

    Then this:

    http://www.damninteresting.com/coley’s-cancer-killing-concoction/

    You want to think it’s tin-foil-hat but, I and a collaborator have been months into research and writing a book on the gut biome and I have come to believe that the right live bacteria in the right place are your targeted chemo therapists. Perhaps it’s more likely that someone in like 1890 might use the only thing available. From that last link:

    “The records showed that after the wound became infected with a commonplace bacterium, Streptococcus pyogenes, the patient went through several bouts of fever. With each attack of fever the tumour shrank until eventually it disappeared entirely, leaving only a large scar under the left ear. Coley surmised that the infection had stimulated the German’s immune system– as evidenced by the repeated fevers– and that it was this immune response that had caused the eradication of the cancer.

    “The story so convinced Coley that he– perhaps cavalierly– contrived to contaminate his next ten suitable sarcoma cases with Streptococcus. His initial approach was to inject a solution of live bacteria deep into the tumour mass on a repeated basis over several months. The first patient to undergo this treatment was a bedridden man with inoperable sarcoma in the abdominal wall, bladder, and pelvis. Using this experimental method, the patient was cured spectacularly. He staged a full recovery, and survived another twenty-six years before dying from a heart attack. But subsequent results were mixed; sometimes it was difficult to get the infection to take hold, and in two cases the cancer responded well to treatment but the patients died from the Streptococcus infection.”

    Well, it was only 1890 and as the paper claims in the fist link, medical science is pretty much complete shit on most cancer. They’d immediately apply antibiotics for a Strep, without even thinking of a possible upside.

    …We’re over 300+ pages into the book, publisher loves. Hopefully we’ll talk soon.

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    • Peter Attia  February 5, 2014

      Richard, immune-based therapy for cancer is what I did my post-doc in with Steve Rosenberg at NCI. You should definitely read his story: “The Transformed Cell” — one of the most important books I’ve read about science. The story of Coley is one of many, but unfortunately, to date, there seems to be a ways to go in this field. But when it works — which I’ve seen with my own eyes — it’s amazing. The immune system is beautiful.

    • Jeff  February 6, 2014

      Another great book re. Coley and the history of immune-based therapy for cancer is “Commotion in the Blood”

    • Peter Attia  February 7, 2014

      Indeed. I know Hall, also.

  25. Willsy  February 5, 2014

    Hi Peter, please keep up the good work. What you’re doing with NuSi is vitally important.

    I wish we’d known more about diet when my wife was diagnosed with GBM at the age of 34 (one week after the birth of our 2nd child) . She died 16 months later. We did ask about diet after her diagnosis, but the doctors thought it irrelevant. Note, she’d been a very high consumer of sugar all her life….

    For the individual who referred to CMV infection and GBM – I actually met the lead researcher (done at Karolinska in Sweden) at a dinner party. There are a couple of things to remember, firstly, the extension of life with GBM is not necessarily a good thing – my wife asked to have her life ended four times. Secondly, my understanding was that they were looking at CMV as being causative in GBM – one of the samples they tested was not infected with CMV. My limited understanding would be that this would disprove the theory, unless you go for multiple mechanisms. Perhaps CMV could increase the likelihood/speed of progression….

    We have to find a way of reducing the number of people who ‘get’ cancer rather than overly focusing on those with existing disease. I hope, ultimately, NuSi can help in the former.

    (reply)
    • Peter Attia  February 5, 2014

      This is so tragic. Can’t even imagine what your family went through. So sorry to hear this. Agree with your point about extending survival if quality of life is not improved. And I agree about prevention being the key.

  26. tw  February 5, 2014

    Hi Peter,

    Thank you for your insightful commentaries.

    As a current patient with Hodgkins (nlphl), does this particular strategy (keto) add weight to treatment for immune system cancers? (I am athletic eat low carb and am in otherwise good shape).
    Are there any brief suggestions you might add here to enhance treatment (abvd)?
    I appreciate that you may be restricted from providing specifics and hope that I have not overstepped.

    Thank you.
    tw

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  27. Tom Ramsey  February 5, 2014

    This is not related to the essay on cancer metabolism. I’m very curious about the attached link, a story of a high fat (non-carb? certainly non-sugar) diet setting up/triggering a pre-diabetic condition. Weird.

    http://edition.cnn.com/video/data/2.0/video/bestoftv/2014/02/04/newday-van-tulleken-twins-diet-experiment.cnn.html

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  28. Ari  February 5, 2014

    Great article and makes the metabolism of cancer understandable for non-professionals (like me). I just finished the book “Cancer as a Metabolic Disease” by Dr. Thomas Seyfried and I must say it was a little too heavy reading. He has had some success especially with gliomas, but the glucose level in blood must be quite low: target 55-65mg/dl. To achieve that energy restriction is necessary (fasting). Glucose and Glutamine need to be decreased and fasting affects both. In addition to this ketosis is necessary. It reduces inflammation and replaces glucose with Ketone bodies, which can not be used by cancer cells as energy. The brain thrives using them. Ketosis needs to be at level 4 to 4.5 mM. Both targets are tough and it is obvious, that this therapy can not be applied to patients in a very weak condition.

    (reply)
    • Peter Attia  February 5, 2014

      From a practical standpoint, outside of a calorie-restricted KD, the way to get to sustained level of BHB at 4 mM likely requires new foods that also provided exogenous BHB and/or AcAc.

    • Jeff  February 6, 2014

      Re. Peter’s suggestion for foods that provide exogenous ketone bodies:

      Richard Nikoley’s blog reports that potato starch, which is virtually all resistant starch, does not kick one out of ketosis and has no effect on blood sugar. It would make sense that not only is resistant starch not not anti-keto, but is perhaps pro-keto because, as I understand it, resistant starch fully ferments to short chain fatty acids in the colon, and is not at all absorbed in the small intestine.

      Paul Jaminet’s blog proposes that specific amino acid isolates can supplement a keto diet to improve keto status and prevent muscle wasting. He reports that leucine and lysine are purely ketogentic and not at all glycogenic. Jaminet and various people in the muscle training world suggest that BCCA spare muscle on keto diets.

      Maybe a good medium-term cancer keto strategy is a rather severe diet of little more than fat, MTC oil, BCAA (i.e. leucine plus the other required BCAAs), lysine, and potato starch? My thought is that this would drive extremely deep ketosis, maybe prevent muscle wasting while also providing protein restriction, and provide bulking and immune regulation to the colon.

    • Boundless  February 11, 2014

      > … the way to get to sustained level of BHB at 4 mM likely
      > requires new foods that also provided exogenous BHB and/or AcAc.

      You proposed this in at least one of your videos, as well, and in that case, I don’t think it was as a therapeutic adjunct. The proposal is pretty jaw-dropping, and I’m surprised it hasn’t generated more comment here. You’re proposing an entirely new type of human food (not just “supplement”, I note).

      Speaking as a layperson merely interested in optimal diet, this raises a tsunami of questions, precisely none of which I expect you to spend any time answering in the near term.

      Are we speaking of keto foods (KF) containing actual acetoacetate (AcAc) and ?-hydroxybutyrate (BHB), or just precursor compounds, as Jeff suggests above?

      Can BHB and AcAc be directly ingested and passed into the bloodstream, or do they have to be protected from the upper GI?

      What would KF replace in the dietary profile? Some fats, perhaps?

      Would the product have a decent room temperature shelf life?

      Any guesses as to any risks from over-consumption?

      Would there be problems consuming KF on an otherwise non-keto, or even elevated glycemic diet?

      I’m guessing that if ketogenic diet turns out to have a role in cancer treatment, that the most effective avenue to bring KF to market might be as a therapeutic agent. Whether or not there are patent opportunities here could affect the fortunes of that effort.

      Actually, it would be great if it turns out to be something people can brew at home, so early adopters won’t have to wait out the commercial, political and bureaucratic sieges. The chances of a novel KF being considered GRAS from the outset appear to be nil.

      Bringing KF to market as a supplement, much less a “food”, would be challenging, as you indicated in the video. Long-term food safety testing would be needed, and the usual glycemic confounding would likely need to be avoided (even though the food industry never does this for the junk they sell today).

    • Peter Attia  February 11, 2014

      No good deed…

  29. Yossi Mandel  February 5, 2014

    Not directly relevant, but the saddest funniest thing I’ve read on how research is done:

    http://www.edge.org/response-detail/25497

    Edge asked 100 scientists what idea of science is ready for retirement, and Dean Ornish suggested the randomized controlled trial as a high standard (not that he doesn’t make some valid points about how they are done). Between the lines of what he says I hear what he doesn’t say, “RCTs are history because the outcome of one didn’t agree with my hypothesis that vegetable diet is it.”

    (reply)
  30. rs711  February 5, 2014

    Hi Dr. Attia,

    The dysfunction of the mitochondrial complexes appears to ‘pollute’ the inner-membrane space with excessive ROSs & ‘electron leakage’…Do you suppose cancer could plausibly be an adaptation to such fuelling issues? (as often seen with T2DM patients for example) Or do you think the cause is more upstream?

    Thanks!

    PS: trying to square this with Peter @ Hyperlipid’s Proton Series…

    (reply)
    • Peter Attia  February 5, 2014

      Not sure, and it probably varies by cancer. There are likely many triggers to the problem.

  31. Steve  February 5, 2014

    If you’re looking for old discussions of the alternative hypothesis, I can beat that NYT article. Recently I was reading Herodotus’ Histories (circa 440 B.C.), and I had to laugh when I came across this passage:

    “Finally [the Ethiopian king] came to the wine, and, having learnt the process of its manufacture, drank some and found it delicious; then, for a last question, he asked what the Persian king ate and what was the greatest age that Persians could attain. Getting in reply an account to the nature and cultivation of wheat, and hearing that the Persian king ate bread, and that people in Persia did not commonly live beyond eighty, he said he was not surprised that anyone who ate dung should die so soon, adding that Persians would doubtless die younger still, if they did not keep themselves going with that drink – and here he pointed to the wine, the one thing in which he admitted the superiority of the Persians.

    “The [Persians], in their turn, asked [the Ethiopian king] how long the Ethiopians lived and what they ate, and were told that most of them lived to be a hundred and twenty, and some even more, and that they ate boiled meat and drank milk.”

    Maybe it doesn’t have quite the rigor of a randomized controlled trial, but at least it’s interesting.

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  32. Kobe  February 5, 2014

    Hi Peter,
    are there any known results from clinical trials regarding the influence of a LCHF diet on the chances of getting cancer?

    Great article, as always. “The Alternative Hypothesis” made me smile.

    (reply)
    • Peter Attia  February 7, 2014

      Not that I’m aware of. Primary prevention trials (what you describe) are almost unheard of in any disease, especially cancer.

  33. Allison  February 6, 2014

    Thanks for this article, Peter, I’ve been waiting. Because of a nasty cancer that was diagnosed at 39, which has since metastasized, I eventually went paleo and have recently started following Seyfried’s recommendations with good success. Your site has been extremely helpful to me in the past few years, and I look forward to digging into some of these links. Any and all articles you do about cancer are really appreciated.

    (reply)
    • Peter Attia  February 7, 2014

      I’m sorry to hear that Allison. One thing I would also consider is having your tumor specimen analyzed for insulin receptors. A few folks (Lew Cantly and Dom D’Agostino) are able to do this, though there is no commercial (i.e., CLIA) test for this. It would be a helpful step to be sure that your tumor is indeed sensitive to insulin (and therefore give you greater likelihood that this approach will be successful).

  34. JJ  February 6, 2014

    Another masterpiece Peter.

    Simply, thank you again.

    You take subjects I am fascinated by but do not have enough time to study (otherwise I would become a science junkie) and extract a concentrated form of meaning.

    Information per word = density of Relativistic Heavy Ion Collider.

    (reply)
    • Peter Attia  February 7, 2014

      Thank you, JJ. I wish I could always write short pieces…most of the time I don’t have the time (cf. Mark Twain).

  35. Mike  February 6, 2014

    Thanks for your insightful post, Dr. Attia.

    Tumor initiating cells appear to have enhanced glucose uptake mechanisms in brain cancer:
    http://www.nature.com/neuro/journal/v16/n10/full/nn.3510.html

    Could nutritional ketosis enrich for tumor initiating cells?

    Tumor heterogeneity strikes me as a formidable challenge for therapeutic design and intervention.

    (reply)
    • Peter Attia  February 7, 2014

      Do you mean select for them? If so, why?

    • Michael Zorniak  February 11, 2014

      Summarizing from Flavahan et al., 2013 (Nature Neuroscience): Similar to hypoxia and acidic stress, glucose restriction appears to promote a brain tumor initiating cell phenotype in primary human cultures. Moreover, non-tumor initiating cells adopt a tumor initiating cell phenotype from this deprivation. The authors identified Glut3, a neuronal glucose transporter, as a mechanistic target of this enrichment, which has five times more affinity for glucose compared to Glut1. Glut3 is highly expressed in high grade gliomas and correlates with negatively with survival.

      In the context of a calorie-restricted ketogenic diet, Glut3 mRNA expression decreases in rat neurons (Cheng et al., 2003, Endocrinology). Thus, tumor initiating cells may have a competitive advantage for glucose uptake in the brain.

      With modest decreases in serum glucose during nutritional ketosis, brain tumor initiating cells may be epigenetically primed to respond to decreased glucose availability via Glut3 upregulation. Depending on the differential upregulation of Glut3, the net effect may be an increase in brain tumor initiating cells and paradoxical decrease in tumor volume since non-tumor initiating cells don’t express as much Glut3. This would potentially create a more aggressive tumor if a patient were to increase carbohydrate intake.

      As a side note, I just moved to SD for a postdoc at TSRI. I’m also an avid cyclist and would love to meet up for a ride to discuss volunteer opportunities at NuSI!

    • Michael Zorniak  April 22, 2014

      Great review on the impact of diet on stem cell physiology: http://www.cell.com/cell-stem-cell/abstract/S1934-5909(14)00059-9

      Caloric restriction appears to enhance self-renewal of stem cells, and presumably cancer stem cells.

      Effects of ketogenic diets are unclear, but may be similar due to reduced insulin and IGF-1 signaling. With increased DNA repair, genomic stability, and immunosurveillance in this dietary state, the net effect on tumor incidence and growth would be very interesting to study.

      What do you think the net effect would be?

  36. Amy B.  February 6, 2014

    As a nutritionist who’s beginning to get into helping people with low-carb and ketogenic diets for all sorts of conditions, I’d like to inject some general insights.

    As Peter as suggested (with BHB of ~4mM and blood glucose in the 55-70 range), the ketogenic diet as adjunct therapy for cancer is a pretty different animal from a garden-variety low-carb diet. It is much stricter, and there are “extras” to throw in that can bump up ketones and lower BG a little (fasting, low-level activity like slow walking, liberal use of coconut & MCT products, etc.).

    While the overall purpose of a KD for cancer is to “starve” the cancer while simultaneously nourishing *healthy* tissue (via ketone bodies and fatty acids), the ketogenic diet is most definitely not a miracle cure. I specifically used the phrase “adjunct therapy” because one of the good things about using a KD in conjunction with standard chemo/radiation treatments is that it seems to reduce the severity of the negative side effects of these. (Less GI distress, less nausea, less exhaustion — all of which might contribute to a patient’s appetite remaining strong enough to offset at least some of the cachexia.)

    I’m not sure keto diets can do much *by themselves.* But they seem to add a powerful wallop to the conventional methods. What they’ve done in many cases is not eradicate the cancer, but extend life, and perhaps more importantly, improve the QUALITY of that extended life. A nutritionist named Miriam Kalamian has been in practice for years helping people implement keto diets for cancer. (She first got into it to help her son, who had a form of brain cancer. He eventually did pass away, but he was able to spend many more years with his family–*good* years–than anyone had predicted.) She has a lot of experience. You can check out her work here: http://dietarytherapies.com/

    As for a KD being prophylactic, like another commenter said, time might tell. It would be interesting to get a prospective cohort of people together, keep them on a very low-carb diet for several years and see what happens. Pretty sure that study will never get funded, though. And as much as I love to hang my hat on low-carb, keto, Paleo, and all that, cancer is a wild, wild beast. It seems to “adapt” to, bypass, or override everything that gets thrown at it. A ketogenic diet is certainly a fantastic, science-based, logical, *non-toxic* intervention, but it’s likely not the magic bullet we want it to be. Some cancers seem to respond better to it than others.

    That being said, we need a lot more research here, because even if it’s not a silver bullet by itself, clearly there’s *something* to the glucose/insulin/IGF-1 stuff, and I would love to see more research done on conventional treatments and pharmaceutical interventions in the context of a ketogenic diet, because the results might reveal very different (and presumably more promising) outcomes than when patients are following a Standard American (read high-carb, high seed oil) diet, or worse — chugging Ensure shakes, ice cream, or whatever they can keep down per their conventional oncologists just to “keep the calories up.”

    (reply)
    • Peter Attia  February 7, 2014

      Great points, Amy. I, too, believe that KD in its strictest form (calorie restricted with exogenous ketones keeping K/G > 1), plus other modalities such as hyperbaric O2 and select chemo might be the ultimate strategy, but this my speculative opinion based on biologic intuition and animal data.

    • Boundless  April 13, 2014

      > … exogenous ketones …

      Looks like EKs all by themselves have a material effect:
      “Ketone supplementation decreases tumor cell viability and prolongs survival of mice with metastatic cancer.”
      http://www.ncbi.nlm.nih.gov/pubmed/24615175
      Summarized by Patrick Arnold at:
      http://patrickarnoldblog.com/can-ketone-supplementation-cure-cancer/

      I’m guessing that Patrick had some role in formulating the EKs used.

    • Carmen  August 2, 2015

      Dear Amy, this is Carmen from Peru. I am investigating about KD cause I am a medical doctor and an oncology patient I don’t know if it could be possible that you bring me some way for contact with Miriam Kalamian. Thank you very much and excuse my spanglish.
      Carmen

    • JohnN  July 6, 2016

      Amy,
      I agree that KD is at best adjuvant therapy against cancer. There’s a 2015 paper on Chen.Sci. that seeks to exploit the large difference in Delta Psi (the mitochondrial membrane potential) between regular cell in KD (low voltage) and cancerous, glycolytic cells (high voltage). I don’t have the details but the researchers plan to deliver 3-bromopyruvate, the so-called Trojan Horse of energy substrate, to the latter to destroy them.
      How effective is 3-BMP versus Peter Pedersen’s John Hopkins group’s claims is a side note to my point that the large difference between Delta Psi is a unique property and should be fully exploited.
      John
      “The energy blocker inside the power house: mitochondria targeted delivery of 3-bromopyruvate”

  37. MattE  February 6, 2014

    Steve,
    I just stumbled onto this blog. Love it. I’m a PhD scientist studying cardiovascular health and only recently (embarassingly) really come to understand diet, exercise, and the role of carbs et al in their ‘proper light.’
    This and other posts are fascinating. I recently had the pleasure of hearing Lew Cantley talk about the use of PI3K pathway inhibitors (many companies are pursuing these) to shut down the Insulin/Glut4 mechanism and starve cancer cells (I’m guessing you’re aware of this story though you don’t mention it here). Flip side of the coin from attacking cancer by diet (see question from Anonymous above). I’m not at all sure diet/glucose starvation/PI3K inhibition of cancer is headed for a cure (maybe for some), but I can imagine it having a dramatic effect on at least slowing progression (for many).
    Thanks for a great blog. Some of the most valuable time I’ve spent on surfing the net in a long while.

    (reply)
  38. Maryann  February 6, 2014

    Jimmy Moore has an interview he is re-running with Dr. Thomas Seyfried on his LLVLC Show today, with the topic of ketogenic diets for cancer (episode 777).

    (reply)
  39. Dave  February 7, 2014

    Just recently research has proven that cancer is not a disease of the DNA. I wonder how long it will take until these results are accepted. This article is particularly interesting;

    http://robbwolf.com/2013/09/19/origin-cancer/?utm_content=buffer80ddb&utm_source=buffer&utm_medium=twitter&utm_campaign=Buffer

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  40. Norm  February 7, 2014

    Having read Explanation 1 and explanation 2, is there anything in our diet that damages mitochondria or causes genetic insult?

    (reply)
    • Peter Attia  February 8, 2014

      Probably.

    • Boundless  February 8, 2014

      > … is there anything in our diet that damages
      > mitochondria or causes genetic insult?

      The context for this question, I presume, is that although the later stages of most cancers may have a common etiology (fermentation metabolism), the triggers for the initial cellular upset are myriad.

      I expect that the list of triggers would include things we might ingest. Obviously this includes food contaminants known to be carcinogenic such as dioxins, benzene, etc. You already avoid those. Any number of food additives are popularly suspect (and a diminished issue if you eat raw foods, although I consider pesticide/herbicide uptake and GMO to be open questions). I further assume triggers include inflammatory foods of many sorts (e.g. Omega 6 industrial seed oils), as well as foods that cause intestinal permeability and are apt to be the provokers of auto-immune problems, such as gluten-bearing grains, and the zein protein of corn. I consider nitrites to be an open question. Acrylamide is avoided by avoiding high temperature cooking. This is far from a complete list.

      Does excess sugar itself pose a trigger threat? Great question, and it might be multiple threats (as it adds insulin resistance which may set cells up to become cancerous, then provides the actual cancer fuel).

      Interestingly, an LCHF diet (with attention to which fats, as well as focus on substantial raw food content) is apt to both be very low in trigger foods, and provide some benefit from the low and stable glucose level in the blood. We may not know for some time just how protective LCHF is against cancer, so remain vigilant about triggers.

      Mainstream cancer research, of course, is still largely stuck in the somatic (gene) theory, and there’s a hazard there. If they can’t figure out how a potential adverse agent might cause DNA damage, they tend to deprecate its carcinogenic potential.

      With cell phones, for example, the claim is that the radiation is too low to be ionizing. But what if the real hazard is merely thermal – standing waves overheating mitochondria for example. Anyone concerned about this can substantially mitigate the thermal hazard by using a BlueTooth headset (which emits 1/100th the RF power vs. cellphone) and by not keeping the actual phone against your body all day long. A tinfoil hat probably doesn’t provide much protection. 🙂

    • samwise  February 20, 2014

      “…is there anything in our diet that damages mitochondria or causes genetic insult?”

      Norm,

      Peter at Hyperlipid writes a lot about this topic and has many in depth articles if you are so inclined. Here is a link to one of many articles in the proton series about how hyperglycemia causes mitochondrial damage:

      http://high-fat-nutrition.blogspot.com/search/label/Protons%20%2826%29%20Chowdhury%20and%20Crabtree%20play%20with%20mitochondria

  41. annique  February 9, 2014

    Peter, thank you for a terrific overview, it answers nagging questions I’ve had ever since I started looking into ketogenic diet as adjuvant to chemotherapy (and even separately looked at hyperbaric oxygen treatment). I am very sad however, as it’s likely too late for my dad, he is recently hospitalized and has been given days-to-2weeks. However, he is not in much pain yet and a ‘hail mary’ attempt is not out of the question.
    I am most interested in metformin at this point.
    He has been ketogenic with great success during chemotherapy last year for the original colon cancer. His colon is clear. This was after three years of failed treatments. However the cancer had already metastasized to the liver and treatments since then seem to have made it very aggressive, the decline has in fact been dramatic in the last two months since a chemo-embolism treatment.
    In my understanding, while trying to deliver chemo directly to the site is perhaps useful, doing the embolism part is the last thing anyone would want to do – cutting off oxygen is exactly what helps cancer cells resist chemo, isn’t it?

    In any case, do you have any further information on the trials using metformin that you mentioned?
    I would be very grateful for any links or names. I know this is asking much, but If it is at all possible for you to send them to me by email, I’d appreciate it – I am in transit to him right now and my email is easy to get, but a fast enough connection to load some web pages is not always available. I can then pass them on to someone who can look them up.

    I had concluded a month ago that metformin might help, as it decreases the liver’s glucose production and since he’s been severely hypocaloric lately due to jaundice, cachexia and general malaise, those cancer cells have to be relying pretty exclusively on the liver’s gluconeogenesis.
    Shutting off the spigot seems like a good idea.
    Do you know if they can get glucose from anywhere else? Does there have to be no food at all in the digestive system, complete fasting, so that the colon microbiome shouldn’t be able to produce any either?
    Any thoughts or ideas at all, much appreciated. And if none, thank you yet again for the state-of-the-art overview and the background links already provided. You do a public service.

    (reply)
    • Peter Attia  February 9, 2014

      Annique, I’m sorry to hear about your father. Unfortunately, the trials I know of investigating metformin are in the adjuvant setting (i.e., post surgical treatment, but with no evidence of tumor) or even the neoadjuvant setting (i.e., prior to first treatment). i’m not aware of stage IV trials. Sadly, it sounds like your father may be in an advanced ECOG stage for which there may not be as many opportunities for clinical trials. I’m sorry I can’t be of more help.

    • annique  February 9, 2014

      Peter, thank you very much for the reply and the insight.

    • neilfeldman  February 9, 2014

      Annique. I am a Stage IV mRCC (renal cell carcinoma) patient who convinced my oncologist to let me take Metformin (500mg ER) after I provided him with this research paper:

      http://www.ncbi.nlm.nih.gov/pubmed/23773243

      However, be aware that various kinds of tumors can “run” on fuels other than glucose. Some of them can ferment amino acids like glutamine. So restricting glucose is not a slam dunk. Still, Metformin is a very common drug given to Type II diabetics and it can’t hurt.

  42. Alec  February 9, 2014

    Yes, the Van Tulleken/BBC Horizon story was appalling. I actually contacted Dr Attia about it in a slight panic, which of course look silly now. Still, it would be great to hear any thoughts he has on the programme.

    (reply)
  43. Don Mastromatteo  February 12, 2014

    Peter, Though I am not a DR or very smart for that matter I have been digesting your writings and videos for the past 6 weeks as I have started a LCHF lifestyle trying to get healthy. Ironically I read this post yesterday and then last night I found out a customer of mine was just diagnosed with Stage 4 lung cancer. I do not know the type only that he has this late stage type of cancer. I am assuming that at this stage there is little conventionally that can be done that bears any form of true optimism to arresting this disease. I know it is difficult to have a lay person such as myself to offer advice (actually I might recommend a movie Cancer the Forbidden Cures) but not sure what he will be doing in the fight of his life. But based on your writings do you think cutting the sugar (carbs) from his diet would have any benefit, especially this late?

    Either way I truly appreciate what you do and your delivery that allows the common man the ability to understand the complex.
    Don

    (reply)
    • Peter Attia  February 13, 2014

      Don, lung cancer, in general, does not appear to be one of the cancers that is particularly sensitive to glucose, insulin, IGF, etc. So I’m not sure a reduction in sugar will have any effect, especially at an advanced stage. Possible, but I have no idea.

  44. Boundless  February 15, 2014

    > Explanation 2: Cells become cancerous because they undergo some form of genetic insult.

    What may be another hit on the somatic (gene) theory of cancer was just published.
    “Premature Termination of Reprogramming In Vivo Leads to Cancer Development through Altered Epigenetic Regulation”
    http://www.cell.com/retrieve/pii/S0092867414000154

    The fulltext is paywalled, but the summary contains a provocative statement:
    “We also demonstrate that iPSCs derived from Dox-withdrawn kidney tumor cells give rise to nonneoplastic kidney cells in mice, proving that they have not undergone irreversible genetic transformation.”

    (reply)
  45. Gemma  February 17, 2014

    Currently, Monica Hughes, a PhD biologist, is searching for options and fighting for the treatment of her husbands’s glioblastoma. The story was recently posted at Free The Animal blog. Monica just posted her comment leading to their posts about the state and progress of treatment: http://freetheanimal.com/2014/02/medical-insurance-helping.html#comment-560143

    (reply)
    • Peter Attia  February 17, 2014

      Yes, I have connected with her and wish her and her husband my best.

  46. piotr  February 17, 2014

    Hello, One question bother me so much :” Why our stupid bodies prefer glucose if keton bodies seems to be so much healthier?”

    (reply)
    • Peter Attia  February 17, 2014

      Think of it in terms of flexibility and adaptability.

    • piotr  February 17, 2014

      Yeap, I understand that but on the other hand even if we follow typical keto diet, we still cannot fall below certain level of glucose in our blood while it’s not difficult for our bodies to live without keton bodies.

    • piotr  February 17, 2014

      .. but of course I am a layman, just a curious layman:)

    • piotr  February 17, 2014

      and maybe our bodies just don’t behave in optimal way..sorry for spamming

    • Ted  February 20, 2014

      There are at last appearing some really interesting and potentially fruitful new approaches to the understanding of cancer(s). Inter alia, there are proposals that cancer biochemistry is a very ancient phenomenon from an evolutionary point of view, dating back to times when this planet’s atmosphere was oxygen poor (why do animals, plants etc also develop cancers? – the ‘disease’ must have been present within the architecture of our evolutionary predecessors many millions of years ago).

      If you even partially accept this way of looking at things, then the low-oxygen glucose mechanisms are not ‘stupid’, just a retrogressive switch, initiated by one or more stimuli, leading to a throw back to metabolic pathways that were ‘mainstream’ in earlier times.

      See Paul Davies fascinating talk at http://www.youtube.com/watch?v=yoQYh0qPtz8

  47. Divya  February 19, 2014

    Peter, I just finished listening to your awesome ted talk. Thank you for your sharing your knowledge:)

    (reply)
  48. John  February 19, 2014

    Is it possible that higher authorities know this but do not disclose this because the financial shift this would cause? Lots of money treating cancer. Lots of money in agriculture. Not enough livestock.

    (reply)
    • Peter Attia  February 19, 2014

      I doubt it. Cognitive dissonance is a more powerful force than conspiracy.

  49. Debbie  February 20, 2014

    I also just listened to your TED talk; it was wonderful, and I sent it to a doctor I know, an obese diabetic guy who is the epitome of the brilliant, kind, dedicated doctor.

    After eating a fairly low carb diet for awhile, I’ve added more protein and way more fat recently. I lost 80 pounds over 25 years ago, and have maintained it, but now that I feel such incredible energy – normal energy – I realize I’d been underrating protein and of course fat all these years. (The low fat mainstream message has also subtly emphasized that we don’t need that much protein and I probably wasn’t eating more than 5 -6 ounces per day.) So, now I eat about 12 ounces of meat or fish per day and a lot of coconut oil. I just dump a big glob into my salad at night.

    Just this past week I eliminated the last of the real carbs – 8 xylitol hard candies before bed, which totaled 40 grams of carbs. I had a headache for two days, which was no big deal. But here’s the problem – suddenly I’m not sleeping! I’ve always woken up a lot at night, but will fall right back to sleep. So, I get enough hours altogether. But now I’m really not sleeping. Do you know if this is a temporary situation they when I’m more adapted to ketosis will subside?

    Thanks so much for what you’re doing.

    (reply)
    • Peter Attia  February 22, 2014

      Sounds like a bit of an adaptation period. Should pass.

  50. Chris  February 21, 2014

    Peter,

    First, wonderful work. I learn a ton from you, and I appreciate your sophistication.

    Second, I’ve had an interesting experience with ketosis that perhaps you or a knowledgable reader of yours can comment on.

    I’m 29, very athlletic (7% BF, bench press 1.9x my weight, run 5:20 miles, 40 pullups, etc.), and have no concerns about bodyfat. I turned to keto because, 1. I’m a brain tumor survivor, and 2. not to be cliche, I wanted to be bulletproof. I’m a tech exec and need to be at the top of my game at all times. Your work and others made me aware of ketosis and the possible benefits it could provide for the mind & body. I therefore switched from a moderate fat, moderate protein (140 grams on 170 weight) veggie dense diet, which was about 30% carbs and working fine for me, to a VLC paleo diet. Here’s what happened, subjectively and objectively:

    Objective Changes While in Ketosis:
    -Lost 8 lbs, probably water; body fat may have crept up by a tiny bit, but that’s subjective (mirror assesments and pinching my abs)
    -My LDL skyrocketed to 155, from around 100; HDL is 93.
    -My triglycerides lowered to 70, from 85.
    -My fasting glucose ROSE to 110-120, and my postprandial glucose always drops by 10+ points.
    -My blood ketones were typically between .5 to 1.5
    -My weight lifting decreased by about 15% on sets of 1-8 reps

    Subjective:
    -My focus was great during intermittant fasts – got a bit of a “high” from it, including some mental energy boosts. I didn’t really experience this to a discernable degree while in ketosis – though my ability to stay on task for hours at a time was definitely there.
    -This is my biggest gripe: my memory sucked – I couldn’t keep track of details in conversations I had at work, and totally dropped the ball time and time again. It wasn’t caloric deprivation – I was consuming just as many as before, with tons of coconut butter, mana, MCT oil, grass fed liver, beef, pasture-raised eggs… the works. I also made sure to take in 5g+/- of sodium, and supplemented with iodine, selenium, magnesium, whey protein, B’s for my MTHFR c677t homozygous mutation, etc.
    -My motivation declined. I felt less excitement for things – whether it be sex, work, achievement, going out at night, etc. I was flat, or emotionally dull.
    -I may very well have had 0 instances of “staring off into the distance” to regain my thoughts over the course of the 5 months in ketosis.
    -Reintroducing carbs made me more easily distracted (bad), but more energized, excitable and most importantly, my memory returned (great!).

    MY QUESTION:
    Does it sound like I may be genetically or epigenetically (especially in consideration of my anaerobic muscles’ needs) tuned to needing higher levels of clean carbs, and that ketosis may not be right for my brain? Fasting blood glucose going up, memory deficits and motivation issues all while in ketosis would seem to indicate such, but I’d love a professional’s opinion before I give up on ketosis. Or, more generally speaking, you may be more comfortable answering: Do you believe that some people, for whatever the reason, may be worse off while in ketosis (mentally, at least), and stand to benefit from 100+ grams of carbs /day?

    Thanks so much!

    (reply)
    • Andre  February 26, 2014

      The fasting glucose you can possibly ignore, its called Randle effect and seems to go up on VLC, but it is believed to not equiate to higher glucose uptake in the cells, no problem here.
      Are you by chance APO e4 homozygote?
      Did you supplment DHA?
      Did you stop veggies entirely?
      Did you consider doing just moderate aerobic workout? (instead of intense)
      Did you try increasing sleep to 8-10 hours?
      Did you supplement methylfolate and methylcobalamin?
      How was your stress level?
      How much carbohydrates did you reintroduce? Are you still able to maintain ketosis?
      Did you supplement Potassium?
      How many days a week did you work out?
      Did you get your actual T3,T4 levels, for some Iodine is not enough?
      Did you get Testosterone and Estradiol measured?
      What IF regime did you do? Did you do ketogenic ad libitum + IF? How exactly?

      There are a couple of possible theories to explore as you are doing just about everything.

      All in all this is a pretty intense regime and you might be overdoing it. KD + IF is not so well explored as a maintenance diet. I do KD-R + fasting 2x a year for prevention and only if I dont have any stress. I read somewhere that Fasting + Stress is a pretty bad idea and might lead to adrenal fatigue, which might explain some of your symptoms.
      Even though you were in ketosis, some part of your lifestlye might give you high ROS and impact your hippocampus (memory).

      My best bet to an answer: You are overdoing one of the things you do (workout, fasting, nutrition…) or underoing (sleep, meditation…) others it in a certain way that limits some pathway producing some hormone(s) or increasing ROS, that apparently a glucose based pathway can produce or improve (given that you really didnt change anything else), affecting memory and motivation. We are all so different and you are also a special with the c677t and god knows what other variants.
      In brief: Yes, some people, with some lifestyle factors & environment & genes, my not be able to do VLC as simple as others.

      Key ideas:
      How quickly can you reproduce the memory problems? If you could try again, would be interesting if NAC and ALA supplementation helps (check ROS theory).
      If you are not supplementing 1g DHA, that would be another thing to try.
      Potassium could contribute.
      T3 could be a problem, I would have tried supplementation (careful) based on blood labs. Workout less.
      High cortisol, low testosterone. Remove stress, reduce workout, dont fast while stressed or recovering from workout.

    • Chris  March 2, 2014

      Hi Andre,

      Thanks so much for your response. Here are my answers to your questions:

      Are you by chance APO e4 homozygote? No I am not.
      Did you supplement DHA? Yes – 800mg DHA (400mg EPA) /day + 1 krill oil. I also eat a fair amount of low mercury seafood.
      Did you stop veggies entirely? No – I ate tons of veggies (5-10 servings of greens /day), while remaining in ketosis.
      Did you consider doing just moderate aerobic workout? (instead of intense) Yes – I actually dropped my aerobic down to almost nothing, and only did 4 days/week of weightlifting (from 5-6 days weightlifting and 3 days cardio for the last 15+ years)
      Did you try increasing sleep to 8-10 hours? Yes – tried for 8+ hours, but always found myself naturally waking up after 7. With moderate carb (150 grams), I can easily sleep for 8-9 hours, and have a little more trouble getting out of bed in the morning than when I’m in ketosis or low carb.
      Did you supplement methylfolate and methylcobalamin? Yes (Homocystex Plus and Methyl B-12 5,000, sublingually).
      How was your stress level? Moderate (physical, mental, emotional), although I feel like I got nervous / stressed a little more easily while in ketosis than moderate carb.
      How much carbohydrates did you reintroduce? Are you still able to maintain ketosis? I’m at 150+ grams/day right now. I have purposely taken myself out of ketosis, as I felt it was negatively impacting my job performance. The interesting thing is that, anecdotally speaking, I feel I was able to focus for longer periods while in ketosis, but my memory suffered terribly. I also feel more optimistic and my libido has increased, after reintroducing carbs. I do feel more energy fluctuations with the carbs (more energized at times, but also more tired at times).
      Did you supplement Potassium? Yes. 1 pill /night.
      How many days a week did you work out? 4x, from formerly doing 6-7.
      Did you get your actual T3,T4 levels, for some Iodine is not enough? No. Though, I do take iodoral (1x 12.5mg) /day.
      Did you get Testosterone and Estradiol measured? No.
      What IF regime did you do? Did you do ketogenic ad libitum + IF? How exactly? Ketosis, then 1-2x /wk IF via one serving of BP coffee (MCT, butter) + BCAAs in the morning, for a total fast of 16-20 hours.

      Re: adrenal fatigue & stress, it’s definitely possible. I tried some adrenal support formulas, which included rhodiola & other adaptogens. I know adrenal fatigue is a complex (and controversial) matter – but to that point, if ketosis was in fact causing adrenal fatigue (and the list of symptoms I experienced), and adding moderate carbs back in brought me to a good place… I naturally feel inclined to stick with the carbs.

      Re: overdoing/under doing something, that’s certainly possible. In regards to sleep, if I was under doing it, it was only because ketosis prevented me from staying asleep for as long as I wanted to (even with the addition of melatonin, gaba & magnesium). It also reduced my sleep efficiency (less time in deep & REM stages). Regarding workouts & fasting, I reduced my workouts to the lowest levels in 10+ years, and only fasted 1-2x /wk, on non-workout days.

      This week I’m going to stick with carbs, but next week I will try ketosis again and see if I can reproduce the memory issues again. Regarding your suggestion and the ROS suspicion, I am already taking NAC + ALA (as well as ALCAR).

      Having done both (ketogenic & moderate carb), and observing the differences, it seems like I’m much better suited for moderate carb, despite all of the promises of ketosis. I have the discipline and desire to experience ketosis & its benefits, but even with very careful experimentation, supplementation, etc., ketosis doesn’t seem to work for me and my memory, optimism, libido & excitement / passion. (Not to mention, my bench press increasing from 270 to 305 lbs within just 2 hours of 2 cups of ice cream, after 4 months of stagnation in ketosis! 🙂

    • Andre  March 5, 2014

      Christ, you are tracking and taking more stuff than I do 🙂
      Get your T3,T4, TSH levels now and once you try it next time every week. For some this gets disturbed on low-carb and that can explain quite some of the problems. Probably you are already in a very quiet and dark environment (I sleep with earplugs and face mask), so you can sleep as long as you need to?
      Well, next time try it with less exercise and 8h sleep. Install f.lux on your machine and reduce blue ligth in the evening to make sure your circadium rhythm is not disturbed.
      Your peak performance will suffer unless probably you try those super starches Peter uses. I dont train at peak.

      For some also the adaption phase is quite long and difficult if not supplemented with loads of extra salt, magnesium, potassium, up to 6 weeks. For those actually a continous vs drastic reduction of sugar might be better.

      If its not the thyroid and sleep doesnt help, then yes, there is another probably currently unknown probably genetic factor that will prevent you from going into deep ketosis with adverse effects.

      If that memory effect is reproducible I would try an enormous amoung of MCT oil and see if that counters its effects (giving you brain mitochondria some extra energy).

      Actually my apo e4 question was meant the other way. Most e4 I have encountered thrive on low-carb. So odds are you are e2 and e3.

      One more thing, there are studies showing you should not fast when stressed, it could send your body & mind into hibernate mode (decreased libido and all that bunch). Thats why I am not a fan of IF, but rather KD-R and some extensive fast all couple of months…

      In summary try
      – have good sleep & stress level before you start
      – dont workout that much, I run 4x a week max, even fasted, with intermittent sprints + some moderate muscle
      work
      – do not fast initially
      If it fails
      – double DHA
      – triple MCT and other saturated fats

      In any case get your t3,t4,tsh levels, beta-ketones and blood sugar as well.

      post results!

  51. Debbie  February 23, 2014

    Thanks so much.

    (reply)
  52. Duffy  February 23, 2014

    Dr, Attia,

    I am a Type II Diabetic who transitioned to a low carb diet (Atkins) 1 Jan. 2013. At the time I weighed more than 292 Lbs and had an A1C of 8.6. I was taking the maximum dosage of Actos Plus Met. Since that time I started an exercise program as well as continued with the diet. I have lost 62 Lbs and eliminated the Actos from my meds and reduced my metformin to 2000 mg a day. My A1C is now 6.3. In your writings you have mentioned several times the effects of metformin on the body. In this blog you alluded to several things it does but only detailed a single item. Would you consider writing a blog on this topic so those of us who take the drug can better understand its effects on our bodies as well as its potential effects on athletic performance? I just crossed over 1 million meters rowed and have had some issues in training that I would like to understand better if they are being affected by my metformin. I am hoping to eventually get off this drug as well. Thank you in your efforts to share this type of information with lay people. I wish you the very best in your pursuit to become the best Dr. you are able.

    (reply)
    • Peter Attia  February 23, 2014

      Impressive progress, Duffy. I have no idea if metformin is harming your progress. In theory it’s possible, if it’s preventing your liver from exporting glucose at the moments of “top end” power, but that’s never been studied to my knowledge, so at best it’s a mechanistic guess.

  53. Duffy  February 23, 2014

    Dr. Attia,

    Thank you for the kind words of encouragement. Could you consider writing a blog detailing all metformin does or is theorized to do in the body?

    (reply)
  54. Andre  February 26, 2014

    Knowing that CHO, Insulin, IGF impacts most cancers we can avoid this with VLC.
    We also know that blood glucose under a VLC diet seems to increase slightly (assuming not overweight good health),
    Thus, are the study results that blood glucose below 100 up to 75 decreases our risk for disease irrelevant for us fat-burners (Randle effect, blood glucose not equal glucose uptake) and those only apply to carbo burners? Or should we strive to reduce blood glucose below 100 under VLC and if so, how?
    This is espeically intersting, nowing that some cancers can thrive even on low blood sugar and extract what they need, can they?

    I am VLC for over a year, with daily moderate exercise and I hit 95 fasting glucose, 5% hba1c, unmeasurable CRP, ok fructosamine.

    (reply)
    • Peter Attia  February 26, 2014

      It’s not year clear to me, based on the limited data and mechanistic understanding, whether glucose removal matters more or less than ketone addition in some of these cancer models. My gut tells me any dietary strategy to cancer (treatment, not prevention, which is another story) will still require adjuvants, such as hyperbaric oxygen and/or chemo.

    • Andre  February 26, 2014

      Peter, actually I was thinking about prevention only. Being VLC should we minimize further among where it naturally seems to flow and do we have any blood lab we can use ? (Is blood glucose still useful, including fructosamine, hba1c?)

      Assume VLC and a healthy, low-toxin etc lifestlye, Insulin and IGF minimized, Ketones up to 1mmol. What then remains is glucose supply for cancer cells, that I would like to understand if there is need/use to minimize this further (from around 100). However, according to Randle, blood glucose increases on VLC playing against me.

      Should we on VLC – being fat-adapted and likely keto-adapted – try to decrease blood sugar to the 75 level that is suggested by some big studies (not differentiating VLC dieters)? Because VLC gives me something around 95-105, to down that further would probably require ketones of 4mmol and stuff that impacts glucogenesis? Or just leave it float around there and relax? Do we know?

      Hba1c is not useful due to the longer lifespan of in healthy people?
      Blood glucose is not useful as it cant measure glucose uptake (Randle)
      Fructosamine then?
      Do we have any tests to validate how we are giving disadvantage to cancer cells?

    • Peter Attia  February 26, 2014

      All good questions. Most I don’t know the answers to, though.

  55. niki  February 27, 2014

    Dr. Attia,

    First of all I woudl like to thank you for the time and effort you invest in posting these great articles on your blog!

    Second, I have a question about getting my ketone/glucose ratio at or above 1 (in light of advancing metastatic cancer).
    I eat a dairy-free (except for butter) ketogenic diet, keep my carbs below 20g/day (purely from non-starchy veggies). Protein around 0.8g/kg bodyweight/day and fats coming from nuts (mainly macamamia, almonds), avocado, olive oil, butter and coconut oil and limited amounts of 85% dark chocolate. Doing this I have only been succesful at getting K/G >1 twice (ketones 4.4 and 4.9, glucose 2.6 and 3.1). Both times by restricting both calories (1000kcal/day) as well as protein (a little below 0.8g/kg bodyweight/day) to a low leveI. Both times I felt fine, except for hunger and some lightheadedness.
    My question to you is, can you recommend any products to me that would help me get a sustained K/G ratio above 1 as advised by Dr. Seyfried, seen as a KD-R diet alone usually gets me only a K/G around 0.5.

    Thanks so much!

    (reply)
    • Peter Attia  February 27, 2014

      Not in general, no. Very person specific. Plus, for many this requires some combination of the following: caloric restriction, MCT, exogenous ketones.

    • niki  February 28, 2014

      The exogenous ketones was actually what I was referring to. All I can find thus far is Ketoforce (have not tried this yet). Any similar/better synthetic ketone products you know of that could be of help to me?
      To you knowledge, does taking synthetic ketones only increase circulating ketones or could it also help push blood glucose from a ‘normal’ fasting range to about 2.5 – 3 mmol/l?(perhaps by indirectly limiting need for gluconeogenesis?)

    • Peter Attia  February 28, 2014

      Several variants should be on the market this year.

  56. jw  February 27, 2014

    Thoughts?

    Biomarker Profiling by Nuclear Magnetic Resonance Spectroscopy for the Prediction of All-Cause Mortality: An Observational Study of 17,345 Persons
    http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001606

    Applies to both cardiac and cancer deaths.

    (reply)
    • Peter Attia  February 27, 2014

      I don’t think it tells us much beyond the association. Certainly contains no causal info.

  57. Przemek  February 27, 2014

    I am 42 y old. Male. I am 1.8m and 74kg 9-10% body fat. I race bicycles. Wanted to go down 4-5kg and my dietitian said ‘try low carb’
    I did. I thought I give it a try…
    I also did a lot of reading.
    I started 01.01.14 – 40g carbs a day. For the last 9 days (very similar to last weeks) I ate 2.2g fat per kg body, 1.6g protein.
    I feel very well. Last Sat did a 5h ride on a bike, 3500kcal with some 20-50min heavy going (270NP, which is quite hard for me). No carb consumed dring or prior to the ride. No energy dips felt at all. Actually felt strong…

    Had a blood test yesterday. Fasting glucose and cortisol came out bad.

    How come there is so little mention of low carb high cortisol relationship on your blog…? In fact when one does a search for cortisol on the blog it comes out in four posts and no proper treatment, no mention…

    My results
    LDL (not calculated) 107
    LDL calculated 79 (funny, I though, heaving read all the web stuff, that it would be other way round, though both within the norm)
    HDL 101
    Trigri 50
    Glucose 99.6
    HbA1c 5.1
    Cortisol 792 (normal range 171-536)
    Testosteron 23.2

    What am I doing wrong? I am sure I cannot be alone in the above position. How many people test their cortisol levels..?

    (reply)
    • Peter Attia  February 27, 2014

      So let me get this straight, you feel great, but your am cortisol is a bit high? What is your question/concern? (I’m not looking for the response, “My cortisol is too high.”)

  58. Przemek  February 28, 2014

    Hi,
    Apologies I have not been more specific.
    I have a problem with:
    1. Higher level of glucose (top end of the normal range)
    2. Very high level of cortisol and effect it can have if remains that way for long
    3. No drop in weight I was 74-75kg in Dec 2013 and still am the same weight today.

    I understand that cortisol is released to mobilize amino acids from tissues to increase the availability of glucose through gluconeogenesis. The less glycogen we have stored the more pronounced cortisol release. This especially is true during high intensity long training sessions (like my cycling, 5-6h with 2-3 of hard riding or just 1-2h hard training session). I also do two times a week some weights and cross training to keep up overall body strength (this is 500-700kcal per h sessions).

    If the above is true, I would suspect that LC diets result in an increased exercise-induced cortisol response.

    I have been consuming c 1.6-1.7g of protein per day for the last 8 weeks This is probably too much as it should have been c 1g (per kg of body mass).
    Is it fair to assume that this excess protein was converted into glucose via gluconeogenesis? Hence elevated glucose levels and no weight loss (my body was burning those proteins and not fat)

    The thing is that from what I read, had I consumed say 1g of protein (so much less) my body would still use proteins to synthesise glycogen (thanks to elevated cortisol levels, which in turn is a result of low glycogen levels in my body and heavy training)??

    Elevated cortisol levels can result from various factors: low carb diet, heavy aerobic training, too much protein, stress, too much caffeine (others?).
    In my case at least three played a role (first three).

    I understand that for somebody who is overweight and does little to no exercise going low carb with appropriate level of protein (not too much) the cortisol response may not be as big hence his/her body indeed accesses lipids as source of energy, hence weight loss occurs as expected.

    In my case I have recorded zero weight loss. FYI my daily calorie intake for the last 9 days was 2300kcal. Earlier than those 9 days it was c 2000kcal which was too low.

    Should I be supplementing with say UCAN around my training and how much? 30g pre session and 30g during plus 30g UCAN protein enhanced after?

    Many thx Peter
    It would be great to see some comments from other endurance athletes.

    Przemek

    (reply)
    • PIETER  April 25, 2014

      Please see the latest video from Dr Lustig on the weight issue. It could be that the decresed intake of glucose is resulting in an increased amount of muscle mass and less fatt mass. As Lustig says the scales do not tell you anything. Fat Chance 2.0 is the video.

  59. Gemma  February 28, 2014

    Dear Dr Attia,
    what is your opinion on Polly Matzinger’s Danger Model of immunity? Here is for instance a very informative radio interwiev with her from 2010, also about Coley’s toxins that you mentioned and cancer treatment (1 hour long, sorry):
    http://www.peoplespharmacy.com/2010/08/07/751-coleys-toxin-cancer-and-immunology/
    “Dr. William Coley was a cancer surgeon at the turn of the 20th century. In an effort to improve the treatment he could offer his patients, he created a toxin that made them really sick. If they recovered from their fever, however, they were often cured of their sarcomas.
    A century later, cancer researchers are taking a new look at Coley’s toxin and how it might help us understand spontaneous remissions and the role of the immune system. In exploring this topic, we encounter an innovative immunologist who has developed a new paradigm for how the immune system works.”

    (reply)
    • Peter Attia  March 1, 2014

      Read “A commotion in the blood” and “The transformed cell”

  60. Gemma  March 1, 2014

    — Read “A commotion in the blood” and “The transformed cell”
    ——————————————————————
    Thank you, it definitely sounds like good reading. However, “The transformed cell” is from 1992, Matzinger published her Danger Model in 1994 or so. Here in the above mentioned interwiev in 37:35 (file MatzingerFull) she tells what was according to her wrong in Rosenberg’s approach.
    And here it is again from her talk UCD Dublin (February-March 2012) in 32:30 – 37 min
    http://youtu.be/1eSiAUHDhyA?t=32m30s

    Coincidentally, my son is currently in bed with very high fever and Streptocosus pyogenes thriving in his throat (and penicillin, of course, I am not risking anything). But I told him that for consolation that “every cloud has a silver lining”.

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  61. Tim Claason  March 3, 2014

    I recently stumbled on an article written a couple years ago that says “…a study by a team of researchers at Johns Hopkins and elsewhere shows that lymph gland cancer cells…can use glutamine in the absence of glucose for cell replication and survival, particularly under low-oxygen conditions, which are common in tumors.”

    Would you expect that other cancer types would share this characteristic (using glutamine in the absence of glucose)?

    FWIW, the study found “When the investigators used a glutaminase inhibitor, cancerous growth of B cells was stopped in petri dishes.”

    (reply)
    • Peter Attia  March 4, 2014

      Hard to day, and it’s always dangerous to spend too much time looking at tumor lines vs. actual tumors. The mutations can have little resemblance to the clinical cancer.

  62. Taben Hale  March 3, 2014

    I wonder what your old biochem lab partner from Queen’s would have to say about this blog. You should get in touch with her to discuss. (seriously!)

    (reply)
    • Peter Attia  March 3, 2014

      Hmmmm, not sure how to get a hold of her. Let me check. Shall I apologize or apologase?

  63. Taben Hale  March 3, 2014

    Apologase for sure. Anyway, I’m at U of Arizona now. Get in touch. Would be good to catch up…and talk science.

    (reply)
  64. uma  March 5, 2014

    sir,
    Thanks for the great info.
    1) Have you read law carb fraud and what do you think of it?

    2)I do not live in america. In my country , the whole wheat we get is most of time whole and real and is a staple food. Most of the people do not seem to have a problem eating it since many years. This is not the refined version. People eat less refined and there are no canned food here. I am wondering if all the wheat problems apply here?

    3) Secondly, there are studies that show the benefits of grains and legumes. Why cant a person pursue a balanced diet incorporating more of veggies, some fat, some protein (all from good sources) and some wholegrains /lentils etc. It almost seems going against nature to count carbs while having vegetables. I tried ketosis diet for 10 days and suffered constipation and had hypothyroid like symptoms. It might be great for others. Why do we have paleo, atkins, carb backloading and all these complications when we can just have a simple balanced diet with regular exercise?

    am sorry if these questions sound trivial to you but I really wanted to know your thoughts. thanks

    (reply)
    • uma  March 5, 2014

      unless ofcourse one is suffering from certain issues and need to follow a diet prescribed to help deal with the issue ( I am talking about life in general). I hope you find time to let me know what you think.

  65. Bjorn  March 5, 2014

    You refer to Valter Lungo in your text. His very recent study is making big headlines in all major newspapers in Sweden today like “Meat quadruples the risk of dying prematurely of cancer”.
    What is your comment to Lungos study and his conclusion that it is in fact high protein intake that elevates free IGF-1 and causes cancer, not the carbohydrates?
    http://download.cell.com/cell-metabolism/pdf/PIIS155041311400062X.pdf?intermediate=true

    (reply)
    • Bjorn  March 5, 2014

      His name is Longo of course 😛

    • Peter Attia  March 5, 2014

      See response to other comment.

  66. Kirill  March 5, 2014

    Hi Peter,

    The new study about risks of high protein diet and its connection to cancer are all over the web. Do you have any insights into this issue? Please kindly comment. Here is what is says:

    <>

    (reply)
  67. rd  March 5, 2014

    Dr. Attia – What’s your take on the Longo/Crimmins study out this week with the screaming headline that high protein (20%+) diets cause cancer and diabetes rates to rise in those of middle age?

    (reply)
    • Peter Attia  March 5, 2014

      Zoe did a more eloquent job than I would have: http://www.zoeharcombe.com/blog/

    • Tim Claason  March 7, 2014

      She did do a good job. I’d been trying to figure out what seemed fishy about the study, and Zoe’s article cleared it up for me.

      As one of Zoe’s commenters mentioned, you should note that several of this study’s authors founded/work for L-Nutra, a company that makes plant-based products that “increase longevity”.
      http://www.l-nutra.com/index.php/about/team

  68. Ron  March 5, 2014

    Why does the media insist on sensationalizing this stuff, let alone interpret findings as they see fit? [They] seem to always be one-sided about everything. What ever happened to impartial, objective journalism? I’m one to believe that the media is totally responsible for the obesity epidemic. The “Studies” and the “Media” feed off each other! When a journalist starts out a sentence with “A new study…”, my BP goes up 10 points!

    Every time something like this surfaces, doesn’t it damper the NuSi’s objective? – the one step forward, two steps back theory!

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  69. Andrew  March 5, 2014

    I am an 18 year old male and have always been a pretty normal weight and never thinking much about diet. I picked up running and cycling about a year ago and was poorly misguided into eating a low protein, low fat, high carbohydrate diet with little meat. My weight got down to about 130 (I am 5’10”) and was looking rather gaunt. As a freshman in college majoring in science I was astounded at the complexity of your talk, An Advantaged Metabolic State: Human Performance, Resilience & Health. I began experimenting about three months ago reducing carbohydrates. To eliminate other variables in the experiment I pretty much ate identical foods as you did in What I actually eat, part II – “IFIK” (circa Q3 2012).
    Any-who, over the 3 months I have noticed a lot of changes. Overall I feel a lot better. I however immediately gained weight. I’ve gone from 130 to 150 pounds. Some of this is muscle, as I have also started rock climbing. Some is definitely fat. I can see and grab a little tire under my belly button and the love handles. Again I feel much better but I am not anywhere near as lean. Without getting into a ton more details, is there any quick reason you think I gained weight?
    P.S. My mom says I look healthier.

    (reply)
    • Peter Attia  March 6, 2014

      I bet you look healthier! 5’10” at 130 is even light for a pro cyclist.

  70. Donna  March 6, 2014

    I just want to thank you for your amazing, inspiring and informative writings! I cannot express how interesting your blog is. Thanks for sharing your insights and research with all of us!!!

    (reply)
  71. Shelley  March 8, 2014

    I was obese and diabetic and not doing well at all, I saw myself spiraling into a bad place. I started the KD about ten months ago after watching your video on TED and feel amazingly better and have lost 65#!! I am 5’11” was 255# and now about 190# I thank you for all my success honestly you saved my life. I know this system works… I live it and I breathe it everyday, after the first month this was the easiest thing I have ever done to lose weight. This is my lifestyle now and I will remain in it……BUT BUT BUT, I am confused now after my husband has had testicular cancer five times since he was 17 and its back again I have been researching like crazy to try and help him. The confusing part is you read about KD sounds great I know it works then you read about a alkaline diet for cancer and all the meat and eggs are acidic so its bad. Then another cancer place sites that you should not eat cooked meat because its dead food. Some say protein some so absolutely not. Then the new study on Low Carb diets just came out to say it causes cancer…but they don’t site any stats just print it in the Huiffington Post! When I talk to his regular Dr.’s about this they are clueless and offer more surgery. What is your opinion on this issue? Meats are acidic and eggs and protein….so in the long run is it the sugar that hurts and feeds the cancer (as by any PET scan you can tell it does) or is it the acid foods from protein and or sugar?? We are juicing and supplementing and doing anything we can but I’m on info overload……HELP! Thank you!

    (reply)
  72. Robert Coberly  March 14, 2014

    I’m just catching up to this, from earlier in the thread: “From a practical standpoint, outside of a calorie-restricted KD, the way to get to sustained level of BHB at 4 mM likely requires new foods that also provided exogenous BHB and/or AcAc.”
    Right. Kieran Clarke of Oxford U, and Richard Veech of NIH, are working on the butanediol ester with beta-hydroxybutyrate, for human consumption. Metabolizes promptly, basically you get two equivalents of ketone body from each molecule. Veech has published the safety studies. Their startup company is TdeltaS, there is a website. They’ve been working on this for years, I understand they have a biosynthetic synthesis method.

    D’Agostino, from your suggested readings, and others are working on glyceryl tri-hydroxybutyrate also aiming for a food supplement I believe.
    A triglyceride of a ketone body, very clever. This is mentioned in “Ketone Body Therapy: From ketogenic diet to oral administration of ketone ester. ” Hashim SA Md1, Vanitallie TB Md. – a recent paper, check PubMed, full text available.

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  73. Boundless  March 20, 2014

    Possible new avenue to exploit:
    “The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth”
    http://www.nature.com/nature/journal/v452/n7184/abs/nature06734.html
    “This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis.”

    Once researchers stop digging in the dry hole that is the somatic theory of cancer, they may rapidly find all sorts of exploitable things.

    (reply)
  74. Mike Reinhart  April 17, 2014

    Maybe I missed it, but I see nothing about Peter Pedersen and Young Hee Ko’ s work at Johns Hopkins. They discovered over 12 years ago that a small cheap molecule- 3 bromopyruvate- would bring both glycolytic and Krebs cycle synthesis of ATP to a total halt, killing any cancer cell that it entered. Just as important, it enters cancer cells at a substantial rate because only they possess abundant membrane transporter for small carboxylic acids, thus little or no toxicity to normal cells. Use of 3brpa has been held up over ten years for some really screwy reasons: 1) a patent squabble- one of the discoverers was actually fired from Johns Hopkins for asserting that the patent rights were hers and the university licensed the patent to another individual. This individual May in fact be starting clinical trials (PreScience Labs LLC) but the original discoverer continues to work independently and still submits new patents. The researchers were initially looking for inhibitors of cancer cell hexokinase II. This enzyme binds to a voltage dependent anion channel on the outer mito membrane, and they assert that this is the step that immortalizes the cell. Could there be a nicer tie in to the role of sugar in cancer? 2) Pharmaceutical companies aren’t interested be they can’t see a profit (the stuff is CHEAP!). In addition, the compound itself can’t be patented. I can provide citations or just search Young Hee Ko and Peter Pedersen. To see a one hour amazing lecture delivered at the NIH by Dr Pedersen, visit singlecausesinglecure.org and follow the links – I found it by accident and was STUNNED!

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  75. Cindy B  April 21, 2014

    Thanks for a great article. It actually reinforces my belief that the “job” of cancer cells is to reduce the amount of glucose in the blood. It would help explain why cancer cells use the least efficient means to convert glucose to ATP if the cells aren’t actually trying to produce energy- just clean up the glucose before it can make a mess in the body. I figure it was probably a way to deal with times when people had excess carbohydrates- eg. Feasting, times when fat wasn’t readily available, etc. We just overtax the system with our Western diet.

    (reply)
  76. PIETER  April 23, 2014

    Is the liver able to produce ketones when a person has liver cancer and thus fight the liver cancer this way?

    (reply)
    • Peter Attia  April 23, 2014

      I don’t know the answer the this, but my hunch is that it depends on the extent and severity of the disease and the amount of normal liver parenchyma that remains.

  77. James  May 3, 2014

    Peter, great article and I believe you achieved your goals (or at least the targets set for you!). My wife and I have come to similar conclusions in our research on sugar and its relationship to cancer cell growth (or inhibition).

    With respect to why cancerous cells do not respond to hormonally-based signals telling them to stop growing, have you looked at the lack of presence of monosaccharide receptors on the cancerous cells as the cause?

    http://www.ncbi.nlm.nih.gov/pubmed/10756839

    Furthermore, could the lack of those receptors be caused by an insufficient dietary intake of proper nutrition so that those receptors are not created properly (or at all)?

    Thank you in advance for your thoughts and for all you have written!

    (reply)
  78. Doug  May 23, 2014

    Thanks for putting this together – very helpful in understanding some of the background to this approach. Can metformin be taken concurrently with chemo, radiation and other standard-of-care treatments? The great thing about the Seyfried et al approach (restricted ketogenic diet) is that it can be done along with most conventional treatments so you don’t have to pull a Steve Jobs and forsake the standard treatments, which do sometimes work. I don’t currently have cancer but I did have a melanoma safely removed several years ago (I had just turned 30!) and cancer seems very prominent in my family, so I am watching the progress of this approach very closely.

    (reply)
    • Peter Attia  May 23, 2014

      Until proven otherwise, refraining from standard of care in cancer is not something I would ever advise. Think addition, not substitution.

  79. Bill  May 23, 2014

    “Until proven otherwise, refraining from standard of care in cancer is not something I would ever advise.”

    I think I can appreciate why you may feel the need to say this, but much of the standard of care in oncology seems about as evidence based as current medical nutrition dogma. And in many cases perhaps as destructive.

    I suspect that what has been done to millions of breasts, prostates, and thyroids in the name of cancer treatment, for example, will ultimately be remembered in somewhat then same way as leeches and bloodletting. (Can’t help but recall the great line from the original Star Trek, when the crew goes back in time and Bones says something like, “Jim, we can’t leave him in the hands of 20th century medicine!”) And many of the chemo and radiation protocols seem to have very little supporting evidence, with any benefits marginal at best and adverse affects significant to say the least.

    From what I know about it, some oncology is absolutely fantastic, even curative, but far from all. Not an easy situation to navigate if you are sick and scared.

    (reply)
  80. Kyrani Eade  May 28, 2014

    I found that cancer is about stem-cell mediated immunity erroneously ignited in the body. It can be easily reversed. I had stage 4 ovarian cancer, spread to the uterus, cervix, colon and both lungs. And had type 2 diabetes at the same time. The doctors treated me for the diabetes but threw their hands up about the cancer. I went on to make my discoveries and reversed both. That was 20 years ago.
    Have a look here: http://www.kyrani99godnscience.wordpress.com/2013/09/20/the-big-c-cancer-explained/
    kyrani Eade

    (reply)
  81. Nick  June 13, 2014

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047616/

    What about an article like this the Reverse Warburg that says Ketones fuel tumor growth?

    (reply)
  82. Gale Hawkins  August 20, 2014

    Thanks so much for this fine 1000 word overview of the subject how cancer cells feed. It was the suggestion I start on Enbrel for my AS (ankylosing spondylitis) and its connection with cancer development over time that got me to researching again. Funny part is I learned a low carb/protein but high fat (MCT type fats) was good for AS. After only 10 days on this diet my joint pain is down by 50%+ and my mobility is up by the same amount (subjective data 🙂 ) plus I have lost a couple pounds. This AM I blew a .023 BAC% reading (.125 on the metric scale) using a $15 meter off eBay but have more studying to do to understand the meaning of these acetone readings. I do hold an OD degree from SCO, Memphis TN 1986 which is helpful understanding research. Will read more of the links you added at the end. Thanks again!

    (reply)
  83. Kelly  September 4, 2014

    Re: 2010 TED talk where Dr. William Li introduced the crowd to “anti-angiogenesis therapy”… https://www.youtube.com/watch?v=B9bDZ5-zPtY
    Very cool. Kill blood supply, kill the cancer. Stop the blood supply from developing, stop the cancer from developing..

    I read through this fascinating paper today that describes the mechanisms by which calorie restriction (CR) helps to fight cancer: http://www.cancerandmetabolism.com/content/1/1/10

    Check these quotes out from the paper:
    “Calorie restriction consistently and robustly decreases systemic leptin levels… Leptin… impacts angiogenesis…”

    “Calorie restriction decreases chronic inflammation. The transcription factor NF-?B … is activated in response to … inflammatory molecules and is responsible for inducing gene expression associated with … angiogenesis.”

    “PAI-1 is also involved in angiogenesis … Circulating levels of PAI-1 are consistently decreased in response to CR.”

    Now consider:
    In many ways, the ketogenic diet, when done correctly with the appropriate amount of protein, manipulates the exact mechanisms… Why?

    Because the Keto diet mimics calorie restriction. It tricks the body into thinking that nutrients are scarce by keeping insulin, mTOR and leptin low… This puts the body into “maintenance and repair” mode – without starving you to do it.

    Rosedale covers much of these concepts in this post: http://drrosedale.com/blog/2011/11/22/is-the-term-safe-starches-an-oxymoron/#axzz3CJOLVzQE

    Keto diet – 2 birds, one stone.

    Fascinating.

    Love your blog. Thanks so much for the education.
    Kelly T – Ft. Collins, CO

    (reply)
  84. George  October 1, 2014

    In April, after treatment and having no-evidence-of-disease (NED) for 11 months, our 11-year-old son was diagnosed with relapsed metastatic osteosarcoma (bone cancer) with inoperable tumors on his hip and spine. Osteosarcoma is a rare cancer to start with, and usually metastasizes to the lungs, where it can often be treated successfully with surgery. Our son has had no detectable lung metastasis, only in his hip and spine. This type of bone-only re-occurrence is called “multi-focal,” and it is observed in less than 2% of osteosarcoma relapses. There is no standard of treatment for this kind of multi-focal disease, and unfortunately, the statistical prognosis for this miserable disease after metastases is grim.

    However, having been on a ketogenic diet (KD) myself for 2 years and after having read this blog post, I began immediately pushing for putting him on a KD as an adjunct to conventional treatment (chemotherapy and radiation). My wife was a bit skeptical until she saw the massive glucose uptake by these tumors in his initial PET scans. The oncologists and oncological nutritionists were both skeptical and fearful. (That’s another story.)

    Keeping a child who has been used to carbohydrates and sweets his whole life on a KD has been a challenge, but we have been quite successful at it. As I had become proficient in baking with almond and coconut flours (and using sucralose as a sweetener), I was able to concoct low-carb high-fat substitutes for almost all of his favorite carb foods. Our goal was to limit his carbs to under 40g per-day, and he still gets plenty of healthy vegetables and protein. His routine laboratory tests have consistently shown blood glucose levels in the fasting range (60-90 mg/DL) and moderate to high ketones in his urine.

    After the first two rounds of chemotherapy and 8 weeks on the KD, the smaller spinal tumors were undetectable on the PET scan and the PET activity of the larger hip tumor had decreased by 79%. After four-rounds of chemotherapy, the tumors had become undetectable by PET scan. After this scan, we started radiation therapy on his hip as well as adding a low-dose of metformin (500mg/day), and we are about to complete the seventh and final round of this chemotherapy.

    The probability of the this particular chemotherapy being active against this disease was about 25% (and it was the best shot we had), so we are very pleased with the results so far. We cannot, of course, separate out the effects of the KD (if any) from the chemotherapy, but we believe that using a metabolic treatment in combination with conventional cytotoxic chemotherapy and radiation can only help. Nevertheless, as one oncologist told us, “you can fit a million cells on the head of a pin, and it takes about 1 centimeter of cells in a tumor to become visible on a PET scan,” so we know that “no evidence of disease” does not necessarily mean cancer free.

    Going forward, there is no “conventional standard of treatment” for this disease. We are very interested in using hyperbaric oxygen in combination with a KD based on both the work of D’Agostino and researchers at MIT who have demonstrated that cancer cells can survive on glutamine in the absence of glucose in a hypoxic tumor environment, but not in an oxygen-rich environment. In addition to other chemotherapies, we are also closely watching developing immunological approaches to treating this disease.

    (reply)
    • Peter Attia  October 2, 2014

      Can’t wait until we have the right kind of clinical trails to give us answers to these questions. I suspect your intuitive is correct about multi-modality therapy–metabolic, cytotoxic, immunologic.

  85. Steve(UK)  January 31, 2015

    Very interesting Peter. I would like to add my understanding to the discussion. I’m not a scientist or healthcare professional, but I too have tried to look at the subject of Cancer with fresh eyes – in much the same way you have with diabetes.

    IMHO Cancer is all about oxidation of biomolecules leading to cellular dysfunction via DNA/RNA mutation. All aerobic organisms have had to develop anti-oxidant defence mechanisms against pro-oxidative internal processes and external carcinogens. Our cell membranes, proteins and RNA/DNA can be severely compromised by these actions. Our defences are now being overwhelmed by an environment containing hundreds of pro-oxidative sources. I also think there is a major modern co-factor which is being over-looked.

    All the observed effects(glucose utilization, disrupted apoptosis, unchecked cell growth etc) are (IMHO) simply symptoms of dysfunction. My own research has identified all the main causes of Cancer as being generators and promoters of Reactive Oxygen Species(ROS) free radicals (Superoxide, Singlet O2, Hydrogen peroxide and Hydroxyl – amongst others). These ROS are generated both endogenously and exogenously via dozens of mechanisms in huge quantities(by the trillion?). All the main carcinogens (Ionizing radiation, UV, Smoking, Alcohol), as well as a considerable percentage of the IARC Class 1 carcinogen list , all contribute to DNA mutation via ROS.

    Is this just a coincidence?

    I don’t want to explain too much in a single comment, but I think I can explain all of the characteristics of cancer(increased incidence in the elderly, overall increase in incidence, association with modern life, same promoter causing multiple types of cancer, metastases, spontaneous remission, cancer in the young, poor treatment outcomes and survival rates, dietary and lifestyle factors and more) in a single unifying theory.

    Apologies if this is a little short and matter-of-fact. It’s a huge subject which is difficult to do justice in a couple of paragraphs and your TED talk suggested more ‘straight talk’ to be beneficial to the debate.

    (reply)
  86. Terry  March 18, 2015

    Here is a link supporting this by a Harvard trained surgical oncologist:

    http://www.integrativeoncology-essentials.com/2013/02/an-over-the-counter-ancient-medicinal-berberine-fights-cancer-and-diabetes/

    (reply)
  87. mbj  June 27, 2015

    Peter, I’ve read your post with great interest. In it you say “Over a dozen clinical trials are underway right now investigating this strategy in the cancers that appear most sensitive to this metabolic effect – breast, endometrial, cervical, prostate, pancreatic, colon, and others.” Since some time has passed since you posted your piece, do you have any information about the progress or outcomes of these trials? I’d really like to know who to contact to get more information.

    I have stage IV pancreatic cancer (exocrine) with metastases in both lungs. I was diagnosed about 14 months ago. My diet is focused on getting plenty of protein and vegetables, is not low-fat, and does include grains and fruit, with occasional treats that have sugar. My oncologist has said that she does not recommend that I go on a Paleo diet and that my current diet is fine, but I’d like to hear your thoughts on this. Do you think that I should go on a KD? If so, can you point me in the direction of any legitimate (not based on anecdotal evidence) studies that demonstrate the advantage of KD for someone with pancreatic cancer? Also, if so, what % of calories should be carbs? I’ve seen one KD that suggests carb intake should be 2-4%, which seems very low and would be quite difficult to maintain. Anything you can provide will be much appreciated! Thank you!

    p.s. Since the beginning, I’ve been taking 1000 mg of Metformin/day

    (reply)
    • Peter Attia  June 29, 2015

      Sorry to hear about diagnosis. There really are no studies pointing definitely to one diet or another. But it’s hard to make the case that a diet that promotes hyperinsulinemia is the right choice in the case of most cancers.

    • Bob Niland  June 29, 2015

      Here’s a recent paper on ketogenic diet and cancer (published earlier this month):
      PLOS|ONE: Non-Toxic Metabolic Management of Metastatic Cancer in VM Mice: Novel Combination of Ketogenic Diet, Ketone Supplementation, and Hyperbaric Oxygen Therapy
      http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0127407
      Yeah, mice, but still. And note that the diets were ad libitum, and not calorie-restricted as might be expected if you’ve read Seyfried’s book.

      The exogenous ketones used in the trial may not be generally available, but there is one commercial product available from time to time (Patrick Arnold’s KetoForce). Dilute H2O2 has also been suggested as an alternative to hbO2.

      One of the paper’s authors (D’Agostino) has a web site with links to useful resources.

      re: Do you think that I should go on a KD?

      Do not expect anyone to give you a definitive answer, and if they do, question it. Anyone who distrusts the Standard of Care, based on the apparently dead-end somatic theory of cancer, needs to fully take charge of their own case, do their own research, and make their own decisions.

  88. Kimberly  July 12, 2015

    Recent research shows that high levels of growth factor significantly increase the risks of colorectal, breast, and prostate cancer. It also has been determined that a protein that binds to the growth factor seems to neutralize it and reduce the risk of these malignancies. My question being, how does Sermorelin use tie into these findings? It was my understanding that Sermorelin use leads to higher levels of growth hormone which slows the aging process, thus, reducing cancer risk. In light of this research, however, it seems that just the opposite has been proven.

    (reply)
    • Peter Attia  July 13, 2015

      I would not consider sermorelin to be a longevity agent. Things that increase GH later in life likely reduce longevity.

  89. ed  September 23, 2015

    I’m under the impression that Cancer patients often die from Starvation most directly. At one point in history, measuring ketones on the breath was even a (late) measure suggesting cancer. If this is true, am I right to suppose that inducing nutritional ketosis may be of limited use to a later-stage patient? Perhaps that’s irrelevant and certainly not a rebuttal against prophylatic ketosis. Also, would it be beneficial for a keto-adapted person to consume glucose prior to a FDG-PET scan? Otherwise, it seems like a false-negative (“miss’) could occur.

    (reply)
    • Uncle Roscoe  January 13, 2016

      The starvation symptom in the final stages of cancer has been referred to as “wasting away”. It’s known as cachexia: https://en.wikipedia.org/wiki/Cachexia

      Cancer cachexia represents the replacement of specialized cells which burn glucose and fat with do-nothing cells which ferment only glucose. It’s no coincidence that this transition happens in an insulin-resistant environment with way too much glucose. It represents the replacement of human cells which are incapable of importing the abundant glucose with cancer cells which use the glucose.

  90. Eliza Bulla  January 10, 2016

    A ketogenic diet has been known to work.

    (reply)
    • Uncle Roscoe  January 14, 2016

      The rEally great thing about a ketogenic diet for cancer is that it has no down side. Switching from carb ingestion to fat ingestion does not rely on the chemical pathways argued back and forth between Warburgh advocates and consensus oncology.

      Trying a ketogenic diet for cancer merely relies on the fact that humans can use either fat or sugar, but cancer can use only sugar.

      Sure, the pathway science is quite important in defeating the wrong-headedness of the cancer-is-genetic crowd, but it’s not necessary for any individual cancer patient.

  91. Garrett  January 28, 2016

    Hi Peter, I’m a grad student training to be an epidemiologist at a top-ranked US public health school and I am a HUGE fan of yours and Gary Taubes’ work. For years, my dream has been to work with NuSI to test these Warburg/excess glucose/cancer theories. If there really is a causal effect between glucose/sugar and cancer, the implications are so massive, we might have another cigarette smoking > lung cancer type situation on our hands. If a link like that can be established, then bigger changes in policy and public opinion and surgeon general’s reports etc. could one day happen. I am super passionate that this theory HAS to be tested and the experiments to prove it have to be expertly designed. Please contact me if NuSI is looking for a dedicated worker for this cause. I would be willing to put in tons of hours and work for low or no wages. Thanks!

    (reply)
    • Peter Attia  January 30, 2016

      Garrett, I’m no longer at NuSI.

  92. Ron  January 30, 2016

    Peter, what happened (NuSI)?

    (reply)
    • Peter Attia  February 1, 2016

      I am no longer at NuSI.

  93. Michael  February 1, 2016

    Hi Dr. Attia,

    Your last comment was a surprise to me. What happened at NuSI? Are you still intimately involved in nutritional research?

    (reply)
    • Peter Attia  February 1, 2016

      No, I am no longer at NuSI.

    • Dougie  February 1, 2016

      I’d love to know what happened too. This is a bit of a downer to my day. That said, david bowie recently died and even more recently the mighty dons were found guilty in the ASADA/WADA supplemets scandel. So life has been worse.

      I get the feeling you don’t want to publicly say it, but this has shaken my faith in NuSI a bit. You can always email me, or message me on twitter or facebook. I won’t tell the world (I haven’t got my radio show anymore, had to quit that 🙂 …….year 12 and footy was too time consuming)

  94. Michael  February 1, 2016

    for what’s it’s worth, your interest in nutrition lit my passion to become involved. I will be submitting my research proposal spring of this year focusing on nutritional ketosis, so I can evaluate this further during my residency in dermatology. I hope you pick back up this endeavor at some point, as you have enlightened many people to think and question dogma. Thank you.

    (reply)
    • Peter Attia  February 1, 2016

      Thanks, Michael. I’ll be as involved as ever in the space of health, but my interests have grown quite a bit broader than nutrition.

  95. lorenzo  February 1, 2016

    I have followed you for years, I have asked my doctor for an “upgraded” blood work but he doesn’t know what to do with it…any suggestions, where can I go to have someone look at LP(a), ApoB, etc.. and make sense of it all?

    (reply)
  96. David  February 3, 2016

    What?! I thought NuSi was a ‘legacy’ project?!

    (reply)
  97. Norm  February 4, 2016

    Hi Peter,

    I’m sure your readers would appreciate if you could do a short post on “why I left Nusi”. Thanks

    (reply)
  98. Palak Kundu  February 20, 2016

    Dear Dr. Attia:

    I’m a medical student at Stanford going into radiation oncology, and I’ve seen an increasing number of patients adopting ketotic diets. Often times the question of how this metabolic state can affect their radiation treatment comes up, so I was wondering if you knew of any relevant literature.

    Thanks,

    Palak

    (reply)
    • Peter Attia  March 4, 2016

      Check with Dom D’Agostino. He’s looking into this question.

  99. tony  March 6, 2016

    throw us a bone. Its been 51 weeks since you posted a new story on here.

    (reply)
  100. David  March 13, 2016

    And what a podcast it was! Excellent discussion on longevity and one that requires a more in depth conversation, perhaps on a subsequent podcast. I’m curious about the change in direction on the nutritional aspect though?

    (reply)
  101. Colleen  March 15, 2016

    I really enjoyed the STEM podcast. You mentioned HbA1c could be a poor marker and I think that you were using something else but the discussion never got back there. For those of us who are not going to go around with a continuous glucose monitor, what do you look at? Maybe you can get back to this topic on a different podcast.

    (reply)
    • Peter Attia  March 16, 2016

      You will be wearing a CGM soon I hope!

  102. Milan  March 25, 2016

    Hello, I’m wondering if taking Metformin + being on a ketogenic diet is potentially dangerous in a non-diabetic. My gut feeling says that there should be no real harm but I am concerned about hypoglycaemia. Any help is appreciated.

    (reply)
    • Peter Attia  March 27, 2016

      The more interesting question (to me) is if metformin adds (much) benefit in this situation…

  103. Doug  March 29, 2016

    My wife has a 3cm adenocarcinoma on her lower left lung. She is going for a biopsy on her adrenal in the morning because it lit up slightly on the PET. So surgery or chemo depending the outcome of that biopsy. When I mentioned keto, low cal, restricted sugar/carb to the Oncologist he said “there are all kinds of theories but none are proven”. Ignorant but expected.
    So we broke out our copy of Keto Clarity. We have been eating paleo/primal but know that is not enough. We are praying that they can get a biopsy and it is negative so they can remove her left lower lung lob and she can be “cured”.

    (reply)
    • Peter Attia  March 29, 2016

      Sorry to hear this, Doug, but don’t be discouraged by ignorance.

  104. Patti  April 7, 2016

    As a nurse practitioner I have many patients who come in already on Statins for ” high Cholesterol”. I have been told by my pharmacist that stopping/ weaning them off, is dangerous because of ” rebound elevations beyond their starting point”. Is this true? How can I help these folks who with normal TRGs likely do not need the medicine?
    Thank you for all your wonderful teaching.
    Grateful in Spokane

    (reply)
    • Peter Attia  April 7, 2016

      I dunno about the “rebound phenomenon.”

  105. Avner  July 11, 2016

    Hello, when you state: “though not uniformly the case, most cancers do indeed appear to have defects in their mitochondria that prevent them from carrying out oxidative phosphorylation”. Do you know if squamous cell carcinoma is defected in this sense?

    (reply)

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