Monthly Archives: September 2011

An Anti-Cancer Diet

Our cancer series resumes today with some tentative advice for cancer patients. (Note: This post is designed for solid tumor cancers, not blood cancers. However, most of the advice would also be applicable to blood cancers.)

This series began with Toward an Anti-Cancer Diet (Sep 15, 2011). There we advocated trying to shift cells away from the cancer phenotype via 8 anti-cancer strategies.

Future posts will explore in detail how to implement those strategies via diet and lifestyle. Today, I’m just going to give a general overview of what I would do if I had cancer.

Eat the Perfect Health Diet

This may sound self-serving, but it’s my best advice. Our diet is designed to optimize health generally, and that’s exactly what you want to do against cancer.

I said in the introduction that cancer is a disease in which cells lose their “humanness” – their proclivity to collaborate with other human cells to create a human organism. Instead, they lose recently evolved features and “remember” an identity similar to that of our distant evolutionary ancestors from the early days of multicellular life. This regression is possible because we retain the genes of our primitive evolutionary ancestors, and silencing of only a few hundred genes may cause a human cell to resemble, genetically, bacteria or fungi.

Many gut bacteria can take on two modes of behavior – a commensal or harmless phenotype, or a virulent harmful phenotype – depending on whether their environment is benign. In beneficial environments, bacteria tend to be cooperative with their host; in harsh environments, bacteria begin to look out for their own interests “selfishly,” and begin to display virulence traits which harm their host but help them move to a better environment.

Something similar may happen with “proto-cancer” cells. In a healthy environment, they are pleased to cooperate with their host – to retain their “humanness.” But in a harsh environment, they are more likely to withdraw from their neighbors and go their own way. An abused cell is more likely to become a cancer cell.

This may sound like anthropomorphization, but the metaphor is probably sound. Bruce Ames has remarked upon the fact that almost every compound is a carcinogen in large enough doses. Why? Because any unbalanced environment is harsh, and any harsh environment makes the cell more likely to develop the cancer phenotype.

It’s not only by discouraging “cancer virulence” that a good diet helps. A healthy diet also optimizes immune function.

Immune function is highly variable. Under stress, we suppress immunity so that all the body’s resources are available to meet “fight or flight” needs. Contrariwise, peaceable happiness is stimulating to immune function. A nutrient-rich diet, savory meals, happiness, calm, restful time spent in conversation – all of these things tell the body it has no pressing concerns and that available resources can be devoted to immunity and healing.

After cancer diagnosis, from a similar medical condition, those who are under stress tend to succumb to cancer, while those who are happy, cheerful, and sociable tend to recover from it. It is believed that this difference is primarily due to improved immune function in those under less stress.

I believe that a healthy, tasty diet is also a stimulant for immune function. Make your food nourishing and enjoyable.

Specific Dietary Aspects

A few aspects of an anti-cancer diet deserve special mention. Let’s look at the PHD Food Plate:

Some aspects I would emphasize for cancer patients:

  • Safe starches. I recommend obtaining 400 to 600 glucose calories a day, mainly from safe starches. I believe it is important to avoid a glucose deficiency, since glycosylated proteins are the means of intercellular coordination, and defects in glycosylation are characteristic of the cancer phenotype. (See, eg, this paper.) You don’t want to aggravate this with a self-induced glucose deficiency.
  • Low omega-6 meats. Omega-6 fats can be very damaging to mitochondria and can promote metastasis. Our needs for them are minimal, and they are everywhere. It’s important to choose foods that minimize omega-6 levels. Among meats, prefer seafood, shellfish, and red meats; obtain eggs, milk, and organ meats from pastured and naturally raised animals. Eat tropical plant oils like coconut and palm.
  • Omega-3 and omega-6 balance. The diet should include some marine sources of omega-3 fats, like salmon or sardines.
  • Bone broth soups and gelatin (cooked collagen). Collagen is 30% of our body’s protein and forms much of the extracellular matrix scaffolding which is crucial to maintainance of tissue health. The extracellular matrix is broken down in cancer. An anti-cancer diet should be rich in cooked joint tissue, such as can be found in Ox Feet Broth soups. Vitamin C and sulfur, discussed below, are also required for collagen formation; be sure you’re not deficient in these.
  • Fermented vegetables, yogurt, and acids. A diverse portfolio of gut bacteria can be helpful to the fight against cancer by several mechanisms. Probiotic flora from fermented  foods help shield against the entry of cancer-promoting pathogens to the body through the gut; they generate by-products, like short-chain fats and vitamin K2, which have anti-cancer effects; and they can modulate immunity in a favorable direction. Acids such as vinegar and lemon juice can also favorably modify gut bacteria.
  • Vegetables, herbs, and spices.Fiber is probably beneficial against cancer. Butyrate, which is produced by gut bacteria from the digestion of many types of fiber including “resistant starch” from safe starches, has anti-cancer properties. Moreover, many vegetables and traditional herbs and spices have been shown to have anti-angiogenic effects. Foods with anti-angiogenic properties include:
    • Garlic.
    • Tomato.
    • Green tea.
    • Dark chocolate / cocoa.
    • Maitake mushroom.
    • Bok choy.
    • Kale.
    • Many berries.
    • Cherries.
    • Ginseng.
    • Turmeric.
    • Oregano.
    • Parsley.
    • Polyphenol-rich extra virgin olive oils.
  • Organ meats and egg yolks. It’s important to be well nourished, and organ meats like liver and egg yolks tend to be rich in micronutrients. They are much better than plant foods for compounds like phospholipids. In particular, choline (and its phospholipid form phosphatidylcholine) is important for methylation status and epigenetic functioning – an important element in cancer prevention.
  • Sea vegetables, sea salt, and seafoods. These are good sources of trace minerals such as iodine, which is a critical anti-cancer nutrient.

In general cancer patients should focus on the foods in the apple of the PHD Food Plate more than the “pleasure foods.” However, there’s nothing wrong with some berries, dark chocolate, pistachios, and whipped cream for dessert, and some red wine with dinner. Above all, it’s important to enjoy your food. Try to obtain from every meal a sense of pleasure and well being!


Much more could be said on this topic than I’m going to say today. One could make a very long list of supplements that might help against cancer (also a long list of those that hurt). However, the crucial five from my point of view are in our recommended supplement list:

  • Vitamin D
  • Vitamin K2
  • Iodine
  • Selenium
  • Magnesium

The tricky one here is the iodine. Iodine dosage should be built up very slowly from a low level, so as not to disrupt thyroid function. (Hyperthyroidism can strongly promote cancer, and hypothyroidism can inhibit immune function and healing, so any thyroid dysfunction is a serious risk.) Start at 500 mcg or less, and increase the dose no faster than a doubling per month. If you get either hypothyroid or hyperthyroid symptoms from an increase in dose, back off a bit (eg instead of going directly from 500 mcg to 1 mg per day, go to 500 mcg and 1 mg on alternate days). Be patient, but try to build up to 12 mg/day over a 6 month period. Then stay there. Be sure to get 200 mcg/day selenium along with the iodine.

I also recommend a multivitamin, for general nourishment; and make sure there is no deficiency of vitamin C, zinc, copper, or chromium. Also, when it comes to antioxidants, more is not better. Avoid most antioxidant supplements other than glutathione, vitamin C, selenium, zinc, copper, and manganese.

For magnesium, I recommend taking a 200 mg oral supplement of magnesium citrate or a magnesium chelate. Epsom salt baths might not provide magnesium, but they can be a useful source of sulfur (in the form of sulfate) which assists collagen formation.

Vitamin C is an unusual case. It supports collagen formation, and for this purpose and to avoid a deficiency I strongly suggest taking 1 g per day. In higher doses, vitamin C may be helpful because it has anti-viral properties (see Fighting Viral Infections by Vitamin C at Bowel Tolerance, Sep 26, 2010), and most cancers are probably viral in origin. Linus Pauling, of course, advocated high doses of vitamin C – either taken orally to bowel tolerance, or intravenously. However, there are arguments on the other side. Vitamin C can protect cancer cells from immune attack, and also makes them resistant to chemotherapies. Clinical trials have not yet proven high-dose vitamin C therapy, but it may help against a subset of cancers caused by viruses sensitive to vitamin C therapy.

If sufficient amounts are not obtained from diet, then choline should be supplemented.

Intermittent Fasting, Intermittent Ketosis, Intermittent Protein Restriction

This is an extremely important cluster of strategies that are probably highly effective against cancer.

Their common trait is that all three promote autophagy, or “self-eating,” which is both a means for cells to cope with resource scarcity and a central part of the intracellular immune response.

When resources are abundant, cells allow aged organelles and junk proteins to accumulate. When resources are scarce, they turn on autophagy and digest unnecessary components, recycling the resources.

Autophagy is the dominant innate immune mechanism inside cells – the primary way cells kill bacteria and viruses.

Autophagy also recycles damaged mitochondria, which can be digested, enabling remaining healthy mitochondria to multiply. The result is a healthier mitochondrial population.

Since viruses and damaged mitochondria promote cancer, autophagy helps transform cells from the cancer phenotype back to the normal human phenotype.

Fasting, by inducing resource scarcity, promotes autophagy. Scarcity of amino acids, which can be achieved by a protein restricted diet, also promotes autophagy. And ketosis, which is part of the metabolic profile of starvation, also promotes autophagy.

Note in my section heading the shared word: “intermittent.” We don’t want to sustain fasts or protein scarcity too long; that could create malnourishment and cause more harm than good. Permanent ketosis may promote fungal infections. The most helpful course is probably to follow these strategies intermittently:

  • Engage in daily intermittent fasting: eat only within a 6 to 8 hour window each day. Within the fasting period, eat some coconut oil or MCT oil to promote ketosis.
  • Eat high protein for a few weeks while engaging in resistance exercise to build muscle; then low protein for a few weeks.

A Note on Ketogenic Diets

Since we wrote our book, we’ve become a bit less excited about the therapeutic potential of ketogenic diets.

Ketogenic diets have demonstrated effectiveness in brain cancers, and several considerations suggest that they would be helpful against all cancers:

  • Cancer cells are dependent on glucose metabolism, a phenomenon called the Warburg effect. In ketosis, blood glucose levels can be decreased – a fall from 90 to 65 mg/dl is achievable – and reduced glucose availability should retard cancer growth.
  • Mitochondria do well on ketones, and some studies had shown that provision of ketones can restore the ability of mitochondria to trigger apoptosis, or the programmed cell death of cancer cells.

It’s too early to judge, but a few scraps of data published recently have made ketogenic diets seem a bit less exciting then hoped.

First, the group of Michael Lisanti has published work suggesting that tumors can evade the metabolic restrictions of a ketogenic diet by manipulating neighboring normal cells. The idea (here is an overview) is that cancer cells release hydrogen peroxide, which causes a stress response in neighboring cells, stimulating them to release lactic acid, which the cancer cells can metabolize. This process can happen nearly as well on a ketogenic as on a normal diet, so the effectiveness of a ketogenic diet in starving the cancer cells is reduced.

The Lisanti group results are hardly conclusive – indeed so far as I know no other group has supported their claims – and there are plenty of skeptics. Jimmy Moore gathered responses from a panel of low-carb experts.

Second, clinical experience with ketogenic diets has not yet shown them to be highly effective. The sort of data we have is well represented by a recent report in Nutrition and Metabolism. Sixteen patients with advanced metastatic cancer were put on ketogenic diets. The results:

One patient did not tolerate the diet and dropped out within 3 days. Among those who tolerated the diet, two patients died early, one stopped after 2 weeks due to personal reasons, one felt unable to stick to the diet after 4 weeks, one stopped after 6 and two stopped after 7 and 8 weeks due to progress of the disease, one had to discontinue after 6 weeks to resume chemotherapy and five completed the 3 month intervention period.

The conclusion: a ketogenic diet “has no severe side effects and might improve aspects of quality of life and blood parameters in some patients.”

Clinical trials with control groups and more statistical power are needed to evaluate whether ketogenic diets have therapeutic effect. For now, I think the most prudent course is intermittent ketosis and intermittent ketogenic fasting, rather than a continuously ketogenic diet.

UPDATE: Mario makes a great point in the comments: fasting prior to chemotherapy reduces toxicity to normal cells but increases toxicity to cancer cells. It is quite likely that a ketogenic diet might have the same effect during chemotherapy. So the combination of intermittent ketogenic dieting with chemotherapy should be given consideration.

Circadian Rhythm Enhancement

Many diseases become more likely, or more severe, if circadian rhythms are disrupted. Enhancement of circadian rhythms may be therapeutic for these diseases.

I’ve blogged about circadian rhythm therapies for hypothyroidism (“Intermittent Fasting as a Therapy for Hypothyroidism,” Dec 1, 2010) and for sleep disorders, psychiatric disorders, neurodegenerative disorders, and obesity (“Seth Roberts and Circadian Therapy,” Mar 22, 2011).

Well, cancer is another disease for which circadian disruption may be damaging. The International Agency on Research on Cancer (IARC) has recently classified “shiftwork that involves circadian disruption” as “probably carcinogenic to humans.”

It’s plausible that circadian enhancement may be therapeutic for cancer. Tactics that enhance circadian rhythms include:

  • Exposure to mid-day sunlight.
  • Sleeping in total darkness during hours of darkness.
  • Confining eating to daylight hours.
  • Socializing – especially, looking at faces and talking – during daylight hours. Seth Roberts found that looking at images of human faces can substitute for actual socializing.
  • Exercising during daylight hours. Even low-level activity – like standing instead of sitting – helps.
  • In people who are melatonin deficient due to a brain immune response, supplementation of melatonin just before bedtime.

Curiously, circadian rhythm disruption seems to make chemotherapy more effective. Also, timing treatments to match circadian rhythms may double their effectiveness.

Exercise and Other Lifestyle Factors

A number of lifestyle factors are important for cancer recovery. David Servan-Schreiber’s Anti-Cancer has an excellent overview of the evidence.

A recent study in the Lancet found that every additional 15 min of daily exercise beyond 15 min a day reduced all-cancer mortality by 1%. Exercise appears to be therapeutic even for late stage cancers. A meta-review found that two and a half hours of exercise a week could lower a breast cancer patient’s risk of dying or cancer recurrence by 40 percent, and could reduce a prostate cancer patient’s risk of dying from the disease by about 30 percent.

However, exercise should not be exhausting. Rather, it should be restful and relaxing; or build muscle. Resistance exercise on the “Body by Science” model of one intense workout per week, with more time spent in restful recovery than in stress, is probably a good strategy. Long walks outdoors in nature, and relaxing exercises like yoga or tai chi, are also great approaches to cancer therapy.

Being sociable, happy, calm, and optimistic are all important factors for cancer recovery. Those who have companions they love, and a purpose for living that makes them happy, have the best prognosis. Be grateful for what you have, and make your body understand that life is worth living.

Dealing with Anorexia and Nausea

Anorexia and nausea can seriously impair the ability of cancer patients to eat a nourishing diet and maintain their strength.

I haven’t had time to research this aspect of the disease yet, but there do seem to be some dietary and lifestyle interventions that help.

For instance, exercise can correct anorexia.

Among dietary interventions, ginger has been reported to reduce chemotherapy-induced nausea, reducing incidence in one study from 93% to 55%. (Hat tip: Healthy Fellow.)

Ginger teas are a traditional Asian folk remedy. Slice some ginger root in water, boil it on the stove, add some rice syrup for sweetness, and drink up!

Under-Utilized Therapies

There are a few therapies which are rarely prescribed, but might be more helpful than chemotherapies in treating cancer:

  • Low-dose naltrexone.
  • Anti-viral drugs.
  • Anti-fungal therapies.

Low-dose naltrexone is taken at night before bed. It temporarily blocks opioid receptors, which leads the body to increase production of endorphins and enkephalins – immune compounds which interact with opioid receptors. The following day, the naltrexone is gone and the opioid receptors are working again, but the endorphins are still around. Taking LDN thus increases endorphin levels. Endorphins inhibit cancer proliferation, and may enhance anti-cancer immunity. Here is a recent paper on anti-proliferative effects of LDN against ovarian cancer: Here is a recent paper on LDN plus alpha lipoic acid as a therapy against pancreatic cancer: For a general overview, see

Viruses cause or contribute to most cancers, and thus anti-viral drugs have great potential. A few cancer-causing viruses are famous, such as the Human Papilloma Virus for which there is a vaccine; however, most of the viruses that cause cancer remain unknown, though we know they exist because genetic mutations that impair viral immunity greatly increase cancer incidence.

Mario Renato Iwakura recently sent me a link to a paper that nicely illustrates the potential of antiviral therapies against cancer. Cytomegalovirus, also known as human herpes virus 5, is a common virus that infects 40% of adults worldwide and 50% to 80% of Americans. However, it is found in almost 100% of human tumors. It seems to be difficult to get cancer if you haven’t been infected by cytomegalovirus.

From the paper abstract:

Medulloblastomas are the most common malignant brain tumors in children…. Human cytomegalovirus (HCMV) is prevalent in the human population and encodes proteins that provide immune evasion strategies and promote oncogenic transformation and oncomodulation…. Remarkably, all of the human medulloblastoma cell lines that we analyzed contained HCMV DNA and RNA and expressed HCMV proteins at various levels in vitro. When engrafted into immunocompromised mice, human medulloblastoma cells induced expression of HCMV proteins. HCMV and COX-2 expression correlated in primary tumors, cell lines, and medulloblastoma xenografts. The antiviral drug valganciclovir and the specific COX-2 inhibitor celecoxib prevented HCMV replication in vitro and inhibited PGE2 production and reduced medulloblastoma tumor cell growth both in vitro and in vivo.

Tumor growth declined by 72% when treated with Valcyte (valganciclovir) and an NSAID drug. A press release notes that these drugs have “relatively good adverse effect profiles” and that “antiviral drugs are selective and largely affect infected cells.”

Yet another antimicrobial approach that may be helpful against cancer is antifungal therapy. Most cancer patients develop systemic fungal infections, and fungal infections such as Candida promote metastasis and tumor growth, and may also suppress anti-cancer immunity. An effective antifungal therapy may significantly retard cancer progression.


Much more remains to be said, and it’s certain that we’ll refine these suggestions after more thoroughly studying the literature. But I think this basic approach to an anti-cancer diet can’t be too far wrong.

Our prayers and best wishes go out to all those who are battling cancer.

Onion Rings

Our series on American food has included a number of finger foods; we’ve done Chicken Wings, Hamburgers, Chocolate Chip Cookies, and French Fried Potatoes and Sweet Potatoes. But we can’t leave out onion rings.


You’ll need with a batter, made of 4 egg whites, 1 tbsp cream (or milk), and a pinch of paprika, salt, and pepper to taste:

Slice a yellow onion (we like the taste better than sweet onions) and separate it into rings:

Finally, prepare a coating. We like puffed rice, or puffed rice with mixed nuts, ground in a food processor:


Place the rings from one onion with 1 tbsp potato starch and salt and pepper in a Ziploc bag:

Shake until the rings are evenly coated. Then dip them in the batter:

And then the coating:

Lay them out on a cookie sheet and bake for 15 minutes at 400ºF (200ºC):



They taste great alone or with a dipping sauce: we tried melted butter, ketchup, and our Pacific sweet and sour sauce.

Around the Web; Autumnal Equinox Edition

Shou-Ching and I would like to extend our thanks to Denny and Aimee Perrin, proprietors of Aimee’s Livin’ Magic, for inviting us to speak to the monthly Locavore Dinner last week. It was a delightful group of people, and Shou-Ching and I had a great time. It was also a lovely setting, looking out over an inlet from the Maine coast. If you ever find yourself passing through York Maine, check out their shop and art gallery at 254 Cider Hill Road (Maine Rte 91).

I’ll be speaking again next Sunday, October 2, to the Living Paleo in Boston group, on the topic “Common Pitfalls of Eating Paleo.” Thanks to Amit and Shilpi Mehta for hosting the event and suggesting the topic.

[1] Music to read by: Andy Williams tries to remember:

[2] Interesting posts this week: Brian Cormack Carr gave a very nice review of our book at Paleo Diet News.

Emily Deans discussed some papers which Jamie Scott found: evidence that gut dysbiosis may be a cause of autism, and proof that serotonin-depleted individuals are more prone to anger and irritability. This last is why anger and irritability are symptoms of brain infections: the immune response in the brain, driven by interferon-gamma and designed to deprive pathogens of tryptophan, dramatically reduces brain serotonin levels.

Speaking of Jamie, he has moved to a new site (, and this week discussed a paper I had been holding for a blog post: proof that plants can be toxic via RNA as well as protein. See Plant RNAs Found in Mammals in The Scientist. (PS: Jamie, you can import your old blog’s content into your new blog.)

Dr. William Davis’s new book Wheat Belly is doing well: it’s #78 on Amazon as I write this. Here is an interview in MacLean’s. I haven’t read the book yet, but Melissa McEwen has.

Some steps forward in the obesity discussion: Peter at Hyperlipid is following up on JS Stanton’s lead regarding mitochondrial dysfunction in obesity. CarbSane chips in with evidence for metabolic diversity among the obese. Stephan Guyenet discusses evidence that humans over-eat and gain weight on a junk food diet.

Dr. John Briffa joins the “Taubes v Guyenet” discussion. He thinks compliance will be a big issue for unrewarding diets. In another post, Dr Briffa makes one of our favorite points: in weight loss, the first key is to never be hungry.

We associate protozoal infections with the tropics, but some protozoal infections are significant health threats in the US, including Toxoplasmosis, Giardiasis, and Babesiosis. LymeMD discusses how Babesia establishes chronic infections.

Beth Mazur finds a great quote from Wendell Berry :

People are fed by the food industry, which pays no attention to health, and are treated by the health industry, which pays no attention to food.

This reminds me of an observation made by Stan the Heretic: if medicine were about patient health, doctors would recommend chocolate rather than statins. Dennis Mangan is also on the chocolate bandwagon.

Yet another study has come out disputing the XMRV – chronic fatigue link.

Bruce Charlton likens the procedure of modern science to a “Texas Sharpshooter”: whatever it hits, is where the bull’s-eye gets painted. But unconventional approaches to science can sometimes prove highly productive. Recently, an advance was made by letting the public solve a puzzle as a communal game.

Kristen Michaelis of Food Renegade has a great rant about the loss of our freedom to produce and consume the food of our choice. Kristen gets a well-deserved Instalanche. Related: Richard Nikoley on how we’ve “advanced” from being socially powerful to socially powerless, and Andrew Badenoch of Evolvify explains that libertarianism – which I suppose could be called the institution of civilization – is non-Paleo; Paleo society did however benefit from the option to choose among competing bands.

Dr. Ron Rosedale discusses the influence of diet upon multiple sclerosis.

Finally, Dr Steve Parker asks, “Why did the cannibal eat the trapeze artist?

[3] Nice hat:

bird image

[4] Cool comments this week:

Daniel on the desirability of maintaining a high dietary choline: folate ratio.

Sweet Feather discussed the risks of high iron levels to those with the common genetic defect of hemochromatosis and how to adapt one’s diet to it.

Shelley’s comment on “ear rock” induced vertigo led me to this NPR video on how to cure vertigo with the “Epley maneuver”.

GeeBee posted photos of her food – quiche and pork pies. I especially liked the quiche.

[5] Saudi Arabians get the strangest diseases: Lemon tree growing in ear syndrome:

Saudi doctors successfully removed a lemon seed stuck inside a woman’s ear for nearly two months, ending fears that the seed could have sprouted, a newspaper in the Gulf kingdom reported on Thursday….

“The seed could have grown and generated branches but the wax in the woman’s ear has prevented fluids from reaching the seed.”

Via Rantburg. Of course, that doesn’t beat the Irishman who died of spontaneous combustion. No word if alcohol or cigarettes were involved.

[6] Shou-Ching’s Photo Art:

[7] Not the weekly video: For your amusement, Chinese bicycle acrobats:

[8] Heavenly bodies: This is the Milky Way above the Himalayas, photo by Anton Jankovoy:

From the Daily Mail via Barry Ritholtz.

[9] Weekly video: From the golden age of cinema, Robert Benchley explains “How to Eat“:

A Paleo Pregnancy Pitfall?

On Saturday’s Around the Web I linked to a study [1] that tied low-carb dieting early in pregnancy to obesity in the child at age 9. This made Ana concerned:

I’m somewhat worried about the pregnancy diet study. Actually I am trying to conceive, 3 months ago my husbund and I changed my diet to Paleo.

Now I see this study and even though I feel great, better than before, I’m not sure, how much credibility would you give it?

I presume that perhaps there could be too little fat, and with that too low calorie intake for a pregnant woman, perhaps that could be the case, opinions please!!!

We certainly don’t want Ana to be stressed out, and it’s hard to turn down three exclamation marks, so I thought I’d interrupt the cancer discussion to address her concerns.

The Study

The study [1] claimed two things:

  1. Women who ate less than a thousand carb calories per day during the early part of pregnancy were more likely to give birth to babies with an overly silenced gene for the Vitamin A receptor RXR-alpha.
  2. Babies born with an overly silenced gene for RXR-alpha were more likely to be overweight at age 9.

Let’s look at the second point, which is more solid, first.

RXR-alpha silencing is associated with obesity

Here is the data:

It looks like it’s normal to have about 50% RXR-alpha methylation in this promoter region and if you have 80% methylation, you’re likely to become a pudgy 9-year old.

How solid is the correlation? They replicated it in a second cohort. Their first study produced two epigenetic marks that were strongly associated with childhood obesity, RXR-alpha and eNOS. A replication study confirmed the RXR-alpha but not the eNOS association.

How plausible is it that RXR-alpha silencing would contribute to obesity? Very plausible, because RXR-alpha is the hub of a network of genes regulating most aspects of metabolism and cell activity.

Vitamin A binds to two types of nuclear receptor, RAR and RXR. When it binds to RXR, a vitamin A – RXR complex is imported into the nucleus. This then looks around for a partner. Partners of RXR-alpha include:

  • Vitamin A – RAR complexes.
  • Vitamin D – VDR (vitamin D receptor) complexes.
  • T3 thyroid hormone – TR (thyroid hormone receptor) complexes.
  • LXR (liver X receptor).
  • CLOCK, the circadian rhythm regulation gene.
  • PPAR-gamma (peroxisome proliferator-activated receptor), a regulator of lipids whose deficiency leads to high cholesterol and hyperglycemia.
  • MyoD, a factor that triggers muscle creation.
  • Many others; a list can be found at Wikipedia.

The vitamin A – RXR-alpha complex “dimerizes” with these other nuclear receptors, forming a new complex that acts as a transcription factor to turn on gene expression. Most of those other partners cannot act to turn on DNA transcription unless they dimerize with RXR.

This means that the absence of RXR-alpha would be functionally equivalent to being low in vitamin A, vitamin D, T3 thyroid hormone, CLOCK, and all those other partners. It is like being born a sun-starved hypothyroid with messed up circadian rhythms who can’t form muscle and is hyperglycemic and dyslipidemic.

All of those things are associated with obesity.

RXR-alpha silencing might be a universal component of the metabolic damage in obesity:

[A]n association between increased RXRA methylation and adiposity is consistent with the observation of strongly diminished RXRA expression in visceral white adipose tissue from obese mice (35).

Personally, I think it’s very likely that silencing of RXR-alpha promotes obesity. This is the most solid part of the paper. They have data, and the mechanism makes sense.

Conclusion: some babies are getting off to a bum start in life due to epigenetic silencing of an important gene.

Does maternal diet affect RXR-alpha silencing?

This is the really weak part of the paper. Here was their data:

When I say this was their data, this was all of it. No scatter plots, no information about how other characteristics of the diet correlate with RXRA methylation, no information about health or lifestyle characteristics of the various carbohydrate intake cohorts so that we can evaluate the possibility of confounding factors.

It is unlikely that low carbohydrate intake was causing the problem. Aside from the fact that dietary carbohydrate intake is only weakly correlated to any factors seen by the baby in the womb (eg blood glucose, insulin, etc), 261 g/day is a substantial amount of carbohydrate – well above physiological needs. So the low-carb quartile included women in glucose deficiency, glucose moderation, and glucose excess; the other quartiles only women in glucose excess. If a glucose deficiency caused RXRA hypermethylation and glucose excess caused RXRA, there would have been a much larger scatter in RXRA methylation levels among the low-carb quartile compared to the 3 higher-carb quartiles. But we can see from the graph that the standard deviations are the same in every quartile.

So there is likely to be some other factor besides carbohydrate intake that was responsible for the RXRA hypermethylation. What are the possibilities?

One possibility alluded to in the paper is that the women had low carbohydrate intake because they were starving. The paper notes that “famine during pregnancy is associated with obesity in the adult offspring (5).” However, I am unaware of recent famines in Southampton UK.

Another possibility is an excess of some other macronutrient. Those mothers who ate fewer carbs were eating more fat and possibly more protein. Given the ubiquity of vegetable oils in modern fats, the increased fat was probably largely omega-6. This raises two possibilities:

  • High maternal omega-6 intake causes RXRA methylation.
  • High maternal protein intake causes RXRA methylation.

Both possibilities have support from studies in rodents: maternal high protein intake and maternal omega-6 fat intake are both associated with obesity in offspring. For more on the risks of high protein, see The Danger of Protein During Pregnancy, Jul 12, 2010.

Another possibility is that the low-carb high-fat diet produced a vitamin A excess. As we discuss in the book, this is a common problem, especially among people taking a multivitamin; probably due to widespread vitamin D and vitamin K2 deficiencies, large numbers of people exhibit evidence of impaired health with vitamin A intake above 10,000 IU/day. As a fat-soluble vitamin, vitamin A intake is more or less proportional to fat intake.

If a balance between vitamin D and vitamin A is needed because the vitamin D-VDR complexes and vitamin A-RXR complexes have to be in proper proportion, then the body may respond to an excess of vitamin A and a deficit of vitamin D by upregulating VDR expression and downregulating RXR expression. Such downregulation may be achieved by RXR-alpha methylation.

Another possibility is some confounding factor that happens to be correlated with carbohydrate intake. In the US Nurses Health Study, nurses with the lowest carbohydrate intake were “rebels” who rejected not only the health advice to eat vegetable-rich and whole-grain rich diets, but also every other standard bit of health advice. The low-carb nurses smoked more, exercised less, and drank more alcohol and more coffee.

So it could be maternal smoking, lack of exercise, or drinking too much alcohol or caffeine that causes RXRA hypermethylation and childhood obesity.

Another possibility, raised in the comments by Amber, is that mothers of the obese children were obese themselves, ate low-carb diets for weight control reasons, and passed on their obesity to their children. It is indeed the case that obese mothers tend to have children who are obesity-prone, and it is suspected that epigenetics may be responsible for this “inherited” obesity. If low-carb diets have indeed become popular among the obese mothers of Southampton UK, then this is a possibility that must be considered.

Low-Carb Paleo Pitfalls?

Should Ana modify her diet because of this study?

I think it’s important to avoid a glucose deficiency. But I don’t think it’s necessary to eat 1,000 calories per day of carbs to achieve that.

I think it’s important to eat a moderate amount of protein, neither too much nor too little; and to limit the amount of omega-6 fats eaten.

I think it’s a good idea to avoid alcohol or excessive consumption of bioactive beverages like coffee during pregnancy. Also to avoid smoking, and to get some exercise and sun exposure.

If you’re doing all these things, I don’t think you need to be concerned. Ana says, “I feel great, better than before”; that’s good evidence that she’s well prepared for a healthy pregnancy.


The paper presents solid evidence that hypermethylation of RXR-alpha in the womb predisposes children to become obese at age 9.

The paper gives us essentially no evidence at all as to what causes hypermethylation of RXR-alpha in the womb, except that it correlates with low carbohydrate consumption in the women of Southampton UK.

I hate it when journals do this. If you’re going to link carb intake to RXRA methylation, give some real data and analysis. Probably the authors are saving their dietary analysis for a future paper. The carb graph was included as a “teaser” to make the work seem more interesting.

There are many known health dangers which are known risk factors for obesity and which correlate with low carbohydrate consumption in the general population. So until more evidence emerges, I think there’s little here for low-carb Paleo dieters to be concerned about.


[1] Godfrey KM et al. Epigenetic gene promoter methylation at birth is associated with child’s later adiposity. Diabetes. 2011 May;60(5):1528-34.