Category Archives: Disease

Neu5gc, Red Meat, and Human Disease: Part I

A number of people asked for comments on the most recent red meat scare, including Nicole, Ryan, and Mishkin on the blog, JT Olds on Twitter, and others on Facebook. You probably saw some of the headlines:

The article Nicole linked is a bit more scientifically inclined: “Possible Link Between Red Meat Consumption And Increased Cancer Risk Identified” (IFL Science). Here’s the press release version from UCSD: “Sugar Molecule Links Red Meat Consumption and Elevated Cancer Risk in Mice”. In the blogosphere, Stephan has summarized the issue in the context of a post on red meat and cancer.

The headlines are based on a paper [01] that reported that, in mice genetically altered to lack a sugar (Neu5gc) that humans also lack, feeding Neu5gc and injecting anti-Neu5gc antibodies generates inflammation which can promote the growth of cancers.

Significance of Neu5gc

The paper itself is a rather artificial scenario whose significance will be determined by future work. So analyzing this single paper would not be interesting. But I think it’s worthwhile to look into the broader idea that eating Neu5gc-bearing meats might be inflammatory or a source of autoimmunity.

In terms of PHD recommendations, this could affect the relative emphasis we place on different meats. If Neu5Gc is a true health risk, then we would want to emphasize seafood more and red meat less.

Another benefit to thinking about Neu5gc is that it may give us some insight into what a PHD “autoimmune protocol” should look like.

Background: Evolutionary History of Neu5gc

All cells in multicellular organisms are coated in carbohydrates, and the carbohydrates terminate in one of 43 sialic acids. In mammals, two forms of predominate: Neu5Ac and Neu5Gc. Each mammalian cell has tens or hundreds of millions of molecules of Neu5Ac and Neu5Gc on its surface. [02]

Neu5Gc is made from Neu5Ac, but the gene for making Neu5Gc was inactivated in the human lineage shortly before the emergence of Homo. The mutation occurred 3.2 million years ago and reached fixation – that is, all ancestral hominids had come to have the mutated gene – 2.9 million years ago. [03] This very rapid fixation indicates there was strong selection in support of the mutation.

In fact, this mutation by itself may have led to a speciation event, after which our ancestors could no longer mate with other apes. From that point on, Neu5gc-less females had difficulty producing children with males who retained the Neu5gc gene, because they would form antibodies against Neu5gc-coated sperm, making fertilization unlikely. [04]

Why was losing Neu5gc selected in our ancestors? Two possibilities are likely:

  • Loss of Neu5gc improved brain function.
  • Loss of Neu5gc (temporarily) reduced vulnerability to (ancestral) pathogens.

It should be noted that Neu5Gc has been lost independently in some other mammals as well – ferrets and new world monkeys. New world monkeys such as capuchins and spider monkeys also experienced a brain expansion, and ferrets are notably smart, so either explanation might be relevant to these cases of “convergent evolution.”

Neu5gc and Brain Function

Carbohydrates are extremely important for intercellular interactions. Indeed, the incorporation of carbohydrates into cell membranes and extracellular matrix is what made possible the rise of multicellular life.

In no organ are intercellular interactions as complex or consequential as in the brain. Not surprisingly, then, carbohydrates including the sialic acids are important to brain function.

The human brain is extraordinarly rich in sialic acids: neural membranes have 20 times more sialic acids than membranes of other human cell types. Animal brains are also enriched in sialic acids relative to their other tissues, but not as much as in humans; the human brain has 2-4 times more sialic acids the brains of other mammals. [05]

Curiously, though, Neu5gc is rare in the brains of all animals. Neu5gc is strongly suppressed, by about 98%, in the brains of all vertebrates, suggesting that its presence inhibits brain function. [06] It appears that Neu5gc is somehow toxic to brain function.

Loss of the gene for Neu5gc completely eliminated Neu5gc from the hominid brain. If Neu5gc does impair brain function, mutational inactivation of Neu5gc would have improved brain function. If so, the mutational inactivation of Neu5gc could have been driven by the same evolutionary forces that, soon after, selected for the tremendous expansion of the hominid brain.

Incidentally, dietary sialic acids — except for Neu5Gc – appear to be nutritious for humans, and especially for the developing infant brain. Breast milk is exceptionally rich in sialic acids, almost all of it Neu5Ac. Formula, by contrast, has much lower levels of sialic acids (0.21 mmol/L compared to 3.72 mmol/L in breast milk). Breast fed infants have nearly twice as many sialic acids in saliva than formula fed infants, confirming that milk sialic acids are taken up by the body and utilized.

Animal studies show that sialic acids in breast milk nourish the brain. Sialic acids facilitate neurotransmission between neurons. When piglet milk is supplemented with sialic acids, brain sialic acid levels are increased, and the piglets learn faster and make fewer mistakes in maze tests. [05] Rodents also perform better on tests of learning and memory after sialic acid supplementation. [07]

Not only does formula have fewer sialic acids than breast milk, cow milk based formulas have some Neu5Gc. [05] It has been observed that formula-fed infants have lower IQs than breast-fed infants. Sialic acids might help explain that. The lack of nourishing Neu5Ac and the presence of toxic Neu5Gc in formula might lastingly impair brain function in formula-fed infants.

Neu5Gc and Infection Risk

As the outermost molecules in the carbohydrate coat surrounding cells, sialic acids are the first contact point for pathogens seeking entry to the cell, and for immune cells seeking to detect whether the cell is native or foreign.

There has been a “Red Queen” evolutionary arms race in which pathogens evolved ways to utilize sialic acids for cell entry, or to hide from the immune system; and animals evolved changes to their sialic acids to frustrate the pathogens. [08]

Many pathogens interact with sialic acids in order to adhere to and gain entry into the cell. Pathogens generally rely on a single specific endocytic route for cell entry. This often requires binding to a specific sialic acid as the initial point of attachment.

Pathogens that specifically utilize Neu5Gc to enter cells include canine and feline parvoviruses [09]; pathogens that specifically utilize Neu5Ac include adeno-associated viruses and the minute virus of mice (MVM) [10].

A human pathogen that uses sialic acids to enter cells is the malaria protozoan. Plasmodium falciparum causes severe disease in humans and enters cells via Neu5Ac; Plasmodium reichenowi causes milder disease in chimpanzees and gorillas and enters cells via Neu5Gc. Plasmodium falciparum appears to have evolved recently – possibly reaching its current form only 10,000 years ago when the rise of agriculture and animal husbandry brought humans and mosquitos into closer proximity – while Plasmodium reichenowi is thought to resemble the ancestral form that would have afflicted hominids and apes 3.5 million years ago.

Possibly, the gene for Neu5Gc was inactivated to protect ancestral hominids from malaria. With the loss of Neu5Gc, hominids would have become immune to P. reichenowi. [11] [12]

Unfortunately, after P. falciparum’s adaptation to Neu5Ac which is overabundant in humans, we now suffer from more severe malaria than chimpanzees or gorillas (the “malignant malaria” mystery). [13]

In addition to entry points for microbes, sialic acids can be entry points for microbial toxins. For example, Shiga toxin from shigatoxigenic E. coli binds to Neu5Gc. [14]

Sialic Acid Concealment and the Gut Microbiome

The immune system is sensitive to the composition of the carbohydrate coat on a cell. White blood cells have a number of sialic acid detectors on their surfaces (called Siglecs, for sialic acid Ig-superfamily lectins). Some, which bind to human sialic acids, inhibit immune responses. Others, which bind to non-human sialic acids, activate immune responses.

Thus, when white blood cells contact a cell bearing human sialic acids, the immune system interprets it as “self” and tamps down immunity. When it detects foreign sialic acids, the immune system treats the cell as “foreign” and is more likely to attack it.

Some microbes – including commensal gut microbes – have been living in humans long enough that they have learned to take up sialic acids, chiefly Neu5Ac, and incorporate them into lipopolysaccharides on their cell membranes. This suppresses immunity toward them. [15]

A number of human pathogens have learned the same trick. Pathogens that incorporate sialic Neu5Ac into their cell membranes for the purpose of mimicking human cells and evading human immune defenses include Escherichia coli K1, Haemophilus influenzae, Pasteurella multocida, Neisseria spp., Campylobacter jejuni and Streptococcus agalactiae. [16]

Due to this “molecular mimickry” of human molecules, it has been suggested that these bacteria – especially Haemophilus influenzae and Neisseria spp. – may be sources of autoimmunity. [17]

While some bacteria can synthesize sialic acids themselves, most obtain it from their environment. These bacteria release enzymes called sialidases to cleave the sialic acids from food in the digestive tract, from surrounding cells, or from mucus. [15] Bacteria can obtain Neu5Ac from human tissue and mucus as well as food, but Neu5Gc only from food, chiefly beef and pork.

Neu5Gc in Human Tissue

Although humans can no longer synthesize Neu5Gc, we still have all the cellular machinery for utilizing it. When dietary Neu5Gc is absorbed into the body and enters cells, it can be incorporated into glycoproteins bound for the cell surface glycocalyx, just as Neu5Ac is.

As a result, Neu5Gc of dietary origin appears at low levels on the surface of human cells.

Neu5gc is found at high levels in all mammals except humans, ferrets, and new world monkeys; birds and reptiles do not produce Neu5Gc at all, and fish and shellfish produce only low levels. So, of the four major meat groups – beef, pork, chicken, and fish – Neu5gc is obtained predominantly from the red meats, beef and pork.

Among human cells, Neu5Gc appears at highest levels on tumor cells, especially metastatic cells. [21] This makes Neu5Gc a potential target for cancer therapy.

Neu5Gc as an Immunogen

Neu5gc expressed on cell walls is a potential immunogen. When pig organs are transplanted to humans, Neu5Gc is the second most important cause of rejection, after the α1,3-galactose (αGal) epitope. [20]

Anti-Neu5gc antibodies have been found in 85% of humans. [18] It is thought that antibodies form in early childhood after dietary Neu5Gc is incorporated by certain gut bacteria into lipooligosaccharides that can generate antibodies. Some of these antibodies may cross-react with compounds human cells form from dietary Neu5Gc; these human molecules are then known as “xeno-autoantigens.” [21]

Summary

Neu5Gc from mammalian meats, such as beef and pork, is incorporated into the cell surface coats and walls of gut microbes and some human cells, mainly in the gut and in tumors. Neu5gc in bacterial walls is immunogenic and 85% of people have detectable antibodies to Neu5Gc. Eating beef and pork supplies antigens for these antibodies, potentially triggering inflammation. There are concerns that this inflammation may have negative health effects.

Next up: Neu5Gc and autoimmunity.

Note: May Perfect Health Retreat

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References

[01] Samraj AN et al. A red meat-derived glycan promotes inflammation and cancer progression. Proc Natl Acad Sci U S A. 2014 Dec 29. pii: 201417508. [Epub ahead of print]. http://pmid.us/25548184.

[02] Kraemer PM. Sialic acid of mammalian cell lines. J Cell Physiol. 1966 Feb;67(1):23-34. http://pmid.us/5327858. Was 21

[03] Hayakawa T, Aki I, Varki A, Satta Y, Takahata N. Fixation of the human-specific CMP-N-acetylneuraminic acid hydroxylase pseudogene and implications of haplotype diversity for human evolution. Genetics. 2006 Feb;172(2):1139-46. http://pmid.us/16272417. Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1456212/. Was 22

[04] Ghaderi D et al. Sexual selection by female immunity against paternal antigens can fix loss of function alleles. Proc Natl Acad Sci U S A. 2011 Oct 25;108(43):17743-8. http://pmid.us/21987817. was 2

[05] Wang B. Molecular mechanism underlying sialic acid as an essential nutrient for brain development and cognition. Adv Nutr. 2012 May 1;3(3):465S-72S. http://pmid.us/22585926. Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3649484/. Was 31

[06] Davies LR, Varki A. Why Is N-Glycolylneuraminic Acid Rare in the Vertebrate Brain? Top Curr Chem. 2013 Mar 8. [Epub ahead of print] http://pmid.us/23471785. was 8

[07] Wang B. Sialic acid is an essential nutrient for brain development and cognition. Annu Rev Nutr. 2009;29:177-222. http://pmid.us/19575597. was 32

[08] Varki A. Colloquium paper: uniquely human evolution of sialic acid genetics and biology. Proc Natl Acad Sci U S A. 2010 May 11;107 Suppl 2:8939-46. http://pmid.us/20445087. was 51

[09] Löfling J et al. Canine and feline parvoviruses preferentially recognize the non-human cell surface sialic acid N-glycolylneuraminic acid. Virology. 2013 May 25;440(1):89-96. http://pmid.us/23497940. was 54

[10] Wu Z et al. Alpha2,3 and alpha2,6 N-linked sialic acids facilitate efficient binding and transduction by adeno-associated virus types 1 and 6. J Virol. 2006 Sep;80(18):9093-103. http://pmid.us/16940521. was 55

[11] Varki A, Gagneux P. Human-specific evolution of sialic acid targets: explaining the malignant malaria mystery? Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14739-40. http://pmid.us/19717444. was 57

[12] Martin MJ et al. Evolution of human-chimpanzee differences in malaria susceptibility: relationship to human genetic loss of N-glycolylneuraminic acid. Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12819-24. http://pmid.us/16126901. was 58

[13] Rich SM et al. The origin of malignant malaria. Proc Natl Acad Sci U S A. 2009 Sep 1;106(35):14902-7. http://pmid.us/19666593/.

[14] Byres E et al. Incorporation of a non-human glycan mediates human susceptibility to a bacterial toxin. Nature. 2008 Dec 4;456(7222):648-52. http://pmid.us/18971931.

[15] Varki A, Gagneux P. Multifarious roles of sialic acids in immunity. Ann N Y Acad Sci. 2012 Apr;1253:16-36. http://pmid.us/22524423. Full text: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3357316/

[16] Severi E, Hood DW, Thomas GH. Sialic acid utilization by bacterial pathogens. Microbiology. 2007 Sep;153(Pt 9):2817-22. http://pmid.us/17768226. Full text: http://mic.sgmjournals.org/content/153/9/2817.long.

[17] Harvey HA, Swords WE, Apicella MA. The mimicry of human glycolipids and glycosphingolipids by the lipooligosaccharides of pathogenic neisseria and haemophilus. J Autoimmun. 2001 May;16(3):257-62. http://pmid.us/11334490.

[18] Zhu A, Hurst R. Anti-N-glycolylneuraminic acid antibodies identified in healthy human serum. Xenotransplantation. 2002 Nov;9(6):376-81. http://pmid.us/12371933.

[19] Takahashi T et al. N-glycolylneuraminic acid on human epithelial cells prevents entry of influenza A viruses that possess N-glycolylneuraminic acid binding ability. J Virol. 2014 Aug;88(15):8445-56. http://pmid.us/24829344.

[20] Park JY et al. α1,3-galactosyltransferase deficiency in germ-free miniature pigs increases N-glycolylneuraminic acids as the xenoantigenic determinant in pig-human xenotransplantation. Cell Reprogram. 2012 Aug;14(4):353-63. http://pmid.us/22775484.

[21] Samraj AN, Läubli H, Varki N, Varki A. Involvement of a non-human sialic Acid in human cancer. Front Oncol. 2014 Feb 19;4:33. http://pmid.us/24600589.

Farewell Mathias

Longtime readers will remember Mathias and Zachary, the unfortunate children suffering from Neurodegeneration with Brain Iron Accumulation, a genetic disorder that leads to horrifically painful spasms beginning in early childhood, and death as a teenager. I wrote about their case in Ketogenic Diet for NBIA (Neurodegeneration with Brain Iron Accumulation), February 22, 2011.

The ketogenic version of PHD had remarkable effects for the NBIA kids. Mathias and another boy who tried the diet, Zachary, regained control their limbs, and the spasms and pain went away. Kindy, Mathias’s mom, wrote in 2011:

Both boys have begun smiling and laughing all the time.

Nothing inspires happiness more surely than the cessation of extreme pain!

My speculation is that a ketogenic (or high-fat) diet helps in NBIA by allowing Coenzyme A, the crucial enzyme which is under-generated in NBIA, to be redistributed from organs like the liver and muscle, where it is manufactured in abundance, to the brain where it is most needed. On a ketogenic or high-fat diet, more CoA is created and it is more often bound in water-soluble forms (such as acetyl-CoA, acetoacetyl-CoA, and HMG-CoA) that can cross cell membranes and enter the brain.

Mathias and Zachary continued to do well on our diet for over three years. Kindy recently wrote:

Zach is actually doing really well.  He is following your diet still (not into the ketogenic range but otherwise following it more or less precisely) …  He is off nearly all of his medicines and is able to do things that he never could in his life.   He is not well – but he is not in pain and has no spasms, and is doing school work etc.

An aside: I’ve been hearing recently from a number of people who experienced great benefits in neurological conditions – NBIA, epilepsy, migraines, and others – following the ketogenic version of our diet, and later transitioned to the regular version of PHD with more carbs and less fat, and continued to maintain all the neurological benefits they had first achieved on the ketogenic diet. Perhaps it was not the ketosis that was crucial, but some other aspect of PHD, such as reduction of inflammation or improved nutrition.

Mathias also was doing very well, until he developed pneumonia last summer. Possibly his genetic mutations disturbed immune function; in any case, the pneumonia led to fatal complications. Kindy wrote:

I want to let you know that on June 23, Mathias died of septic shock.  He went into the hospital 10 days prior with pneumonia and we were packing to go home on the following Friday when he got a sudden fever.  The doctors asked us to stay one more day – his lung x-rays were clear but they were concerned about the fever.

On Saturday, his fever went to 41 degrees Centigrade.  On Sunday, it went to 42 degrees.  Despite every available antibiotic and all other attempts to save him, Mathias died peacefully with a strong heart (153 beats per minute – and breathing on his own).

He was surrounded (even in Intensive Care) by his whole family, plus his aunt, and two of his long time helpers – plus two of his nurses and two doctors.  We thought it would be a few more days and we were all hugging him, and laughing with him and telling him stories.  From one second to the next, his heart stopped.

We choose to believe that Mathias decided – down to the last second – what and how he was going to leave his earthly body.  He had no cramps, no spasms, no pain. He just let go surrounded by love.

We are privileged and honored to have known such a brave, smiling, incredible person.  He did more and affected more people in his 9 years of life than most people do in their entire lives. He was always happy, always smiling – a gift to everyone around him.

Thank you for being part of the forces around his life who helped support him, love him, and provide him with the best life that was possible for him. Thank you from the bottom of our hearts!

Mathias RIP

Farewell Mathias. May you rejoice in God’s kingdom, where all love and all are lovable, and all tears are wiped away. Requiescat in pace.

Update: Attacking Ankylosing Spondylitis with PHD

In January I wrote about Steven Morgan’s recovery from Ankylosing Spondylitis on a modified version of PHD. Steve generously shared his email address and has been trading ideas with other Ankylosing Spondylitis (AS) sufferers.

Steve had a flare of his AS recently after drinking some dirty water on a camping trip, so he has had to re-recover from AS. He recounts his recent experiences here:

Commentary

AS sufferers often see symptoms flare when consuming starch. This may be, as Alan Ebringer has argued for the last 20 years, because the disease is caused by a Klebsiella infection in and around the gut. Infiltration of Klebsiella into lymph nodes around the gut can lead to formation of antibodies that cross-react between Klebsiella lipopolysaccharides and our native HLA-B27 and collagen. These autoantibodies can generate autoimmune attacks on collagen, a characteristic of all the spondyloarthropathic diseases. [1] [2] [3] [4] [5] [6] [7]

Klebsiella is a carbohydrate-metabolizing bacterium; in cell cultures, any carbohydrate – glucose, fructose, galactose, and compound sugars such as sucrose, lactose, and starch – will facilitate Klebsiella growth. This has led Ebringer to advocate a diet low in carbohydrate for AS patients. Since resistant starch is the largest source of carbohydrate fiber in modern diets, that means a low-starch, low-carb, high-protein diet.

The general tendency of PHD is the opposite: we recommend getting about 30% of calories as carbs, and 5/6 of all carb calories from glucose. On a natural whole foods diet, this means that starches are a significant part of the diet.

PHD is generally a gut-friendly, fiber-rich diet. A diverse gut flora is associated with good health, and achieving a diverse gut flora requires a diet rich in carbohydrate fiber including resistant starch from cooked-then-cooled starchy foods.

This raises a tension in many gut diseases:

  • Symptoms flare whenever starches and other foods rich in carbohydrate fiber, such as the FODMAP bearing fruits and vegetables, are eaten.
  • However, there cannot be a full recovery until a complete gut flora has been restored, which requires feeding probiotic bacteria with starches, fruits, and vegetables.

Ebringer’s recommendation of a low-carbohydrate diet is palliative but not necessarily curative. It reduces symptoms, but it doesn’t by itself roll back the infection or bring about growth of a beneficial gut microbiome.

As a temporary therapeutic measure to facilitate a full recovery, I often suggest using dextrose in place of starches as a source of carbs, along with steps to support immunity and development of a probiotic gut flora.

Dextrose is pure glucose. It is rapidly absorbed in the small intestine and therefore is unavailable to gut bacteria. Dextrose can therefore provide enough carbs to support immune function, mucus production, collagen repair, and general good health, without providing any fiber to gut bacteria.

Steps like consumption of liver, sun exposure, intermittent fasting, and circadian rhythm entrainment will further support immune function and aid suppression of the infection that caused the disease.

During this period of low-fiber dieting, eating fermented vegetable juice and other sources of probiotic bacteria can help displace bad bacteria from the gut. As probiotic microbes become more dominant in the gut, normal whole foods can gradually be restored, allowing a probiotic bacterial population to grow in place of the pathogenic bacteria.

Steven has largely followed this plan of attack, with success. It should work for all the spondyloarthropathic diseases including rheumatoid arthritis. I’d love to hear from others who try it.

References

[1] Fielder M et al. Molecular mimicry and ankylosing spondylitis: possible role of a novel sequence in pullulanase of Klebsiella pneumoniae. FEBS Lett. 1995 Aug 7;369(2-3):243-8. http://pmid.us/7649265.

[2] Ebringer A et al. Molecular mimicry: the geographical distribution of immune responses to Klebsiella in ankylosing spondylitis and its relevance to therapy. Clin Rheumatol. 1996 Jan;15 Suppl 1:57-61. http://pmid.us/8835505.

[3] Tani Y et al. Antibodies to Klebsiella, Proteus, and HLA-B27 peptides in Japanese patients with ankylosing spondylitis and rheumatoid arthritis. J Rheumatol. 1997 Jan;24(1):109-14. http://pmid.us/9002020.

[4] Rashid T et al. The potential use of antibacterial peptide antibody indices in the diagnosis of rheumatoid arthritis and ankylosing spondylitis. J Clin Rheumatol. 2006 Feb;12(1):11-6. http://pmid.us/16484874.

[5] Ebringer A et al. A possible link between Crohn’s disease and ankylosing spondylitis via Klebsiella infections. Clin Rheumatol. 2007 Mar;26(3):289-97. http://pmid.us/16941202.

[6] Rashid T, Ebringer A. Ankylosing spondylitis is linked to Klebsiella–the evidence. Clin Rheumatol. 2007 Jun;26(6):858-64. http://pmid.us/17186116.

[7] Rashid T et al. The link between ankylosing spondylitis, Crohn’s disease, Klebsiella, and starch consumption. Clin Dev Immunol. 2013; 2013:872632. http://pmid.us/23781254.

Does PHD Immediately Normalize the Bodyweight Set Point?

The results from the Perfect Health Retreats continue to surprise me.

Retreat attendees come for all sorts of reasons. In terms of weight, they have so far had a fairly similar profile to the general middle-aged population, with almost half being obese and another quarter overweight. That’s enough obese and overweight participants to give us insight into the effects of our advice for weight loss.

Weight Loss Experience at the Perfect Health Retreat

When I was preparing my Ancestral Health Symposium talk on weight loss, I noticed a remarkable pattern that I didn’t have time to discuss in my talk. The pattern was that the amount of weight loss during retreats was proportional to the excess weight of the participants.

Here are some charts, with the amount of weight loss during the retreat plotted against BMI. From our 2013 retreats, which lasted 30 days, I’ve plotted just the obese participants:

01 Weight Change During 2013 PH Retreats

And from our May 2014 retreat, which lasted two weeks, I’ve plotted the obese and overweight participants:

02 Weight Change During 2014 May PH Retreat

You can see that the amount of weight lost in this short period is roughly proportional to starting BMI. It tracks remarkably closely to a straight line. I’ve put the equations for the lines underneath each figure.

If weight loss follows these straight lines, then you can easily envision what would happen to someone with a high starting BMI, say 50, who lived at the retreat permanently. He would lose weight rapidly at first. As his weight (and BMI) declined, his rate of weight loss would slow, tracking the line. As he approached a destination BMI in the 20-29 range, his rate of weight loss would approach zero. His weight would stabilize at this destination BMI.

(Parenthetically, let me comment on a few features of the charted data. First, it doesn’t surprise me that the destination BMI in the 2013 retreats was higher than that in the 2014 retreats; our program was still under development in 2013, the retreats are much more optimized now; for example, the 2013 retreats were held in a rather dimly lit facility with few windows, yet we know that circadian rhythm entrainment is huge for weight loss. Second, it doesn’t surprise me that the 2014 data is noisier than the 2013 data; the shorter retreat means that other factors, such as jet lag from traveling to the retreat, influence outcomes more significantly; also, in May 2014 we didn’t weigh anyone at the retreat so weights were self-reported from home by guests, making the weights not as reflective of the retreat environment and the time between weighings somewhat variable. Third, it doesn’t surprise me that the rate of weight loss at the 2014 retreat was slower than at the 2013 retreat; 2014 retreat participants were explicitly encouraged not to restrict calories, and wine, snacks, and desserts were served daily, whereas in 2013 the proprietor encouraged some calorie restriction and did not serve alcohol.)

The destination BMIs – the weights at which the fitted lines indicate weight loss would stop – are remarkably close to normal weight.

Implications for a Body Weight “Set Point”

Obesity researchers have found the concept of a body weight “set point” to be useful in explaining obesity. However, they generally find that the “set point” is well above normal weight, even after weight loss interventions.

Our Perfect Health Retreat weight loss experiences are consistent with the existence of a set point. However, Retreat experiences are best understood as telling us that:

  1. The body has a desired weight – a set point – that weight inexorably migrates toward.
  2. The pressure or force driving weight change, as indicated by the rate of weight change, is proportional to the deviation of actual weight from the set point. A larger deviation from the set point creates a greater pressure for weight change and a more rapid migration toward the set point. As the set point is approached, the rate of weight change slows down.
  3. In the context of our retreats, in which people follow the Perfect Health diet and lifestyle, the set point is reset to a normal weight within a few days of their arrival at the retreat.

If PHD does indeed reset the set point to normal in a few days, it is consistent with the theme of my Ancestral Health Symposium talk: it is diet and lifestyle that determine weight; fix those and your weight will inexorably normalize.

But this conclusion is radically contrary to the beliefs of academic obesity researchers. The general view is that changing the set point is extremely difficult, in part because the determinants of the set point extend back in time many decades:

Your heredity and your environment-starting back at the moment of your conception-determine your set point. Over the long term, excess food and insufficient exercise will override your body’s natural tendency to stay at its set point and lead to a higher, less healthy set point.

This implies that normalizing the set point will also require years or decades, because that is how long it takes for the influence of past set-point-raising factors to expire.

The Center for the Study of Nutrition Medicine, led by the distinguished obesity researcher George Blackburn, advises that one can’t sustainably lose more than 10% of body weight in six months:

Scientific evidence supports losing no more than 10% of your body weight at a time. It turns out that the body’s set point and its many regulatory hormones dictate the effectiveness of the 10% loss. That’s the amount of weight you can lose before your body starts to fight back. Many clinical studies have confirmed this phenomenon. Of course, some people can lose more than 10% at a time, but precious few can then maintain that loss.

After you maintain your new, lower weight for 6 months, you can repeat the cycle and reset your set point again by losing another 10%.

Is Dr. Blackburn’s conclusion, confirmed by “many clinical studies,” valid for PHDers? To test that, we need a longer time series.

The largest weight losses at the Perfect Health Retreat have been about 10% of body weight in 30 days. If Dr. Blackburn is right, then after people on PHD lose 10% of the body weight – i.e., after one or two months on PHD – then we should see weight loss stall or enter a yo-yo pattern for the remainder of six months, until the set point adjusts lower and weight loss can resume.

Alternatively, if PHD immediately and permanently resets the set point to a normal weight, the rate of weight loss in PHDers should track a straight line just like in the retreat data. We should see continuous weight loss with no stalls – although there will be a steady slowing of weight loss as a normal weight is approached. In the long run, weight is normalized permanently, and there is no weight regain as long as the person remains on PHD.

Which is it?

The long-term pattern of weight loss on PHD

Fortunately we have a few cases in which PHD readers have faithfully followed our advice, tracked their weight closely, and shared the data with us.

Before I discuss their weight loss experiences, let me describe the weight loss path we would expect to see if the pattern observed at the retreats holds up. The weight loss pattern observed at the retreats is described in a simple equation:

06 weight loss formula 1
Here w is body weight, sp is set point, τ is a characteristic time for weight loss, and Δw is the change in weight achieved in a retreat of length Δt.

Those of you who took calculus will recognize that as a differential equation which we can integrate. It leads to the following formula for weight as a function of time:

07 weight loss formula 2
Here e is a mathematical constant that is about 2.718. This is the formula for what is called an “exponential decay.” Weight starts at w(0), the weight at time zero, and it decays steadily toward the target weight, sp. The characteristic time, τ, is the time needed to progress 63.2% of the way toward sp.

So if PHD is really re-setting the set point to a normal weight within a few days, after which the set point doesn’t change — it just stays at the same weight, normal — then we should see weight loss follow this exponential decay.

OK, now let me get to cases.

The case of Jay Wright

Previously on this site we discussed Jay Wright’s weight loss journey. Here is his weight in blue, and I’ve fitted an exponential decay to it in red:

05 Jay Wright Weight History after starting PHD

It’s a pretty good fit with a set point of 151 pounds and a characteristic time of 146 days.

Jay’s weight loss took place in 2011. In several years since then, his weight has remained stable around 170 pounds. I believe Jay’s height is 5’10”, so his BMI at 170 pounds is 24.4 and his BMI at the fitted target weight of 151 pounds would have been 21.7.

As you can see by reading Jay’s story, during his period of weight loss he was intentionally restricting calories to 1200 calories per day; but when he got to his goal weight of 170-175 pounds he stopped restricting calories and ate to appetite. I’ll speculate that intentional calorie restriction may lower the set point by a few BMI points, say from 24.4 to 21.7, so that Jay’s “set point” during his weight loss period was 151 pounds but it reverted to 170 pounds once he began eating ad libitum.

The case of Isaac Knoflicek

Our second case was posted by Isaac Knoflicek on the PHD Facebook group a few weeks ago. Here was his weight loss chart. He described it this way:

~110 lost, first chunk was bike commuting, then after about a year of that I started PHD and the weight came off like crazy.

Isaac gave me his weight loss data. Here is what happened after he began PHD:

04 Isaac Knoflicek Weight Loss History after starting PHD

As you can see, it’s a great fit to an exponential decay – an even better fit than in Jay’s case.

Isaac is 6’3” (190.5 cm) tall, so the target weight of 191 pounds is a BMI of 23.9 – absolutely normal.

Although Isaac’s data ended in early 2013, he wrote, “I’ve spent the last year and a half making smaller tweaks but generally staying around the same weight.” That’s consistent with him having gotten close to his target weight; and with his set point having been permanently reset to a normal weight, so that there is no biological pressure for weight regain.

Here are Isaac’s before and after photos:
08 IsaacKnoflicek before09 Isaac Knoflicek after

Implications

Every obese person who has come to our retreats has lost weight (save one whose weight was unchanged), and in most cases weight loss tracked closely to the same pattern for all participants: a linear relationship between weight loss rate and starting BMI. The line reaches a zero weight loss rate near a normal BMI.

The implication is that for nearly all retreat participants, PHD actually fixes all the factors of overweight or obesity and leads to a normalization of the body weight set point. Although our experience at the retreats is still limited, the statistics are good enough to infer that PHD should work for most, if not all, non-diabetic obese people.

Another implication is that it’s possible to normalize set point in just a few days. If set point wasn’t normalized in a few days, weight loss rates over a 14-day retreat could not track a straight line.

Very likely, the reason the set point has appeared persistently high to academic researchers is that the weight loss approaches they have studied don’t actually address most factors in obesity. My Ancestral Health Symposium talk explains that weight is set by a multifactorial process and if multiple obesogenic factors are left uncorrected, the set point will remain elevated.

A third implication is that there is a characteristic physiological time for weight loss, and it may not be possible to accelerate weight loss much. The fastest rate of weight loss we observe is about 4 months to move 63% of the way toward normal weight from current weight. Based on rates of weight loss at the retreats, 6 to 8 months is more typical.

Fourth, it’s not obvious that calorie restriction is either necessary or desirable for long-term weight loss. If all calorie restriction does is temporarily lower the set point by a few BMI points, without affecting the characteristic time for weight loss τ, then calorie restriction may have little effect on either the ultimate weight or on how long it takes to reach it. Calorie restriction may be an energy-sapping, misery-inducing tactic that succeeds only in reducing weight slightly for a few months, with no long-term benefit. And it may have health risks.

Finally, the “last ten pounds problem” has produced a lot of angst. People often lose weight successfully to a weight about 10 pounds above their personal target, then find it extremely difficult to lose the last 10 pounds. We can now see why the last ten pounds can be so hard to lose. First, any minor defect in diet or lifestyle may raise the set point slightly. Second, weight generally rises with age, and people may use their younger weights as targets; so they may be underestimating their body’s physiological weight target. But mainly, it may just be that weight loss becomes very slow once you are within ten pounds of the set point. At 10 pounds above the set point, it takes 6 months to lose 6 pounds, even if you do everything perfectly. That’s only 1 pound per month. From 4 pounds above the set point, it takes 6 months to lose another 2.4 pounds – only 0.4 pounds per month. Then the pace of weight loss slows further. Once the rate of weight change slows to 0.1 pounds per week or less, it will appear to have gone to zero.

Conclusion

To convince skeptics, we will need more data. But I’m going to jump directly to these conclusions:

  • For most people, PHD (including both diet and lifestyle practices) will cure obesity – in the sense of normalizing body weight set point – in a few days.
  • Although the set point is normalized almost immediately, weight loss takes time. Even if you do everything perfectly, it takes about 6 months to shed 63% of excess weight, a year to lose 86%, 18 months to lose 95%, and 2 years to lose 98%. The last few pounds take a long time to go away.

Curious if I’m right? If you are overweight and would like to test this personally, come to our retreats and help us generate more data.

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