Three Podcasts

I’ve been on several podcasts and radio shows recently, and three shows are now available online. They are:

  • Nourish Balance Thrive with Christopher Kelly. We talked about caring for infants, since our Luke is 5 months old and Christopher has a 15 month old daughter. We also discussed the retreats, the healthfulness of low-carb diets, and other topics.
  • Clarity2Thrive with Ben Lowrey. We talked about the importance of intermittent fasting, why fats are a healthy part of the diet, circadian rhythms and longevity.
  • Live Toxic Free with Debra Lynn Dadd, a prominent green consumer advocate. This is a live radio program serving the Washington DC area, and I was the first guest of the new year. We covered a broad range of topics. For those who prefer reading to listening, Debra has produced a transcript.

Enjoy!

P.S. We still have a few spaces available for the May Perfect Health Retreat. If you are interested, visit here for more info or email me at paul@perfecthealthretreat.com.

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Tuesday Sale: Perfect Health Diet for $0.99

As part of the Buck Books Weight Loss Event, you can buy North American ebook editions (Kindle, Nook, etc) of Perfect Health Diet all day Tuesday for just 99 cents. Link:

If you haven’t yet bought a copy of the book – you should! We never repeat book content on the blog, so even if you’ve read all our blog posts, you’ll find lots of new material in the book.

And the book’s advice produces excellent results. Here is a sampling of recent Amazon reviews (last 6 months) in which readers mention their health results:

  • This diet works really well for me. My energy level has increased.… I also have a more positive relationship with food now…. It is the least restrictive diet I’ve come across. – sdstudent619
  • The diet is working out great – ended up with the lowest triglycerides of my entire adult life for my physical exam bloodwork after only a couple of months! – Dan Chung
  • The foods I crave and love most are central to this healthy way of gaining proper nutrition. Not so strange as it sounds now that I understand the science behind it. – Jo J Pihl
  • I lost over 15lbs – and I was not even trying to lose weight – I was just trying to improve my overall health. Never thought about watching calories through the process. My weight settled into a nice range and has stayed there without effort for months so far. – Gene
  • I have made many changes in my diet based on the recommendations in this book, and I already see positive results, such as clearer thinking. – A. Lee
  • I feel better, have lost weight and believe I’m smarter about what I eat because of this book. – Jberto
  • As a Biologist I DO heartily recommend this book…. Your body will start reacting almost immediately (within days) for the better and at last will be totally satisfied (which is the reason cravings will be eliminated). – Annemieke Akker
  • This book is great. I’ve been on the diet for about two months and have already lost ten pounds, and I feel a lot healthier. – Taylor
  • Lost already 12 pounds in 6 weeks. Simple advice with big impact. – Charlie
  • I have been waiting for this book all my life. I have tried every diet with no success. I knew there had to be a diet that was nourishing but also did not create constant cravings. I have been on this diet for just a few days, but already feel much better and have less cravings. – Healthy pursuit
  • I have been low carb for a couple of years but after the first 40 #s I am just stuck…. After I got the book I started immediately with adding potatoes and rice and lost 2 # this week. – Mary Joe Fant
  • It’s been said before…but it really is the sanest book on health. No exaggeration or gimmicky ideas, just very sound and practical information that completely makes sense. I am rereading for the fourth or fifth time and still having dozens of epiphanies. This is one book I am buying for as many loved ones as I can convince to accept it. I started on zero-carb, lean-meat-and-veg Paleo, and became painfully thin and developed some health problems, and now I have gained weight, but in a good way–I get some compliments on looking toned or, once, to my surprise and delight, like a runner (though I exercise little). And I have fixed several other problems. I am just dying to give this to everyone … I really can’t understand how this book is not the most popular health book in existence. – Mallory Osugi
  • Great info on healthy nutritious eating. My weight gain stopped and I have more than enough energy to exercise. I don’t feel constantly starved or missing smth. – Amazon customer
  • What a good book. I`ve had problems with my body weight for almost 7 years – lost quite a few kilos after a fast and could never regain them back /so I`ve been underweight for all this time/. What`s more, if had a flu and lose lets say half a kilo – I couldn`t get it back. And that has been going on since 2007. Had several lots of medical tests – nothing wrong could be found apart from chronic gastritis (NOT H. pylori). I`ve tried numerous supplements, numerous dietary modifications, gym, gym+calorie counting – probably everything that sounded reasonable/without being stupid:)/- unfortunately nothing worked. I was forcing myself to eat large portions 4-5 times a day just to hear comments from my friends how skinny I was and that I was probably not eating enough (a friend told me ones that if I was kept on going the way I did I would probably disappear at some point in the near future). My energy level was also quite low – something that was never the case before 2007. Anyway – in January this year I dropped down to 60kg /on 176 cm frame/ and at that point I came across the book ‘Perfect health diet’. As soon as i got onto the diet I started putting on about a half a kilo per a week until i reached my perfect weight ~ 74kg/ of course I was going to a gym as well/. My energy level skyrocketed and I was able to do harder workouts compare with when I was a student 16-17 years ago. So in my case – the diet worked and I would highly recommend it (I used Macadamia nut oil as a staple oil – the highest in Monounsaturates and relatively low on saturates( read tons of literature about the saturates – there is still some controversy:)/ and fish as main source of protein /I dont really like meat/. The theory in the book makes pretty good sense – the evolutionary theory, the body needs for Carbs/Proteins/Fat ect. Some of the studies quoted can be questioned but still you can find others on pubmed that back up the theory. Overall – highly recommended book! — Nikolay K.
  • I just wanted to let people know that this is one of the best books ever written and should be taught in schools. It has changed my life for the better and you will see results straight away if you follow it. — Floyd Woolley
  • I’ve lost a fair amount of weight after reading this book and am feeling a lot better as well. – Wilmer (UK)
  • Life Changing!! At last a real understanding of how we Should see food. I’ve lost 14Lbs in 4weeks and my energy levels have improved, the recipes are tasty and would recommend this way of eating to be for life, not just for christmas (or after it). — Mark Barnes-Williams
  • Excellent Athletic Diet. So many Paleo or predominantly health centred diets largely neglect many aspects of diet that are needed for athletic performance, focussing solely on longevity, weight loss and chronic illness. Whilst the PHD covers all these areas extremely well it also tailors its advice for users wanting to compete at a high sporting level and use diet to optimise performance. So far the PHD has done this for me, all my performance based markers have improved and in the last month my bodyweight has increased by 7 lbs. It really is perfect. – Ryan Mounsey

Enjoy, and thank you to all readers who leave Amazon reviews!

Buck Books Promotion: Perfect Health Diet for $0.99

Have you held off on buying our book? Good news: we’re having an ebook sale MondayTuesday!

For 24 hours only, on Tuesday January 20, Perfect Health Diet will be part of a Buck Books Weight Loss Event. You’ll be able to buy our book, and 14 other quality books, for $0.99 in ebook format (including Kindle and Nook).

Here are the books in the event:

Author Book Title
Loren Cordain The Paleo Diet Revised
Paul Jaminet Perfect Health Diet
Jeremy Hendon The World’s Greatest Weight Loss Secret
DaNelle Wolford Have Your Cake and Lose Weight Too!
Jonathan Bailor The Calorie Myth
Nick Loper Treadmill Desk Revolution
Brooks Hollan The Lean Life
Linda Spangle Friends with the Scale
Lynn Manning Fit & Healthy Family
Drew Manning Fit2Fat2Fit
Darya Pino Rose Foodist
Patricia Smith (Alison Golden) Break Free From Emotional Eating
Nate Miyaki The Truth About Carbs
Ari Whitten Forever Fat Loss
Stephen Reed The Lean Fast Diet

 

If all you want is a copy of PHD for $0.99, visit Amazon.com (or other ebook sellers) on Monday to purchase Perfect Health Diet: Regain Health and Lose Weight by Eating the Way You Were Meant to Eat:

If you would like emails from Buck Books telling you when books are available for $1 or less, sign up for the Buck Books Weight Loss Event email list.

 

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

Interested in a luxury vacation combined with an education in how to be healthy for the rest of your life? Science classes, cooking classes, movement and relaxation classes, personal health coaching, gourmet food, all on a magnificent beach, with hot tubs and salt water pools? Come to the Perfect Health Retreat! Spaces are currently 2/3 filled and the retreat is expected to sell out early. Visit here for more info or email me at paul@perfecthealthretreat.com.

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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.