Speculation on how innocuous proteins become the targets of our immune systems, and result in allergies, asthma, celiac, arthritis, lupus, and other inflammatory autoimmune diseases.
Inflammation
It all starts with chronic inflammation. In most cases diet is the predominant source of inflammation, but infections (bacterial, viral, fungal) may also contribute. Inflammation sets the stage for faulty processing of proteins at the focal location where lymphocytes and antigen-presenting cells are congregating.
Antigen Presentation
At this point a major mistake occurs. Cells that have been alerted to danger by inflammatory cytokines, start to internalize and process proteins in the vicinity, so that peptide fragments of the “antigens” can be displayed on their surfaces in the clutches of major histocompatibility complex proteins. The problem arises when self proteins are internalized, processed and displayed as candidate peptides.
Basic Triplets of All Allergens and Autoantigens
I have looked at dozens of allergens and autoantigens, and they all have one peptide sequence in common, a triplet of basic amino acids. The impetus for this article was finding this morning that one of the autoantigens for Hashimori’s thyroiditis is thyroglobulin, the serum carrier of thyroid hormones. I checked the sequence of thyroglobulin and it has two of the rare basic triplets.
Thyroiditis Autoantigen Is Thyroglobulin
I checked the Pubmed literature to see if thyroglobulin is naturally taken up by cells, since I have been trying to figure out the receptor for basic triplets. What I found was an article on the binding of thyroiditis autoantigens to mannose receptor. The idea of the paper was that the autoantigens in this case were heavily glycosylated and maybe the mannose receptor that is involved in antigen presentation of glycosylated antigens, would bind the selected autoantigens as well. I didn’t get much past the title of the paper.
Candidates for Allergen/Autoantigen Receptor
What I put together was the fact that antigen presenting cells use mannose receptor to internalize antigens. This places this receptor in the right place and the right time to be a receptor for basic triplets. But what would a basic triple binding protein domain look like and could mannose receptor be a candidate?
Structure of Thyroglobulin
I downloaded a structure for mannose receptor and began looking for a surface region that would bind carbohydrates, aromatics and basic amino acids. The critical amino acids in all of these cases are aromatic amino acids, phenylalanine, tyrosine and tryptophan. Tryptophan is at the heart of most carbohydrate binding proteins. Since the mannose receptor is a member of the carbohydrate-binding lectins, I expected to find tryptophans on the surface of the mannose receptor. I just looked for the tryptophan that binds the carbohydrates. It was exactly as I predicted. The mannose receptor should be able to form very stable tryptophan/arginine-like ladders with basic triplets.
I made a figure of the mannose receptor bound to a carbohydrate (red and grey). One of the exposed tryptophans (yellow) is bound to the carbohydrate. Several other tryptophans could be exposed and oriented toward a basic amino acid spread over the surface of the tryptophan in place of the carbohydrate. A similar kind of structure is used by importin to transport proteins with nuclear localization sites (NLS, basic quartets) into the nucleus. Many proteins with NLSs are also autoantigens, e.g. lupus.I think that the peculiar circumstances that lead to allergy and autoimmunity result in the binding of self-proteins or allergens to mannose receptor and result in antibody production.
Why the Mannose Receptor?
Why does the mannose receptor make mistakes? The exposed tryptophan may also bind numerous plant products. In fact, the phytochemicals, e.g. alkaloids, flavonoids and terpenoids, are an abundant and varied group of chemicals that would bind to the exposed tryptophan of the mannose receptor and compete for binding with basic triplets. Protection offered by plant “anti-oxidants” may be due in part to this activity.
27 comments:
"In fact, the phytochemicals, e.g. alkaloids, flavonoids and terpenoids, are an abundant and varied group of chemicals that would bind to the exposed tryptophan of the mannose receptor and compete for binding with basic triplets. Protection offered by plant “anti-oxidants” may be due in part to this activity."
In other words - chocolate, coffee, tea? - All my favorites (sigh)
But I think that it is good in this case. The phytochemicals would block the presentation of self-antigens and prevent autoimmunity. It may be that people with autoimmunity and allergies were at some time devoid of sufficient phytochemicals in their diet during and also subjected to inflammation.
It is too early to do more than just present some obvious implications of the hypothesis.
Hi Dr. Ayers,
Thank you for discussing yet another WONDERFUL topic (that's been on my mind!)
MBLs... Thoughts? mannose-binding lectins? My immuno text is out of date but it does say we make these.
What about fructose-binding lectins? Is this why fruit (excessive) may trigger hibernation in bears and other animals? Combined with other triggers that indicate bountiful food and environmental fecundity (like omega-6 in nuts seeds and excessive berries... incl borage primrose hemp etc)??
-G
G,
If this topic has been on your mind, you are my kind of people! Alas, few think of causes.
Most lectins are dumb. They just bind oligosaccharides. These are the typical plant lectins found conspicuously in legume seeds.
Other lectins are membrane proteins that bind to very specific oligosaccharides. Note that if they bind to a glycosyl (sugar) residue that is linked to other sugars, i.e. an oligosaccharide, such as the blood group antigens, then they won't bind to the single sugar, because once the sugar is bound through its reducing group, it no longer has the same recognizable shape. Thus, the "mannose" receptor should be called a "mannosyl" receptor, because it binds to mannosyl units in oligosaccharides and not to mannose.
From my perspective, I would not expect there to be fructose lectins, that would bind fructose and I don't know about fructosides, oligosaccharides with fructosyl units at the non-reducing end. There are fructans made from the fructose in sucrose, but I don't think humans make any enzymes that bind them, because they are part of dental plaques, for example.
I think that the mannose lectins in your text were the mannose receptors. After the seed lectins were discovered, it was thought that lectins only existed in plants. Then it was found that removing the terminal sugars from glycoproteins caused them to bind to surface receptors, i.e. lectins.
It is strange for you to be juxtaposing omega-6 oils and fructose, that are inflammatory with hibernation that must be inherently anti-inflammatory. Am I thinking in primate and not mammalian terms? Do bears need salmon to quench their inflammation before retiring?
Thanks for your comments, especially on what may be esoteric to many.
Dr. Ayers,
You are too funny -- thank you for your patience...I question too many things! I told Dr. Davis a few months ago when I had the luck to come across your blog (I think via Chris Highcock of ConditioningResearch.com, bless his beautiful soul) that I was going to quit b-l-o-g-g-i-n-g. OK... I was j/k... but you impressively know your drug-ceuticals and even better know your nutra-ceuticals (proanthrocyandins, flavonoids, spics and carotenoids) and anti-inflammatory diets.
MBLs have been on my thoughts because they are related to immune defenses and vascular diseases, much like Lp(a) another extension of our immune system which is highly HIGHLY related to CAD in the great majority of our trackyourplaque.com members. Both Lp(a) and MBLs act in place of complement/fibrinogen (and opposite heparin's actions???) to assist when vitamins are low. For Lp(a), vitamin C and E and for MBLs...?? vitamin A and D...?? I dunno yet.
You mention antigen presentation in this post. Microbes (viral, bacteria, mycobacterial, etc) have mannose as well as fructose on their outer surfaces (LPS, etc). Perhaps our primitive innate immunity developed 'stupid' lectins to neutralize and negate microbes? Perhaps, take it even further since there is a master purpose for all things in life (I truly believe)... what if Nature even jimmy-rigged lectins to neutralize thyroid glands and other glands in order to support hibernation, weight gain, and insulin resistance? Fat storage prior to harsh cruel winters was essential for survival just as the skill-to-kill for predators at the top of the food pyramid determines survival. At Yellowstone (which my family and I just visited), we learned a little known fact that the grizzlies subsist on moth grubs (high in vit D and omega-3s) prior to the stark Idaho/ Wyoming/ Montana winters. You'd think that they obtained omega-3s from all the great trout but I think the native cutthroat-trout are being diminished by non-native fish. No chestnuts, berries or nuts in Yellowstone either... just elk, bison and deer babies and infirm prey but they have to share with other predators (wolves, coyotes, etc).
I concur with you -- bears definitely need a lot of omega-3s to counter the pro-inflammatory induction of hibernation. Perhaps this may be why polar bears and Alaskan bears survive better than inland onces? More access to omega-3 sources (seal blubber, salmon, etc)??? Animals which mate only annually are very interesting to me (like ??humans?).
Different polymorphisms of MBL genes are related to a variety of autoimmune diseases (Sjogren, SLE, etc) and diff variants are associated with even less HIV vertical transmission with vitamin A supplementation (cool, eh?). Like Lp(a), higher MBL concentrations are more often associated also with certain vascular complications in Type 1 diabetes.
I'm certain fructose is related -- what biochem changes are nec to go from mannosyl to fructose/fructosyl?? Fructose has a very special place in human metabolism -- it completely bypasses our insulin pathways initially (until a single carbon-chemical change converts fructose to glucose). Why?
*heee* What's the purpose of mannosyl receptors? It's heparin related I bet...right?
-G
Art, I have a little bit of a puzzle for you. A little over a year ago, I was bitten on both arms by some type of insect (not sure what type)-- a pimple like lesion was the result- which inflammation extending out about an inch radius (of course the pimple like lesion remained small but looked like a boil.
Just about 5 days ago- i was seemingly bitten by the same type of insect and this time over the course of 3 days had inflammation around the wound that had a 4 inch radius-- prompting my doctor to give me antibiotics-
Is it possible that because i'm been following an anti-inflammatory diet -- low in grains, low in polyunsaturated fat, low in fructose-- and high in animal fats that my body could just not form a good enough response to quench the infection before it really got worse?
Is there anyway we can boost our immune system while on your type of eating pattern? I already take 1000 mg of vitamin c a day.
I'm worried because I think I've seen you before say that an anti-inflammatory diet opens the doors a bit for infection-- I would really hope that i wouldn't get taken out by a little bug.... but then again, why is it that my immune system responded so strongly to the bite in the first place (even on high fat diet which seems to turn down my immune response)-- especially because my body's response was def greater than last years. Can you desensitize or normalize your bodies response to these types of things. Do we need to beef up the immune system of this diet? Because I can tell you, my immune system was way more active before high fat.
thanks for your great blog.
Aaron,
I cover a lot of ground and play with concepts, unfortunately it can get pretty confusing. We are dealing with some of the most complex systems that I have ever attempted to integrate. Medicine handles them unsuccessfully and I try to do better.
I talk about inflammation on several different levels. Inflammation is an adaptation for the defense of a group of cells, tissue, against infecting bacteria. The tissue can do a little to attack the bacteria, but the big immunological guns all get off loaded from the blood vessels that penetrate the tissue.
The crux of defense is molecular recognition of the pathogen. That means that molecules on the surface of individual cells in contact with the pathogen have to specifically bind and change shape to pass a signal into the cells to trigger the danger signal -- activation of NFkB. When NFkB is activated, five dozen new genes are expressed and inflammatory signal molecules, e.g. IL-1, IL-6, TNF, spread the danger signal to adjacent cells, open up the blood vessels to offload lymphocytes and neutrophyls, and inflammation is observed.
This is a local response. With the wrong diet, this inflammatory signally can happen in tissue/organs throughout the body and chronic, systemic inflammation occurs.
Inflammation is a process that proceeds through recover to reach the starting, uninflamed state again. The goal is to optimize inflammatory signaling to involve only the minimum amount of tissue needed to stop the infection. Involving more tissue is wasteful and shortens life expectancy.
Chronic inflammation means that with each local infection, there is a tendency to involve more tissue, because recovery is attenuated and infections spread. This may mean that pathogens are more safely handled or it may mean that pathogens that manipulate inflammation to damage tissue and block some immune systems, may promote infections.
The bottom line, is that I have no idea what is happening with your insect bites. I assume that your doctor excluded possible spider and tick-borne diseases. I personally have been treating any such bites ASAP with either campho phenique (phenol/camphor) or Vicks Vaporub (mentho/thymol/eukalypto/camphor/terpentine). Those are penetrating anti-microbial and anti-inflammatory.
I don't think that the size of the inflamed area is an indication of the effectiveness of your immune system and I wouldn't expect that you would become more susceptible to infections unless you severely overdo the typical recommendations. It is hard to get to immunosuppression with the kinds of supplements that I recommend. In most cases, they just remove the problems of chronic inflammation and stop compromising the immune system. I don't understand most of the claims to stimulate the immune system. That usually just means counterproductive systemic inflammation.
I don't encourage what I would call a high fat diet, but if you don't get your energy from carbs, then that does mean more fats coming into the diet via meats. More exercise throughout the day means that more carbs can be eaten without inflammatory results, because the blood sugar will not be elevated or require insulin production.
I hope this addressed your questions. If not, just keep asking.
Dear Dr.Ayers
I have been following your blog with interest and recommending it to my friends. I find it very informative. What is your views on immunization and childhood diseases in regards to allergy and autoimmunity.
I am currently living in England and I am surprised how common is allergy and extensive immunization programme on kids. I wonder about any correlation. Where i came from, during my childhood the kids were encouraged(!!!)to catch the common diseases by families getting their children in touch with sick kids. Chickenpox, measles, mumps, rubella, whooping cough were so common in kids at that time and government immunization programme were so poor. In my opinion kids that went through this diseases without any problem grow and become healthier adults with much less allergies and stronger immunity. I would like to thank you again for creating this blog and sharing your views with us.
Suat,
Immunization is a complex subject, especially in my case. My background is similar to yours, I had the typically spread versions of most of the infectious diseases as a kid and was only immunized for polio, tetanus and small pox.
We homeschooled our three daughters into college, and I was opposed to immunizations, because in most cases the immunizations didn't provide the claimed protection, e.g. whooping cough epidemics occurred in immunized populations, or caused more morbidity than the diseases. I also objected to what I thought was profiteering in the immunization contracts.
My daughters only got immunizations against the protein toxins, e.g. tetanus, diphtheria, unless the local schools required specific immunizations to participate in sports or orchestra. Then we were going to spend a sabbatical in Singapore and travel in Malaysia and Indonesia. To get back into the US after traveling, we were required to get a major upgrade in immunizations. By that time the youngest girl was six, so it wasn't quite as threatening.
Hygiene and diet have been more effective against most infectious diseases than immunizations, in my opinion. Diet is also responsible for the compromised immune systems and chronic inflammation that results in most diseases in the US and UK. I don't think that immunizations have been a major contributor to most illness today, but they have eliminated most of the immunity that is normally transmitted by mothers to babies.
Thanks for the comments.
Thanks for the response!
The doctors did not rule out anything. In fact, they said that if I didn't see what bit me, they wouldn't be able to tell. I didn't ask for them to send blood to someone who would.
I live in a garden unit-- so spiders are a problem-- but they are very small (I do my best to clear them)-- I am also located in chicago, outside the range of recluse spiders-- but not wolf spiders!
I've heard of itch mites biting in august and september when they fall from trees (also a problem in northeastern illinois-- also, I'd heard cases of herpes on arms that look similar-- but the doctor said nothing of this.
I like your suggestion to put some type of anti-microbial right away-- I don't know why this logic escaped me-- I wonder if aloe str from the plant is also a good treatment.
I'm wondering what you mean by "I don't encourage what I would call a high fat diet"
does that mean you think its more beneficial to eat low anti-nutrient carb foods such as potatoes and fermented non-gluten grain carbohydrates (similar to kitavans?)
to my knowledge you don't have problems with fats and proteins in meat vs carbohydrate foods, correct?
Normally i usually eat a little fermented yogurt in morning. Then a grass fed burger and salad for lunch (with olive oil)+ small fruit. And then usually fish/chicken/steak for dinner with greens and a sweet potato+ small fruit.
Aaron,
I am compelled to quibble over the little details, because the carbs are in the details and inflammation is in the carbs/blood sugar.
Your diet sounds wholesome (potentially low carb, but not high fat), but if you let the food processors construct something with the same names, it could be deadly, so I quibble.
The yogurt is great, as long as it is not sweetened (the processors would love to load it up with high fructose corn syrup). Even fruit can provide too much fructose, so I think of fruit for flavoring and not for sweetening. The saying should be eat plenty of "--- and vegetables." I don't consider fruits to be healthy.
Then comes the "burger". I hope that you mean bunless. The buns and bread are usually empty calories. Actually they are hyperglycemic blood sugar additives. So meat on a salad with peppery olive oil and vinegar and plenty of herbs and spices sounds healthy.
Then the sweet potato and fruit. Minimize. Leafy vegetables are better and to make anything with starch safer for your body, it is best to keep it al dente-- minimal cooking to make the starch less available to contribute more slowly to blood sugar. I think that we should all eat like diabetics and worry about our blood sugar -- it should be uniformly minimal without peaks and valleys after meals. I don't recommend potatoes, because of the high starch and some people (Stephen) avoid the alkaloids (but maybe they block immunogen presentation in autoimmunity.)
I think that it is also healthy to explore a wide variety and eat ample amounts of spices and herbs.
I think that Aloe is anti-inflammatory because of mannans. If I were you, I would apply Vicks if there is any redness. You were probably responding to a venom and all is done by now. I would also hunt down the single spider that has made a meal of you. Perhaps it has already moved on.
Trust me-- it has been it a spider slaughterhouse in my place :)
I made assumptions that most paleo people would when I wrote down a rough est. of my diet.
of course, no beef with bread (it would usually be on a salad with olive oil and vinegar)
only a little fructose fruit
no added sugar greek yogurt <--- for some reason I tolerate this much better than even regular yogurt or kefir
I would assume the best diet would be the one that maintains the integrity of our dna the best-- and minimizes glycation reactions.
Is it possible that a high fat intake could cause more damage over time in the body by increasing the amount of mitochondria we have -- and therefore, there is more damage from the byproducts of metabolism (I've seen studies that show increased lifespan in rodents from increasing uncoupling proteins-- thereby sparing the body from beta oxidation of fats. I am also making the assumption that the storage and use of glycogen from carbs does not have as many damaging byproducts-- if insulin is not raised much.
any comments on this? maybe this is why you can actually get by on a higher carb diet. IF insulin is kept low and you really never over eat.
I've seen people on almost all fat and protein diet-- and they just seem to show signs of faster aging-- just think of the inuit.
But at the same time-- I've seen studies that show our body has better antioxidant capacity when we lower veggie consumption!! makes me wonder about plant chemical too!
Aaron,
You have touched on most of metabolism.
The mitochondrial involvement in oxidation stress, aging and apoptosis is interesting. The problem seems to me to arise from handling the high energy electrons typically derived from the NADH+ of glycolysis or from the TCA cycle in the mitochondria. The energy is used to make ATP in the electron transport chain in the inner membrane of the mitochondria. The depleted electrons are dumped onto oxygen to make water. The problem comes from disrupted flow of electrons through the ETC and accumulation of intermediates (depleted by uncouplers) that contribute their electrons inappropriately to other molecules and generate reactive oxygen species (ROS). Glutathione and vitamin C can be used to stop ROS and oxidative stress.
A high intracellular glucose concentration can contribute to this problem and that is one reason to avoid high blood sugar. Fatty acids can also contribute to the problem by revving up beta elimination and the ETC from their entry into the TCA cycle.
Most plant "anti-oxidants" don't get out of the stomach, but may alter gut flora and trigger uric acid increase in the blood and hence provide an increase in system-wide anti-oxidants. Phytochemicals may be involved in complex signaling in the gut.
Storage and mobilization of glycogen is important in regulating blood sugar. Problems may arise in the signaling needed to control blood sugar in all of these cases.
My gut feeling is that if we just get our diets within a broad general range and away from the more typical extremes, then metabolism is robust enough to keep us healthy. One indication that we are at an extreme, is that we are unstable, i.e. unhealthy. Thus, getting sick or showing signs of aging are an indication of a dietary problem. Unfortunately, sickness for the medical industry is a time to rejoice and invoke medication and treatments for the symptoms while leaving the cause unexamined.
Thanks for the stimulating comments. I hope that I addressed at least most of them.
Hello again and thanks for the reply Dr.Ayers.
I would like to ask one more question. I mentioned you about my background, one of the other thing was( actually still is ! comparing the Europe/Japan/US/Australia) the high rate of infant mortality. Could that be the reason for the lower autoimmune diseases and allergies in my country comparing the above mentioned countries. With very little access to health service(it was available for the priveleged and rich) it was sort of a natural selection for us. It was not unusual for the parents to loose baby before they reach second years of their life. I believe that the ones with stronger immunity had much more chance of making through whereas in developed countries everybody had the chance because of the great healthcare.
I would be very happy to hear your opinion.
Thanks in advance
Suat,
I think that the high infant mortality in the US comes from poverty, diet and medicine.
The US has a large population that receives poor prenatal care because of poverty. This population is also low on essential nutrients, i.e. omega-3 oils needed to avoid preeclampsia. Low income diets are highly inflammatory, i.e. high carbs and vegetable oils, whereas in other countries the cheap diets may be locally produced vegetables and grass-fed poultry or fish.
The US has a high level of diet-based inflammation, which lowers fertility and produces a high incidence of pregnancy and infancy disorders. The overuse of obstetricians, instead of midwives, also leads to excessive high risk interventions, e.g. inductions, pitocin, Cesarean sections. The result is a high rate of pregnancy complications, low birth weights/prematurity, and compromised infants. Low rates of sustained exclusive breastfeeding further contribute to unhealthy babies and toddlers. Availability and use of formula results in inflammation and elevated infant mortality.
Immunizations and childhood infections probably make a very minor contribution to infant mortality statistics by changing the genetic composition of the populations.
An interesting statistic is that infant mortality rises with the population of obstetricians.
Thanks for the comments and questions.
This has been a stimulating exchange for me as well. I may not always be the most technical person (because finding good studies can be a chore), but I feel I ask the right questions.
I've always kind of felt that human requirements for vitamins a minerals are low. How else could most people in the US grow big on fake foods, added vitamin foods, and foods that have such a negative pathology on our guts.
I am also inclined to think that insulin also plays a smaller role than most people think if they maintain a low fat body percentage. If you aren't gaining weight-- you just aren't stimulating insulin to the point of damage-- and this is precisely the effect that people are looking for in foods that don't stimulate insulin-- and why cultures like the Kitavans don't have to worry about carb intake.
The goal of my studies in nutrition has to do with trying to figure out the best to eat for longevity. I realize that most of what i study in nutrition may just be academic once genetic therapies come into play because they will almost certainly have a larger effect on total lifespan that any kind of nutritional manipulation.
It's also my gut feeling the best diet for strength and robustness (for the moment) may clash with the best diet for longevity. This goes back to what I was mentioning before when i talked about how I worry a little about the fact that a high fat diet definitely increases the number of mitochondria (when carbs are kept low). Which may increase genetic damage over time vs just consuming enough carbs to stay around maintenance. I'm very interested in the pathology of mitochondria in the aging process.
We also know that people who eat for growth also do not have the same type of longevity as those that eat for just leanness. This effect is mirrored in the increased longevity in people who are very short-- just look at the height of Jeanne Clement! Or just look at many Asian cultures that have great longevity, and not a lot of muscle mass.
And lastly, many of the positive effects of antioxidants come precisely from their effects of slowing down reactions. If I was trying to heal a would as fast as possible-- or have as much energy as possible-- I would "not" want to slow down any reactions. While if I was subject to inflammation around my body, or just wanted to slow down how much junk my mitochondria throw out-- I want antioxidants. And it's almost funny that they was mirrored in some of ray peat's work on animals who consumed super low polyunsaturated fat diets-- And while i don't stand by some of his positions-- it's easy to see that animals on his low polyunsaturated diet had increased vitamin requirements because they had increased respiration when nothing was inhibiting their energy system from producing copious energy. As a human, I'm willing to sacrifice some energy-- to have a longer life! This may involved consuming some polyunsaturated fats-- and antioxidants.
---- and here is a sick thing to consider. While polyunsaturated fats do cause increased glycation reactions. There overall effect might just be to increase your lifespan at the expense of having a less optimal functioning system because of a larger amount of glycated tissue- "you may live longer, but look older and have more glycation and decrease in the general functionality in tissues" in the effect that they increased uncupling proteins at the expense of beta oxidation.
Hey Art-- just wondering if you got a chance to read my last comment? It's easy to miss comments on blogs-- I'm interested to hear what you might say about my hunch that a diet that produces the most robust possible person is different from the one that produces the best longevity.
Sorry if I'm hounding you!!
Aaron,
oops. I read, but thought I had answered.
You have a lot of big picture questions and all I have is big picture speculation. My focus is avoiding disease, which is somewhat different from increasing longevity. The oldest people have typically been 70-90 yrs old for the last several millennia. That hasn't changed, but infectious and degenerative diseases have. I am trying to push back the degenerative diseases caused by dietary inflammation. This also seems to lead to higher quality of life, i.e. more active and youthful.
Your focus seems to be on increasing lifespan. It seems to me that most of the cues for inflammation, e.g. oxidative stress, also cause damage and probably decrease lifespan. The early work with superoxide dismutase pointed in that direction. So my impression is that increasing lifespan will include minimizing inflammation.
The work with antioxidants and longevity seems flawed to me, because most phytochemicals never leave the gut and have their impact on gut flora and the immune system cells temporarily resident in the gut. Thus, many dietary antioxidants impact overall oxidation stress by altering blood uric acid.
So, my feeling is that much of the discussion of diet and health/longevity will eventually focus on genetically engineered gut flora and prebiotics to control them. Food will be considered by its impact on the gut flora.
I don't think there will be a need to make tradeoffs between health and longevity.
Mitochondrial metabolism and control with the rest of the cell is very important. None of the major components of the mitochondria is coded by the tiny, vestigial mitochondrial genome. Mitochondria protein mRNAs are transported to the mitochondrial surface and translated there, prior to transport across or into the mitochondrial inner membrane. Signaling to change mitochondrial metabolism is complex and outside of my current comfort zone, but it is obviously very important. For example, it is a major cue for apoptosis.
I don't think that attacks on DNA are a big deal, outside of sun damage. I would rank the accumulation of contributors to chronic inflammation as more important for longevity. My guess is that purging one's body of cryptic bacteria entering by leaky bowel episodes and migrating to local sites of inflammation are more important over the long haul.
Over the next ten years and perhaps twenty, I would expect diet to still trump any personal genetic initiatives on health impact, including longevity.
Glycation product metabolism and signaling is still in its infancy. I am a carbohydrate chemist by training and I have been sadly remise in not getting up to speed, but there have not been big breakthroughs that have come to my attention. It seems obvious that had blood sugar is not handled well by humans. Humans are not well adapted to eat sustained large amounts of sugar (especially fructose) or starch. Similarly, we can't handle large amounts of omega-6 polyunsaturated fats. Both of those produce high levels of glycation products and inflammation. There are lots of pharmaceutical approaches to handle the subsequent symptoms, but the obvious answer is to stop eating the unhealthy foods.
To the bottom line. I think that robust health will not be incompatible with long life, but there are many ways of reaching robust health and not all will lead to longevity. Many elite athletes, seem to be robustly healthy, but exhibit signs of high inflammation. Lots of runners die young, because of unhealthy diets. I am a shocked by the number of athletes in college who have profound inflammatory degenerative disease symptoms. Their sports programs have unhealthy diets. The prevailing attitude is that bodies just wear out. The symptoms of wear are just poorly mismanaged chronic inflammation.
I hope that I approximated an answer. Thanks for your continued input.
If you believe that most anti-oxidants work by increasing uric acid-- why consume plant compounds at all (veggies)? Especially considering that elevated uric acid levels are implicated in inflammation.
Lets's consider tea for example-- it has known anti-oxidant effects- and anti-inflammatory effects- but, would you argue that these effects are because of an increase in uric acid?
Would our bodies be better overall if we could supply them with everything they need to run on-- such as meats and fats-- without anti-nutrients-- and without inflammatory foods (such as sugar and polys)-- would our bodies be at such a state they wouldn't benefit from addition fruits and veggies?
Is it possible that additional anti-inflammatory foods are not needed-- or is our natural inflammation level turned up so high--that we might always benefit from anti-inflammatory veggies to a degree?
Aaron,
Uric acid is the major anti-oxidant in blood and elevating serum uric acid is associated with lower oxidative stress and increased longevity in lab animals. It seems to me that if plant "anti-oxidants" increase serum uric acid, then they will act as if they are lowering oxidative stress. Fructose causes lots of metabolic problems that lead to oxidative stress and an increase in serum uric acid.
Uric acid is similar to CRP, IL-6 and beta-amyloid, in that they are all responses to minimize damage. Uric acid can be a problem if the serum level is elevated and there is chronic mechanical damage/inflammation, e.g. joint trauma in an obese person. The net result is uric acid crystals and gout. Precipitation of the uric acid in the crystals can actually lower serum uric acid.
In the case of tea, I don't think that the anti-oxidant capability of its phytochemicals is important. I think that it is the bind of the phytochemicals to particular proteins that is responsible for its therapeutic effects. I also think that the effects would be dramatically different if administered IV rather than orally. Even here, I think that most of the impact is in the got and then secondary events impact the rest of the body.
Is the body adapted to a constant supply of phytochemicals? I think so. Plants produce chemicals that enhance their own survival and proliferation, and animals adapt to optimal use of plants as resources. We are left sorting out the selection forces that shaped the evolution of plants and animals.
Humans have an inactivated gene for uricase and cannot convert uric acid into allantoin for secretion. Thus, we have much higher serum levels of uric acid than most mammals and higher longevity and decreased incidence of cancer has been attributed this increased level of uric acid.
I don't understand some of the sources of oxidative stress/inflammation that contribute to age related chronic inflammation, so these sources may provide an increasing requirement for plant phytochemicals. It may also be that phytochemicals are needed to protect other nutrients during digestion. The stomach, for example, doesn't just secrete HCl and enzymes, but rather orchestrates a series of oxidation/reduction reactions, involving dietary iron and sodium chloride, that could be very destructive to fragile omega-3 oils. The composition of meals does matter and many phyto-antioxidants may be consumed early in digestion.
A practical observation is that there is an almost ritual use of large quantities of unusual herbs and spices in specific parts of the world. Phytochemicals are used as antimicrobials, but their persistence and prevalence suggest other uses beyond nutritive and anti-oxidative.
Thanks for your continuing long-winded answers!
Are you familiar with the book "the sugar fix"?
It is basically a 300+ page book bashing fructose and high uric acid.
I'm familiar with uric acid being a good anti-oxidant-- but what do we have to say to the multitude of studies this author quotes to show elevated uric acid causes inflammation and even elevated blood pressure. Many of negatives he associated with high uric acid I could confirm because my family usually has high levels-- even without high fructose consumption. I know were just one family, but I feel scientists need to look closer at how uric acid effects us.
As an adjunct to the above. I also see that you supplement vitamin c-- a supplement that has been shown in some places to reduce uric acid-- if you really take the position that uric acid is positive-- why take c. I've always pondered that humans may just be one of those creatures that just rely more on glutathione to just recycle the small amount of vitamin c we injest. This would make sense considering a diet high in animal products-- and low in sugar.
Lastly-- why I have curtailed my usage of olive oil and veggies in general-- and even scaled back tea to once or twice per day-- but I have been experimenting with using small amounts of digestive bitters before my typical high fat meals-- I wonder if this will have protective effects for the animal fats. This seems to be in line with what healthy cultures have done for generations-- i will keep you posted on how it effects my digestion.
While researching the sodium bicarb idea for healing SI mucosa, I ran into a lot of references to low stomach acid as a bigger problem than too much. I was intrigued by this page
http://www.evitamins.com/healthnotes.asp?ContentID=1037005 which says in part:
"One of the major functions of stomach acid is to initiate the digestion of large protein molecules. If this digestive function is not performed efficiently, incompletely digested protein fragments may be absorbed into the bloodstream. The absorption of these large molecules may contribute to the development of food allergies and immunological disorders."
If this is so, it seems that with a high protein diet that this may be important final step to keep immune health going. Probiotics, GSE, and glutamine are recommended on other sites, as well as the bitter herbs recommended here, which seems to complement what Dr. Ayers suggests. Apple cider vinegar/lemon juice are also mentioned in other places, which fits with what my chiro. recommended. If this is so, it seems that with a high protein diet that this may be important final step to keep immune health going. Am thinking this may be part of why I am still struggling with some issues (which is preferable to going to extreme diet restrictions).
Curious to know Dr. Ayers thoughts on this.
Tanya,
I am baffled by most of the discussions on stomach acid. To start at the beginning, stomach cells don't produce acid directly and it is a complex process chemically. Production of stomach acid is further complicated by infection with Helicobacter pylori. Hp infection stops the lining from producing acid. Drugs that stop stomach acid production, help the spread of Hp and further suppress acid production. Nobody seems to know much about acid reflux, but I suspect that it is also caused by inflammation and may be also related to Hp infection.
At the link that you cite, they were advocating adding a salt, betaine-HCl, to increase stomach acid. This is silly. The betaine is a weak base and when it is neutralized with HCl, you get the salt. That just means that it acts like a buffer to maintain a particular pH, it is not going to acidify any more than adding NaCl. Betaine is, however, an interesting compound that may interfere with heparin-based signaling.
The point here is that alteration of stomach acid levels is not caused by the contents of a single meal and indicates more profound problems, such as the most likely, Hp infection.
I don't buy the impact of stomach acid levels on protein digestion and some consequence of proteins slipping through. That isn't consistent with how digestion works. The peptic enzyme hydrolyze proteins differently than the subsequent pancreatic proteases. This is interesting with respect to antimicrobial peptide production, but I don't think that there is going to be a systematic impact on immunity. Those proteins and large peptides do not get across an intact intestine. Leaky gut is required. COX inhibitors would be more likely problems.
Vinegar and lemon juice are not going to acidify the stomach. They contain weak acids, acetic and citric acids, that will actually act as buffers and neutralize stomach acid. That doesn't mean that they are not useful, because they are very helpful in dissolving biofilms.
Carbs are much bigger problems than proteins, especially animal proteins. In most cases, animal proteins are adapted to animal function, whereas plant proteins are only concentrated in seeds and those are protected or toxic to seed eaters. Vegetarians have to wisely prepare food to avoid the natural toxicity of plants, the health problems of starch/sugar and numerous vitamin/mineral deficiencies.
The low carb diet that I recommend trades carb calories for fat calories, not carb for protein. Leaf vegetables and minimal fruits are retained. Dairy/eggs are easy sources of protein and fat. Drizzling olive oil is encouraged. Most people should check their tolerance for grains.
Hello Dr Ayers.
Whilst I realise this is a huge topic and dogs have different systems to ours, I was wondering if you had any information in relation to canine allergies - dust mite, pollen, mould. My dog (nearly two years) had a local allergic reaction (muzzle and chin) to allergens.He is currenly going through desensitisation injections. However, I want to provide the best possible environment for his immune system to re balance (if this is ever possible!). He has a fish and potato diet - but my concern is I am now readin potatos are not recommended due to starch/carb content. However, he is a very active dog. The alternative vet is also prescribing aloe vera (all natural juice) and minimal vaccines/flea/worm control. Is there anything I could try? I read about mannose here - do you mean d-mannose. I used to take this for periodic cystitis - is this the same product?
Kind regards
Deborah
Deborah Campbell,
I think that the answer to allergies in dogs is fairly simple. Dogs are not designed for starch. The only reason that starch and vegetables are used in dog food, is because they are cheap. If you want a healthy dog, in my opinion, the best food is raw whole small animals. That is not appropriate for most owners to tolerate, but that is what will get rid of the allergies and essentially all other maladies.
I know that is hard to hear, so I would recommend adjusting the diet from small animals to what you can tolerate. All of the other vet recommendations, in my opinion are related to marketable products that treat symptoms.
Your dog should be getting most of his calories from fat, not from carbs. Saturated fats are much healthier than carbs and will help him to keep his weight under control.
Thanks for your comments.
hello dr ayers,
I recently started to have Rhematoid arthritis symptoms (swollen MCP and pain)after beginning to take arginine supplement for cold hands/feet. I have been concerned with autoimmune issues as both mother and father expressed autoimmune diseases at fairly young age. My question is could Arginine or Citrulline contribute to Rhematoid arthritis. I don't quite understand the mechanisms but i inferred that proteins bind to citruilline and become antigenic. Im male and 32 and in pretty good health but have been diagnosed with empty sella and bouts of low testosterone. thanks
Hello Dr Ayers, I have allergy. But I have amazing symptom, my face starts to burn when I eat. I have not eaten wheat and yoghurt, sugar and drunk milk for a year. I had a candida diet. But I couldn't get well. What should I do? Thank you so much
Kind regards
Derya Sözen
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