Synuclein and Amyloid Diseases

NSAIDs, such as ibuprofen and aspirin are possible treatments to inhibit the aggregation of proteins (synuclein, beta amyloid) on charged polymers in amyloid diseases, such as Parkinson’s disease, Alzheimer’s disease, etc. Contradictory studies show that intracellular aggregate formation may be protective, since dimers are more toxic than aggregates.

The list of amyloid diseases is long and there are few effective treatments. In each case a protein starts to accumulate in fibers that form amyloid plaques inside or outside the cells. The large aggregates outside are toxic. Inside it appears that the large aggregates are not as toxic as small clumps, oligomers, of the protein.

The amyloid proteins are stacked up in the fibers in a very organized way, so that the same portions of the protein are lined up on each side of the fibers. Outside the cell, the regions with basic amino acids interact with heparin, and in Alzheimer’s disease, for example, the beta amyloid plaque is half heparin. In test tube experiments, fiber formation from protein solutions is accelerated by adding heparin.

Amyloid fibers also form inside cells in the case of the tau fibers of Alzheimer’s disease or the synuclein aggregates in Parkinson’s disease. In theses cases, there should not be any intracellular heparin, and it is not known what polyanion (RNA?) serves to accelerate fiber formation in these cases.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and aspirin, reduce the incidence of Parkinson’s and Alzheimer’s diseases. It has recently been shown that in test tube experiments, NSAIDs also decrease the formation of amyloid fibers from synuclein.

Amyloid fibers can be stained by Congo Red and thioflavin. Curcumin is the active component of tumeric and it has a structure related to Congo Red. Curcumin has been shown in recent studies to block synuclein amyloid formation.

In addition, the heparin in the fiber complexes can be stained with berberine. Berberine is a traditional herbal treatment for arthritis. It would not be surprising if it was also effective against Alzheimer’s amyloid plaque.

The large extracellular plaque aggregates appear to be toxic, but the small, oligomeric aggregate of protein appear to be the toxic form in cells. Recent experiments show that facilitating the formation of large intracellular aggregates minimizes the toxicity in animal models of Huntington’s and Parkinson’s diseases. It appears that the large visible aggregates are not the form that kills the cell.

For the time being, the only safe treatments that focus on amyloid fiber formation are the NSAIDs, curcumin and perhaps berberine.

references:
Hirohata M, Ono K, Morinaga A, Yamada M. 2008. Non-steroidal anti-inflammatory drugs have potent anti-fibrillogenic and fibril-destabilizing effects for alpha-synuclein fibrils in vitro. Neuropharmacology 54(3):620-7.

Pandey N, Strider J, Nolan WC, Yan SX, Galvin JE. 2008. Curcumin inhibits aggregation of alpha-synuclein. Acta Neuropathol. 115(4):479-89.

Bodner RA, Outeiro TF, Altmann S, Maxwell MM, Cho SH, Hyman BT, McLean PJ, Young AB, Housman DE, Kazantsev AG. 2006. Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseases. Proc Natl Acad Sci U S A. 103(11):4246-51.

Outeiro TF, Kontopoulos E, Altmann SM, Kufareva I, Strathearn KE, Amore AM, Volk CB, Maxwell MM, Rochet JC, McLean PJ, Young AB, Abagyan R, Feany MB, Hyman BT, Kazantsev AG. 2007. Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's disease. Science. 317(5837):516-9.

Is a Belly Bad?

A protruding midsection can mean many different things. It can be obesity, starvation/kwashiorkor or sarcopenia. It can mean there is a layer of fat outside, sagging organs poorly supported by weak abdominal muscles or fat surrounding the organs and stretching the muscles outward.

Alternatively having the same “lean” profile at 60 as at 16 could be a sign of a decline of muscle and an increase in fat surrounding organs. You can always have a porthole put in to see what is going on, or you can check the calendar and your C-reactive protein level.

If you are over fifty and your doctor has told you that your CRP, a measure of inflammation, is starting to creep up, then you are starting to suffer from age-related loss of muscle, sarcopenia. That is, you have begun to replace your muscle mass with fat, and the fat is producing inflammatory signal molecules, cytokines, that are the same as those produced by your immune system cells in response to an infection.

Most of the symptoms we associate with aging are just poorly managed chronic inflammation, as a result of replacing muscle with fat. The fat is metabolically lethargic, so you actually need less food, as your muscle mass declines. The result is that it is progressively easier to put pounds on. That is the bad news. The good news is that building muscle requires at least one of the inflammatory cytokines produced by fat, IL-6, so gaining muscle should be easier until you get back into shape. Losing weight is also anti-inflammatory, if the loss is fast enough to produce a fasting physiology.

All of the diseases associated with increasing age are just the accumulation of problems that result from increasing levels of chronic inflammation. Most of the increase is the result of inflammatory diet, but the increasing inflammation also decreases the desire to be physically active, with the result being a loss of muscle mass. Adjustment to an anti-inflammatory diet and lifestyle, can reverse the aging process.

It is also possible to be physically active and have a youthful muscle mass, but still have an inflammatory diet. The result will still be chronic inflammation, and cryptic inflammatory diseases that accumulate with time and produce sudden failures of joints, coronary arteries or cancer. Estrogens are also naturally anti-inflammatory, so women will find that menopause reveals any inflammatory diet/lifestyle that has been hormonally camouflaged. Thus, menopause may produce any of the typical signs of inflammation, e.g. acne, depression, back problems, arthritis, etc.

The bottom line is that a weak gut and/or extra body fat will cause problems at any age. And at any age, the diseases that are associated with inflammation can be minimized or avoided by an anti-inflammatory diet and lifestyle/exercise.

HIV TAT and Methamphetamine -- TNF

HIV infection and methamphetamine both cause inflammation of the brain and together they are paralyzing.

What’s worse than a TNF typhoon resulting from methamphetamine use? The answer is a TNF typhoon resulting in dementia from HIV infection of the brain.
Combine methamphetamine with HIV in the brain and the result is a Parkinson’s type of paralysis.

This sounds like very morbid subject matter to pursue out of curiosity, but if you put heparin into the equation, as I always do, it all becomes very interesting.

Here are pieces to the big picture:

HIV, the AIDS virus, infects cells of the immune system and causes chronic inflammation. The inflammation causes a disruption of heparin metabolism and since heparin is a major part of the matrix that holds together the endothelial cells that line the capillaries that feed the brain, the capillaries leak, i.e. there is a leak in the blood brain barrier. HIV-infected cells can pass out of the capillaries and into the brain. Here comes the insidious part, HIV produces a protein called TAT.

I drew a graphic of TAT with the basic amino acids in blue. The sequence of this nasty little protein shows how it gets around. It is secreted from cells, attached to heparan sulfate proteoglycans. It sticks tightly to heparin (yellow and red stick figures, sticking to ribbon of TAT), because of the patches with three and four adjacent basic amino acids. Frequently, the TAT will just be secreted and then sweep over the surface of the infected cell and be brought back into the cell on the circulating HSPG.

DPVDPNIEPWNHPGSQPKTACN
RCHCKKCCYHCQVCFIKKGLGI
SYGRKKRRQRRRPSQGGQTHQ
DPIPKQPSSQPRGDPTGPKE

A protein with three adjacent basic amino acids will get swept into a cell. All allergens that I have examined have this internalization triplet of basic amino acids. TAT is so powerful, that if it is chemically linked to the larger fluorescent protein from jelly fish (left with green, fluorescent amino acid derivative down the center), the whole fluorescent protein is dragged into cells.

The TAT can move from the HSPGs of an HIV-infected cell to neighboring cells with HSPGs. The TAT then gets taken into the cytoplasm of the next cell. Four adjacent basic amino acids are the signal that transports a protein to the nucleus and into the nucleus. It is in the nucleus that TAT really causes trouble. The TAT can move from an infected immune cell in the brain to neurons. TAT can kill neurons and stimulate other cells to produce TNF.

Methamphetamine also causes a TNF storm in the brain. This is a quick way to start the wasting symptoms that TNF in known for -- it is also call cachexin, after the wasting process of cachexia. If methamphetamine is given to someone with neurological symptoms of HIV, then the neuropathology is further exaggerated into a Parkinson’s type of paralysis. The TNF production of both is additive.

TNF production by methamphetamine brings up the consequences of the very closely related compound amphetamine (Adderall, Dexedrine) used by children and young adults (college age) as a treatment for ADHD.

reference:
Theodore S, Cass WA, Nath A, Maragos WF. 2007. Progress in understanding basal ganglia dysfunction as a common target for methamphetamine abuse and HIV-1 neurodegeneration. Curr HIV Res. May;5(3):301-13.

What If Medicine Was Scientific?

A view of the future of medicine, if the health of each patient was the highest priority.

2020 Somebody read the biomedical literature and decided to save a few bucks on the national healthcare system.

It has been a couple of years since everyone began favoring their right butt cheek. The “BioMed” subcutaneous, WiFi, microchip implants were controversial, but the economic argument was compelling. In the first year after the BioMed became mandatory and implantation accompanied every office visit, the expenditure on medical treatment in the US dropped by 10%. There was a lot of complaining about what a literal “pain in the butt” the prevention program was, but the prodding of the BioMed got results.

Once subQed, the BioMed enforced a simple dietary and exercise regimen. Violation of the regimen produced progressively more severe itching of the cheek, until the real “pain in the ass” set in. Surcease from this sorrow was Poetic in its justice. Sufferers could pay for temporary relief in conveniently marked toll stalls, called “Craigs.” There was a certain amount of public opprobrium associated with use of these facilities, but they brought relief. Those compelled to use the stalls complained of being “Idahoed.”

The prescribed diet was high in omega-3 oils and complex carbohydrates, but proscribed large amounts of starch, sugar and other hyperglycemic carbohydrates. Ten minutes of daily solar exposure (vitamin D) on the cheeks was monitored by the BioMed and “mooning” was replaced in the vernacular by “BMing.” Twenty minutes of daily exercise was enforced based on the BioMed’s analysis of physiological (pulse, blood pressure, blood sugar) and physical (GPS, accelerometer) measurements. Sustained, sedentary activity was not possible.

The BioMed provided identity verification for each patient and every datum on the patient was accessible by any medical official. Absolute privacy was provided by a variant of Apple’s DRM. Prescriptions for each patient were verified at purchase and were confirmed by access to a wireless expert system. Correct timing of medication was enforced by BioMed reminders. Compliance soared.

In the second year, 2 BM, office visits began to plummet. Doctors in private practice saw their incomes drop by 20% and there was already talk of a surplus of medical staff. Prices of the stocks of the major food processors began to drop as people shifted away from fast food, common vegetable oils, corn and soy products, and began to purchase more local meat and produce. Breastfeeding gained new popularity spurred by the introduction of the BioMedNip, a nipple implant to enhance the health of newborns.

The third year, 3 BM, brought appreciation for the BioMed and “kiss my cheek” was first used as an invocation of good luck. The decline in chronic inflammation decimated cases of depression, obesity, arthritis and allergies. Detection rates for cancer and degenerative diseases of the elderly plateaued. Cancer and geriatric specialists took credit for the efficacy of their latest therapies. Infant mortality in America began to approach that observed in developed countries. Pharmaceutical stocks tanked. Lactation fashions reach the catwalks. Hospital closures begin. Advertising for cold medications, drugs and baby formula is banned. American worker productivity soars.

It is amazing that at any given time, the US is just a couple of years away from medical utopia. The cure for chronic inflammation, diet and exercise, is available to all.

Medicine Can Treat. Why Can’t It Cure or Prevent?

Prescription for all diseases: Anti-inflammatory Shock Treatment

Cancer death rates may be finally slowing. Why has it taken so long? Medicine has some cobbled-together treatments for allergies, asthma, Alzheimer’s and atherosclerosis, but all of these are still increasing. Cures and prevention are always ten years away. Something is fundamentally wrong with medicine and the fatal flaw is obvious in the biomedical literature. Causes are not mentioned. Treatments are tested and evaluated. Pharmaceuticals are developed for therapy, not for cures.

Examination of medical websites reveals a public interested in why they get sick, but there is no explanation. There is a recent tendency connected to the concept of personal medical solutions, to attribute sickness to the unique genetics of the individual. Certainly there are some molecular genetic diseases, but this obscures the issue. In most cases the genetics only gives a predisposition. Biomedical research does not pursue why some people get the disease and others with the same genes do not.

The research literature shows abundant evidence that various diets and lifestyles dominate the outcome in health, but the medical industry fails to apply these factors. Why should someone spend a lifetime on drugs, if two weeks of intensive diet/lifestyle therapy provides a cure? Is a surgical intervention preferable over a gut flora exchange?

There is compelling evidence that chronic inflammation due to diet and lifestyle is the foundation for most degenerative and autoimmune diseases, and yet simple changes to avoid or eliminate inflammation are not emphasized by doctors to prevent or cure most diseases. It is quite possible to design a one-size-fits-all primary treatment for all diseases, an “Anti-inflammatory Shock Treatment.“ It would be a two week controlled diet and exercise program that provided the anti-inflammatory benefits of controlled carbohydrates, adequate protein, balanced omega-3/6 fatty acids, anti-oxidants, vitamins, exercise and meditation. Careful control of probiotic gut flora would be a priority. This system could be designed based on current research and would be generally applicable. The prescribed system for each patient would match severity of the disease with intensity of the anti-inflammatory intervention.

Lectins - Heat’em and Eat’em

Lectins are proteins common in seeds. They bind to sugars attached in chains to proteins, i.e. glycoproteins, and are displayed on the surfaces of cells that line the gut. Lectins could inhibit digestion of raw beans, but cooking makes them digestible.

Fear of lectins is puzzling. Lectins are proteins that have binding sites on their surfaces for specific single or small sequences of sugars. They are present in seeds to protect the seeds from herbivores.

A seed is mostly food (starch, protein, fat) for the plant embryo that will grow from it. This is also true of a chicken egg and just like the egg, the seed contains defensive proteins to inhibit the growth of bacteria, fungi and egg/seed eaters.

The egg has enzymes to degrade bacterial walls and proteins that bind iron, vitamins, etc. needed by bacteria and humans. Eating many raw eggs can lead to vitamin deficiencies. Boiling the eggs, unravels the defensive proteins and makes them digestible and nutritious.

Seeds block being digested by containing proteins that foul the digestion system of would be devourers. For example, soybeans have trypsin inhibitor that binds to our digestive enzyme and makes eating raw soybeans nonproductive and uncomfortable. Boiling soybean meal to produce a curd, i.e. tofu, agglutinates the denatured soy proteins, including the lectins and washes away the soy trypsin inhibitor. Tofu is free of digestion inhibitors and lectin activity.

It is not an accident that lectins bind to human red blood cells. The sugars displayed on the surface of red blood cells are the blood group antigens. Different sugars on the end of the sugar chains decorating RBCs characterize the A, B and O antigens. These same sugars are present on the surfaces of various bacteria. Immune systems don’t produce antibodies to self antigens, so a person with type A blood produces antibodies only to B antigen sugars it encounters on bacteria. A person who is type AB doesn’t produce antibodies to A or B sugar antigens. There aren’t antibodies to O, because that sugar structure is the basis upon which both A and B are made, and some of the
structure is present on all RBCs. Lectins are specific for A or B or other common bacterial sugar antigens.

I did some modeling to show a lectin with lactose (red and gray) bound to sticky tryptophans (yellow) in two places on the surface. In one case a lysine (blue) is draped on the other side. That shows that sugars bind both to aromatic amino acids and to the hydrophobic arms of basic amino acids.


Some people think that humans and other mammals must be protected from lectins and that this protection is shown in human and cow’s milk in the form of antibodies against lectins. This seems to be a misunderstanding. For example, human antibodies secreted in breast milk are secretory IgAs. These antibodies are glycoproteins, i.e. they are proteins with attached sugar chains. Some lectins will bind to these antibodies, because of the attached sugars. These are not lectin-specific antibodies, but rather glyco-specific lectins. The lectins are binding to the glycoprotein antibodies, not the other way around.

It is possible for people to be allergic to lectins, but this is unlikely. For example, peanut allergies involve proteins other than the peanut lectins.

There are some dangerous lectins. For example, ricin is a very nasty, but effective, toxin produced by the castor plant. Ricin is a lectin, in that it binds very specifically to sugars found on the surface of gut cells of insects and humans. After the ricin binds to surface proteins, it is brought into the cells where it chops up the protein synthesizing machinery. That is a dangerous lectin. It takes very little ricin to kill each cell and only a tiny amount to kill a human. Ricin is a terrorist toxin. Yet oil extracted from castor beans contains so little contaminating ricin that it is safe to eat. [Castor oil is wonderful to apply to aching feet overnight for painfree, luxuriously soft feet in the morning.]

The bottom line is that seed lectins add to the nutrition of cooked beans and grains that have been the foundations for several thriving civilizations. The longest living members of the bean and grain cultures are typically older and more fit than comparable individuals with a modern, inflammatory diet based on omega-6 oils.

A Paleolithic Perspective on Biomedical Literature

Homo sapiens seems to be inflammation prone, based on its assortment of biochemical deficiencies. All of the following lead to inflammation: hyperglycemia, vitamin C deficiency, fish deficiency, vitamin D deficiency, grilling meat. Is this an adaptation to agriculture and high population/communicable disease risk?

I was just visiting Diet Rosso and his article on the paleolithic diet flashed me back to some thoughts that I had on the evolutionary benefits of inflammation. So, Rosso made me think about this.

Inflammation is a big health problem in the US. All of the major diseases are inflammatory and all are exacerbated by the inflammatory US diet. But why is the fast food diet so inflammatory? Why is our corn/soy agricultural economy so hazardous to our health?

Corn and soybeans provide a good balance between carbohydrates, fats and protein. The amino acid composition of the combo is also fairly good, and corn and soy oils are high is unsaturated fats. So why does a corn/soy diet lead to degenerative and autoimmune diseases?

I think that the answer is that inflammation is getting a bad rap; as long as our immune system produces effective local responses to pathogens, we are pleased, but when the immune system cranks it up in response to a deluge of disease, we complain. I argue that our current inflammatory response to fast food is just a slight embellishment of the first dietary-based increase in inflammation that provided adaptive protection against the dangers of agriculture.

As I see it, agriculture had a series of dramatic impacts on the evolution of plants, animals and humans, in particular. Taming of plants and animals altered the human diet. Agriculture also institutionalized grilling and grouling, which meant bringing together carbs and protein at high temperatures. The result was an increase in dietary starch, seed/grain oils and advanced glycation endproducts (AGEs). There was also a decrease in fish, leafy vegetables and complex carbohydrates/fiber. Agriculture also led to a dramatic increase in population density.

I imagine that the first villages or very large family groups that resulted from sustained planting of harvestable crops resulted in plagues. Lots of people in close proximity with minimal hygiene is a prescription for infectious disease. Agricultural development required an immunological adaptation to higher loads of communicable diseases. That adaptation was inflammation triggered by agriculturally-associated diets high in starch and low in browsed veggies.

Hunting/gathering, especially along coasts, provided dietary vitamin C, as well as a high ratio of omega-3 to omega-6 fatty acids. Early humans defective in the ability to synthesize vitamin C or omega-3 fatty acids, would not suffer if they ate plenty of leaf veggies. Wild fish and game, as well as leafy veggies, have a high ratio omega-3 to omega-6 fatty acids, so these people would be safe from inflammation-based disease and infertility.

Agriculture focused on seed harvest results in a dramatic shift in diet and disease. Communicable disease was not a problem for hunter/gatherers, because of the necessarily widely distributed small population groups. Agriculture concentrates populations around the crop lands and increases the benefits of physiological energy expenditures on heightened immune activity to provide consistent protection against pathogens. Agriculture required chronic inflammation for disease protection.

Inflammation triggered by cues in the agricultural diet would have a high selective advantage. Individuals who increased their chronic level of inflammation in response to high blood sugar, compounds produced during cooking, i.e. AGE, vitamin C deficiency, vitamin D deficiency (low exposure to sun) and/or omega-3 oil deficiency, would have survival advantage in high population densities associated with agriculture.

The fast food diet is nothing more than an exaggeration of the agricultural diet and it produces and an exaggeration in the human adaptation to agriculture, high chronic inflammation and a suite of inflammatory diseases. Metabolic syndrome is another name for high chronic inflammation. Obesity is inflammatory. A sedentary lifestyle is inflammatory and aging is a suite of symptoms associated with inflammation. Hunter/gatherers didn’t show the same signs of aging as modern humans, and probably had comparable longevity (although there were many other risks.)

Lastly, I want to ponder the modern decline in fertility. Fertilization and implantation requires suppression of inflammation in the female reproductive system. Semen is uniquely rich in omega-3 oils and women who have a high frequency of unprotected coitus with a man with a high level of omega-3 in his semen, are much more likely to become pregnant and carry a pregnancy full term. The fetus requires high levels of omega-3 fatty acids for brain development and can rapidly deplete the omega-3 fatty acid a mother with a deficient diet. Omega-3 deficiency is associated with preeclampsia.

Early males and females with an inflammatory agricultural diet would tend to be infertile, because of omega-3 oil deficiencies and chronic elevated inflammation. Periodic exposure to an abundance of omega-3 fatty acids, such as feasting on migrating salmon, would synchronize fertility and subsequent births. It is humbling that a current research program in land-locked regions of South America uses cans of anchovies to remedy the same pregnancy problems that plague North America and its inflammatory fast food diets.

Niacin Flush

Niacin is a B vitamin that is cheap and highly effective at raising HDL and lowering LDL. HDL and LDL were previously called good and bad cholesterol, resp., but since the data from numerous studies show that they don’t have a big impact on health, it is probably easier to just call them heavy and light reflecting less and more lipid content. If you still want to adjust your blood lipids, then niacin is more effective than the costly statins. Unfortunately, niacin also causes an uncomfortable (itchy and hot) flush.

The niacin flush is part of the inflammatory process that includes the classic tetrad of symptoms: rubor (redness), calor (increased heat), tumor (swelling), dolor (pain). Flushing in response to niacin shows that the immune cells in the skin respond to ingested niacin that is flowing through the capillaries. Mast cells in the skin have receptors that bind niacin and the cells secrete inflammatory prostaglandins. The prostaglandins act on the capillaries to cause dilation and flushing. Mast cells have secretory granules that fuse to the cytoplasmic membrane and release their contents outside. The granules contain histamine, heparin and tryptase. The histamine stimulates histamine receptors on pain/itch nerves and the tryptase stimulates receptors on a second set of pain/itch nerves.

Prostaglandins are produced by membrane bound enzymes on the surface of mast cells. When the mast cells are stimulated, additional enzymes are added to the surface through fusion of the secretory granules. The combined enzyme complex produces prostaglandins by releasing arachidonic acid (ARA) from phospholipids of the membrane (phospholipase A2, PLA2), converting the ARA to an epoxide prostaglandin (cyclooxygenase, COX-1) and stepwise producing additional prostaglandins. These prostaglandins cause the dilation of capillaries that is seen as flushing.

Niacin also binds to receptors on fat cells, adipocytes, and blocks release of fatty acids from the triglycerides stored in these cells. It is this action that is responsible for the increase in HDL and the lowering of LDL in blood serum.

An extension of the niacin skin flushing reaction is the use of this response to demonstrate the presence of arachidonic acid and a functional immune system in the skin. A recent study used topical application of niacin and skin reddening to test the idea that schizophrenia exhausts ARA as a result of inflammatory processes in the brain. Tests showed a tendency for schizophrenic episodes to be accompanied by a diminished flushing response to niacin. This result also suggests that a lowered system-wide ARA level should show up in a predisposition to gut problems.

It would be very interesting to test the interplay between inflammatory provocations, e.g. infection, serum omega-6/omega-3 fatty acids, and measures of inflammation, e.g. C-reactive protein on niacin flushing. Inflammatory depletion of ARA may be important in the decline in the integrity of tissues that is observed in inflammatory diseases of the gut (Helicobacter-based ulcers, IBD, Crohn’s disease, celiac), autoimmune diseases (arthritis, atherosclerosis), skin diseases (vitiligo), etc. It would also be interesting to test the impact of helminth infections to reverse ARA depletion.

reference:
Benyó Z, Gille A, Kero J, Csiky M, Suchánková MC, Nüsing RM, Moers A, Pfeffer K, Offermanns S. 2005. GPR109A (PUMA-G/HM74A) mediates nicotinic acid-induced flushing. J Clin Invest. 2005 Dec;115(12):3634-40.

Antioxidants or Fermenting Gut Flora?

Long life is the result of a good diet and exercise. Plant antioxidants are eaten to sop up the reactive oxygen species (ROS) and omega-3 fatty acid-rich fish oils are consumed to reduce the production of inflammatory prostaglandins. Avoiding inflammation that has been linked to essentially all degenerative and autoimmune diseases should make us live better and longer. Unfortunately it is more complex than that, and studies in the simple nematode, Caenorhabditis elegans, show that your gut flora may have something to say about your longevity.

C. elegans nematodes live in the laboratory fed on Escherichia coli, the common colon bacterium. Since the bacteria are the sole diet of the worms, to change the worm’s diet, mutant bacteria must be used. To study the impact of various vitamins on longevity, mutant bacteria unable to synthesize particular vitamins were fed to worms and their average length of life was measured.

Deleting coenzyme Q (10) resulted in a surprising increase in longevity. It was assumed that since coQ10 was needed for effective bacterial electron transport, the disruption would result in an increase in inflammatory ROS. What actually happened was that the bacteria shut down their use of aerobic metabolism and turned on fermentation.

Fermenting bacteria are probiotic in human guts and it appears that the same is true of worms. These results suggest that probiotic, fermenting gut flora may be profoundly important in determining longevity. What we eat may determine how long we keep eating.

reference:
Saiki R, Lunceford AL, Bixler T, Dang P, Lee W, Furukawa S, Larsen PL, Clarke CF. 2008. Altered bacterial metabolism, not coenzyme Q content, is responsible for the lifespan extension in Caenorhabditis elegans fed an Escherichia coli diet lacking coenzyme Q. Aging Cell. 7(3):291-304.

Menstrual Pain is Inflammatory

Inflammation is essential to the menstrual cycle. At key points inflammatory prostaglandins are made from omega-6 arachidonic acid to trigger ovulation and menses, the discharge of the blood-engorged lining of the uterus. Chronic diet-based inflammation can result in disrupted ovulation, infertility due to an inability to suppress an inflammatory response to egg implantation, menstrual pain/cramps and premature birth.

Several studies have shown that reducing diet-based inflammation by eating supplements containing long chain omega-3 oils, e.g. fish oil, decreased menstrual pain and cramps. The reduction in chronic inflammation was associated with decreased production of inflammatory prostaglandins that are the cause of the pain and intense uterine contractions. Normally, the diet would provide a balance of omega-3 and -6 fatty acids, which would yield a mixture of anti-inflammatory and inflammatory prostaglandins, and produce an effective discharge through more moderate uterine contractions.

A more recent evaluation of numerous studies on the impact of omega-3 oils on pain associated with menstruation, arthritis, inflammatory bowel disease, etc., showed a uniform decrease in inflammation and pain. The simple summary is that an inflammatory diet rich in omega-6 vegetable oils leads to pain, suffering and premature aging. A more normal diet with a balance of omega-3 and omega-6 fatty acids leads to health and reduced aging.

Typical symptoms of an inflammatory diet are: menstrual cramps, infertility (gestational problems: preeclampsia, prematurity), joint pain, back pain/sciatica, acne, allergies, asthma, autoimmune diseases. There is increasing evidence that obesity not only produces inflammation, but that an inflammatory diet can lead to obesity. An inflammatory diet, especially if augmented with antibiotics, disrupts the normal gut flora and leads to an inflammatory replacement flora that supports chronic inflammation throughout the body.

Chronic inflammation and much of the damage caused by chronic inflammation is reversible by a shift to an anti-inflammatory diet and lifestyle (described elsewhere on this blog.)

references:
Deutch B. 1995. Menstrual pain in Danish women correlated with low n-3 polyunsaturated fatty acid intake. Eur J Clin Nutr. 49(7):508-16.

Goldberg RJ, Katz J. 2007. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain 129(1-2):210-23.

Bell RF. 2007. Food and pain: should we be more interested in what our patients eat? Pain. 129(1-2):5-7.

Leptin and Diabetes

Fat cells produce the hormone leptin. Early experiments showed that leptin could ameliorate some of the effects of mouse models of type I diabetes, but it was always thought that the leptin just improved the activity of the small residual amounts of insulin produced by the rats. A recent experiment with genetically insulin deficient NOD mice, shows that leptin expressed by a virus infection reverses the symptoms of diabetes.

The NOD mouse strain is defective in the hormone, IL-2, that preserves tolerance to self proteins. As a result, a high percentage of the NOD mice develop symptoms of type I diabetes melitis, high blood glucose and ketosis. These animals will die without injected insulin.

In recent experiments, the NOD mice showing symptoms of diabetes were injected with a strain of adenovirus that had been engineered to express leptin. The leptin-expressing NOD mice displayed a rapid reversal of diabetes symptoms and began to gain weight normally. The high blood sugar and ketosis in NOD mice was stimulated by glucagon release in response to lack of insulin. Leptin stopped the glucagon release and reduced additional production of glucose by the liver and lipid oxidation that yielded the ketosis.

Muscle access to glucose in the NOD mice was restored by leptin by the induction of insulin-like growth factor 1 and its receptor. The NOD + leptin mice had normal blood sugar, but ate half the normal amount and had no body fat.

These are very promising results for type I diabetics, because it indicates that insulin injections are not the only approach to treatment. Stimulation of leptin production may be very useful and this new approach is being intensely investigated.

reference:
Yu X, Park BH, Wang MY, Wang ZV, Unger RH. 2008. Making insulin-deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci U S A. 105(37):14070-5.

Anti-inflammatory Octopus

I always envied the neurophysiologists who studied the giant axons of lobster, because they could always eat their failed experiments. I was working on a fungal disease of soybeans. It had no gourmet prospects. My revenge came decades later, when I took a “research” trip to Tuscany to study the impact of Mediterranean cuisine on inflammation. Fish, cephalopods, red wine and tiramisu were my test materials and I was the test organism. For a month, I felt no stress, no inflammation and no pain. Recent research articles support my subjective conclusion that seafood and red wine from Siena to Venice are anti-inflammatory.

Recent tests of the fatty acid composition of Mediterranean fish and octopus show that the ratio of omega-3 to omega-6 fatty acids in the fish and octopus is roughly 2:1. (In contrast, the US ratio is 1:20) The omega-7 fatty acid, palmitoleic acid, which appears to act as an anti-inflammatory hormone, was also present. The prominent place of seafood in the Mediterranean diet and the high omega-3-rich fatty acid composition of that seafood, combined with the absence of the inflammatory, omega-6-rich vegetable oils, corn, soy, safflower, of the inflammatory US dietand the use of olive oil, go a long way to explain the relatively low incidence of inflammatory diseases in people who eat a Mediterranean diet. Just add some sunshine and exercise, and you will live better and longer.

Oh, by the way, the tiramisu was my daughters’ project to evaluate local variation of that dessert throughout Italy. So we ate tiramisu at a different restaurant each day for a month. The differences were amazing and the best tiramisu in Italy is ...

But the bottom line is the same. The Mediterranean diet is nothing more than another variant of the anti-inflammatory diet and lifestyle that I have been discussing throughout this blog. Biomedical research says that the US diet is killing us. You can go to Tuscany or you can just shop, cook and live wisely wherever you are.

references:
Ozogul Y, Ozogul F, Cicek E, Polat A, Kuley E. 2008. Fat content and fatty acid compositions of 34 marine water fish species from the Mediterranean Sea. Int J Food Sci Nutr. Oct 29:1-12.

Ben-Youssef S, Selmi S, Ezzeddine-Najai S, Sadok S. 2008. Total lipids and fatty acids composition of the coastal and the deep-sea common octopus (Octopus vulgaris) populations: a comparative study. Nutr Health. 19(3):195-201.