Thursday, February 26, 2009
Here I will provide a few examples to illustrate that medical advice is frequently, if not usually, wrong about diet, nutrition, cause of disease, appropriate drug use and whether to spend a few unprotected moments basking in sunshine.
The Sun Is Not the Enemy, but Sun Blockers Can Increase Skin Cancer
Medicine is supposed to provide instructions on how to handle dangerous chemicals and procedures safely and to enhance health. Solar radiation is dangerous and will cause skin cancer if used inappropriately, but solar radiation is also needed to produce vitamin D in skin. The public response to the medical mandate to limit solar exposure to reduce radiation-based skin cancer resulted in increased use of solar-blocking lotions. Unfortunately, the result was that some people spent more time in the sun, assuming that avoiding sun burns meant that they were avoiding skin cancer. Unknowingly they had shifted their skin exposure down from doses sufficient to kill cells and cause inflammation, to levels sufficient to just cause solar mutagenesis -- the lower exposures were optimal for skin cancer production.
Spare the Sun and Spoil the Child
Babies and children are the most sensitive to solar radiation induced skin cancer and need protection from over exposure, but the public response to medical advice has been to avoid prudent exposure to the sun. Now kids in the U.S. are showing symptoms of rickets, a vitamin D deficiency disease common during early industrialization, in which air pollution, urban poverty and factory work limited solar exposure. Babies in strollers are completely covered. One frightening consequence of this over-reaction could be a resurgence of poor bone growth that in the 1920’s resulted in the development of the now-trendy Cesarean section procedure to accommodate women with malformed pelvises due to rickets.
Rickets Is Rampant
Ubiquitous vitamin D deficiencies due to inadequate sun exposure is compounded by inadequate sources of dietary vitamin D and inappropriate medical interventions. Most vitamin D deficiencies go unnoticed, because the typical symptoms of deficiency mimic other forms of inflammation. When serum levels of vitamin D are actually measured and found to be inadequate, supplements of 600-1000 iu/day of vitamin D3 are prescribed. Unfortunately, there is seldom followup testing and a recent study indicates that most treatment for vitamin D deficiencies is inadequate -- much higher doses, ca. 2-5000 iu/day are required to reach optimum levels. Most people are and remain vitamin D deficient.
Scourge of Scurvy
Vitamin C deficiencies are also a problem. Most people get enough vitamin C to avoid losing their teeth (vitamin C is needed for collagen production), but subclinical deficiencies still produce chronic inflammation. The major cellular anti-oxidant is glutathione, but vitamin C is another major defense against reactive oxygen species (ROS). An increase in ROS triggers oxygen stress and inflammation. Deficiency of vitamin C indicates that more vitamin C is being used up than is being replenished in the diet. Numerous metabolic disturbances associated with other deficiencies or infections can result in vitamin C depletion and chronic inflammation. Most people are vitamin C deficient.
Vegetable Oils Are the Problem, Not the Cure
Medical advice to avoid saturated fats in meats and shift to omega-6-rich vegetable oils is a major contributor to chronic inflammation and modern degenerative diseases. The original claimed association between saturated fat consumption and cardiovascular disease was tenuous, but produced a glacial shift in diet toward consumption of omega-6 fatty acids, e.g. corn and soy oils. The medical dependence on measurements and treatments of LDL, has outweighed the actual data in the biomedical literature -- LDL levels are not important in cardiovascular disease. Drugs that lower LDL, serum cholesterol, are only effective in reducing heart disease, if they lower LDL by lowering inflammation. The risk factor is the inflammation, not the LDL level. Agricultural practices that use grain over grass further reduce the omega-3 fatty acid content of meat and increase the inflammatory omega-6 fatty acid level.
Statins Are a Problem, Not the Cure
Statins are broad spectrum disrupters of the function of many different enzymes and proteins. They were originally isolated from fungi based on their ability to poison bacteria, i.e. they are antibiotics. They disrupt fat metabolism and thereby lower LDL levels, but they also cause many undesirable and potentially dangerous side-effects. One of these actions is to block inflammation triggered by activation of the inflammation transcription factor, NFkB. By blocking NFkB activation, some statins lower inflammation and thereby decrease cardiovascular disease. This activity is similar to aspirin, which acts on COX-2 as well as directly on NFkB. Both statins and aspirin (NSAIDs) have multiple activities on numerous areas of cellular metabolism. The activities of both include reduction in inflammation, but they also produce other undesirable side effects. Chronic inflammation is better treated by diet, exercise and traditional herbs and spices, rather than more dangerous statins.
Water Is Miraculous, but just Satisfy Your Thirst
If you are thirsty drink tap water. There is no improvement in health by drinking some extra amount of water each day. Drinking water in plastic bottles from magical sources provides no improvement in health. Much of the “spring water” with designer labels is only locally bottled tap water. The plastic bottles are an ecological disaster and the “purified” water in the bottles is contaminated with compounds leaching from the bottles. If you want a constant source of water, bottle your own tap water. If you want to avoid the minor contaminants added to avoid bacterial contamination of municipal water supplies, use a simple point-of-use filter.
Starch Is the Problem
Starch is rapidly converted into blood glucose and that spike in blood sugar causes major problems. The foundation of the old food pyramid, grains, is no different than table sugar in being hyperglycemic, i.e. rapidly raising blood sugar. A large muscle mass and high physical activity can minimize the rise in blood sugar, by using up the sugar for muscle energy as it enters the blood. Unfortunately, most people do not have enough muscle and are not physically active enough to be protected from the starch and sugars in their diets. The result is chronic inflammation in the form of metabolic syndrome and degenerative diseases, e.g. diabetes, allergies, depression, acne, infertility, cardiovascular disease, autoimmune diseases and cancers.
One slice of white bread with a meal may be too much starch for some people. The maximum for most people is: one half of a ripe banana or one half cup of a starchy entree such as pasta, potato, rice, or one of the two buns on a burger. The starch needs to be spread over several meals. Eating too much starch with a meal produces intense hunger, as the blood sugar rapidly rises, triggers insulin release and a subsequent crash in blood sugar. Don’t believe any of the diets that recommend starches to replace fats. Many “lite” diet foods are more unhealthy than the higher fat originals that they replace. Replacing saturated fats with saturated starch is dangerous. The temporary high blood sugar level produces the increased health risks routinely associated with diabetes.
Insufficient Food Is the Problem -- Insufficient Minerals
It takes only 2-3000 Calories per day to energize most people. That means that most people can eat their day’s worth of calories with the sandwich plate at a fast food restaurant. That meal will provide an overdose of starch and sugar, but will be deficient in vitamins and minerals. A major dilemma is that it takes so little food to provide adequate energy for a low activity lifestyle, that the choice must be made between obesity and vitamin/mineral deficiencies. Eating just enough to satisfy energy needs results in deficiencies, but eating more to avoid vitamin/mineral deficiencies, results in obesity. The only solutions are to eat supplements to supply needed vitamins, minerals, antioxidants, etc. or increase physical activity and body muscle mass, so that more can be eaten without producing obesity. For most people the solution is a combination of increased physical activity and supplements. That combination is also found to reduce inflammation and the associated risk of degenerative diseases.
It’s the Stupid Diet
The obsession of medicine with drugs and invasive procedures provides additional health risks for patients. Many researchers complain in the biomedical literature that there is insufficient focus on the cause of disease and too much emphasis on the study of the impact of specific drugs on disease symptoms. The result is that in most cases the symptoms are treated and the disease becomes chronic. Of course this also means that the patient is a permanent consumer of health care.
The foundation of all healthcare should be to improve the lifestyle of the patient. Diseases don’t just happen. The biggest contributions of immediate family to disease of an individual are not defective genes, but rather defective diet and lifestyle habits. Our healthcare system is too no fault. People are sick because there is something wrong with how they live. They eat too much or they eat the wrong foods. They don’t get enough exercise to develop a healthy muscle system to support their joints. Most importantly, bad diet and lifestyle choices produce chronic inflammation. Drugs can reduce chronic inflammation, but will also produce additional side effects that will also require interventions. It makes more sense to attack the original causes of inflammation.
Every treatment program should address the pervasive contribution of chronic inflammation by including a diet and lifestyle inventory and an assessment of the cause of the disease that is being treated. An appropriate anti-inflammatory diet and a path toward a more active lifestyle should be the foundation of every treatment plan.
Thursday, February 19, 2009
Aricept, an acetylcholine esterase inhibitor used to treat Alzheimer’s disease and other conditions that benefit from enhanced accumulation of acetylcholine, is an example of a molecule with multiple hydrophobic rings that binds to an enzyme.
I want to discuss aricept as an arbitrary example that I just looked up to illustrate the lack of specificity of statins that I will characterize in another article as little more than molecular skeleton keys that work on many different enzymes.
I have presented two diagrams of the structure of Aricept. It has two isolated rings on the left and then a fused pair of rings on the right. The major chemical feature here is the inability of the rings to hydrogen bond with water. The result is that water next to the faces of the rings is highly structured in a high energy configuration. Two rings will be at a much lower energy if they are stacked together, because two of the surfaces will no longer be exposed to water.
Typical low energy, noncovalent bonds in water, such as ionic bonds are readily broken by the thermal, kinetic energy of water -- they get knocked apart. The energy of these bonds is only 1-2 kcal/mol. In contrast, the stacked hydrophobic rings are quite stable, because it takes ten times the energy to separate them, 20 kcal/mol.
Aricept binds to acetylcholine esterase, the enzyme that degrades the neurotransmitter acetylcholine by at least three stacked rings. These ring structures are shown in the close up of the tunnel leading to the enzymes active site near the yellow tryptophan on the left. Part of the enzyme shown by the white, ribbon-like twists of the amino acid backbone have been removed over the tope of the grey-red and blue aricept molecule, to make it easier to see.
I also showed the aricept in the tunnel with the surface of the protein shown to indicate how the aricept slips and sticks in the enzyme and blocks its activity.
The aricept is bound to yellow tryptophans at both ends and the middle ring is bound to the hydrophobic ring of orange tyrosine. The geometry of the interaction is important, but many other molecules with fewer rings would also bind to the same hydrophobic, aromatic ring amino acids. Acetylcholine, which can form hydrogen bonds with the paired electons of the acetyl oxygens, will just slip across the surface of the hydrophobic rings on its way into the enzymatic tunnel.
Statins were found by testing fungal extracts for molecules that would inhibit an enzyme (HMG-CoA reductase) in lipid metabolism. The normal lipid substrates for that enzyme would also be expected to bind to the surface of rings in the acetylcholine esterase enzyme. In fact, I would expect to find molecules from fungal extracts that would inhibit acetylcholine esterase.
I demonstrated the nonspecificity of all of these binding events with the aromatic rings in the active sites of enzymes by having one of my students check for the binding of a flat hydrophobic molecule, metformin, one of the common drugs for treating type II diabetes, to a common bacterial enzyme, beta galactosidase. Kinetic studies demonstrated competitive inhibition of typical beta galactosidase substrates, which indicates that the metformin binds the aromatic amino acids that are known to be involved in binding of the sugar substrates, e.g. lactose, of the enzyme. I would not be surprised if the statins are transported into cells by the same organic cationic transporter that transports metformin.
I am setting the stage for a discussion in a future article of what kind of activities would be expected from fungal molecules that were identified by the statin screening. It is not surprising that the statins have many activities other than reducing LDL. The only statins that are effective in treating cardiovascular disease are those that also lower inflammation. It is also not surprising that statins have many side-effects.
Wednesday, February 4, 2009
Can the AHA be correct in promoting omega-6 PUFAs? Doesn't this conflict with the broad therapeutic action of omega-3 PUFAs, EPA/DHA, against inflammatory diseases?
The dietary shift from saturated animal fats to polyunsaturated fatty acids (PUFAs) from vegetable oils paralleled the shift from infectious diseases to inflammatory/degenerative diseases as predominant killers in the Western world. Treatments for degenerative diseases associated with aging have improved, but these diseases have become more prevalent and the age of onset has decreased. And medical costs have skyrocketed. Omega-6 vegetable oils seem to be the problem, but the American Heart Association (AHA) has recently given these PUFAs a clean bill of health.
Why the AHA Conclusions Seem Just Wrong
The rise of inflammatory/degenerative diseases follows the shift to processed foods rich in omega-6 PUFAs (corn, soy, cottonseed, safflower oils) and simple carbohydrates (grain starch, sugar, high fructose corn syrup), but the AHA presents scientific data to exonerate omega-6 PUFAs. The central problem is that the AHA’s conclusions are not based on a conceptual framework to explain cardiovascular disease. Instead, conclusions are derived from experiments in which various diets are fed to people and consequences are analyzed. With some diseases, in which there is a simpler cause and effect relationship, this approach might lead to useful answers, unfortunately, the inflammatory component central to cardiovascular disease can have multiple, alternative origins and simple experiments yield misleading conclusions.
Experimental Basis for AHA Support for Omega-6 PUFAs
- Conversion of short PUFAs found in the diet, e.g. LA, to the long PUFAs that serve as the precursors of cellular hormones. But conversion is thought to be inefficient, so that less than 1% conversion occurs and short PUFAs have little impact on cellular long PUFA concentrations. Moreover, the brain does not perform the conversion and the high brain content of DHA is supplied on demand from DHA circulating in the blood.
- There don’t appear to be any direct, inflammatory derivatives of LA (C-18), but after it is converted to AA (C-20), the arachidonic acid is the starting point for the conversion to most of the inflammatory and anti-inflammatory cellular hormones, e.g. prostaglandins, leukotrienes and lipoxins. Thus inflammation is initiated by AA-derived products, but resolution and return to normal physiology is also based on other AA-derived products.
- Increases in blood plasma AA are associated with anti-inflammation, not inflammation.
- Increases in dietary AA and/or LA result in a decrease in cardiovascular disease. Replacing dietary saturated fat with PUFA leads to a reduction of disease by 25-50%. Higher serum LA translates into less disease.
- Increases in dietary LA result in lower serum cholesterol and LDL, but paradoxically they also lead to a narrowing of arteries.
- The relative amounts of dietary PUFAs (USA) are LA 15grams/day, AA 0.15g/d, ALA (omega-3, C-18, linolenic acid) 1g/d, EPA/DHA <>
Statins Lower Cardiovascular Disease by Lowering Inflammation (LDL Not Important)
The JUPITER study showed that the statin Crestor was effective in lowering heart disease, because it lowered inflammation. Individuals with chronic inflammation responded to Crestor by lowering inflammation. Lowering of LDL levels, however, was not related to decreasing disease. Elevated LDL levels may reflect inflammation.
Relating the JUPITER results to the AHA conclusions suggests that LA and AA may reduce inflammation and as a consequence also reduce serum LDL.
Inflammation Is the Cellular and Tissue Response to Many Stresses
The list of pathogens that trigger inflammation is long and includes specific signals from viruses, bacteria, fungi and protozoa. Pathogen-caused damage, as well as physical trauma, cause inflammation. Disruption of cellular metabolism and energy flow by vitamin, mineral, amino acid, or fatty acid deficiencies or excesses all produce inflammation. One of the difficulties of diagnosis is the overlapping of symptoms originating from numerous sources of underlying inflammation. Herniation of vertebral disks, for example, can be triggered by physical trauma, but it also may be initiated by the intestinal inflammation of gluten-based celiac. Acne and depression are common symptoms of chronic inflammation that may result from dietary deficiencies, gum disease, gluten sensitivity, etc. All of these examples respond to anti-inflammatory diets.
It is difficult to identify the sources of inflammation in experimental studies. In cardiovascular disease, the sources of inflammation are commonly not known in individual cases and the cardiac symptoms are treated. In reality, these are actually many different diseases, all with different sources of inflammation, pigeon-holed under the same symptom, a cardiac event. The most effective long term treatment for the dispart group is general suppression of inflammation. Any specific treatment of a root cause only works on a small subset of the group and would be considered ineffective. Thus, statins are considered effective against heart disease, because they reduce inflammation that is common to the whole group. Reduction of LDL is inadvertently used as a measure of control of inflammation and has become inappropriately designated as a risk factor. Directly lowering LDL has no impact on heart disease, but it is easy to measure. Inflammation is hard to measure and finding the source of inflammation is harder still.
Omega-6 Vs. Omega-3 Is Another False Dichotomy
Just as there is no opposite to inflammation, omega-6 and omega-3 fatty acids are not in opposition. The action of aspirin is the big clue. Aspirin changes the structures of the enzymes involved in converting AA into inflammatory prostaglandins and leukotrienes, with the result that anti-inflammatory lipoxins are produced instead. Aspirin is a biochemical switch that mimics the natural transition of the cellular machinery from producing enzymes that accentuate inflammation, to enzymes and signals that are the next step in the cycle, repair and restoration of normalcy.
Omega-6 PUFAs are needed for both inflammation and restoration of normal cellular functions. Some of the enzymes produced during inflammation are needed for the reset to normalcy. The difficulty comes when inflammation is sustained, components are depleted and the cycle cannot be completed. The result then is chronic inflammation, the symptoms of metabolic syndrome and degenerative diseases.
Why Did Demonizing LA and AA Seem Right?
It seems wise not to trust medicine, dietitians and the food industry, because they have made so many lamentable mistakes making dietary suggestions that have shortened so many lives. Professional societies like the AHA also frequently give silly advice, because the advice doesn’t reflect the best information from the biomedical literature. So it makes sense to be skeptical.
In this case the AHA appears to be right, only because established views were supported by straightforward experiments. What determines if an excess of dietary LA and AA is going to be a problem with inflammation is the absolute amount of AA and EPA available on the surface of immune cells. PUFAs are attached as part of the phospholipids of the lipid rafts on the membrane surface of immune cells that have received a inflammatory signal, e.g. bacterial lipopolysaccharide. There is usually adequate AA to be converted by enzymes on the cell surface to produce further inflammatory signals. The problem comes if there is so much AA that the EPA never made it to the lipid rafts. The result would be inadequate EPA conversion to anti-inflammatory prostaglandins and failure to return to normalcy. This would be a particular weakness in the presence of a large depletion of the EPA pools during sustained inflammation and chronic inflammation would result.
Thus, the AHA promotion of omega-6 PUFAs is half right. They should have said that omega-6 fatty acids are not a problem, if there is adequate EPA/DHA and no sustained inflammation. Unfortunately, the Western diet provides inadequate EPA/DHA and deficiencies that constantly produce inflammation. Of course, those enjoying an anti-inflammatory diet and lifestyle have biochemical tolerance for the AHA’s suggestions. Others eat vegetable oils at their peril.
Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ, Engler MM, Engler MB, Sacks F. 2009. Omega-6 Fatty Acids and Risk for Cardiovascular Disease. A Science Advisory From the American Heart Association Nutrition Subcommittee of the Council on Nutrition, Physical Activity, and Metabolism; Council on Cardiovascular Nursing; and Council on Epidemiology and Prevention. Circulation. 2009 Jan 26. [Epub ahead of print]