For many, the morning cup of coffee is a can’t live without ritual. There are studies that show moderated daily coffee is healthy for you (some of that here). For me, it kind of makes me shaky. I drink it few and far between. That’s a personal thing, of course. However, when I do drink it, I always put butter in it. As weird as it sounds, it’s actually the best thing you can put in your coffee.
When I get in line at Starbucks, I order a plain black coffee and ask them for a side of butter. They give me some pretty odd looks, but what I already know is that every Starbucks has butter packets on hand to go along with their oatmeal. And what’s more? It’s Kerrygold Irish butter. And that’s grass fed.
So what health benefit would one get from this?
Coffee can be a starting point for health, but it can also be an ending point just as easily. People order / make their coffee in all shapes and sizes. Some people add sugar laden creamers or hormone laced milk. While others might just add a little cinnamon. Those concoctions offer vastly different health profiles. Having just sugar and caffeine first thing in the morning sets up impending doom for the rest of your day. You are almost sure to crash out at some point, only to find yourself digging around for candy or a muffin.
The first health benefit you get from putting only butter in your coffee is that you are leaving out the bad stuff. A huge part of a healthy lifestyle is what you don’t eat. The butter is a fat, which will also help blunt blood sugar spikes.
Butter is almost a pure fat. That’s going to scare a lot of you, but really, it shouldn’t. Fat is good (mostly). And the idea that fat is a villain has been almost entirely debunked at this juncture. Saturated fats can actually improve your blood lipid profile (here).
Grass fed butter is loaded with Vitamin K. Wait, what? Vitamin K is awesome. And it’s sure great for the heart. There is K1 (phylloquinone), found in leafy greens, and Vitamin K2 (menaquinone), which is found in animal foods. Vitamin K2 is especially important because it helps keep calcium out of your arteries.
So far, what do we have? Putting butter in your coffee means skipping garbage sugary or hormone laced concoctions. Your arteries are less likely to be subject to calcification. You reduce your risk of coronary heart disease (here).
But hold up, its going to get better.
Person drinking coffee with butter in it…..meet Butyrate. Butyrate is a fatty acid and it is anti-inflammatory. Inflammation is pretty much the cause of all evil in the body. When excessive inflammation lurks, so does bad healthy profiles. Butyrate is shown to lower inflammation (here).
CLA (conjugated linoleic acid) is found in grass fed butter and it has been linked to reducing body fat mass. Yep, your old coffee was plumping you up, your new coffee is slimming you down! You can see a study here.
But how gross does it taste?
I get this question all the time. The answer is that it taste great. And no, I’m not just saying that. You have to stop thinking of it as butter, and start understanding that at the end of the day, it is just heavy cream. If you put butter and cinnamon in your coffee, it taste amazing. Now, again, we are talking grass fed butter here, not just any old butter. The most popular is Kerrygold butter, but if you have a store that sells local products you can likely find whatever suits you.
The point in all of this? Your morning coffee can be a true health bomb!
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The proverbial brick wall of bad dietary advice is a-crumblin’. This week brings truly world-changing news in the field of nutrition.
On May 8, the Academy of Nutrition and Dietetics (formerly the American Dietetic Association) made its official comments on the 2015 Dietary Guidelines for Americans, and recommend dropping saturated fat from nutrients of concern due to the lack of evidence connecting it with cardiovascular disease.
However, because past advice from the Academy and others has caused issues with ALL of our body systems, I would also argue that this is actually earth-shattering news in the world of cardiology, nephrology, lipidology, endocrinology, pulmonology, orthopedics…. you get the point.
The Academy supported the scientific process used by the Dietary Guidelines Advisory Committee (DGAC) in drafting its recommendations for the 2015 Dietary Guidelines for Americans, but had somewhat different interpretations:
- They supported the DGAC in its decision to drop dietary cholesterol from the nutrients of concern list and recommended that it also drop saturated fat from nutrients of concern, citing a lack of evidence connecting saturated fat with cardiovascular disease;
- Expressed concern over blanket sodium (salt) restriction recommendations in light of recent evidence of potential harm to the larger population;
- Supported an increased focus on reduction of added sugars as a key public health concern; and
- Asserted that enhanced nutrition education is critical to any effective implementation.
Why is all of this so earth-shattering? Well, it brings an end to the era of jumping to conclusions and issuing recommendations before we had the science. It brings an end to a big experiment on the American people and, by extension, the rest of the world, which has failed miserably. It is an acknowledgment that the recommendations to restrict fat, most particularly saturated fat, which led to the recommendation to eat more than half of our energy intake EVERY day from carbohydrates was…WRONG! Yes, the food pyramid, eating sugared cardboard products and highly processed vegetable oil instead of real foods like meat and eggs were all just, I have to say it again, plain WRONG.
As an obesity physician who sees the fallout from the previous guidelines in the poor health of my patients every day, I am thrilled. I am thrilled because this means that more people will be helped. More people can realize that much of the reason that they are obese, have diabetes, high cholesterol, or metabolic syndrome is NOT all their fault. Yes, I really just said that. (What? Not blame a fat person for being fat? Uh, exactly. )
This is not news for the community of bariatrics physicians. We knew that fat was not the cause of the disease we treat nor for the related diseases, such as diabetes or metabolic syndrome. In fact, when the U.S. Department of Agriculture and later the American Dietetic Association (now the Academy of Nutrition and Dietetics) began recommending reducing fat and pushing an increased intake of carbs was exactly the years when our obesity and diabetes epidemic began. Just a correlation? We have much reason to think it is far more than correlation and is actually the cause.
That’s why in a recent TEDx Purdue talk I gave it the title “Reversing Type 2 diabetes starts with ignoring the guidelines.” The guidelines have been misguided for years, and work against patients with obesity, Type 2 diabetes, or metabolic syndrome.
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“Essential minerals” – what are they?
The word “minerals” means different things in different sciences. In geology, ‘minerals’ are chemical compounds that are not made by biological organisms – quartz would be an example. In biology, however, the word “mineral” refers to chemical elements, (not chemical compounds) – any element except hydrogen, carbon, nitrogen, and oxygen (which are considered too ‘organic’ to be called minerals).
An “essential mineral” is a mineral that is required by organisms for survival or at least for health. Thus, the essential minerals include the elements calcium, chlorine, chromium, cobalt, copper, iodine, iron, magnesium, manganese, molybdenum, phosphorus, potassium, selenium, silicon, sodium, sulfur, and zinc. The elements boron, nickel, tin, and vanadium are also suspected to be essential minerals. Proponents of germanium supplements claim that germanium is an essential mineral, too, but there is not yet enough evidence to include it in the list.
The essential minerals (which now we’ll just call ‘minerals’) play fundamental roles in all living organisms. Many of them are active parts of enzymes that perform chemical conversions – for example, the sugar-metabolizing enzyme Cytochrome C Oxidase contains copper and iron atoms. Other minerals are structural components of certain tissues – such as silicon, which strengthens connective tissue and nails. Still others serve as regulators and signallers – as with potassium, which is involved in controlling the activity of nerve cells.
Bioavailability of minerals
Minerals enter the body mostly as components of food. But elemental minerals (such as sulfur in the form of yellow sulfur crystals), are generally not bioavailable. To become bioavailable, mineral atoms must be combined with other elements to form chemical compounds. For example, most of the body’s sulfur comes from sulfur-containing amino acids in food proteins. Similarly, the body gets most of its manganese not from nodules of manganese metal, but from manganese-containing substances in food – that is, from plant and animal tissues in which the manganese is already incorporated into enzymes similar to those that our own bodies will make from it.
There is thus a great deal of mineral recycling going on in the biosphere: mineral compounds travel from one organism to another when the latter eats the former. But not all of the minerals found in biological organisms are the result of such recycling of mineral compounds. Some minerals enter the biological world when elemental minerals (such as manganese metal) are converted to chemical compounds (such as manganese carbonate) in the soil or elsewhere – the result both of non-biological chemical reactions and of conversions by bacteria and other microorganisms. As elemental minerals get converted to mineral compounds, these simple inorganic compounds become bioavailable to plants. The plants then perform the conversion to more complex organo-mineral compounds (such as manganese-containing enzymes) which makes them bioavailable to other organisms – to animals, for example.
Transport of minerals into cells
When mineral compounds are consumed in food, the body must somehow absorb the minerals from the digestive tract and make them available to the tissues and cells where they are needed. The process is not a simple one. The minerals cannot simply diffuse into our tissues and through cell membranes into the interior of cells – if they could, their concentrations would fluctuate in accordance with whatever amounts of minerals we happen to consume at any given time. Instead, the mineral-containing compounds (or charged mineral atoms taken from these compounds) are transported into (or out of) cells by transporter proteins – molecular devices embedded in cell membranes that recognize the minerals and allow only certain kinds to pass through the membranes. This system permits cells and tissues to regulate their internal concentrations of minerals.
Looked at from an engineer’s viewpoint, an organism’s mineral transport system serves as a regulatory device for maintaining adequate, but non-toxic, levels of mineral atoms inside cells.
The number of different kinds of transporter proteins present in a single organism is amazing. In plants, for example, there are many hundreds of different transporter types, each specialized for certain minerals, for certain tissues, and for certain conditions. Some transporters perform only “export” operations (that is, they allow certain minerals to leave the cell but not to enter it). Others are ‘importers’. Each is regulated by the conditions around it as well as by signals coming from inside or outside the cell.
Despite the large number of different transport types, a given transporter does not necessarily have the ability to specialize in a single mineral. While each transport protein seems to have a certain mineral it ‘prefers’ to transport, many of them handle additional minerals to a lesser degree. This overlap in functionality can be thought of as ‘crosstalk’ (as in a poor-quality telephone cable that allows the leakage of information between phone lines).
The system of transporter proteins and their regulation is now the focus of intense research, and rapid progress is being made in understanding it. One fact that becomes ever clearer is that the system is extremely complex. Absurdly complex, in fact – like many of the other systems found in nature.
Much of the molecular complexity in living organisms resulted not from necessity but merely from the fact that organisms develop by evolution, not by design. Evolution does not produce elegant or well-designed organisms, it produces organisms whose ancestors managed to survive even in the worst of times. Survival doesn’t require elegance – it requires adequacy, redundancy and luck. The need for redundancy gives rise to organisms that resemble Rube Goldberg machines – a mish-mash of subsystems interacting in ways that any sane designer would take to be a joke.
Consequently, the mineral transport systems we find in nature seldom break down completely, but they never work in an optimum fashion. And they do not lend themselves to simple fixes or enhancements.
The complexity of this system of natural mineral transporters is unfortunate from our standpoint. Although its multiplicity of parts with overlapping functions makes it less likely to fail completely when some of the parts are defective (as they always are), this multiplicity also makes the transport system resistant to improvement. An elegant and well-designed mineral transport system would be one with a relatively small number of different transporters, each completely specialized with respect to minerals, the direction of transport, and the range of conditions under which it operates. Such a system would be relatively easy to enhance: for example, if one wished to enhance a particular type of vanadium transport, one might develop an inhibitor for the old vanadium transporter and develop an artificial vanadium transporter with desired properties, and supply the two together to the body as a combination treatment. But the natural mineral transport system would foil such an intervention: any inhibitor we might develop for one transporter would quite likely affect other transporters as well, since there is so much overlap in their functionality. And the effects of the artificial vanadium transporter would be partially nullified by regulatory responses of the natural transporter system.
Nevertheless, attempts have been made to develop artificial transporters that override the natural ones. No attempt is made to inhibit any of the natural transporters – instead, the intention is to overwhelm them by transporting minerals into cells faster than the natural transporters can get rid of them. This approach has led to the development of several simple artificial transporters which have been used with some success for certain kinds of biological enhancement. Three such artificial transporters are: 2-aminoethylphosphonic acid (AEP), aspartic acid, and orotic acid. They are “artificial” only in the sense that in biological organisms they ordinarily play roles other than that of mineral transporters. Specifically, orotic acid is used in the biosynthesis of DNA and RNA. Aspartic acid is an amino acid that is incorporated into proteins. As for AEP, almost nothing is known about its natural role, and very little effort has been made to find out.
These three artificial transporters have become well-known in the nutritional supplement world because of the work of Hans Nieper, M.D., who studied them clinically for many years. Of the three transporters, Nieper considered orotic acid to be the most useful. He and his collaborators developed a variety of mineral derivatives of orotic acid, of which five are currently available as nutritional supplements in some countries, including Germany and the United States. These are: calcium orotate, lithium orotate, magnesium orotate, potassium orotate, and zinc orotate.
Crude tools are better than none at all
The above survey of mineral transporters should have made it clear that our current technology for enhancing the role of minerals in our bodies is still quite primitive. We have available, as mineral supplements, a few ‘artificial’ transporters that are capable of overriding the natural transporters in some situations, but which lack any regulatory features of their own. The natural transporter system, on the other hand, while overflowing with regulatory features, lacks the basic separation of functions one would find in a rationally designed system. Natural transporters evolved without any consideration of human interests or desires – basic survival was all that counted. Both sets of transporters can therefore be considered highly flawed.
Considering the fact that natural transporters at least have a track record of seeing our ancestors through some very bad times, whereas the new artificial transporters have only their brute force capabilities to their credit, is it sensible to use these crude new tools to enhance the old ones? The answer is “yes”. It makes as much sense as using any other biomedical technology of the early 21st Century – all of it is primitive, but it’s the best we have. Despite the ridiculous statements one sometimes hears – to the effect that “the human body is Nature’s masterpiece” – the fact is that, like other living organisms, the human body is a ramshackle construction that barely works even when we’re young and healthy, and fails us completely in the long run. We should therefore seek out and utilize methods for controlling or improving the way our bodies work – with appropriate caution and attention to unintended side effects. After all, we know what happens when we rely on our unenhanced bodies: our health deteriorates, we grow decrepit, and we die. Only by making use of the tools that we discover and develop will we have any chance at all of avoiding this fate.
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There are several categories of what I’ll call ‘artificial mineral transporters’ – that is, substances that are employed to enhance the passage of minerals through the intestinal wall into the blood, from the blood into the tissues, or through cell membranes into cells. (See the article Mineral transport.) Among these transporters are: colloids, amino acid chelates, carbohydrate chelates, plant chelates, and organic salts. In addition, I’ll discuss a category called ‘inorganic salts’ which are neither artificial nor transporters, but are simply a form in which minerals often occur in foods. We’ll take a brief look at each of these types.
These are simple mineral compounds such as magnesium sulfate or potassium chloride. (Carbonates, such as lithium carbonate, are usually classified as inorganic salts, although it would be more logical to consider them organic.) The body is accustomed to dealing with minerals in this form, but doesn’t always do a good job of controlling absorption. Although mineral absorption increases when there is a mineral shortage, and decreases when mineral levels are high, the body’s mineral transport system often misregulates minerals that share the same transport channels. For example, when copper and zinc salts are consumed together, they compete with each other for transport into the body. An excess of zinc can therefore cause a deficiency of copper.
If one’s purpose in using mineral supplements is to force the body to use more minerals than it normally would, the inorganic salts would be a poor choice.
Colloids are materials made up of solid particles of such small size that when dispersed in water they remain in suspension rather than sinking. “Colloidal mineral” supplements consist of mineral salts or other mineral compounds converted into colloidal form, either by grinding or by rapid crystallization.
Most colloidal substances are poorly bioavailable, since the colloidal particles, small as they are, are nevertheless far too large to be intestinally absorbed whole, and nearly all of the active ingredients are trapped in the interior of the particles, where they cannot come into contact with the transport channels in the cells of the gut. However, if a colloidal substance can dissolve into the coating of the gut, it would then release all of its mineral material for potential absorption. At this point, the material would no longer be a colloid and its absorption characteristics would become those of its components – i.e., inorganic salts, chelates, or whatever.
The word ‘chelator’ refers to a substance consisting of molecules that bind tightly to metal atoms, thus forcing the metal atoms to go wherever the chelator goes. The bound pair – chelator plus metal atom – is called a ‘chelate’. Chelators of nutritional interest include amino acids, organic acids, proteins, and occasionally more complicated chemicals found in plants.
One particular chelator that we specifically want to exclude from this discussion is EDTA (EthyleneDiamineTetraacetic Acid), which is used in a controversial treatment called “Chelation Therapy”. It involves injections of EDTA into the blood to remove (often imaginary) metallic “toxins”.
We are interested here in chelators that are intended to carry mineral atoms into the body, or into the cells themselves, in larger amounts than the body would normally allow. It is proposed that the chelators are treated as desirable molecules by the recognition systems in cell walls, and are therefore given entry into the cells, along with their baggage of mineral-atoms. When this process occurs in the cells lining the digestive tract, the minerals gain entry to the bloodstream; when it occurs in the cells lining the blood vessels, the minerals gain entry to other body tissues.
Amino acid chelates
Amino acids have three basic parts: the amino ‘group’ (i.e., group of atoms), the acid group, and the R-group. It is the R-group that determines the name and specific character of an amino acid – determining, for example, whether the amino acid is aspartic acid or lysine or tryptophan.
Amino acids can act as chelators when they react with positively charged metal atoms, forming a strong chemical bond. The metal atoms of interest here are those that serve as dietary minerals. (These are listed in the article List of dietary minerals.) To take a specific example, a chelate can be formed between the amino acid arginine (the chelator) and zinc (the mineral).
Certain combinations of minerals and amino acids do not form good chelates because the chemical bonding is too weak. For example, if you try to use the amino acid glutamic acid as chelator and sodium as the mineral, you can get monosodium glutamate, which is considered to be merely an “organic salt”, not a chelate. Monosodium glutamate undoubtedly exhibits some small degree of chelation, but this is outweighed by its character as a salt. Generally speaking, sodium and potassium form poor chelates.
Many minerals form good chelates with amino acids. Some, like lead and cadmium, have no known function in the body and are considered purely toxic. Others can be toxic in high concentrations, but are required by the body in lesser amounts. The latter include: boron, calcium, chromium, cobalt, copper, iron, magnesium, manganese, molybdenum, nickel, tin, vanadium, and zinc.
The argument in favor of using amino-acid-chelated minerals goes like this:
The body is very efficient at absorbing amino acids. Dipeptides (two amino acids linked together via the amino group of one amino acid and the acid group of the other) are especially well absorbed thanks to a dedicated transport system found in cells of the intestinal wall. When mineral atoms are strongly bonded (i.e., chelated) to dipeptides they get dragged by the dipeptides across the intestinal lining and into the body.
Furthermore, amino-acid chelation bypasses the competitive interactions that can occur between different minerals when they are absorbed as salts. (See the “Inorganic salts” section above.) Use of chelated minerals avoids this problem since they are transported by different mechanisms.
How valid is this argument? It’s hard to say, since very little published, impartial research has been done. Albion Laboratories, Inc. – the leading producer of amino-acid chelates – has sponsored many studies of its products, but these cannot be considered impartial. However, the case for amino-acid chelators of iron is a good one and is supported by a number of independent studies. The situation is less clear for other minerals. On the other hand, Albion’s products are widely used for animal and plant nutrition, and that says a lot for these substances, since farmers tend to be pragmatic and are not easily fooled about the health of their crops and animals. It seems likely, therefore, that amino-acid chelates can effectively override the normal mineral regulatory mechanisms both in plants and animals, including humans. (Albion, incidentally, has an excellent collection of research newsletters that focus on medical, veterinary and agricultural usage of minerals.)
This category of chelates is based on a large number of chelators which are called ‘organic acids’. A partial list of the organic acid chelators of interest in nutrition would include: gluconate, lactate, citrate, erythorbate, oxalate, saccharate, succinate, fumarate, 2-aminoethylphosphonate (AEP), picolinate, and orotate. (Grammatical note: chemical names ending in ‘-ate’ can equally well be expressed as ‘-ic acid salt’. For example, ‘zinc lactate’ is the same thing as ‘lactic acid salt of zinc’ or ‘zinc salt of lactic acid’.)
These chelators are called ‘organic acids’ because they are substances found in living organisms and they contain carbon atoms. The bond that forms between organic acids and mineral atoms is a relatively weak one, and is called a ‘salt bond’ or ‘electrostatic bond’. This means that the mineral atom can easily be pulled from the chelator by another molecule (such as a water molecule), or they can be separated by random jostling. Since the purpose of mineral chelation is to cause the mineral atoms to accompany the chelators through cell membranes (i.e., through the walls of the intestines, blood vessels, or other tissues), the organic acids perform only moderately well as chelators.
Gluconate is the most widely used of the organic acid chelators, and has a decades-long record of effectiveness and safety. It is frequently used to correct mineral deficiencies, to treat inflammatory acne, to regulate CD8 T-cells, and for anorexia. Zinc gluconate can also suppress hepatitis symptoms in dogs. There is, however, no reason to think that the gluconate is a highly efficient chelator.
A number of minerals are available as picolinate supplements: boron, chromium, copper, magnesium, manganese, molybdenum, selenium, vanadium, and zinc. Chromium picolinate is widely used to enhance athletic performance, and has been well studied. Vanadyl picolinate shows great promise as a glucose regulator in diabetes. The other picolinates have received very little attention from researchers. It is known that the bioavailability of zinc, copper and magnesium increases significantly when it is combined with picolinic acid in the diet, and that zinc picolinate is superior as a chelate to zinc gluconate and zinc citrate. This scanty information suggests that the picolinates are relatively effective chelators and mineral transporters.
We have a bit more information about the orotates. Magnesium orotate showed good results in studies of athletic performance, both in healthy men and cardiac patients; it improves blood lipid profiles and inhibits arterial plaque formation. Lithium orotate (a freely available nutritional supplement), is at least as good a source of lithium as lithium carbonate (a prescription drug) which is used for treating mental conditions such as manic-depression (bipolar disorder), autism, obsessive-compulsive disorder. Lithium carbonate has also shown benefit in treating the effects of alcoholism. The other orotates have received little research attention except from their developer, Hans Nieper, whose scientific methods left a lot to be desired. The orotates do, however, have a many users and a correspondingly large amount of anecdotal information. For example, calcium orotate is regarded as a good appetite suppressant and cognitive stimulator.
Comparison of chelators
A few researchers have tried to answer the question of which types of chelators produce the highest bioavailabilities of minerals. Theirs were veterinary studies and, unfortunately, they used animals that had first been rendered mineral-deficient by being fed special mineral-deficient diets. This method does not provide information about relative bioavailabilities for the condition we are interested in here, namely: the condition of being a non-mineral-deficient human. We are interested in increasing our intracellular mineral concentrations beyond the levels allowed by ordinary nutrition and by the body’s normal regulatory processes. (See the article Mineral transport.)
The general impression one gets from looking at the published research on this subject is that inorganic salts are adequate mineral sources for correcting dietary mineral deficiencies in healthy people, but that more specialized sources are needed for correcting deficiencies due to disease, or for by-passing the body’s mineral regulators in order to achieve higher-than-normal mineral levels. For these purposes organic salts appear to be better than inorganic salts, and amino-acid chelates appear to be better than the organic salts. Among the organic salts, the picolinates and orotates appear to offer advantages over other available forms.
Future research may paint a rather different picture of the relative values of different mineral transporters than the one painted here. For example, the apparent superiority of the picolinates and orotates is based on indirect evidence, since there is hardly any published research directly comparing the efficacy of these forms with other mineral forms. The orotates remain largely neglected by researchers, and so have the picolinates – with the one exception of Chromium Picolinate. The relative value of different chelators and other transporters may turn out to depend strongly on which mineral one is dealing with, and upon various other factors. For now, our decisions about which mineral supplements to use will have to be guided by the smattering of knowledge available and by our own willingness to experiment with them.
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Heard about CardioPeptase, the proteolytic enzyme sometimes known as serrapeptase or serratiopeptidase? Chances are you haven’t, until now. It’s only been available as a nutritional supplement in the US for the past two years. Yet for over 30 years serrapeptase has been gaining wide acceptance in Europe and Asia as a potent analgesic and anti-inflammatory drug. It’s been used to promote wound healing and surgical recovery. Recent Japanese patents even suggest that oral serrapeptase may help treat or prevent such viral diseases as AIDS and hepatitis B and C. But perhaps its most spectacular application is in reversing cardiovascular disease. In fact, serrapeptase appears so effective in unblocking carotid arteries that one researcher – Dr. Hans Nieper, the late, eminent internist from Hannover, Germany – called it a “miracle” enzyme.
Does this all sound a little too miraculous to be true? Read on. There’s a solid scientific rationale for each of these heath benefits, and they all have to do with the fact that serrapeptase is “proteolytic” (literally, protein-dissolving).
Proteolytic enzymes (also known as proteinases or peptidases) are ubiquitous in nature, being found in animals, plants, bacteria, and fungi. Human beings produce such well known peptidases as trypsin and chymotrypsin to help digest our food, but we also generate countless others to control virtually every regulatory mechanism in our bodies. For example, various peptidases are involved in initiating blood clotting (thrombogenesis) and also in dissolving clots (fibrinolysis); in evoking an immune response and quelling it; and in both promoting and halting inflammation. The mechanism in each case is the ability of the enzyme to cut or cleave a protein target into two or more pieces, usually at very specific cleavage sites. The same mechanism makes it possible for peptidases to inactivate HIV, the AIDS-associated virus, by pruning the viral proteins necessary for infectivity.
The medical use of enzymes as anti-inflammatory agents goes back many years. In the early 1950s it was discovered that intravenous trypsin could unexpectedly relieve the symptoms of many different inflammatory conditions, including rheumatoid arthritis, ulcerative colitis, and atypical viral pneumonia. Subsequently intramuscular enzyme injections were found to be beneficial in counteracting post-surgical swelling (edema), treating thrombophlebitis and lower back strain, and rapidly healing bruises caused by sports injuries.
At that time the mechanism of the anti-inflammatory effect remained obscure. Today it is believed to involve degradation of inflammatory mediators, suppression of edema, activation of fibrinolysis, reduction of immune complexes (antibody-antigen conglomerates), and proteolytic modification of cell-surface adhesion molecules which guide inflammatory cells to their targets. (Such adhesion molecules are known to play an important role in the development of arthritis and other autoimmune diseases.) It’s also thought that the analgesic effect of proteolytic enzymes is due to their cleavage of bradykinin, a messenger molecule involved in pain signalling. However, according to another theory, peptidases such as trypsin may be acting not as anti-inflammatory agents but rather as accelerants of the inflammatory process, thereby shortening its duration. Whatever the mechanism, many studies of proteolytic enzymes over the years have demonstrated their effectiveness in relieving pain and inflammation independently of steroids or nonsteroidal anti-inflammatory drugs (NSAIDs).
Fortunately we don’t need to rely on intramuscular injections any more to enjoy the benefits of proteolytic enzymes. Around 35 years ago researchers showed that enterically-coated enzymes such as trypsin, chymotrypsin or bromelain were orally active. Oral proteolytic enzymes have been used successfully ever since for inflammatory conditions. Recently the intestinal absorption of orally administered serrapeptase has also been demonstrated. To achieve an ideal therapeutic effect, however, it is essential that any enzyme preparation be properly enterically coated so as to release the enzymes in the intestines (where they can be absorbed) and not in the stomach (where they can be digested).
The proteolytic enzymes in common use today derive from bacteria (serrapeptase grown from Serratia marcescens cultures), plants (bromelain from pineapple stem and papain from papaya), and animal sources (trypsin and chymotrypsin from hogs or cattle). They’re all generally useful, but for many applications serrapeptase appears to be the most useful of them all. In one study serrapeptase was compared to trypsin, chymotrypsin, and pronase (another microbial peptidase) in a rat model of scalding, which is known to induce abnormal activation of fibrinolysis. Serrapeptase was far more effective than any other enzyme in repressing fibrinolysis in this model, in agreement with its documented clinical efficacy as an anti-inflammatory agent.
By the way, in case you’ve got a good memory for details, you might have noticed that a few paragraphs back I said the activation of fibrinolysis, not its repression, is one of the likely anti-inflammatory mechanisms of serrapeptase. The truth is that serrapeptase, like other peptidases, can have seemingly contradictory effects at different times under different circumstances. The essential point of the study just cited is that serrapeptase and the other peptidases inhibited abnormal activation of fibrinolysis, and that this was a sign of their anti-inflammatory activity.
In other circumstances serrapeptase is definitely fibrinolytic, i.e., clot-busting, and it is this property that makes it so useful in treating cardiovascular disease. According to Dr. Hans Nieper, only three 5 mg tablets of serrapeptase daily for 12 to 18 months are sufficient to remove fibrous blockages from constricted coronary arteries, as confirmed in many of his patients by ultrasound examination. But that – is still not the whole story – serrapeptase may well offer additional cardiovascular benefits not considered by Nieper. In particular, researchers have recently proposed that inflammation contributes to the development of arterial blockage. In one study, subjects with higher levels of CRP (C-reactive protein, a marker for systemic inflammation) were found to have a greater risk of future heart attack and stroke, independently of other risk factors such as smoking, high blood pressure, or cholesterol levels. Subjects with the highest levels of CRP who also used aspirin, however, showed dramatic decreases in their risk of heart attack, leading the researchers to speculate that the effectiveness of aspirin in preventing heart attack is due as much to its anti-inflammatory activity as to its anticlotting effects.
Serrapeptase, like aspirin, is both anti-inflammatory and anticlotting; unlike aspirin, however, serrapeptase can melt through existing fibrous deposits. Serrapeptase also lacks the serious gastrointestinal side effects associated with chronic use of NSAIDs such as aspirin. This combination of properties makes serrapeptase just about the perfect remedy for warding off cardiovascular disease, better even than the proverbial aspirin a day. It’s beginning to look more and more as though Dr. Nieper was right – serrapeptase is indeed a “miracle” enzyme.
For optimal results in unclogging arteries Nieper suggests combining serrapeptase with other nutritional factors, including bromelain, magnesium orotate, carnitine, and selenium; see the information packet obtainable from the Brewer Library for more details. To avoid possible pulmonary and ileal irritation, Nieper also recommends not exceeding a dose of about three tablets per day for long-term continuous use.
Because serrapeptase is a blood-thinning agent, it’s wise to consult your physician if you’re already taking any form of anticoagulant therapy (or, for that matter, if you suffer from any serious illness). Despite these cautions, however, serrapeptase has an excellent tolerability profile in general. The Japanese company that first developed serrapeptase, recommends up to six 5 mg tablets per day – two tablets three times a day, between meals – for short-term treatment of acute inflammation due to surgery, wound healing, sinusitis, cystitis, bronchial asthma, bronchitis, and breast engorgement in lactating women. (On a personal note, I feel compelled to add an anecdotal observation – my wife finds that six tablets a day are also effective for relieving the pain and edema of PMS-related breast engorgement.)
If you’re already taking proteolytic enzymes such as bromelain or trypsin for sports injuries, arthritis, multiple sclerosis, or any other condition including PMS, try adding or substituting serrapeptase. You just might be amazed with the results. And if you’re not already taking proteolytic enzymes – what are you waiting for? There’s a miracle named serrapeptase waiting to happen for you now.
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This article addresses two biochemical puzzles about the mineral orotates: how they get into cells and what they do once they’re in.
We begin with the fact that the orotate salts are electrically neutral and relatively stable against dissociation, properties that seem to be crucial for the ability of orotates to participate in intracellular mineral uptake and transport. Dissociation is the process that takes place when a salt is dissolved in a solvent such as water and breaks up into its component ions. Table salt dissolved in water, for example, dissociates into sodium and chloride ions. At physiological pH the orotate salts are much more stable than table salt and will not readily dissociate into free orotic acid plus a mineral ion.
Free orotic acid (OA) itself is known to get into cells by simply leaking (diffusing) through cell membranes, rather than by being actively transported. But diffusion is a relatively inefficient process, which limits the amount of OA that can enter a cell. By contrast, uracil – a compound almost identical to OA, only minus the carboxylic acid group – is taken up efficiently by a transporter protein that binds to uracil molecules and drags them into the cell. This transporter appears to be specific for uracil or similar molecules which are uncharged, but not for uracil’s close cousin OA (which is negatively charged at body pH).
Bind the orotic acid with a mineral, however, and you end up with a stable electrically neutral salt. This property is just what is needed for OA along with its bound mineral to be taken up directly by the uracil transporter. At the same time, neutralizing the charge on OA makes the resulting complex more lipophilic or “fat-loving” than free OA; as a result, the stable orotate complex would be expected to diffuse more easily through the lipid membranes of cells. Essentially just such a mechanism was proposed by Nieper for enhancing the diffusion of mineral ions across cell membranes. Either way – via enhanced diffusion or active transport – complexing a mineral with orotate results in increased uptake of both components of the complex by cells.
That’s still not the whole story of orotate, however. Here and there in his papers, Nieper gives tantalizing clues about the role of the “pentose phosphate pathway” or PPP in mediating the effects of his mineral orotates. The PPP is a well-known biochemical cycle which, among other vital functions, is responsible for synthesizing D-ribose 5-phosphate. D-ribose is of course the sugar which gets incorporated into nucleotides (a process known as ribosylation) and ultimately into RNA/DNA. Was Nieper attempting to signal a deep connection between the ribosylation of orotate and its activity as a mineral transporter?
The answer is yes. To see what Dr. Nieper was hinting at, we need some additional background information on OA, also known as vitamin B13.
Although orotic acid isn’t officially considered a vitamin these days, over 40 years ago it was found to have growth-promoting, vitamin-like properties when added to the diets of laboratory animals. Subsequent nutritional studies in humans and animals revealed that OA has a “sparing” effect on vitamin B12, meaning that supplemental OA can partially compensate for B12 deficiency. OA also appears to have a direct effect on folate metabolism.
Many of the vitamin-like effects of OA are undoubtedly due to its role in RNA and DNA synthesis. (B12 and folate are also involved in DNA synthesis, but at a point downstream from where OA comes in.) Our bodies produce OA as an intermediate in the manufacture of the pyrimidine bases uracil, cytosine, and thymine. Together, these pyrimidines constitute half of the bases needed for RNA/DNA, the other half coming from the purine bases adenine and guanine which are synthesized independently of OA.
The enzyme orotate phosphoribosyltransferase (OPRTase), which is found in organisms ranging from yeast to humans, is responsible for catalyzing the first step in the conversion of orotic acid into uridine. It does so by facilitating the attachment of a ribose plus phosphate group to OA. The net result is the formation of a molecule named OMP (orotidine 5′-monophosphate), which in turn is the immediate precursor to UMP (uridine 5′-monophosphate).
Because the enzyme OPRTase requires magnesium ions for its activity, some researchers wondered whether a magnesium complex of orotic acid might be involved in binding orotate to the enzyme. They found that the true substrate for OPRTase is not orotate itself but rather a magnesium orotate complex. The fact that the complex is electrically neutral compared to the negatively charged orotate ion means that the complex is more easily transportable to the active site of the enzyme. These researchers suggested that the magnesium complex helps position orotate within the enzyme in the proper orientation for conversion to OMP. In the process the magnesium ion in the complex gets exchanged with the magnesium ion bound to the active site of the enzyme, the net result being that one magnesium ion is released.
So far, so good. Following up on Nieper’s hint, we see that orotate-and specifically magnesium orotate-can interact with the pentose phosphate pathway (PPP) to generate OMP and ultimately uridine. But Nieper also pointed out that the mineral-transport activity of the orotates does not necessarily have anything to do with the formation of RNA or DNA. To resolve this apparent contradiction, we must seek out an additional metabolic role for orotate independent of RNA/DNA synthesis
In fact, not all the uridine formed from orotic acid does wind up in RNA or DNA. There are other vital roles for orotic acid and uridine in the body-for example, OA gets taken up by red blood cells where it is rapidly converted to UDP-glucose by way of OPRTase and other enzymes. Here UDP is the nucleotide uridine diphosphate. The red blood cells can then act as a storage and distribution pool for delivering glucose and uridine to tissues such as brain, heart, and skeletal muscle. Because UDP-glucose is a precursor for glycogen (a storage form of glucose), the delivery of UDP-glucose to heart muscle and its conversion there to glycogen might account for some of the cardioprotective effects of orotic acid.
Which brings us right back to Dr. Nieper’s work.
Based on the available scientific evidence, it seems clear that magnesium orotate can get channeled directly into OMP synthesis and ultimately into UDP-glucose, which can then resupply a heart under stress with carbohydrates and nucleotides. Thus a mechanism exists for explaining why magnesium orotate works even better than orotic acid for heart conditions. In contrast, some of the mineral orotates such as copper and nickel either inhibit OPRTase or, in the case of calcium orotate, neither activate nor inhibit the enzyme. This suggests that the body preferentially uses magnesium orotate for promoting uridine synthesis. In a sense, complexing OA with magnesium magnifies the “vitamin-like” properties of vitamin B13.
Another effect of magnesium orotate is to inhibit the development of atherosclerosis when administered orally to humans or experimental animals. The animal study in particular tells us that magnesium orotate performs better than orotic acid, which in turn outperforms magnesium chloride, in inhibiting atherosclerotic changes caused by high levels of cholesterol in the diet. In other words, a synergy exists between magnesium and orotic acid such that the complex they form – magnesium orotate – is more potent than either one alone. Dr. Nieper explained this effect by suggesting that when OA in the magnesium orotate complex is coupled with ribose (ribosylated) in the walls of blood vessels, the magnesium ion is liberated during this process and becomes locally available for activating cholesterol-metabolizing enzymes.
The increase in potency of magnesium in going from a chloride salt to an orotate salt is notable and certainly consistent with Nieper’s ideas about orotate as a mineral transporter. But notice that orotic acid also increases in potency in going from free OA to its magnesium complex, an enhancement consistent with the idea that magnesium orotate gets preferentially directed toward uridine synthesis by OPRTase. It is just this combination of properties – enhanced transport of magnesium, itself known for its anti-atherosclerotic and anti-cholesterol effects, and enhanced synthesis of uridine from orotic acid – that makes magnesium orotate so helpful for treating cardiovascular disorders.
By contrast, the very similar compound calcium orotate has none of the effectiveness of magnesium orotate in lowering serum cholesterol, although it does have other characteristics beneficial for treating arterial disease. The difference in activity between magnesium and calcium orotate can best be explained by the specific effects of magnesium in activating cholesterol turnover as well as by the specificity of magnesium orotate-but not calcium orotate-for activating OPRTase.
As the preceding example shows, the various mineral orotates are likely to be targeted to distinct metabolic pathways in specific tissues. Another example is provided by an experiment involving lithium metabolism in the brain. Lithium is well known for its ability to moderate manic-depressive illness. In an experiment to evaluate lithium-induced changes in brain metabolism, rats were injected with a solution of lithium chloride daily for two weeks. One hour after the last lithium treatment all rats received an injection of radiolabeled orotic acid into the cerebral ventricles. At various intervals thereafter RNA was extracted from rat brains, separated into fractions, and analyzed for radioactivity. The results showed that lithium increases RNA turnover markedly in brain (but not in other tissues such as liver). The authors suggested that lithium acts at the membrane level and that the effects on RNA metabolism are due to changes in the transport of radiolabeled orotic acid-an explanation entirely consistent with Nieper’s idea that lithium combines with OA to yield a transportable complex.
In summary, the evidence tends to support Nieper’s criteria for orotate as an electrolyte carrier, namely, (1) a low dissociation constant, (2) an affinity for specific cellular systems or organs, and (3) a metabolic pathway which liberates the transported mineral within the targeted organ or system.
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The research – conducted by pediatric endocrinologist Robert Lustig at UCSF Benioff Children’s Hospital in San Francisco, and Jean-Marc Schwarz of the College of Osteopathic Medicine at Touro University California – examined 43 obese children who had high blood pressure, unhealthy cholesterol levels, or signs of too much fat in their livers. The children were between the ages of nine and 18.
The children were put on a restricted diet which eliminated added sugar from sodas, sweet, and other foods.
Sugar intake was reduced from about 28 percent of total calories to about 10 percent. Fructose – a form of sugar believed to be particularly bad for health – was reduced from 12 percent to four percent of total calories.
Sugary foods were then replaced with starchier alternatives, such as hot dogs, potato chips, and pizza.
“This ‘child-friendly’ study diet included various no- or low-sugar added processed foods including turkey hot dogs, pizza, bean burritos, baked potato chips, and popcorn that were purchased at local supermarkets,” the study authors wrote.
Each child’s caloric intake closely resembled the amount they ate before the study began. However, the children reported feeling less hungry with the new diet.
“They told us it felt like so much more food, even though they were consuming the same number of calories as before, just with significantly less sugar. Some said we were overwhelming them with food,” Schwarz said.
After weighing themselves daily as part of the study’s requirements, one-third of the children said they could not eat enough food to stop losing weight. The children lost an average of nearly two pounds in just nine days.
“I have never seen results as striking or significant in our human studies; after only nine days of fructose restriction, the results are dramatic and consistent from subject to subject,” Schwarz added.
Blood pressure went down by an average of five points. The triglyceride measurement of cholesterol fell by 33 points, and low-density lipoprotein (LDL, also known as “bad” cholesterol) fell by 10 points. Blood sugar and insulin levels also fell. Glucose tolerance and the amount of excess insulin circulating in the blood improved.
“Every aspect of their metabolic health got better, with no change in calories,” Lustig said, adding that sugar isn’t harmful because of its calories or its effect on weight, but rather “because it’s sugar.”
He stressed the study proves “a calorie is not a calorie.”
“Where those calories come from determines where in the body they go. Sugar calories are the worst, because they turn to fat in the liver, driving insulin resistance, and driving risk for diabetes, heart and liver disease,” he said.
The study was published in the journal Obesity on Monday. The researchers noted that further examination is needed to determine whether the short-term gains in health with low-sugar diets remain present in the longer term.
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From earliest recorded history, a procession of emperors, alchemists and charlatans have searched in vain for the mythical elixir of life. So perhaps it should be no surprise that the hunt for a cure for ageing is the latest investment fad among the gods of our time: US technology entrepreneurs.
Larry Ellison, founder of Oracle, and Peter Thiel, co-founder of PayPal and an early Facebook backer, are among those to have poured personal wealth into the quest. They were joined last year by Google, whose secretive biotech start-up, Calico, is receiving hundreds of millions of dollars from the internet group to support its bid to unlock the secrets of ageing.
Some have mocked such ventures as Silicon Valley hubris. But others believe these west coast visionaries have accurately anticipated the next big breakthrough in medical science: a significant extension in healthy human lifespan.
Finding ways for people to live even longer might sound like the last thing needed in a world whose ageing population increasingly looks like a social and economic time-bomb. But what if life could be extended in such a way that allowed people to remain active and economically productive for longer?
This was the vision set out by Jay Olshansky, professor of public health at the University of Illinois, when he presented a paper to an audience including Sergey Brin, co-founder of Google, two years ago.
“He was asking some interesting questions about what our health priorities should be,” recalls Prof Olshansky. “I told him a cure for cancer would create more problems than it solved because if you save people from one disease you are just exposing them to an increased risk of dying from something else. The aim should be to look at the underlying risk factors behind age-related diseases.”
Prof Olshansky cannot be sure that he influenced Google’s decision to create Calico – short for the California Life Company – but he says its push on ageing research has brought credibility to a field once associated with cranks and dreamers.
Google’s potential to use its powers of data analysis to advance medical science has made big pharma take notice. In September, AbbVie, the US drugmaker, agreed an alliance with Calico that will see the pair jointly invest up to $1.5bn to develop treatments for age-related conditions.
Arguably the most pressing medical challenge posed by an ageing population – and one of the biggest commercial opportunities – is Alzheimer’s disease. Worldwide incidence is projected to triple to 135m cases by 2050 but so far no drug has been found to slow the memory-erasing condition, less still cure it.
Companies have lost hundreds of millions of dollars in failed trials, leading some such as Pfizer and Sanofi to drop out of the race. Others have doubled-down. Eli Lilly, for example, last year embarked on its third late-stage trial after two failures. Trafford Clarke, managing director of Eli Lilly’s neuroscience research centre, says: “We’ll find out in two years whether that was the smartest decision we’ve made or whether we’ll be thinking ‘what possessed us to do that?’”
While an Alzheimer’s drug would be a big prize, a treatment for ageing itself would be even bigger. Calico is one of several start-ups exploring this frontier. Another is Human Longevity, founded by Craig Venter, the celebrated US geneticist, with the goal of “expanding a healthier, high performing, more productive lifespan”.
Some of the most promising science is in the field of regenerative medicine, which involves repairing or replacing malfunctioning cells and tissues.
Prof Olshanksy believes that, rather than trying to cheat death, the priority should be to “close the gap between when you die and when you get frail”. This could produce huge social and economic benefits in reduced healthcare costs and increased productivity and consumption.
Others are more explicit about their desire to extend life itself. “There is nothing built into our biological system that says we can only live for a certain number of years,” says Michael Kope, chief executive of the Sens research foundation, an anti-ageing research charity.
The oldest human on record was Jeanne Calment, a French woman who died in 1997 aged 122. What would be the social implications if such a lifespan became commonplace in future? Mr Kope says the world would adapt. “When we give vaccines to children we don’t say ‘what are we going to do with all those extra people?’ We do it because saving lives is the right thing to do.”
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People often think of external microbes as their worst enemy during an outbreak of influenza or bronchitis, but the body’s own immune system is potentially more lethal. When the body detects foreign microorganisms indicating an infection, it might respond by over-protecting the site of infection. It may race so many antibodies to the infection site that they collect in a cytokine storm. When the infection is in the lungs, for example, this response can potentially block airways and result in suffocation. Medical researchers have identified the causes and stages of the reaction and are working on treatments to weaken an overactive immune response.
At all times, white blood cells circulate in the bloodstream and are the first to sense if a virus or bacteria has infiltrated the body. Immediately, other immune cells, including T-cells and macrophages, are sent to attack the infection. During this stage, a person’s immunity functions properly, and immune cells attack the microbes so they do not get too strong a foothold.
For reasons that are not completely understood, too many immune cells can be sent to the infection site. This happens when a particular type of molecule in the body, known as cytokines, activate the immune cells at the infection site and cause more immune cells to flood the site of infection. This propagates what is referred to as a cytokine storm, where far too many immune cells are caught in an endless loop of calling more and more immune cells to fight the infection. The reaction ends up inflaming the tissue surrounding the infection.
When the infection is in the lungs, this severe inflammation can cause permanent damage. A prolonged cytokine storm will eventually shut down breathing completely. The airways get clogged, and cells no longer properly absorb oxygen. This is what makes the reaction so deadly in certain epidemic strains, such as bird flu. Even bronchitis, other varieties of influenza, pneumonia, sepsis, and possibly rheumatoid arthritis are susceptible to triggering a cytokine storm.
Of course, flu vaccines are usually effective at preventing the flu during its peak season, but they are no guarantee, especially when flu strains mutate after the vaccine has been manufactured. Therefore, researchers are pursuing other methods of preventing this extreme immune response by bioengineering a drug that could slow the snowball effect of antibodies. They hope to force the cytokines to recirculate in the bloodstream, rather than pool in the area of the infection. Experts predict that a major influenza pandemic could kill millions of people worldwide, as it has done in centuries past.