11 posts categorized "Nutritional Supplements"

April 04, 2013

What's Wrong With Nitric Oxide - Part 3


Ask a cardiologist about the effects of nitric oxide, and there’s a good chance you’ll hear about the chemical’s role in dilating blood vessels, lowering blood pressure, and supporting cardiovascular health.

Ask a neurologist about nitric oxide, and you’ll likely to hear about the widespread cellular damage this chemical can cause, and how an excess of nitric oxide in the brain is now thought to be a major contributing factor to degenerative neurological diseases like Alzheimer’s disease, Parkinson’s disease, and ALS.

And, ask an oncologist for yet a third opinion, and you may hear about nitric oxide’s role in either suppressing tumor growth – as a potent tumor–killing agent of the immune system; or, conversely, its role in stimulating tumor growth by triggering angiogenesis, the formation of the new blood vessels tumors need to survive.

So, clearly, nitric oxide has many varied effects within our bodies – some beneficial, and some very harmful. This is the fundamental reason why so many attempts to manipulate nitric oxide levels, either pharmacologically or nutritionally, have met with failure.

As relates to the cardiovascular system, for example, it was initially thought that increasing nitric oxide levels would be the key to correcting what was simplistically assumed to be a “deficiency” of nitric oxide in cardiovascular disease. But this approach is quickly being abandoned, as a myriad of unforeseen (and sometimes fatal) side effects have accompanied nitric oxide–boosting therapies.

Of course, some nutritional supplement companies, and some health practitioners (whose products and recommendations lag decades behind the actual research) continue to recommend that we indiscriminately increase our nitric oxide levels with various nitric oxide–boosting concoctions. But the flaws inherent in such an approach are now well–documented, even if not yet well–publicized.

In light of what we now know about the often harmful effects of nitric oxide, it seems that we’ll want to do everything we can, not merely to increase nitric oxide levels, but to keep nitric oxide production under tight control throughout the body.

A Brief Review

When produced, nitric oxide rapidly reacts with a chemical called superoxide, to form a particularly damaging chemical called peroxynitrite. It’s now believed that this process is largely to blame for many of the harmful effects of nitric oxide.

When nitric oxide–boosting therapies are employed – like the use of the amino acid precursor to nitric oxide, arginine – or the nitric oxide pro–drug, nitroglycerin, the production of peroxynitrite increases right along with nitric oxide itself. And the result has often been a short–term benefit, marred by longer–term harm.

Recent research has found, however, that we may be able to give our nitric oxide metabolism a nutritional “tune–up,” without increasing our burden of harmful nitric oxide byproducts. The answer lies not in “boosting” nitric oxide, but in supplying our body with the nutrients needed to metabolize nitric oxide safely and efficiently.

In the last Integrated Supplements Newletter, we looked at nutritional factors like folic acid, Vitamin B6, and Vitamin B12 which may reduce homocysteine and simultaneously protect the fragile nitric oxide cofactor, called tetrahydrobiopterin.

We saw how antioxidant nutrients like Vitamin E, Vitamin C, selenium, and whey protein isolate may help to reduce the oxidative stress which constantly threatens nitric oxide metabolism.

We even saw how cocoa flavonols and creatine monohydrate may exert especially beneficial effects on nitric oxide metabolism.

Building on these strategies, we’ll now look at other nutritional factors which will help support proper nitric oxide metabolism in the cardiovascular system and beyond.

This Is Your Brain on Nitric Oxide

In the late 1980’s, an iconic public service announcement on television depicted a frying egg, while an actor sternly warned an entire generation of impressionable Americans, “This is your brain on drugs.” And while this PSA offered a powerful visual metaphor of the effects certain drugs can have on brain function, it may serve us well to look a little deeper into the molecular biology of the matter.

It turns out that much of the toxicity associated with neuro–active drugs is ultimately due to the actions of nitric oxide. In fact, the chemical inhibition of the enzymes which produce nitric oxide has been shown to abolish the toxicity associated with both methamphetamine and cocaine.

Study Link – Nitric oxide (NO) synthase inhibitors abolish cocaine–induced toxicity in mice.

Quote from the above study:

Repeated administration of cocaine (45 mg/kg/day) for 7 days to Swiss–Webster mice resulted in a progressive increase in the convulsive response to cocaine and augmentation in lethality rate. Pretreatment with the nitric oxide (NO) synthase inhibitors, L–NAME (100 mg/kg/day) or NO–Arg (25 mg/kg/day), prior to cocaine administration completely abolished the sensitization to the convulsive and lethal responses to cocaine. These findings suggest a role for NO in cocaine–induced toxicity.

Study Link – Role of nitric oxide in methamphetamine neurotoxicity : Protection by 7–nitroindazole, an inhibitor of neuronal nitric oxide synthase.

Quote from the above study:

These findings indicate a role for nitric oxide in methamphetamine–induced neurotoxicity and also suggest that blockade of NOS may be beneficial for the management of Parkinson's disease.

And you don’t have to be a drug–user to be susceptible to the neurotoxic effects of nitric oxide. The damage caused by nitric oxide and its metabolites has been very strongly linked with age–related brain degeneration, and disorders such as Parkinson’s disease, ALS, and Alzheimer’s disease.

Study Link – Nitric oxide neurotoxicity.

Quote from the above study:

NO has many roles in the central nervous system as a messenger molecule, however, when generated in excess NO can be neurotoxic. Excess NO is in part responsible for glutamate neurotoxicity in primary neuronal cell culture and in animal models of stroke. It is likely that most of the neurotoxic actions of NO are mediated by peroxynitrite (ONOO−), the reaction product from NO and superoxide anion.

Study Link – Widespread Peroxynitrite–Mediated Damage in Alzheimer's Disease.

Quote from the above study:

These findings provide strong evidence that peroxynitrite is involved in oxidative damage of Alzheimer's disease.

Studies have found, as well, that mice bred to be deficient in one of the nitric oxide–producing enzymes had decreased mortality, and were significantly protected from many of the manifestations of Alzheimer’s disease:

Study Link – Protection from Alzheimer's–like disease in the mouse by genetic ablation of inducible nitric oxide synthase.

Quote from the above study:

Deficiency of iNOS substantially protected the AD–like mice from premature mortality, cerebral plaque formation, increased ß–amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of ß–amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.

And, in addition to degenerative brain diseases, nitric oxide has also been implicated in other neurological disorders such as migraine headaches:

Study Link – Nitric oxide is a key molecule in migraine and other vascular headaches.

Study Link – Nitric oxide–induced headache in patients with chronic tension–type headache.

Study Link – Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain.

The following study even found that those with migraine headaches may be at increased risk of developing Alzheimer’s disease later in life. The common role of nitric oxide in each disorder helps to explain why.

Study Link – Risk factors for Alzheimer's disease: a population–based, longitudinal study in Manitoba, Canada.

Quote from the above study:

The association of AD with a history of migraines and occupational exposure to defoliants/fumigants is of particular interest because these are biologically plausible risk factors.

Nitric oxide is even suspected to play a major role in the development of the chronic ringing in the ears known as tinnitus:

Study Link – The NO/ONOO– cycle as the etiological mechanism of tinnitus.

Study Link – Pharmacological models for inner ear therapy with emphasis on nitric oxide.

At first glance, it may seem ironic that nitric oxide, a compound deemed so beneficial for cardiovascular health, could be so universally maligned for its harmful role in neurological health.

But of course, we now know that there is much more to nitric oxide metabolism than was once assumed. Though a certain amount of nitric oxide is necessary for cardiovascular function, any excess can be decidedly harmful. As we’ll see, the same general principles (ensuring the proper metabolism of nitric oxide) apply when addressing nitric oxide metabolism in the brain and in the neurological system.

Nitric Oxide – Inflammatory Chemical

One of the ways in which nitric oxide can be produced in the body is via an enzyme known as inducible nitric oxide synthase (iNOS). Immune cells, called macrophages, contain iNOS, and can produce nitric oxide to destroy invading viruses or bacteria, or under other conditions of stress and trauma. This means that nitric oxide is an integral part of our bodies’ immune system and inflammatory response, but it also means that the production of nitric oxide by macrophages can very easily spiral out of control.

Unlike endothelial nitric oxide synthase (eNOS, the form of nitric oxide synthase which produces NO in the blood vessels), iNOS can churn out massive amounts of nitric oxide virtually non–stop. This excess nitric oxide (and the metabolites produced from it) can be particularly harmful to the delicate, lipid–rich structures of the brain. And, as we now know, inflammation and tissue damages often proceeds in a vicious downward spiral, perpetuating even more tissue damage and inflammation. This is a major reason why nitric oxide production needs to be kept under control in conditions of stress, aging, and disease.

As we mentioned in previous issues of the Integrated Supplements Newsletter, we ideally want any inflammatory response of our immune system to be “short and sweet” – sufficient enough to deal with the stress at hand, but not excessive enough to cause a self–perpetuating spiral of tissue destruction.

Reducing Inflammation Safely

It’s now widely accepted that all degenerative diseases share the common thread of excessive and uncontrolled inflammation – including the over–production of nitric oxide. But, for as many anti–inflammatory foods, drugs, and supplements as we have at our disposal, reducing systemic inflammation safely still takes a bit of biochemical know–how.

For instance, it’s well–documented that some “anti–inflammatory” strategies may ultimately be destined to do more harm than good. The dangerous side effects associated with the wildly popular COX–2 inhibitor medication, Vioxx® are a chilling reminder of this; and, in the May 2008 edition of the Integrated Supplements Newsletter, we saw how even many of the “anti–inflammatory” fats often recommended by the health–food and nutritional supplement crowd (omega–3s, for example) may predispose us to tissue fragility and destruction when consumed in excess.

On the other hand, when we attempt to reduce inflammation in a physiologically sound manner, we’ll find that the pieces of the puzzle fit together in such a way as to actually give us far–reaching health benefits.

As relates to nitric oxide, we’ll find that some nutritional substances can serve to reduce the excess production of inflammatory nitric oxide produced by the immune system, while at the same time improving the bioavailability of the nitric oxide produced within the cardiovascular system. The most important nutrient offering such a two–pronged benefit is likely to be the often overlooked mineral, magnesium.

Magnesium and Nitric Oxide

According to data from the United States Department of Agriculture, a full 68% of Americans fail to consume the minimum recommended amount of magnesium each day; and a stunning body of scientific evidence indicates that very few nutritional deficiencies are as widespread, or as deadly, as magnesium deficiency.

Many people know that the electrolyte mineral, magnesium, is involved in “electrical” functions of the body like the heartbeat, and nerve impulses, but very few people realize that the presence of a magnesium deficiency leads to an absolutely massive increase in various markers of systemic inflammation.

The list of biological substances increased in the body when magnesium is deficient reads like a “who’s–who” of inflammatory chemicals. C–reactive protein, substance P, cytokines, prostaglandins, histamine, and of course, nitric oxide all become elevated when magnesium levels are sub–optimal.

Study Link – The nerve–heart connection in the pro–oxidant response to Mg–deficiency.

Quote from the above study:

In rodent models of dietary MgD [magnesim deficiency], a significant rise in circulating levels of proinflammatory neuropeptides such as substance P (SP) and calcitonin gene–related peptide among others, was observed within days (1–7) of initiating the Mg–restricted diet, and implicated a neurogenic trigger for the subsequent inflammatory events; this early "neurogenic inflammation" phase may be mediated in part, by the Mg–gated N–methyl–D–aspartate (NMDA) receptor/channel complex. Deregulation of the NMDA receptor may trigger the abrupt release of neuronal SP from the sensory–motor C–fibers to promote the subsequent pro–inflammatory changes: elevations in circulating inflammatory cells, inflammatory cytokines, histamine, and PGE(2) levels, as well as formation of nitric oxide, reactive oxygen species, lipid peroxidation products, and depletion of key endogenous antioxidants. Concurrent elevations of tissue CD14, a high affinity receptor for lipopolyssacharide, suggest that intestinal permeability may be compromised leading to endotoxemia. If exposure to these early (1–3 weeks MgD) inflammatory/pro–oxidant events becomes prolonged, this might lead to impaired cardiac function, and when co–existing with other pathologies, may enhance the risk of developing chronic heart failure.

And, as relates specifically to nitric oxide, it’s interesting to note that magnesium deficiency has the effect of increasing the “inflammatory” nitric oxide (produced by iNOS), rather than the cardioprotective type produced by eNOS (called constitutive NOS in the following study):

Study Link – Magnesium deficiency in rats induces a rise in plasma nitric oxide.

Quote from the above study:

Magnesium deficiency in rats leads to an oxidative stress involving an increased production of radical oxygen species. The present study was designed to examine the effect of experimental magnesium deficiency on plasma nitric oxide (NO) level and nitric oxide synthases (NOS) activities in rats. The data show that the concentration of NO is markedly increased in plasma of magnesium–deficient rats. This rise in plasma NO results from activation of inducible nitric oxide synthase (iNOS) rather than of the constitutive form (cNOS) of the enzyme. These data are in agreement with previous observations indicating that inflammation occurs during magnesium–deficiency and provide an additional cause of oxidative lesions through formation of peroxynitrite from nitric oxide and superoxide anion.

Study Link – Magnesium–deficient medium enhances NO production in alveolar macrophages isolated from rats.

Quote from the above study:

These results suggest that Mg(2+) deficiency enhances NO production via iNOS by alveolar macrophages.

And knowing that nitric oxide is largely responsible for much of the brain deterioration of Alzheimer’s, it’s interesting to find that there may be a direct correlation between magnesium status and the progression of the disease. The following study found that as magnesium status worsened so too did the progression of Alzheimer’s disease as evidenced by falling scores on cognitive tests:

Study Link – Serum magnesium level and clinical deterioration in Alzheimer's disease.

Quote from the above study:

Our data suggest that there is a relationship between serum Mg levels and the degree of Alzheimer's disease and that the determination of the Mg level at various stages may provide valuable information in further understanding the progression and treatment of Alzheimer's disease.

Because of the multiple roles magnesium plays in reducing systemic inflammation and excessive nitric oxide production, a lack of magnesium can exert effects at every level of biological functioning. As evidence, the widespread magnesium deficiency caused by our modern diet is known to be a major factor in the increasing prevalence of all degenerative diseases of aging, including not only brain diseases, but heart disease, diabetes and cancer as well.

And considering the fact that so few individual foods contain high amounts of magnesium (and the fact that multivitamins never contain sufficient amounts) it’s safe to say that a stand–alone magnesium product is often the single most important nutritional supplement a health–conscious person can take. But, even magnesium alone may not be enough to fully rectify a magnesium deficiency. Other nutritional factors, such as selenium, potassium, vitamin B6, and vitamin D, are also needed for proper magnesium absorption and metabolism.

Study Link – The multifaceted and widespread pathology of magnesium deficiency.

Quote from the above study:

Unfortunately, Mg absorption and elimination depend on a very large number of variables, at least one of which often goes awry, leading to a Mg deficiency that can present with many signs and symptoms. Mg absorption requires plenty of Mg in the diet, [selenium], parathyroid hormone (PTH) and vitamins B6 and D.

Curcumin and Nitric Oxide

In addition to correcting outright nutritional deficiencies, there are many other steps we can take to reduce the inflammatory over–production of nitric oxide.

It seems that nature, in her infinite wisdom, has supplied us with many plant–based anti–inflammatory substances which may impart particularly powerful effects when it comes to scavenging nitric oxide. One of the most notable of such substances is the yellow/orange pigment from turmeric, called curcumin.

Turmeric, a member of the ginger family, is a spice which has been long–used in Indian and Chinese cuisine, and respective systems of medicine. Recent research has uncovered that many of the health–promoting benefits traditionally associated with turmeric may be attributable specifically to curcumin; and interestingly, we find that curcumin may act as a powerful scavenger of nitric oxide.

Study Link – Nitric oxide scavenging by curcuminoids.

Quote from the above study:

The results indicate curcumin to be a scavenger of nitric oxide. Because this compound is implicated in inflammation and cancer, the therapeutic properties of curcumin against these conditions might be at least partly explained by its free–radical scavenging properties, including those toward nitric oxide.

And, although some research indicates that curcumin may be poorly absorbed, there’s reason to believe that curcumin and turmeric may exert their health–benefits despite this fact. Even though turmeric contains only about 3% curcumin at the most, and curcumin is likely to be poorly absorbed, preliminary studies conducted in India (where turmeric is very widely used in cooking) have shown some of the lowest levels of Alzheimer’s disease ever recorded – results which held true for both rural and urban communities:

Study Link – Incidence of Alzheimer's disease in a rural community in India: the Indo–US study.

Quote from the above study:

These are the first AD incidence rates to be reported from the Indian subcontinent, and they appear to be among the lowest ever reported. However, the relatively short duration of follow–up, cultural factors, and other potential confounders suggest caution in interpreting this finding.

Study Link – Prevalence of dementia in an urban Indian population.

Quote from the above study:

In the population surveyed, the prevalence of AD and other dementias is less than that reported from developed countries but similar to results of other studies in India.

If these results have anything to do with turmeric consumption, the chances are good that most of us can benefit from simply adding more turmeric–rich meals to our diet. Curcumin extracts do exist as nutritional supplements, but they are very costly relative to the very inexpensive spice, turmeric.

And research indicates that we can find many other inexpensive ways to reduce the inflammatory effects of nitric oxide as close as the local grocery store. Antioxidant compounds in (green and black) tea, coffee, red wine, cocoa, and pomegranate have all been shown to protect against the inflammatory over–production of nitric oxide.

Study Link – Protection against nitric oxide toxicity by tea.

Study Link – The coffee diterpene kahweol suppress the inducible nitric oxide synthase expression in macrophages.

Study Link – Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway

Study Link – Effects of an aqueous extract of cocoa on nitric oxide production of macrophages activated by lipopolysaccharide and interferon–gamma.

Study Link – Pomegranate juice protects nitric oxide against oxidative destruction and enhances the biological actions of nitric oxide.

As we’ve seen in this series of articles, nitric oxide metabolism can be more than a bit complicated. And despite a frenzy of conflicting nitric oxide research, we’ve seen the unfortunate tendency of both the medical community and the nutritional supplement industry to “jump the gun”, and rush to market products based upon dangerous misinterpretations of the scientific evidence.

But, yet again, only as we look deeper into the research, does the big picture become clear. Only then can we address fundamental biological imbalances, and not merely symptoms or biological markers.

And again, we see that carefully–chosen, time–tested natural foods and nutrients offer us the greatest long–term benefit – with little to no risk. The nutrients and foods mentioned in this series of articles are the substances the human body has always needed to support health, but they are often the substances most conspicuously lacking from our modern food supply.

In the final analysis, nitric oxide is just another example of a biological chemical whose actions can seem baffling and paradoxical when we forget to look first to nature for the answers. Only when we remember our role as a part of nature, will the pieces of the puzzle fall neatly into place.

About Us: At Integrated Supplements, our goal is to bring you the wellness information and products you need to live your life to the fullest. We are dedicated to producing the highest–quality, all–natural nutritional supplements; and to educating the world on the health promoting power of proper nutrition. You can find out more by visiting: www.IntegratedSupplements.com


These statements have not been evaluated by the FDA. No Integrated Supplements product is intended to diagnose, treat, cure or prevent any disease.


What's Wrong With Nitric Oxide - Part 2


Given the sometimes overwhelming complexity of biological systems, there’s an almost unavoidable tendency, even among top researchers, and medical professionals, to simplify matters by labeling certain biochemicals simplistically as either “good” or “bad.”

But rarely in biology do substances wear only black or white hats. More realistically, we find that certain substances produced within the body exert protective roles in some situations, but in other situations, when regulatory and stabilizing systems fail, these same substances may be harmful if produced in excess, or metabolized inefficiently. In other words, in an ironic twist of fate, many biological molecules have the tendency to exacerbate the very bodily damage they were initially produced to protect against.

As an example, many researchers believe that the cholesterol which leads to the production of atherosclerotic plaque in the arteries is initially a protective substance. The thinking is, that as a vital component of cellular structure, cholesterol is drawn to the artery to “patch up” microscopic injuries in the arterial wall. It’s only when various cell–signaling and inflammatory systems go awry, however, that cholesterol is altered from a protective to a pathological molecule, eventually resulting in the build–up of the cholesterol–laden plaque associated with heart disease.

Another example of such a two–faced biological chemical is the gaseous signaling molecule, nitric oxide.

Produced as a protective molecule under periods of stress and trauma, nitric oxide is most well–known as a substance integral for the proper dilation of blood vessels. The blood vessels of people with cardiovascular disease, high blood pressure, insulin resistance, and diabetes are almost always dangerously resistant to the vasodilating effects of nitric oxide; and as such, strategies to increase nitric oxide levels and to restore proper nitric oxide signaling in these patients represent a major focus of current nutritional and pharmaceutical intervention.

But so far, the results of such strategies have failed to deliver much in the way of meaningful benefit – and some have even proven deadly. Such puzzling outcomes speak to the dual nature of nitric oxide, as well as the intricate complexity of its metabolism.

As the big picture of nitric oxide becomes clearer, we now know that while a deficiency of nitric oxide function is strongly implicated in cardiovascular disorders, an excess of nitric oxide, and inefficient nitric oxide metabolism, are known to exacerbate the vascular damage associated with heart disease. Nitric oxide and its metabolites also play particularly crucial roles in the spread of cancer, and the development of degenerative brain disorders like Alzheimer’s and Parkinson’s disease.

In recent years, many companies within the nutritional supplement industry have offered up “nitric oxide–boosting” formulas containing amino acid precursors of nitric oxide such as arginine and citrulline. The marketing behind such products obviously focuses on the supposedly “good” roles of nitric oxide, but the research that exists indicates that such products may possess the potential to do serious harm in certain populations, or if taken over extended periods of time.

So, rather than simply finding ways of “boosting” or suppressing nitric oxide levels to treat or prevent different disorders, our goal will be to find nutritional and lifestyle strategies to modulate nitric oxide production, ensuring proper, healthy, nitric oxide signaling and metabolism in all tissues of the body for a lifetime.

To do this requires that we first take a look at the biological “assembly line” responsible for the production of nitric oxide. Though complicated at first, we’ll find that the answers we seek can be found only by a glimpse into the inner workings of our molecular biochemistry.

The Nitric Oxide Synthases

It’s well–known that our body produces nitric oxide (NO) from the amino acid arginine, and that the production of nitric oxide from arginine is catalyzed by a group of enzymes known as nitric oxide synthases (NOS). At least three (major) types of NOS exist, each classified by the types of tissues and cells in which they are found (the fact that nitric oxide can be produced by several different enzymes, and can be used for many different biological reactions, may be our first clue as to why NO may be beneficial in some instances, and harmful in others).

Endothelial nitric oxide synthase, or eNOS, can be found in the lining of the blood vessels, called the endothelium. The nitric oxide produced by eNOS triggers vasodilation, and is an important factor in regulating blood pressure. Endothelial nitric oxide further supports cardiovascular health by inhibiting the “stickiness” of blood cells called platelets, and preventing platelets from adhering to the endothelium – an early phenomenon in the development of atherosclerosis. It has been noted that all known or suspected risk factors for cardiovascular disease – including high cholesterol, high blood pressure, high homocysteine, high triglycerides, and smoking – involve the reduced bioavailability of nitric oxide within the endothelium.

Neuronal nitric oxide, or nNOS, is found in neurons in the brain and nervous system. The nitric oxide produced by nNOS acts as a neurotransmitter and signaling molecule, and, in precise amounts, may play a role in memory and learning. Disorders of nitric oxide production by nNOS, on the other hand, may play a role in many neurological diseases like Parkinson’s and Alzheimer’s.

Inducible nitric oxide, or iNOS, is produced by cells of the immune system called macrophages. Our immune system makes use of the nitric oxide’s toxic free radical–generating capacity to kill invading pathogens like viruses and bacteria. But unlike eNOS and nNOS, which produce nitric oxide on demand for seconds, or minutes at the most, iNOS is able to chronically stimulate the production of nitric oxide for hours or even days.

Although nitric oxide is a potential free radical regardless of where and how it’s produced, nitric oxide produced by the immune system (in macrophages via iNOS) may be particularly apt to inflict dangerous collateral damage to the tissues with which it comes in contact. As the name inducible nitric oxide synthase indicates, the activity of iNOS is greatly increased under conditions of stress or trauma. It’s now thought that many of the potentially harmful effects of NO may be due to the excess nitric oxide produced from iNOS in the macrophages.

In this edition of the Integrated Supplements Newsletter, we’ll begin by focusing on nitric oxide’s role in the cardiovascular system. We’ll see precisely why trying to “boost” nitric oxide levels via the indiscriminate intake of nitric oxide precursors isn’t advisable. Instead, we’ll find that nitric oxide modulation is akin to performing a tune–up on a high–performance engine, and that we’ll need to make subtle, calculated adjustments to keep our nitric oxide metabolism running smoothly. Given what is now known about nitric oxide (but which many supplement companies continue to ignore), we’ll develop a unique strategy to ensure the proper, healthy, production and metabolism of nitric oxide within the cardiovascular system.

NO and the Cardiovascular System

In recent decades, research has made it clear that all known cardiovascular risk factors (including elevated cholesterol, elevated triglycerides, elevated homocysteine, and smoking) impair nitric oxide metabolism. As such, it’s now well–accepted that disorders of nitric oxide activity underlie the development of cardiovascular disease. Decreased bioavailability of NO is not only a direct cause of the “silent killer” known as high blood pressure (as blood vessels dilate under the influence of NO), but faulty NO signaling can also lead to cell adhesion, proliferation, and ultimately, to the acceleration of arteriosclerotic lesions within the endothelium. Impaired nitric oxide activity has also been associated with insulin resistance and diabetes, and some researchers believe that nitric oxide may be the molecular key to the well–established link between diabetes and cardiovascular disease.

Study Link – Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress.

Quote from the above study:

Cardiovascular disease accounts for at least 85 percent of deaths for those patients with type 2 diabetes mellitus (T2DM). Additionally, 75 percent of these deaths are due to ischemic heart disease. . . The vulnerable three arms of the eNOS reaction responsible for the generation of eNO is discussed in relation to the hypothesis: (1) The L–arginine substrate. (2) The eNOS enzyme. (3) The BH4 cofactor.

In the early days of nitric oxide research (which wasn’t all that long ago), scientists logically assumed that the nitric oxide precursor, the amino acid arginine, when added to the diet, would increase levels of nitric oxide. They therefore reasoned that supplying the body with large amounts of arginine would likely restore proper vascular function (including vasodilation). This hypothesis was often validated in animal studies, and even in some short–term human studies:

Study Link – Oral L–arginine improves endothelium–dependent dilation in hypercholesterolemic young adults.

Quote from the above study:

After oral L–arginine, plasma L–arginine levels rose from 115+/–103 to 231+/–125 micromol/liter (P<0.001), and [ endothelium–dependent dilation] improved from 1.7+/–1.3 to 5.6+/–3.0% (P<0.001).

But as longer–term studies on supplemental arginine began to be conducted in patients with pre–existing heart disease, a seemingly strange trend began to emerge. In many of these studies, the patients taking arginine often fared notably worse than those not taking the amino acid. One important trial even had to be stopped prematurely because of an increase in death in the group taking arginine supplements:

Study Link – L–Arginine Therapy in Acute Myocardial Infarction The Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) Randomized Clinical Trial.

Quote from the above study:

6 participants (8.6%) in the L–arginine group died during the 6–month study period vs none in the placebo group (P = .01). Because of the safety concerns, the data and safety monitoring committee closed enrollment. . . L–Arginine, when added to standard postinfarction therapies, does not improve vascular stiffness measurements or ejection fraction and may be associated with higher postinfarction mortality. L–Arginine should not be recommended following acute myocardial infarction.

Study Link – L–Arginine Supplementation in Peripheral Arterial Disease – No Benefit and Possible Harm

Quote form the above study:

Although absolute claudication distance improved in both L–arginine– and placebo–treated patients, the improvement in the L–arginine–treated group was significantly less than that in the placebo group (28.3% versus 11.5%; P=0.024). . . As opposed to its short–term administration, long–term administration of L–arginine is not useful in patients with intermittent claudication and PAD.

Study Link – Dietary Supplementation With L–Arginine Fails to Restore Endothelial Function in Forearm Resistance Arteries of Patients With Severe Heart Failure.

Study Link – Oral L–Arginine in Patients With Coronary Artery Disease on Medical Management.

Quote from the above study:

Oral L–arginine therapy does not improve NO bioavailability in CAD patients on appropriate medical management and thus may not benefit this group of patients.

In retrospect, it’s not surprising that adding additional arginine to the diet of people with cardiovascular disease often produced negative results. The reason is that, whatever the underlying causes of nitric oxide dysfunction in heart disease, one thing’s for certain – it is NOT due to an arginine deficiency (as arginine is abundantly supplied in the vast majority of diets).

It’s likely that individuals with pre–existing heart disease (or a tendency towards heart disease) suffer from disorders involving several of the enzymes and cofactors which are needed to convert arginine into nitric oxide efficiently. In other words, if nitric oxide production is faulty, then adding arginine to the diet is destined to make matters worse in the long–run, as was found in the above studies. It’s highly likely that overwhelming the nitric oxide–producing system with supplemental doses of arginine may actually impair nitric oxide production, and lead to the production of other, more harmful substances – even in healthy people (we’ll see exactly how this phenomenon takes place later).

ADMA – The First Clue

As supplementing the diet with additional arginine produced many unpredictable and harmful effects, researchers began to wonder what factors could be responsible for impairing nitric oxide production in those suffering from cardiovascular disease and diabetes. One current suspect is an arginine analog called asymmetrical dimethyl arginine, or ADMA, for short. Acting as arginine’s “evil twin”, so to speak, ADMA can “tie up” nitric oxide synthase enzymes and can significantly inhibit NO production. People with heart disease and diabetes almost always exhibit very high levels of ADMA, and ADMA has proven to be a very strong independent risk factor for cardiovascular disease and insulin resistance:

Study Link – Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine.

Quote from the above study:

In an analysis of men who did not smoke, those who were in the highest quartile for ADMA (>0.62 μ mol/L) had a 3.9–fold (95% CI 1.25–12.3, p=0.02) increase in risk of acute coronary events compared with the other quartiles. Our findings suggest that ADMA is a predictor of acute coronary events.

Elevated ADMA levels have even been implicated in erectile dysfunction, a finding which isn’t terribly surprising considering the role of nitric oxide and vasodilation in facilitating the erectile response. Given how important proper NO metabolism is to cardiovascular health, researchers now believe that erectile dysfunction may be among the earliest physical manifestations of heart disease:

Study Link – Elevation of asymmetrical dimethylarginine (ADMA) and coronary artery disease in men with erectile dysfunction.

Quote from the above study:

As elevation of ADMA has been found to be associated with many risk factors for both CAD [coronary artery disease] and ED [erectile dysfunction], our data provide further strong evidence for the close interrelation of CAD and ED. Determination of ADMA may help to identify underlying cardiovascular disease in men with ED.

Where Does ADMA Come From?

In simple terms, ADMA is a byproduct of protein metabolism. Healthy people are usually able to metabolize and eliminate it properly, but in aging and disease, ADMA levels tend to rise. Because kidney disease patients excrete protein metabolites like ADMA less efficiently than healthy individuals, ADMA levels are known to be particularly high in those with kidney disease. And because ADMA is able to increase heart disease risk by interfering with NO production, an elevated ADMA level has been proposed to be the key “non–traditional” risk factor for heart disease in those with kidney disease. In other words, even kidney patients with normal cholesterol, blood pressure, and triglycerides are still very much prone to heart disease simply because of their elevated levels of ADMA.

In patients with heart disease and/or diabetes, but without overt kidney disease, it’s a little more difficult to say exactly why ADMA levels are almost invariably elevated. We do know, however, that the enzyme which breaks down ADMA, called dimethylarginine dimethylaminohy­drolase, or DDAH, is known to be particu­larly susceptible to oxidative damage in­flicted by known cardiovascular toxins like oxidized cholesterol, oxidized polyun­saturated fatty acids, and homocysteine.

For many months now, we at Integrated Supplements have been warning you of the dangers of oxidized cholesterol – found in many processed cholesterol–containing foods and powders, or produced in the body under conditions of oxidative stress. Researchers have recently shown that oxidized cholesterol caused a much greater elevation in ADMA levels than native, unoxidized cholesterol, due to oxidized cholesterol’s (oxLDL) unique ability to impair DDAH function.

Study Link – Novel Mechanism for Endothelial Dysfunction. Dysregulation of Dimethylarginine Dimethylaminohydrolase.

Quote from the above study:

The addition of oxLDL or TNF–a to ECV304 significantly increased the level of ADMA in the conditioned medium. The effect of oxLDL or TNF–a was not due to a change in DDAH expression but rather to the reduction of DDAH activity.

And the following study showed that a lipid peroxidation product produced from the omega–6 fat linoleic acid, called 4–HNE, significantly impaired nitric oxide production by interfering with DDAH activity. The effect was only partially reversed by arginine, but completely reversed by supplying increased amounts of DDAH along with antioxidants:

Study Link – Role of DDAH–1 in lipid peroxidation product–mediated inhibition of endothelial NO generation.

Quote from the above study:

We show that the lipid hydroperoxide degradation product 4–hydroxy–2–nonenal (4–HNE) causes a dose–dependent decrease in NO generation from bovine aortic endothelial cells, accompanied by a decrease in DDAH enzyme activity. The inhibitory effects of 4–HNE (50 µM) on endothelial NO production were partially reversed with L–Arg supplementation (1 mM). Overexpression of human DDAH–1 along with antioxidant supplementation completely restored endothelial NO production following exposure to 4–HNE (50 µM). These results demonstrate a critical role for the endogenous methylarginines in the pathogenesis of endothelial dysfunction. Because lipid hydroperoxides and their degradation products are known to be involved in atherosclerosis, modulation of DDAH and methylarginines may serve as a novel therapeutic target in the treatment of cardiovascular disorders associated with oxidative stress.

Study Link – Lipid peroxidation and nitric oxide inactivation in postmenopausal women.

Quote from the above study:

NO inactivation and the increase in lipid peroxidation may contribute to endothelial dysfunction and to the greater risk for atherosclerosis in postmenopausal women.

And, illustrating just how far–reaching the effects of lipid peroxide–induced disruption of nitric oxide metabolism can be, patients suffering from major depression have been shown to exhibit elevated levels of 4–HNE, decreased activity of DDAH and subsequently, increased levels of ADMA, and decreased plasma nitric oxide.

Study Link – Increased (E)–4–hydroxy–2–nonenal and asymmetric dimethylarginine concentrations and decreased nitric oxide concentrations in the plasma of patients with major depression. 

Quote from the above study:

There is an increase in circulating HNE in major depression. HNE inactivates the cysteine residue in the active site of endothelial DDAH leading to the accumulation of ADMA in the circulation. The ADMA then decreases the production of eNOS. This could reduce the amount of NO diffusing from cerebral blood vessels to nearby neurons and influence the release of neurotransmitters. ADMA also constricts cerebral blood vessels and may contribute to the decreased regional perfusion in major depression. The accumulation of ADMA could explain the increased risk of CHD in major depression. The preservation of DDAH activity and the reduction of ADMA accumulation may represent a novel therapeutic approach to the treatment of major depression.

In the above study, we also find that the potent cellular antioxidant glutathione was able to significantly reduce the level of lipid peroxides and protect the damage inflicted on the DDAH enzyme:

The effects of HNE on DDAH activity were significantly attenuated by the addition of glutathione (P<0.0001).

Taken together, these studies give us good reason to believe that the fundamental disorder of nitric oxide bioavailability seen in aging and disease is due to oxidative stress – particularly oxidative stress driven by products of lipid peroxidation (i.e. oxidized fat and cholesterol).

And researchers in the field are beginning to come to this same conclusion:

Article Link – When the endothelium cannot say ‘NO’ anymore.

Quote from the above article:

The mechanism by which ADMA is elevated in some patients may relate to oxidative stress. ADMA is inactivated by an enzyme named dimethylarginine dimethylaminohydrolase (DDAH); most investigators agree that DDAH plays an important role in the regulation of ADMA levels. DDAH activity is downregulated by oxidative stress, as it is associated with high cholesterol, high glucose, and high homocysteine levels. In these settings, accumulation of ADMA can be prevented by addition of antioxidants in experimental models. Inhibition of DDAH, in turn, leads to elevated ADMA levels, which in turn promote further generation of oxidants, possibly by uncoupling NO synthase. This vicious circle provides an integrative explanation for the interrelation between lack of NO, excess of oxygen–derived free radicals, and progression of vascular lesion formation.

A Nutritional Plan of Attack

To lower our level of oxidative stress, reducing our intake of oxidized cholesterol (from cholesterol–containing powders like powdered eggs, powdered cheese, and whey protein concentrate), as well as dramatically reducing our intake of dietary polyunsaturated fatty acids (omega–6– and omega–3–containing fats) is the only reasonable place to start. In addition, it is likely prudent to supplement with known inhibitors of lipid peroxidation, like Vitamin E, coenzyme Q10 and lipoic acid.

As noted, the above study on nitric oxide and depression showed that the cellular antioxidant, glutathione, significantly reduced the harmful effects of HNE on DDAH, so a supplement of undenatured whey protein isolate (which contains the “building blocks” of glutathione) along with the mineral selenium (also important for glutathione production) are likely to be very helpful as well.

Note: For more information on the role of lipids in oxidative stress, see the November and December 2007 issues of the Integrated Supplements Newsletter.

Homocysteine and Nitric Oxide

In addition to byproducts produced from unsaturated fat and cholesterol, the protein–derived substance, homocysteine, has also been shown to be an important contributor to the burden of oxidative stress. Homocysteine is an amino acid produced in high amounts due to the inefficient metabolism of the amino acid methionine, and elevated homocysteine levels have increasingly been implicated as a major heart disease risk factor in recent decades. If homocysteine does, in fact, cause an elevation in ADMA (and a subsequent decrease in NO production), as is shown in the following study, this would clearly lend molecular–level support to the homocysteine hypothesis of heart disease.

Study Link – Homocysteine Impairs the Nitric Oxide Synthase Pathway Role of Asymmetric Dimethylarginine.

Quote from the above study:

Homocysteine post–translationally inhibits DDAH enzyme activity, causing ADMA to accumulate and inhibit nitric oxide synthesis. This may explain the known effect of homocysteine to impair endothelium–mediated nitric oxide–dependent vasodilatation.

Vitamins B6, B12, and folic acid can reliably reduce homocysteine, which seems to be an important piece of the puzzle given what we now know about homocysteine’s role in impairing nitric oxide production. Folic acid in particular may play several roles in ensuring proper nitric oxide metabolism (more on this later).

And as we look beyond ADMA and DDAH, deeper into the various pathways involved in nitric oxide metabolism, we begin to see yet again, that oxidative stress is the common thread responsible for disrupting all of them.

Nitric Oxide, Superoxide, and Peroxynitrite

As we outlined in the previous Integrated Supplements Newsletter, nitric oxide, being a gaseous chemical, often doesn’t stick around long once it’s produced. Nitric oxide is known to rapidly react with the free radical superoxide (O2–), producing the powerful oxidant, peroxynitrite (OONO–) (remember that oxidizing chemicals like superoxide and peroxynitrite are potent molecular–level drivers of oxidative stress).

Researchers now believe that much of the cellular damage associated with cardiovascular disease (and other diseases in which nitric oxide plays a major role) involves the over–production of superoxide and peroxynitrite from faulty nitric oxide metabolism. In fact, much of the reason that nitric oxide levels are low in cardiovascular disease is because, under conditions of oxidative stress, arginine is converted to these harmful oxidants instead of nitric oxide – yet another reason why supplying additional arginine to the body is wrought with potential danger.

Article Link – Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.

Quote from the above article:

The direct toxicity of nitric oxide is modest but is greatly enhanced by reacting with superoxide to form peroxynitrite (ONOO–). Nitric oxide is the only biological molecule produced in high enough concentrations to out–compete superoxide dismutase for superoxide.

As we’ve seen, the oxidative stress of aging and disease can damage the fragile enzyme DDAH, causing nitric oxide’s “evil twin,” ADMA to become elevated. ADMA competes with arginine for NOS and causes a reduction in nitric oxide production.

But this isn’t even the only way in which oxidative stress can impair nitric oxide production. The synthesis of nitric oxide from NOS requires a cofactor called tetrahydrobiopterin, or BH4, for short. When BH4 is damaged under conditions of oxidative stress (i.e. when it is oxidized), NOS then converts arginine directly to superoxide, and ultimately to the harmful reducing agent, peroxynitrite. Scientists call this effect an uncoupling effect, as damage to BH4 is able to uncouple, or divert arginine synthesis away from nitric oxide and towards superoxide and peroxynitrite. In a vicious downward spiral, peroxynitrite causes the oxidation of even more BH4, and the synthesis of nitric oxide is then even further impaired.

Study Link – Oxidation of Tetrahydrobiopterin by Peroxynitrite: Implications for Vascular Endothelial Function.

Quote from the above study:

Nitric oxide and superoxide react rapidly to form peroxynitrite, which may be the reactive species responsible for many of the toxic effects of nitric oxide. Here we show that BH4 is a primary target for peroxynitrite–catalyzed oxidation because at pH 7.4, physiologically relevant concentrations of BH4 are oxidized rapidly by low concentrations of peroxynitrite. . . Thus, abnormally low levels of BH4 can promote a cycle of its own destruction mediated by nitric oxide synthase–dependent formation of peroxynitrite. This mechanism might contribute to vascular endothelial dysfunction induced by oxidative stress.

Not surprisingly then, damage to tetrahydrobiopterin has been shown to cause all of the cardiovascular risk factors associated with impaired nitric oxide bioavailability; and repairing or preventing damage to tetrahydrobiopterin represents a key strategy in restoring healthy nitric oxide production.

As an example, while it’s common knowledge that high cholesterol levels represent a threat to cardiovascular health (especially when coupled with an environment of oxidative stress, in which significant amounts of cholesterol are prone to oxidation), few people realize that (oxidized) cholesterol may do cardiovascular damage largely through its ability to damage tetrahydrobiopterin, and thus, healthy nitric oxide production. Infused tetrahydrobiopterin has been shown to counter this effect and restore endothelial function in patients with high cholesterol:

Study Link– Tetrahydrobiopterin restores endothelial function in hypercholesterolemia.

Quote from the above study:

In hypercholesterolemia, impaired nitric oxide activity has been associated with increased nitric oxide degradation by oxygen radicals. Deficiency of tetrahydrobiopterin, an essential cofactor of nitric oxide synthase, causes both impaired nitric oxide activity and increased oxygen radical formation. . . this study demonstrates restoration of endothelial dysfunction by tetrahydrobiopterin suppletion in hypercholesterolemic patients.

It’s also been shown that other cardiovascular risk factors, like smoking, may do their damage by impairing tetrahydrobiopterin function as well:

Study Link – Tetrahydrobiopterin Improves Endothelium–Dependent Vasodilation in Chronic Smokers Evidence for a Dysfunctional Nitric Oxide Synthase.

Quote from the above study:

These data support the concept that in addition to the free radical burden of cigarette smoke, a dysfunctional [eNOS] due to BH4 depletion may contribute at least in part to endothelial dysfunction in chronic smokers.

And while we can’t realistically inject ourselves with tetrahydrobiopterin as was done in the above studies, there may be several nutritional strategies which will allow us to optimize the function of tetrahydrobiopterin within our bodies.

Supplementation with the well–known antioxidant, vitamin C, has been shown to protect tetrahydrobiopterin from oxidation, and to restore proper NOS activity:

Study Link – Long–Term Vitamin C Treatment Increases Vascular Tetrahydrobiopterin Levels and Nitric Oxide Synthase Activity.

Quote from the above study:

In vivo, beneficial effect of vitamin C on vascular endothelial function appears to be mediated in part by protection of tetrahydrobiopterin and restoration of eNOS enzymatic activity.

Nitrate Tolerance – More Clues on The Importance of Tetrahydrobiopterin

The nitric oxide–boosting drug, nitroglycerin, has been used for over a century as a vasodilator in coronary artery disease, but a troubling phenomenon, called nitrate tolerance, almost invariably arises with the drug’s long–term use. Researchers have wondered for years why it is that nitroglycerin quickly loses its efficacy, and many theories have been proposed to explain this occurrence. The most likely scenario appears to be that nitroglycerin gradually increases the formation of reactive oxygen species (or, ROS – the molecular–level drivers of oxidative stress) by impairing the bioavailability of tetrahydrobiopterin. Two of the ROS produced in the development of nitrate tolerance are the aforementioned superoxide and peroxynitrite radicals, which, as we’ve seen, further impair nitric oxide production in a vicious downward spiral. Ironically, considering the fact that nitrate drugs are so commonly used as short–term treatments for heart disease symptoms, nitric oxide drugs are known to increase mortality in those with existing heart disease; and the production of superoxide and peroxynitrite from nitric oxide helps to explain why:

Study Link – Long–term nitrate use may be deleterious in ischemic heart disease: A study using the databases from two large–scale postinfarction studies. Multicenter Myocardial Ischemia Research Group.

Quote from the above study:

The Cox analyses with all the variables retained revealed that nitrates were associated with a significantly increased mortality risk (MSMI: hazard ratio 3.78, P =.011; MDPIT: hazard ratio 1.61, P =.019) in patients who had recovered from an acute coronary event. . . These analyses raise concern about the potential adverse effects of long–acting nitrate therapy in chronic coronary disease.

It’s worth noting, too, that the phenomenon of nitrate tolerance – where a nitric oxide boosting substance “works” in the short–term, but is harmful in the long–term – parallels many of the same surprisingly harmful effects noticed in long–term studies where arginine was administered as a nitric oxide precursor. Many nitric oxide–boosting products are often “cycled,” or taken for relatively short periods of time, with a subsequent “layoff” of arbitrary duration. But, if these products “stop working” with continued use (as empirical evidence indicates is indeed the case), it’s fair to assume that the arginine they contain is no longer being converted to nitric oxide efficiently, and is instead being converted into harmful superoxide and peroxynitrite. No supplement company can say with any certainty precisely when this toxic phenomenon begins, or whether “cycling” the product makes it less harmful in the long–term. Thus it’s probably safe to say that the more a person consumes supplemental arginine or nitric oxide–boosting supplements (cycled or not), the greater the potential harm he or she is doing to his or her body.

But, of course, even those of us not consuming nitrate drugs or nitric oxide–boosting supplements can still learn a valuable lesson from what is now known about nitrate tolerance.

If progressive damage to tetrahydrobiopterin (both by nitric oxide itself and its ROS metabolites) is responsible for nitrate tolerance, then many of the same strategies which help to prevent nitrate tolerance may do so by protecting tetrahydrobiopterin (which is our goal as well). Studies show that this is, in fact, the case.

Vitamin C has been used with success to attenuate nitrate tolerance:

Study Link – Randomized, double–blind, placebo–controlled study of the preventive effect of supplemental oral vitamin C on attenuation of development of nitrate tolerance.

Quote from the above study:

These results indicate that combination therapy with vitamin C is potentially useful for preventing the development of nitrate tolerance.

And folic acid, a nutrient which may be able to “pinch hit” for tetrahydrobiopterin, has been shown to prevent nitroglycerin–induced nitrate tolerance as well:

Study Link – Folic Acid Prevents Nitroglycerin–Induced Nitric Oxide Synthase Dysfunction and Nitrate Tolerance.

Quote from the above study:

Our data demonstrate that supplemental folic acid prevents both nitric oxide synthase dysfunction induced by continuous [nitroglycerin] and nitrate tolerance in the arterial circulation of healthy volunteers. We hypothesize that the reduced bioavailability of tetrahydrobiopterin is involved in the pathogenesis of both phenomena. Our results confirm the view that oxidative stress contributes to nitrate tolerance.

And, beyond its role in nitrate tolerance, we find several unique roles of folic acid in ensuring proper NO production and cardiovascular health. The active form of folic acid, known as 5–methyltetrahydrofolate, has been shown to prevent the vascular disruption caused by high cholesterol:

Study Link – 5–Methyltetrahydrofolate, the Active Form of Folic Acid, Restores Endothelial Function in Familial Hypercholesterolemia.

Quote from the above study:

These results show that the active form of folic acid restores in vivo endothelial function in FH. It is suggested from our in vitro experiments that this effect is due to reduced catabolism of NO.

Folic acid is also known to play a role in reducing levels of the previously–mentioned cardiovascular toxin, homocysteine. And homocysteine has been shown to inhibit tetrahydrobiopterin functioning:

Study Link – Homocysteine induces oxidative stress by uncoupling of no synthase activity through reduction of tetrahydrobiopterin.

Quote from the above study:

The results show that the oxidative stress and inhibition of NO release induced by homocysteine depend on eNOS uncoupling due to reduction of intracellular tetrahydrobiopterin availability.

Tetrahydrobiopterin and Depression

It’s also interesting to note that, in addition to its role in producing nitric oxide, tetrahydrobiopterin is also a known co–factor in the production of the neurotransmitters noradrenalin, serotonin, and dopamine.

We saw previously how lipid peroxides can impair proper nitric oxide production; and we referenced studies in which depressed patients were shown to exhibit elevated lipid peroxide levels and decreased nitric oxide levels in their plasma.

Other studies show that reduced availability of tetrahydrobiopterin may not only impair nitric oxide production, but also the production of important brain chemicals (called monoamines in the quote below) in depression.

Study Link – The role of pterins in depression and the effects of antidepressive therapy.

Quote from the above study:

As a raised N:B ratio implies failure to convert neopterin to biopterin, it is possible that reduced availability of tetrahydrobiopterin, the essential cofactor for the formation of noradrenaline, serotonin and dopamine, may exert rate–limiting control over the synthesis of monoamines implicated in the pathogenesis of depressive illness.

Add to this the fact that depression is very strongly correlated with the development of heart disease:

Study Link – Depression as a predictor for coronary heart disease. A review and meta–analysis.

Quote from the above study:

It is concluded that depression predicts the development of [coronary heart disease] in initially healthy people. The stronger effect size for clinical depression compared to depressive mood points out that there might be a dose–response relationship between depression and [coronary heart disease].

And it’s tempting to theorize that disorders of tetrahydrobiopterin function, leading to both impaired nitric oxide function, and impaired neurotransmitter synthesis, may act as a common biological thread tying together both heart disease and depression.

Unlike the symptoms of heart disease, the burden of psychological depression often manifests during the first three or four decades of life – so even young people who are not often concerned with their heart disease risks should still take note of the research presented here. And considering that psychological depression is not only a major health challenge in and of itself, but is also a clear warning sign of impending cardiovascular disease, we can clearly see how valuable integrated and biologically sound nutritional strategies are if we can indeed combat both disorders simultaneously.

As is so common in biology, addressing fundamental defects and nutrient imbalances on a cellular and molecular level, imparts a beneficial “ripple effect” throughout the entire body, whereas treating merely symptoms (with pharmaceuticals, and the “wrong” nutrients) often leads to a whole host of negative side effects.

Further Neutralizing ROS

Many of the nutrients we’ve already mentioned have potent antioxidant and cell–protective effects, and synergistically, these nutrients work together to ensure proper nitric oxide production at each step of the biological “assembly line.”

To Review:

Nutrients to prevent lipid peroxidation and to lower ADMA by preventing oxidative damage to DDAH:

• Vitamin E

• Lipoic Acid

• Whey Protein Isolate

• Selenium

Nutrients for lowering homocysteine levels:

• Folic Acid

• Vitamin B–6

• Vitamin B–12

• Trimethylglycine

Nutrients for protecting tetrahydrobiopterin

• Vitamin C

• Folic Acid

And in addition to these nutrients, several others may play important roles in ensuring healthy nitric oxide metabolism within the cardiovascular system and beyond. Plant chemicals like polyphenols and flavanols (found in such foods as tea, wine, and chocolate), may be able to scavenge superoxide and peroxynitrite radicals, potentially neutralizing these reactive oxygen species before they can trigger NOS uncoupling and the downward spiral of faulty nitric oxide metabolism.

Of course, even though polyphenols are able to quickly deactivate ROS in vitro (in a test tube), there’s still some debate as to how well these plant chemicals do so within our bodies. Our livers usually do an excellent job of “deactivating” these “foreign” chemicals before they reach the bloodstream, and surprisingly few polyphenols actually reach general circulation. It’s been proposed that either these polyphenols stimulate our own antioxidant systems (like those involving glutathione), or that the polyphenol conjugates (conjugation, or the “attachment” of one substance to another in order to improve elimination, is what the liver does to detoxify such compounds) may have antioxidant effects in and of themselves.

For more info, see:

Study Link – How should we assess the effects of exposure to dietary polyphenols in vitro?

But whatever their mechanisms of action, some plant chemicals appear to have remarkable effects on nitric oxide production in vivo (in the body) when consumed orally. The flavanols (a type of polyphenol) in unprocessed cocoa, for example, have been shown to significantly lower blood pressure via nitric oxide–mediated action.

Study Link – Flavanol–rich cocoa induces nitric–oxide–dependent vasodilation in healthy humans.

Quote from the above study:

In healthy humans, flavanol–rich cocoa induced vasodilation via activation of the nitric oxide system, providing a plausible mechanism for the protection that flavanol–rich foods induce against coronary events.

And subsequent studies by the same researchers showed that older individuals had a greater response to cocoa flavanols than younger individuals – indicating that the flavanols may be able to partly correct the decline in nitric oxide function which occurs in aging.

Study Link – Aging and vascular responses to flavanol–rich cocoa.

Quote from the above study:

Flavanol–rich cocoa enhanced several measures of endothelial function to a greater degree among older than younger healthy subjects. Our data suggest that the NO–dependent vascular effects of flavanol–rich cocoa may be greater among older people, in whom endothelial function is more disturbed.

And besides various plant polyphenols, and the vitamins we’ve already mentioned, another, more “non–traditional” antioxidant may have the unique ability to protect against the free radical damage associated with nitric oxide.

Creatine and Cardiovascular Health

Though it’s often though of only as a sports supplement useful for enhancing muscle size and strength, the high energy molecule, creatine (which, unlike some polyphenols, is very well–absorbed) has been shown to scavenge both superoxide and peroxynitrite – the molecules largely responsible for nitric oxide–induced damage.

Study Link – Direct Antioxidant Properties of Creatine.

Quote from the above study:

. . .creatine displayed a significant ability to remove [superoxide] and [peroxynitrite] when compared with controls. . . To our knowledge, this is the first evidence that creatine has the potential to act as a direct antioxidant against aqueous radical and reactive species ions.

We looked briefly at the role homocysteine plays in inhibiting DDAH, and tetrahydrobiopterin – two cofactors required for proper nitric oxide production. So, logically, lowering homocysteine will be an important part of ensuring proper nitric oxide metabolism and cardiovascular health. It’s known that the neutralization of homocysteine requires a chemical process called methylation, and that substances which donate methyl groups (CH3), such as betaine (TMG), SAMe, and choline – all available as dietary supplements – have been shown to lower homocysteine levels.

Because creatine can produce energy substrates quickly, without the metabolic demands of breaking down glucose or fatty acids for fuel, creatine can be thought of as an “emergency” energy molecule. As such, creatine is in very high demand by the most metabolically active tissues like the muscles, brain, and heart (even in non–athletes).

But the production of creatine within the body just so happens to “use up” methyl groups at an astonishingly high rate. It turns out that taking “pre–formed” creatine as a supplement (meaning, that our body doesn’t have to go through the metabolic steps of making it) spares the valuable methyl groups which would otherwise be used for creatine production – methyl groups which can then be used to neutralize homocysteine. And this effect is more than mere biological speculation – oral creatine supplements have, in fact, been shown to lower homocysteine levels significantly:

Study Link – Oral creatine supplements lower plasma homocysteine concentrations in humans.

Quote from the above study:

After four weeks of creatine supplements, [total plasma homocysteine] in [the experimental group] changed by an average of –0.9 micromol/L (range: –1.8 to 0.0), compared to an average change of +0.2 micromol/L in C (range: –0.6 to 0.9) during the same four weeks. The difference in the changes in [total plasma homocysteine] between the two groups was statistically significant (p < 0.01). CONCLUSION: Creatine supplements may be an effective adjunct to vitamin supplements for lowering [total plasma homocysteine].

Given that we must reduce the burden of superoxide, peroxynitrite, and homocysteine in order to ensure proper nitric oxide metabolism within the cardiovascular system, daily supplementation with pure creatine monohydrate probably represents one of the most physiologically sound ways to achieve all of these goals simultaneously – all the while supplying a vital energy substrate to the metabolically active cells of the muscle, brain, and heart.

In fact, it’s probably safe to say that although creatine is remarkably effective for increasing strength and energy production in athletes, those who have avoided taking creatine monohydrate because of its stigma as a mere “bodybuilding” supplement are likely to be missing out on one of the most remarkably health–promoting substances within the entire realm of nutritional supplementation.

And similarly, many people who currently think that they are taking creatine may not be. In recent years, many different types of creatine have been introduced to the nutritional supplement market, each claiming offer benefits above and beyond creatine monohydrate. In recent studies, however, two of the most heavily promoted “new” creatines, creatine ethyl ester, and a brand of “buffered” creatine, have both been shown to be vastly inferior to creatine monohydrate. In direct opposition to the marketing claims of these newfangled creatines, both creatine ethyl ester, and so–called buffered creatines have been shown to degrade into the useless byproduct creatinine much more readily than does creatine monohydrate.

Exposing the lies and misinformation surrounding creatine is best left for another newsletter, but for now, it’s important to realize that the full benefits of creatine, for cardiovascular health, or athletic improvement, can be obtained only through supplementation with pure creatine monohydrate.

The Cardiovascular System – Just The Beginning

Faulty nitric oxide metabolism has been implicated as a common denominator in various degenerative diseases including not only heart disease, but also such disorders as Alzheimer’s disease and cancer.

Fortunately, many of the dietary and supplement strategies we’ve covered here will also serve us well as we examine the effects of nitric oxide not directly related to the cardiovascular system. In the next Integrated Supplements Newsletter, we’ll take a look at nitric oxide’s role in other systems of the body, and in other disorders associated with aging. As we put all of the pieces of the nitric oxide puzzle together, the big picture of nitric oxide will begin to come into even clearer focus.

About Us: At Integrated Supplements, our goal is to bring you the wellness information and products you need to live your life to the fullest. We are dedicated to producing the highest–quality, all–natural nutritional supplements; and to educating the world on the health promoting power of proper nutrition. You can find out more by visiting: www.IntegratedSupplements.com


These statements have not been evaluated by the FDA. No Integrated Supplements product is intended to diagnose, treat, cure or prevent any disease.


What's Wrong With Nitric Oxide - Part 1


Recently, a group of surgeons performing a bowel resection operation on a young man were alarmed to notice the patient bleeding profusely during the surgery. In a frantic attempt to save the patient’s life, as one standard procedure after another failed to normalize the bleeding, the surgeons were eventually forced to perform a full blood transfusion. Though the operation was eventually a success, the physicians were perplexed, as, according to the patient’s records, he wasn’t consuming any medications which could account for such massive and life–threatening bleeding.

But, with a little biological sleuthing, it was soon found that the patient had been taking a very popular nitric oxide–boosting nutritional supplement sold as an “energy and performance igniter” for bodybuilding training. It turned out that the product contained not only various nitric oxide precursors, but several herbal nitric oxide–boosting ingredients which also happen to be potent blood thinners.

The above situation, relayed to us by one of the surgeons performing the operation, is an extreme but telling example of the dangers of accepting the nutritional supplement industry’s hype at face value. In recent years some supplement companies – especially companies specializing in bodybuilding supplements – have been able to convince their customers that there are benefits to be gained by increasing the body’s levels of the vasoactive chemical, nitric oxide. Yet, in an industry never known to let safety concerns stand in the way of profit, any mention of the potential short and long–term side effects of increasing ones nitric oxide levels has been conspicuously absent.

As a vasodilator, or, substance which dilates blood vessels, nitric oxide is known to influence blood flow as well as nutrient and oxygen delivery to cells; and some companies have speculated that increasing nitric oxide to supraphysiological levels, may result in greater increases in nutrient delivery to working muscles, and a subsequent increase in muscle growth.

Nitric oxide–boosting supplements have also been widely promoted for increasing the muscular “pump” – the localized inflammatory swelling of muscle – which is especially evident during weight training.

But the physiology of the blood vessels and blood flow (what scientists call hemodynamics) is infinitely more complicated than many within the supplement industry would have you believe. Despite the impression you may get from reading bodybuilding and fitness magazines, the study of nitric oxide as a biological chemical is still in its infancy, and looking at the existing scientific literature will give any rational, intelligent person reason to think twice about attempting to increase nitric oxide levels. Although nitric oxide is an important signaling molecule essential for life, there’s also reason to believe that purposefully stimulating its production is wrought with both short–term and long–term risks.

In this edition of the Integrated Supplements Newsletter, we’ll set the record straight on what is really known about the biological role of nitric oxide – in particular, we’ll look at its effects on vasodilation, blood flow, blood vessel integrity, bleeding, hemorrhage, septic shock, energy metabolism, exercise performance, and oxidative stress. And in part two of this series, we’ll look at the long–term effects of nitric oxide over a lifetime, and we’ll examine the integral role of nitric oxide plays as an accelerator of aging and degenerative disease.

Nitric Oxide – From Humble Beginnings

In 1867, Alfred Nobel (for whom the Nobel Prize is named), received a patent for an invention which stabilized the highly explosive chemical, nitroglycerin, by combining it with silica. The resulting malleable paste allowed the explosive power of nitroglycerine to be harnessed and controlled, and proved useful in such endeavors as mining and drilling. His invention was, of course, called dynamite.

And, in an odd coincidence, during the latter part of his life, Nobel’s physician prescribed nitroglycerin as treatment for the noted industrialist’s heart disease. Nobel, however, refused to take it, knowing from experience that the chemical caused him headaches. It would take nearly 100 years for science to discover that the factor responsible for both nitroglycerins’ role in reducing symptoms of heart disease, and Nobel’s headaches, was a vasodilating chemical called nitric oxide.

During the mid 1980’s it was discovered that nitric oxide (NO) was the mysterious biological substance which caused the dilation of blood vessels – a particularly shocking revelation considering that this gaseous chemical had previously been known as a mere industrial pollutant.

And in 1998, the Nobel Prize for medicine was awarded to a group of scientists who discovered that nitric oxide played major roles as an endogenous signaling molecule in the vascular, nervous, and immune systems of the human body. Since that time, research into the complex biological role of nitric has exploded, but still a relative newcomer to the biological scene, many questions remain as to the varied functions of this enigmatic molecule.

At first glance, much of the existing research on nitric oxide makes the chemical seem beneficial – it can indeed lower blood pressure by causing a dilation of the blood vessels, which is precisely what has made NO–boosting drugs like nitroglycerin beneficial for cardiovascular patients suffering from angina.

But as nitric oxide research has progressed, the two–faced nature of nitric oxide has begun to come to light. Some studies have surfaced indicating that certain nitric oxide–increasing therapies may have serious and potentially deadly drawbacks. In 2006, a particularly notable study using the common nitric oxide–boosting nutrient, l–arginine, in heart disease patients had to be stopped due to a dramatic increase in death in the treatment group.

Study Link – L–Arginine Therapy in Acute Myocardial Infarction – The Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) Randomized Clinical Trial.

Quote from the above study:

Because of the safety concerns, the data and safety monitoring committee closed enrollment. . . L–Arginine, when added to standard postinfarction therapies, does not improve vascular stiffness measurements or ejection fraction and may be associated with higher postinfarction mortality. L–Arginine should not be recommended following acute myocardial infarction.

And subsequent research has served to dampen the initial enthusiasm for nitric oxide–boosting therapies even further. As with most chemicals which signal cellular stress, nitric oxide can be beneficial or harmful depending upon the amount released, and the energetic state of the cells with which it comes in contact. While, in some contexts, nitric oxide may be a chemical signal for vasodilation, cell growth and adaptation, an excess of nitric oxide has been shown to cause cellular fatigue, cellular damage, and even cellular death.

So, clearly in biology, nothing is as simple as it at first seems, and this appears to be especially true of nitric oxide. As a highly reactive and potentially damaging chemical, the effects of nitric oxide have proven incredibly difficult to predict. As more studies have emerged indicating that nitric oxide–boosting nutrients may be harmful in some treatment groups, many researchers now believe that, in certain circumstances, we should actually take steps to decrease our production of nitric oxide, not increase it.

Study Link – L–Arginine Supplementation in Peripheral Arterial Disease – No Benefit and Possible Harm.

Quote form the above study:

Although absolute claudication distance improved in both L–arginine– and placebo–treated patients, the improvement in the L–arginine–treated group was significantly less than that in the placebo group (28.3% versus 11.5%; P=0.024). . . As opposed to its short–term administration, long–term administration of L–arginine is not useful in patients with intermittent claudication and PAD.

Study Link – Effects of chronic treatment with L–arginine on atherosclerosis in apoE knockout and apoE/inducible NO synthase double–knockout mice.

Quote from the above study:

This raises the possibility that L–arginine supplementation may paradoxically contribute to, rather than reduce, lesion formation by mechanisms that involve lipid oxidation, peroxynitrite formation, and NOS uncoupling.

But, even though the work of world–renowned biologists and chemists clearly shows that nitric oxide is a double edged–sword whose benefits have yet to be harnessed without risk, we need only to open the pages of any bodybuilding or fitness magazine to witness the reckless hucksters of the supplement industry touting products specifically designed to dramatically increase our nitric oxide levels. If their past track record is any indication, we can expect these companies to largely ignore the growing body of research which paints nitric oxide, and nitric oxide–boosting nutrients in a negative light, simply because such research doesn’t help them sell products.

The Products and Their Claims

The advertising for nitric oxide–boosting products in the bodybuilding realm usually centers around claims of increased blood flow to muscles, better nutrient delivery, enhanced “pumps” while training, and overall, an increase in muscular size and strength.

NO–boosting products are also sold as aids to erectile function, and (despite the above–listed studies) to support cardiovascular health. Whatever the claim or target demographic, the underlying mechanism for these products revolves around the same basic biological function – the ability of nitric oxide to dilate blood vessels.

Most nitric oxide–boosting products are formulated with various types of arginine – the amino acid from which nitric oxide is produced in the body. And although simple l–arginine supplements have been available for decades, as studies on the biological role of nitric oxide began to fill medical journals, certain enterprising individuals within the supplement industry decided to blow the dust off of this amino acid, and re–introduce it to the bodybuilding world in the form of novel arginine–containing salts like arginine alpha–ketoglutarate (AAKG) – possibly the most common ingredient in the current group of nitric oxide boosting supplements.

Because both arginine, and ketoglutarate are known to increase arginine levels in the body, it’s reasonable to believe that AAKG may increase arginine levels (and subsequently, nitric oxide) to a greater extent than l–arginine alone. But given the scientific–sounding jargon of many supplement advertisements, many people are surprised to learn that little to no research has been performed on AAKG in relation to nitric oxide levels. And as we have seen, even some studies which look at the effects of orally administered l–arginine (a relatively modest NO–booster at best), still give us reason for concern.

Dozens of other ingredients are often added to nitric oxide–boosting products including other salts of arginine as well as citrulline, an amino acid which is converted to arginine in vivo (in the body). And complicating matters even further is the common presence of compounds (especially blood thinning nutrients and herbs) which can potentially amplify the vascular effects of arginine and its metabolites. Because of this, the risk of excessive and pathological bleeding and hemorrhage is a very real concern even with the short–term usage of some nitric oxide–boosting products. But before we get too far ahead of ourselves, a little perspective on the true biological roll of nitric oxide is probably in order.

A Little Perspective on NO

Because the literature on nitric oxide is often conflicting, it’s important to sketch a bird’s eye view of its function within the body. Those attempting to sell you nitric oxide–boosting formulas often have a tendency to cherry pick the literature, showing you only studies (if they reference valid studies at all), which support their claims in limited contexts. For example, nitric oxide, as the supplement industry has so widely advertised, does indeed cause dilation of blood vessels. And this vasodilation may increase blood flow and allow the cells to temporarily produce energy more efficiently (with less oxygen consumption) under periods of stress.

But it’s important to always remember that the production of nitric oxide, and the dilation of blood vessels, is a defensive response of the body to stressful stimuli. As with all defensive responses, if the body lacks the ability to “shut off” the response, the response self–perpetuates, and the overall effects will be damaging and sometimes deadly. It’s crucial to recognize this fact, because there is often the mistaken belief that biological functions which can be harmful are under “tight control,” and that it’s nearly impossible to harm oneself with mere nutrients or nutritional supplements. But in the presence of certain stressors, we find that a great amount of damage can be done before the body is able to restore balance. As an example, we can see the quintessential illustration of the self–perpetuating nature of the nitric oxide stress response in the phenomena of sepsis and septic shock.

In the previous issue of the Integrated Supplements Newsletter, we saw how the presence of a “leaky gut” can allow bacteria and bacterial components called endotoxin to enter the bloodstream from the intestines, causing chronic systemic inflammation.

When such translocation of bacteria from the intestines into the bloodstream is significant, the condition is called sepsis, or what is often known in layman’s terms as blood poisoning. One of the bodies’ primary responses to sepsis is an increase in the production of nitric oxide. In the very short term, NO can dilate blood vessels and increase nutrient delivery to cells possibly allowing them to counter the stress by increasing their energy production. Very quickly, however, the hypotension (low blood pressure) caused by NO can lead to the exact opposite phenomenon –a dangerous decrease in blood flow to vital organs like the brain and kidneys, and an overall reduction in protective energy production throughout the body.

The vasodilating effects of NO are so strong in septic shock, that the blood vessels remain dilated despite the body’s best efforts to normalize them with vasoconstricting agents like adrenaline. The heart frantically attempts to compensate for the lowered blood pressure by pumping blood at an accelerated rate, but often, to no avail. As the heart soon weakens, blood pressure drops even further, causing blood vessels to leak, leading to bleeding (especially in the lungs, causing difficulty breathing), hemorrhage, cardiac failure, and often, death.

In relation to the surgery patient we mentioned in the introduction, and noting nitric oxide’s fundamental role in this chain of events, we see why none of the surgeons’ interventions worked to stop the young man’s bleeding and hypotension, until they supplied his body with more blood via a transfusion – sufficiently increasing blood volume (and therefore, pressure) and oxygen delivery to stop the bleeding and save his life.

Nitric oxide is so fundamental to the vicious chain of events in sepsis, that strategies for combating sepsis now often involve therapies aimed at dramatically reducing the production of nitric oxide.

Study Link – Nitric oxide in the pathogenesis of sepsis.

Quote from the above study:

In sepsis and septic shock, inflammatory mediators result in the production of increased concentrations of nitric oxide (NO) from the enzymatic breakdown of the amino acid L–arginine. The increased amounts of NO are responsible for changes in vasomotor tone, decreased vasopressor responsiveness, and decreased myocardial function, characteristic of septic insult. Therapeutic strategies designed to reduce the concentration of NO by inhibiting the action of the nitric oxide synthase enzyme, or by scavenging the excess NO, offer the potential to treat directly the vasomotor abnormalities and myocardial depression seen in sepsis and other inflammatory states.

Study Link – Circulatory failure in septic shock. Nitric oxide: too much of a good thing?

Quote from the above study:

One of the characteristic features of septic shock is profound hypotension caused by a decrease in peripheral vascular resistance. This hypotension is unusually resistant to both volume replacement and vasoconstrictor agents.

And it’s important to remember as well, that nitric oxide doesn’t just affect the blood vessels. Cells of the immune system and the nervous system also synthesize nitric oxide, and cumulatively, the nitric oxide produced by various cells can cause massive tissue damage via NO’s free radical–generating capacity.

A quote from the same study:

. . . production of large quantities of nitric oxide leads not only to haemodynamic instability but also to widespread production of nitric oxide–based free radicals which have the potential to cause considerable damage to tissues. Evidence from clinical studies supports this.

So, let’s get it straight right from the beginning: nitric oxide is an inflammatory chemical, which is produced in response to stress, injury, and trauma. Like other inflammatory chemicals, nitric oxide has a role in normal human physiology, but an excess of it, or prolonged stimulation of it is decidedly harmful. Nitric oxide synergizes with and stimulates other inflammatory chemicals, including prostaglandins, and cytokines. NO reduces blood pressure and oxygen utilization, increases lactic acid production, impairs mitochondrial energy production, promotes excitotoxicity, and causes (either directly or indirectly) various types of cell death.

And knowing that nitric oxide is able to overwhelm the body’s hemodynamic regulatory systems should make us think twice about consuming large amounts of arginine, or other nitric oxide precursors or boosters. An abundance of nitric oxide precursors in the body could make even everyday stresses (like workouts) harmful and, in rare cases, even catastrophic.

For example, it’s known that exercise weakens intestinal barrier function, and causes bacteria and endotoxin to be absorbed. Sepsis and exercise share so many inflammatory factors in common, that intense exercise has even been proposed as a model for studying sepsis.

Study Link – Sepsis and mechanisms of inflammatory response: is exercise a good model?

Study Link – Are similar inflammatory factors involved in strenuous exercise and sepsis?

Study Link – Strenuous exercise causes systemic endotoxemia.

Quote from the above study:

Eighteen triathletes were studied before and immediately after competing in an ultradistance triathlon. Their mean plasma lipopolysaccharide (LPS) concentrations increased from 0.081 to 0.294 ng/ml (P less than 0.001), and their mean plasma anti–LPS immunoglobulin G (IgG) concentrations decreased from 67.63 to 38.99 micrograms/ml (P less than 0.001).

So, we should be aware that in exercise, and in sepsis, the same principles of nitric oxide metabolism apply – the difference is merely one of degree. This, of course, is a fact which is conspicuously absent from the advertising of nitric oxide–boosting supplements, but it’s an important fact to recognize if we are to accurately assess the risks associated with these products.

Nitric Oxide and Peroxynitrite – General Toxic Effects

But it’s not simply the vasodilating effects of NO which may prove harmful in excess. As alluded to above, nitric oxide and its metabolites are also able to produce massive amounts of free radical damage – damage which has been shown to be toxic to the well–known “power plants” of the cells, the mitochondria.

As the science of biology advances, mitochondrial function is turning out to be the key to the mysteries of aging and degenerative disease. If you take nothing else from this article, let it be this:

Maintaining healthy mitochondria – mitochondria which are undamaged physically, and which produce energy efficiently – is the key to a long, energetic, happy, and disease–free life.

The energy produced by our mitochondria creates a “force field” of protection around the cell, allowing it to grow, adapt, and survive various stressors. Think of your cells as being constantly protected by an invisible electric fence, the power for which is supplied by the mitochondria – cut the power (damage or poison the mitochondria), and the cell becomes susceptible and increasingly vulnerable to all sorts of cellular stressors. The cells lose the ability to “fight back” and can no longer grow stronger and more resilient in response to stress – eventually they simply wave the white flag of defeat in response to any threat which comes along. Poison enough of these power plants and you accelerate your descent into aging, depression, atrophy, and degenerative disease.

One of the keys to the generally toxic effects of nitric oxide on the mitochondria is the NO derivative, called peroxynitrite (ONOO –). Being a gas, and a free radical, nitric oxide doesn’t stick around long once it’s produced. It rapidly reacts with surrounding molecules, especially the free radical superoxide, producing the particularly harmful oxidizing and nitrating agent, peroxynitrite.

On a cellular level, both NO and peroxynitrite have been shown to decimate mitochondrial function.

In fact, the following study and quote show clearly that NO and peroxynitrite impair mitochondrial function in almost every conceivable way – inhibiting multiple mitochondrial enzymes, chewing up antioxidants, damaging proteins, spilling redox–active iron, as well as causing lipid peroxidation, cell swelling, calcium release, and membrane permeability (all direct precursors to cell death).

Study Link – Nitric oxide and mitochondrial respiration.

Quote from the above study:

Nitric oxide (NO) and its derivative peroxynitrite (ONOO−) inhibit mitochondrial respiration by distinct mechanisms. Low (nanomolar) concentrations of NO specifically inhibit cytochrome oxidase in competition with oxygen, and this inhibition is fully reversible when NO is removed. Higher concentrations of NO can inhibit the other respiratory chain complexes, probably by nitrosylating or oxidising protein thiols and removing iron from the iron–sulphur centres. Peroxynitrite causes irreversible inhibition of mitochondrial respiration and damage to a variety of mitochondrial components via oxidising reactions. Thus peroxynitrite inhibits or damages mitochondrial complexes I, II, IV and V, aconitase, creatine kinase, the mitochondrial membrane, mitochondrial DNA, superoxide dismutase, and induces mitochondrial swelling, depolarisation, calcium release and permeability transition. . . The NO inhibition of cytochrome oxidase may also be involved in the cytotoxicity of NO, and may cause increased oxygen radical production by mitochondria, which may in turn lead to the generation of peroxynitrite. Mitochondrial damage by peroxynitrite may mediate the cytotoxicity of NO, and may be involved in a variety of pathologies.

So, in layman’s terms, nitric oxide and peroxynitrite can act as agents of wholesale cellular destruction, choking the life out of our cells at the most fundamental level. And once the cell is weakened in this way, even “normal” stresses and stimulation can become deadly to the cell.

And such damaging effects on a cellular level are easy to extrapolate to a macroscopic level as in the role of NO and peroxynitrite in degenerative disease:

Study Link – Nitric oxide and peroxynitrite in health and disease.

Quote from the above study:

Since its early description as an endothelial–derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. . . In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorder.

Nitric Oxide, NMDA, and Chronic Fatigue

Given what we now know about nitric oxide’s effects on cellular energy production, it seems especially strange that various nitric oxide–boosting products are being touted as energy boosters and performance enhancers. Many of these products are spiked with caffeine or creatine, both of which may impart energizing effects, but one thing’s for certain – nitric oxide itself certainly does not lead to an increase in energy production. In fact, quite the opposite is true. Some researchers have actually implicated an excess of nitric oxide production as the central metabolic defect underlying the chronic fatigue syndrome.

Without the damage caused by nitric oxide, and the subsequent drain on cellular defenses, stimulation of the excitatory NMDA receptor may simply be a normal physiological event involved in such phenomenon as memory and learning. In the presence of nitric oxide, however, uncontrolled nervous excitation, and cell death may result from the very same stimulation. Nitric oxide has been shown to be a necessary co–factor in the toxic effects of NMDA stimulation by excitatory amino acids. We’ve seen in previous Integrated Supplements Newsletters that the stimulation of the NMDA receptor is often a self–perpetuating sequence which drains cellular energy to the point of cell death.

Study Link – Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures.

Quote from the above study:

We show that the nitric oxide synthase inhibitors, N omega–nitro–L–arginine (EC50 = 20 microM) and N omega–monomethyl–L–arginine (EC50 = 170 microM), prevent neurotoxicity elicited by N–methyl–D–aspartate and related excitatory amino acids. This effect is competitively reversed by L–arginine. Depletion of the culture medium of arginine by arginase or arginine–free growth medium completely attenuates N–methyl–D–aspartate toxicity. . . These data establish that NO mediates the neurotoxicity of glutamate.

Individuals with excess production of nitric oxide may suffer from NMDA over–stimulation, and may be predisposed to chronic pain, fatigue, chemical sensitivity, and they may even be especially susceptible to the negative effects of excitotoxic food additives like MSG and the artificial sweetener, aspartame.

The following study found that the amino acid citrulline (a “byproduct” of arginine’s production of nitric oxide), is consistently elevated in chronic fatigue patients.

Study Link – Levels of Nitric Oxide Synthase Product Citrulline Are Elevated in Sera of Chronic Fatigue Syndrome Patients.

Quote from the above study:

Serum citrulline levels were found to be significantly elevated in CFS patients and, in addition, there was a trend towards higher levels in CFS patients with stronger symptoms. These results provide support for the view that nitric oxide synthase activity tends to be elevated in CFS patients, thus supporting a prediction of the elevated nitric oxide/peroxynitrite theory of CFS etiology.

And it has also been proposed that the link between chronic fatigue syndrome and other related disorders stems from an elevation in nitric oxide synthesis.

Study Link – Elevated Nitric Oxide/Peroxynitrite Mechanism for the Common Etiology of Multiple Chemical Sensitivity, Chronic Fatigue Syndrome, and Posttraumatic Stress Disorder.

In relation to chronic fatigue, it’s interesting to note that chronic fatigue patients often manifest low blood pressure. It’s usually assumed that this low blood pressure has much to do with adrenal exhaustion. The thinking is that the adrenal glands of chronic fatigue patients aren’t sufficiently producing the adrenaline needed for energy and proper blood vessel tone. But if chronic fatigue patients do indeed overproduce nitric oxide, the vasodilating effect of nitric oxide could be another cause of the low blood pressure often noted in these patients.

This possibility opens up multiple avenues for treatment, and not coincidentally, the researchers who implicate nitric oxide in these disorders recommend nutrients and drugs aimed specifically at scavenging nitric oxide, lowering NMDA activity, and restoring mitochondrial function.

For example, the energizing effect of vitamin B–12 is well known, but few people realize that this effect may be due to B–12’s ability to scavenge and deactivate nitric oxide.

Study Link – Cobalamin Used in Chronic Fatigue Syndrome Therapy Is a Nitric Oxide Scavenger.

Other nutrients which may improve energy production by minimizing NO/peroxynitrite–induced damage include Co–Q10, niacinamide, magnesium and vitamin C.

What About Antioxidants?

Noting that the stimulation of nitric oxide is well–known to induce cellular and tissue damage via the free radical activity of peroxynitrite, some sellers of nitric oxide–boosting supplements have taken to formulating their products with a sprinkling of various antioxidants, supposedly acting as some sort of “damage control.”

But while the inclusion of antioxidants in these products may be somewhat beneficial, it’s unclear to what extent these antioxidants actually help counter an “artificially elevated” nitric oxide level. As for now, the inclusion of antioxidants with nitric oxide boosters (like so much else in the nutritional supplement industry) amounts to little more than simply wishful speculation.

But, it’s worth noting that some antioxidants do have unique and potentially positive effects on nitric oxide metabolism, and they may be beneficial in keeping nitric oxide levels within a normal, healthy range – assuming we don’t overwhelm the system with nitric oxide precursors or boosters.

The potent thiol (sulfur–containing) antioxidant, lipoic acid, has been shown to increase nitric oxide–mediated vasodilation in disease states, but not in healthy subjects. This effect is likely a clue that the way to ensure proper, healthy, nitric oxide production lifelong is via reducing our levels of oxidative stress – not by increasing our intake of arginine and similar nitric oxide precursors.

Study Link – Beneficial effects of α – lipoic acid and ascorbic acid on endothelium–dependent, nitric oxide–mediated vasodilation in diabetic patients: relation to parameters of oxidative stress.

Quote from the above study:

The impairment of nitric oxide (NO)–mediated vasodilation in diabetes has been attributed to increased vascular oxidative stress. Lipoic acid has been shown to have substantial antioxidative properties. . . Lipoic acid improved NO–mediated vasodilation in diabetic patients, but not in controls.

It’s known that the nitric oxide response of the blood vessels decreases in aging and disease (meaning that diseased blood vessels don’t respond to nitric oxide by dilating as effectively as healthy blood vessels do), but if, as the above study indicates, oxidative stress (and not lack of arginine) is the cause of the faulty nitric oxide response, then reducing oxidative stress is the most logical and physiologically sound solution – this is why taking arginine supplements won’t necessarily help, and is likely to do more harm, as has been shown in various studies.

Excess Nitric Oxide – Concerns in Exercise

Even people with little biological knowledge seem to understand the simplistic notion that the stress of weight training causes “damage” to the muscle, which, under ideal conditions, the body responds to by growing larger, stronger, or more efficient. Nitric oxide release is a normal response to the stress of training, and the damage which is caused by nitric oxide may be a part of the “damage” of training which the body adapts to by growing larger or stronger.

It’s conceivable that, in otherwise healthy people, and in the short–term, one of the responses to the cellular assault inflicted by nitric oxide and its metabolites may be an increase in muscle growth as a protective measure – assuming other factors like nutrition and rest are accounted for properly. But people taking nitric oxide–boosting products should know full–well, and without any ambiguity, that they are doing further damage to the body, and adding to the stress of training with these products, and not simply “supplying more nutrients to the muscle” as is commonly implied in product advertising.

Similarly, as relates to the “pump” experienced during training, this effect may indeed be partly due to increased blood flow to the muscle, but tissue swelling is a well–known to be a response to tissue damage and fatigue – and is probably not due to the simple dilation of blood vessels. In this sense, because nitric oxide does cause tissue damage and mitochondrial damage (leading to the more rapid onset of muscular fatigue), it’s fair to say that NO may stimulate a “pump” during training. But the fact that muscular swelling during exercise is largely due to a localized (and potentially harmful) inflammatory response, and not simply to increased blood flow as is sometimes implied, means that the marketers of NO–boosting products are simply spinning the science to make their advertising copy seem pleasing to an uneducated clientele.

And noting that nitric oxide decreases energy production on a cellular level, it’s interesting to look at studies which have shown significant decreases in exercise performance when the NO–precursor, arginine, was ingested – especially in endurance sports.

The following study, which looked at the effects of arginine on several metabolic markers during and after a marathon, found that arginine supplementation led to an average finish time 23 minutes longer than predicted.

Study Link – The effect of arginine or glycine supplementation on gastrointestinal function, muscle injury, serum amino acid concentrations and performance during a marathon run.

Arginine supplementation tends to fare a bit better in strength sports, but we can’t necessarily attribute this effect solely to nitric oxide. There are simply far too many metabolic fates for arginine besides NO to make such an assumption valid. Arginine, for example is a precursor to the well–known performance enhancer creatine, increased production of which could easily account for any marginal increases in strength or performance noted with arginine supplementation.

But, even in the highly “cosmetic” sport of bodybuilding, where a good pump is often just as important as improved performance, it’s hard to justify the use of nitric oxide supplements in light of the relevant research.

Unlike some unhealthy lifestyle habits, for which the repercussions manifest over decades, the negative effects of stimulating nitric oxide production can potentially be short–term and catastrophic. As we’ve seen, the threat of excessive bleeding and hemorrhage when nitric oxide is increased is very real.

Along these lines, a particularly strong warning should be made against the use of nitric oxide–boosting products for contact athletes such as football players, hockey players, and martial artists. The last thing these athletes want is high levels of nitric oxide and nitric oxide precursors running through their bloodstream during competition. If stimulated by contact, the over–production of nitric oxide could lead to excessive and uncontrollable bleeding.

The effect of nitric oxide–boosting drugs, such as nitroglycerine, on bleeding has been known for decades, and studies have shown that inhibiting the enzyme from which NO is produced, significantly shortens bleeding time.

Study Link – Effect of nitric oxide synthase inhibition on bleeding time in humans.

Quote from the above study:

These data show that systemic inhibition of NO production shortens [bleeding time] in humans.

And various other studies and reports have linked nitric oxide with excessive bleeding, cerebral hemorrhage, and hemorrhagic shock.

Study Link – Novel roles of nitric oxide in hemorrhagic shock.

Quote from the above study:

Thus, induced nitric oxide, in addition to being a "final common mediator" of hemorrhagic shock, is essential for the up–regulation of the inflammatory response in resuscitated hemorrhagic shock. Furthermore, a picture of a pathway is evolving that contributes to tissue damage both directly via the formation of peroxynitrite, with its associated toxicities, and indirectly through the amplification of the inflammatory response.

Study Link – Nitric Oxide Insufficiency, Platelet Activation, and Arterial Thrombosis

Quote from the above study:

We reported the case of a 29–year–old woman with a hypertensive crisis treated with [the nitric oxide–increasing drug] sodium nitroprusside for blood pressure control who sustained an intracerebral hemorrhage after being normotensive on therapy for 24 hours.

And, lest you think that nitric oxide–boosting nutritional supplements must somehow be safer than nitric oxide–boosting drugs, realize that the “witches’ brew” formulations of many nitric oxide–boosting supplements often contain dozens of vasoactive substances haphazardly thrown together – including shockingly potent blood–thinning agents in addition to arginine substrates.

One such blood–thinning ingredient is rutaecarperine from the herb called evodia rutaecarpa. On a molar basis, retaecarperine has been shown to prolong bleeding time twice as long as aspirin.

Study Link – Antithrombotic effect of rutaecarpine, an alkaloid isolated from Evodia rutaecarpa, on platelet plug formation in in vivo experiments.

Quote from the above study:

On a molar basis, rutaecarpine was approximately twofold more potent than aspirin at prolonging the occlusion [bleeding] time.

So, although the “blood–thinning” effect of nitric oxide and related substances is often simply assumed to be beneficial, such simply isn’t the case. Certainly, blood with an excessive tendency to clot is a risk factor for cardiovascular disease in the long–term, but, on the other side of the coin, blood which doesn’t clot sufficiently can be even more acutely dangerous in situations where bleeding is a possibility.

Very similarly, high blood pressure is a known risk factor for cardiovascular disease, but as we’ve seen, low blood pressure, as a result of excessive nitric oxide production, can often be deadly in certain stressful situations. Clearly, balance is the key, and nitric oxide stimulation can play a major role in upsetting this balance greatly – even in the short–term.

In part two of our series on nitric oxide, we’ll look at the long–term role nitric oxide plays in various degenerative diseases. But hopefully, the research we’ve presented here on the general and shorter–acting effects of NO is already sufficient enough to allow any rational person to look at nitric oxide–boosting products in a whole new light.

With their typical reckless abandon, and biological shortsightedness, the sellers of nitric oxide–boosting supplements are asking you to accept far more risk than you may realize, while offering you far fewer benefits than they promise. But, in many ways, with nitric oxide–boosting products, it’s the same formula we see far too often in this industry – wild baseless speculation, is backed by cherry picked research, and stunningly ignorant oversimplifications of complex biological processes are proffered as the latest in “cutting edge science.”

If you value your health, your longevity, your performance, your intellect, or even simply the money you’ve worked so hard for, you’ll let the current nitric oxide fad run its course – without becoming one of its casualties.

About Us: At Integrated Supplements, our goal is to bring you the wellness information and products you need to live your life to the fullest. We are dedicated to producing the highest–quality, all–natural nutritional supplements; and to educating the world on the health promoting power of proper nutrition. You can find out more by visiting: www.IntegratedSupplements.com


These statements have not been evaluated by the FDA. No Integrated Supplements product is intended to diagnose, treat, cure or prevent any disease.


March 22, 2012

Whey Protein Q&A - Protein Bars and Protein Requirements

BlogProQAC Q. What’s wrong with protein bars?

A. There are  potentially several things wrong with protein bars, beginning with the low quality of protein often used in them (protein bars often contain many of the sub-optimal protein sources previously mentioned in this series of articles –  i.e., powdered casein/caseinate, whey protein concentrate, and/or soy protein).  Some protein bars do contain whey protein isolate, but in all likelihood, even the whey isolate used in protein bars will be nutritionally inferior as well. 

One of the challenges in creating protein bars is preventing the bar from drying out and becoming hard and unpalatable during the shelf life of the product.  To combat this challenge in recent years, whey protein manufacturers have created proteins (including versions of whey isolate) specifically for use in protein bars.  These proteins are purposefully denatured to reduce their affinity for moisture.  The idea is, if proteins are prevented from absorbing and attracting moisture in the first place, this reduces the chance of the protein in the bar subsequently drying out and becoming hard during its shelf life.  But, as we’ve seen, denaturation of whey protein may significantly compromise many of its unique health benefits.

Protein and food bars are also often made with nut and seed butters and oils which are very concentrated sources of polyunsaturated fats, including the omega-6 fat, linoleic acid (e.g., almond butter, peanut butter, sesame butter, canola oil et al.).  At Integrated Supplements, we’ve written many articles on the harmful effects of linoleic acid at the doses currently found in the modern Western diet.  Because of the fats they contain, most protein and natural food bars only serve to exacerbate this excess.  As we’ve documented elsewhere, the research gives every reason to believe that such lipids are disruptive to thyroid function, cellular respiration, immune function, and blood sugar control to name just a few.  Because they disrupt metabolic function by so many different mechanisms, these lipids are among the most “fattening” sources of calories available.

As the ingredients they contain are sub-optimal nutrition, protein bars can hardly be expected to improve most diets.   In fact, the real problem with protein bars may be that they can very easily perpetuate the practice of constant snacking on low-quality, calorically-dense processed foods.  For the health- and physique-conscious individual, it’s important to realize that protein bars will more likely hinder their efforts, rather than help.

By their very nature, protein (and other “food bars”) are among the most calorically-dense foods available – i.e., they contain a high amount of calories relative to the overall weight of the food.  Studies have shown that calorically dense foods can often lead to weight gain, whereas foods which are less calorically dense – i.e., foods like fruit which contain phytonutrients, fiber and water – are more filling, and may thus help with weight loss:

Study Link - A satiety index of common foods.

Quote from the above study:

Protein, fibre, and water contents of the test foods correlated positively with [satiety index] scores.

To the best of our knowledge, studies have yet to investigate how eating protein bars affects overall calorie consumption. 

Of course, with the fast-paced lifestyles of today, it’s easy to see why their convenience has made protein bars staples of many people’s diets.  And while protein bars have never been particularly high-quality nutrition, their quality has steadily declined even further as they’ve been increasingly marketed towards the mainstream market. Over the past several years especially, protein bar manufacturers have learned what junk-food and fast-food producers have known for many decades: nutritional content doesn’t matter much when it comes to the bottom line.  In other words, if a product tastes good, it sells – almost regardless of its nutritional composition.  Of course, users of protein bars will often say they want bars with a certain nutritional composition, but in the end, sales numbers don’t lie – bars with the highest fat, sugar, and calorie content are often the best sellers.

When viewed objectively based upon their ingredients and nutritional composition, the vast majority of protein bars aren’t even close to healthy food options.  But marketing protein-laced candy bars as healthy foods plays into what many consumers already want to believe – that health and fitness can be achieved with almost no effort whatsoever.

Generally, those who replace meals with protein bars are consuming low-quality nutrition which is almost certain not to reduce appetite nearly as well as a healthy balanced meal.  Those who use protein bars between meals are simply snacking on some of the most calorie-dense foods available anywhere – hardly a recipe for health and fitness success. Those who only eat protein bars every once in a while are on the right track, although, all things considered, some traditional candy bars may actually be better choices.

Q. Isn’t it important to eat every couple of hours to keep the metabolism going?  How can a person do this with only “real” food?

A. Maintaining steady blood sugar and serum protein (albumin) levels are important goals of any healthy diet, but constant snacking usually isn’t necessary to achieve this – especially if the chosen snacks contain substances which inhibit the metabolism, as we’ve seen most protein bars and drinks do.

For the general health-conscious individual – especially one looking to lose bodyfat – the key is consuming balanced meals which enhance metabolic function instead of disrupting it.  Along these lines, every effort should be made to consume nutrient-dense meals which contain (at the very least) combinations of protein and carbohydrates.

Properly-constructed meals will support healthy blood sugar, trigger the fed state, and control appetite automatically, without the need for constant snacking.  At Integrated Supplements, we’ve written elsewhere about the types of foods which are likely to stimulate the appetite (e.g., starch), and the types of foods which are likely to reduce it (e.g., dairy/whey protein, fruit, certain types of fiber).

Some people, however (e.g., those with hypoglycemia and related blood sugar abnormalities), may function better on more frequent feedings throughout the course of the day.  If snacks are necessary in addition to the traditional meals of breakfast lunch and dinner, there are many suitable options available “on-the-go.”  These days, most convenience stores carry foods such as fruit, yogurt, cheese sticks, salads, hard-boiled eggs, and milk – all of which are far superior to the protein bars and ready-to-drink protein shakes which are often offered up as healthy convenience foods.

Q. What about those looking to build muscle? Doesn’t it take upwards of 1 gram of protein per pound of bodyweight to maximize muscle growth? 

A. People who work out do, indeed, have a higher protein requirement than sedentary individuals.  Even still, in a misguided attempt to support muscle growth, many bodybuilders and fitness enthusiasts consume more protein (and overall calories) than their bodies actually need. 

Evidence suggests that the often-recommended protein intake of “one gram per pound of bodyweight” for strength-training athletes is a bit high.  Research shows that a more reasonable goal may be 0.8 grams per pound of bodyweight:

Study Link - Evaluation of protein requirements for trained strength athletes.

Quote from the above study:

A suggested recommended intake for [sedentary subjects] was 0.89 g.kg-1.day-1 [0.4 grams/lb bodyweight] and for [strength-training subjects] was 1.76 g.kg-1.day-1[0.8 grams/lb bodyweight].

For a 175-pound individual, 0.8 grams of protein per pound of bodyweight equals 140 grams of protein per day.  Consuming this amount of protein daily may take a bit of planning and preparation, but it’s easily achievable through whole foods and relatively small amounts of high-quality protein supplements like whey protein isolate.

The supplement industry, however, often perpetuates the myth that “hardcore” bodybuilders need to consume significantly higher amounts of protein than this – a convenient lie which often begets a reliance on protein bars and drinks (not to mention large quantities of lower-quality/ less-expensive protein powders).  Similarly, the supplement industry also has a tendency to divert consumer’s attention away from readily-available real food sources of protein and towards protein supplements.  The recent marketing of casein/caseinates as “slow-digesting” proteins is a perfect example of this (milk and other dairy foods are far better sources of casein and muscle-building nutrients than casein/caseinate powders, and almost all real food proteins are slow-digesting). 

In actual practice, therefore, many aspiring bodybuilders simply eat too many calories from low-quality sources.

The ironic part is, they’re not only compromising their long-term health by doing so, but their physiques as well.  The chronically “pudgy” appearance of many would-be bodybuilders is often actually testament to the effectiveness of this sort of supplement marketing.


March 03, 2012

Whey Protein Q&A - Whey Protein Isolate Versus Whey Protein Concentrate Part 3 - Glycation Products in Protein Supplements

BlogProQAC Q. What are glycation products?

A. Glycation products are altered protein structures resulting from the chemical interaction of proteins, sugars, and fats.  Glycation products can be produced both in our foods and in our bodies as well.  When the chemical changes proceed far enough, the resulting structures are called advanced glycation endproducts, or, AGEs, for short. Various glycation products and AGEs have been found to be consistently elevated in the body under conditions of aging and disease.

For example, a particular glycation product, called furosine, has been shown to be elevated in patients with Alzheimer’s disease and diabetes:

Study Link – Plasma protein glycation in Alzheimer's disease.

Quote from the above study:

Recent studies have suggested that formation of advanced glycation end–products (AGEs) in some brain proteins could be associated with Alzheimer's disease…Protein glycation was evaluated in plasma with a highly specific HPLC–UV technique, using furosine, which is the acid hydrolysis product of epsilon–deoxy–fructosyl–lysine Plasma furosine was almost two times higher in subjects with Alzheimer's disease (p<.005) than in controls, but still 50% lower than in diabetic patients (P<.02).

And similar to the glycation phenomenon which occurs in our body under the conditions of aging, certain types of food processing are known to result in the production of high amounts of furosine as well. 

As relates specifically to protein powders, the following study tested the furosine content of several commercially available sports supplements produced using milk based ingredients like whey protein isolate, whey protein concentrate, and casein. The furosine levels the researchers found was shockingly high in products which contained whey protein concentrate:

Study Link – Assessing nutritional quality of milk–based sport supplements as determined by furosine.

Quote from the above study:

Furosine content ranged from 2.8 to 1125.7 mg/100 g protein in commercial sport supplements being usually lower in samples containing mainly whey protein isolates or casein, as compared with whey protein concentrates. It is estimated that 0.1–36.7% of the lysine content is not available in this type of products. The use of high quality ingredients for the manufacture of sport supplements reveals important, since it could be the major source of protein intake of certain group of consumers in high or moderate training regime. Furosine is an appropriate indicator to estimate the nutritional quality of sport supplements. A reference value of 70 mg furosine/100 g protein content in dried sport supplements could be set up for controlling the quality of milk–based ingredients used in the formulation. Samples with higher levels are suspected of use of low quality milk–based ingredients or inappropriate storage conditions.

Knowing that glycation products formed in our body may be partly responsible for the degenerative effects of aging, and knowing that glycation products have repeatedly been associated with various degenerative diseases, it’s logical to think that perhaps eating these same glycated proteins may not be such a great idea if we value our long–term health.

Q.  It’s often assumed that high protein intakes aren’t particularly harmful because the body will simply rid itself of the excess.  Is this true?

A.  Some proteins which have been altered by the industrial processes we’ve been describing are likely to have vastly different toxicity profiles relative to minimally-processed protein foods.  In other words, high protein intakes, per se, aren’t likely to be problematic, but high amounts of protein supplements and industrially-processed proteins may be. 

As a bit of background, mainstream nutritionists and doctors often maintain that the average American diet contains sufficient (and, perhaps, too much) protein, and that even the protein requirements of hard-training athletes are only slightly above those of sedentary individuals.  These same experts sometimes also warn that, not only is high protein consumption unnecessary, but that excess protein intake could tax kidney function, and may, thus, actually be harmful.  The bodybuilding, fitness, and supplement communities, however, have largely ignored these warnings, citing evidence of cultures consuming high protein intakes without apparent harm. 

Slowly, some within the medical community have begun to realize that their peers may have previously underestimated the importance of protein in a healthy diet geared towards fat loss and muscle growth or maintenance.  Perhaps spurred by the low-carb and high-protein diet craze of several years ago, the value of high protein intakes has received increasing justification from the medical community.  It’s common now, in fact, to see various protein-centric diet books - and their accompanying protein-containing snack bars and concoctions - peddled by medical doctors.

But, almost universally, both the medical and fitness crowds completely ignore the uniquely toxic effects of the denatured and glycated proteins commonly found in nutritional supplements.  

As protein supplements and protein-fortified foods have become more widely used across various segments of society, it’s likely that the consumption of glycated and industrially-denatured proteins has increased commensurately.  As such, because protein supplements may have completely unique toxicity profiles relative to traditional protein-containing foods, the health effects of industrially-denatured and glycated proteins should be more widely addressed.

While the human body does possess mechanisms to rid the body of excess protein, “getting rid” of glycated proteins is exactly what the body does not do efficiently – and this is what makes many protein–based nutritional supplements uniquely toxic relative to minimally–cooked protein–rich foods.  We’ve already seen, for example, how altered protein structures may promote the growth of harmful intestinal bacteria.  In addition, eating denatured proteins and glycation products (as many users of protein powder, protein bars and ready–to–drink protein shakes unknowingly do), has been shown to add to the AGE burden of the body, and may be particularly detrimental to kidney function:

Study Link – Advanced glycation endproducts (AGEs) as uremic toxins.

Quote from the above study:

Dietary AGEs may contribute significantly to the total AGE load of the body, particularly in uremia.

So, while high intakes of food-based proteins have not been shown to impair kidney function in healthy individuals, there is significant reason to believe that high intakes of many common protein supplements may.

It has been found, for example, that eating glycated protein causes a major increase in systemic inflammation – including inflammatory disease markers such as C–reactive protein, even in healthy subjects:

Study Link – Diet–derived advanced glycation end products are major contributors to the body's AGE pool and induce inflammation in healthy subjects.

Quote from the above study:

Advanced glycation end products (AGEs) are a heterogeneous group of compounds that form continuously in the body. Their rate of endogenous formation is markedly increased in diabetes mellitus, a condition in which AGEs play a major pathological role. It is also known, however, that AGEs form during the cooking of foods, primarily as the result of the application of heat. This review focuses on the generation of AGEs during the cooking of food, the gastrointestinal absorption of these compounds, and their biological effects in vitro and in vivo. We also present preliminary evidence of a direct association between dietary AGE intake and markers of systemic inflammation such as C–reactive protein in a large group of healthy subjects. Together with previous evidence from diabetics and renal failure patients, these data suggest that dietary AGEs may play an important role in the causation of chronic diseases associated with underlying inflammation.

AGEs are also known to damage blood vessels, and many researchers have implicated AGEs as the major factors responsible for the vascular damage associated with kidney disease and diabetes. Building logically from this, some researchers have proposed a very plausible connection between the ingestion of glycation products in foods and the development of diabetes and subsequent diabetic complications like kidney disease:

Study Link – Possible link of food–derived advanced glycation end products (AGEs) to the development of diabetes.

Quote from the above study:

The formation and accumulation of advanced glycation end products (AGEs) have been known to progress at an accelerated rate under diabetes, and there is accumulating evidence that AGEs play a role in the development of diabetes by inducing islet beta cell damage and/or insulin resistance. Further, there are several animal studies to suggest that dietary AGEs are involved in insulin resistance, visceral obesity and the development of diabetes.

So, despite the common misconception that denatured and glycated proteins are merely inert, or “wasted,” the evidence is overwhelmingly clear that they are, instead, often mildly and cumulatively toxic.


February 11, 2012

Whey Protein Q&A - Whey Protein Isolate Versus Whey Protein Concentrate Part 1 - Oxidized Cholesterol

BlogProQACQ. How is Whey Protein Isolate different from Whey Protein Concentrate?

A. Whey protein concentrate contains between 34% and 80% protein, and contains relatively high levels of lactose, fat, and cholesterol.  Whey protein isolate, on the other hand, contains 90% or greater protein by weight, and negligible levels of lactose, fat, and cholesterol.

Because whey protein concentrates are often used as filler ingredients in animal feed, baked goods, and processed dairy products, great care is often not taken to protect the delicate whey protein structures in the production of whey protein concentrate.  As a result, high levels of denatured and glycated proteins are often formed when whey protein concentrate is produced.

These denatured and glycated proteins (i.e., altered protein structures, and altered protein structures formed when proteins interact with sugars and lipids) greatly compromise the nutritional quality of whey protein concentrate, and may even prove harmful.

Properly-prepared whey protein isolates, on the other hand, are produced using selective filters which rid the product of essentially all denatured and glycated proteins (as well as lactose, fat, and cholesterol).  These are just some of the reasons why, we feel, a properly-prepared whey protein isolate is the only intelligent option for use in whey protein nutritional supplements.

Note: Not all whey protein isolates offer the full benefits of filtered whey isolates – whey isolates produced by the ion exchange method, for example, lack an important whey microfraction called glycomacropeptide.  Additionally, some whey concentrates may be produced so as to minimize the formation of denatured proteins – these whey concentrates, however, would still contain lactose, fat, and most importantly, cholesterol – which is prone to oxidation during the shelf life of the powder.

Q. What is oxidized cholesterol, and what are its health effects?

A. When a cholesterol molecule interacts with oxygen, oxidized cholesterol may be formed.  While unoxidized, or native cholesterol is an important substance needed for the building of cellular structure and hormone synthesis, oxidized cholesterol is metabolized differently, and may be a unique contributor to heart disease and other types of metabolic and hormonal disruption.

Oxidized cholesterol, for example, has been implicated in the development of atherogenesis – the thickening of the arterial wall due to the build-up of fatty material – in other words, the beginning of the clogged arteries of heart disease:

Study Link - Atherogenic effect of oxidized products of cholesterol.

Quote from the above study:

Cholesterol under certain in vitro and possibly in vivo conditions may be oxidized to oxysterols, which are suspected of being initiators of atherosclerotic plaques… Dietary oxysterols are absorbed in the gastrointestinal tract and are selectively transported by the athrogenic lipoproteins LDL and VLDL. The oxysterols cholestanetriol and 25-OH cholesterol have been shown to be atherogenic. Oxysterols are commonly found in dried egg products, powdered milk, cheeses and in a variety of high temperature dried animal products.

As the above study indicates, cholesterol can oxidize inside our body, but it can also oxidize in the foods we eat.  While fresh cholesterol-containing foods, cooked normally, contain relatively low levels of oxidized cholesterol, cholesterol-containing dried, powdered, and “shelf-stable” foods are apt to contain relatively high levels of oxidized cholesterol.  This includes foods such as powdered eggs, powdered milk, powdered cheese, and whey protein concentrate.

Studies have shown that the oxidized cholesterol in such foods is absorbed and is taken up by the cholesterol-carrying lipoproteins, leading researchers to note that dietary sources of oxidized cholesterol may be unique contributors to atherosclerosis:

Study Link - Oxidized cholesterol in the diet is a source of oxidized lipoproteins in human serum.

Quote from the above study:

It is possible that oxidized cholesterol in the diet accelerates atherosclerosis by increasing oxidized cholesterol levels in circulating LDL and chylomicron remnants.

Because the formation of cholesterol oxides is inevitable in any powdered product which contains cholesterol, we feel that all cholesterol-containing powders (and many products made from them, like ready-to-drink protein shakes) should be avoided by any health-conscious consumer.

Studies have found, for example, that the formation of cholesterol oxides in dairy powders steadily increases during the shelf life of the powders – even when the products are stored sealed at room temperature:

Study Link - Determination of Cholesterol Oxides in Dairy Products. Effect of Storage Conditions.

Cholesterol oxidation is likely to be an even greater problem with many ready-to-drink protein shakes which are made with whey protein concentrate powder – and which are then pasteurized at high temperatures, often in the presence of oxidizing agents like unsaturated fats and minerals such as copper and iron.

Ultimately, it’s clear that oxidized cholesterol is metabolized in a fundamentally different way relative to native cholesterol, and is likely to be significantly harmful as a result. 


February 01, 2012

Whey Protein Q&A - Whey Protein And Weight Loss

BlogProQAC Q. Can whey protein help with weight loss?

A. Whey protein is likely to have particular benefits for people looking to lose weight.  Out of the three macronutrients (protein, carbohydrate, and fat), protein is known to suppress appetite the most.  And while this is true for pretty much any protein source, whey protein may assist weight loss for several additional reasons.

The authors of the scholarly article below note that calcium, branched-chain amino acids (which whey contains in abundance), and unique whey peptides are all likely to make whey protein a powerful tool for weight management:

Study link - Role of whey protein and whey components in weight management and energy metabolism.

Quote from the above study:

…the anti-obesity effect [of whey] appears to result from calcium, high proportion of branched chain amino acids, and specific bioactive whey-derived peptides.

Whey protein has also been shown to reduce appetite particularly well – and the whey microfraction called glycomacropeptide (GMP) may be an important factor in this effect.  Studies have found that consuming whey proteins which contained GMP at breakfast led to reduced caloric intake at subsequent meals, relative to consuming whey proteins without GMP:

Study Link - Effects of complete whey-protein breakfasts versus whey without GMP-breakfasts on energy intake and satiety.

Quote from the above study:

[Energy intake] at lunch was lower after whey than after whey without GMP…GMP as a whey–fraction reduced energy intake coinciding with increased concentrations of certain amino acids, irrespective of the concentration of whey–protein. Although between different concentrations of whey–protein differences in hormone responses were observed, these were unrelated to satiety ratings or energy intake.

A recent study published in the Journal of Nutrition found that the long-term consumption of whey protein was associated with lower body weight and lower body fat mass in overweight and obese adults.

The study subjects consumed 56 grams of either whey or soy protein daily, or an equal amount of calories as carbohydrates.  The participants otherwise consumed their normal diets.  After 23 weeks of supplementation, the fat mass of those consuming whey protein was 2.3 kilograms (just over 5 pounds) less than those consuming an equal amount of calories as carbohydrates. 

Study Link – Whey Protein but Not Soy Protein Supplementation Alters Body Weight and Composition in Free-Living Overweight and Obese Adults.

Quote from the above study:

In this study in which energy restriction was not part of the intervention, changes in body weight and composition were small but nevertheless suggest that habitual consumption of supplemental protein may result in improved body composition and incremental, but ultimately significant, weight loss. These data suggest that supplemental dietary protein may reduce the risk of unhealthy weight gain observed in many populations (i.e. 500–1000 g/y).

An interesting aspect of the above study was that the subjects consuming whey protein lost weight and fat mass without consciously restricting calories. 

Similar studies have found that whey protein may allow dieters to not only lose weight, but to maintain significant muscle mass while dieting – an important aspect of long-term dieting success:

Study Link - A whey-protein supplement increases fat loss and spares lean muscle in obese subjects: a randomized human clinical study.

In all, quality whey protein is likely to be an important part of any weight-management program.


May 03, 2011

A Diet For Long-Term Weight Control And Optimal Health Part 5 - The Role of Modern Fats in Heart Disease, Cancer, and Obesity

HeaderPicJan11 In the early days of nutritional research, fat was seen as little more than a dense source of caloric energy.  Only when the biological activity of certain classes of fatty acids began to be investigated, did it become clear that some fatty acids play fundamental roles in cellular communication – including immune function, inflammation, reproduction, and cellular growth.

It was found that certain essential fatty acids acted as precursors for a wide range of inflammatory and immune–related chemicals called eicosanoids.  In the decades since this discovery was made, the breathtaking complexity of fatty acid metabolism has become a major focus of biological research.  Even today, however, the practical application of this research is still in its infancy.

The scientific and medical communities are still armed with little more than the most basic understanding of fatty acid metabolism, yet public health authorities have had a major hand in influencing the fatty acid intake of the American diet for decades.  Largely ignoring the overall nutrient composition of healthy traditional diets, modern authorities have advocated various unprecedented patterns of fat intake.  Saturated fats from meat, dairy and tropical oils were, and continue to be, demonized as contributors to heart disease.  The recommendation to consume polyunsaturated vegetable oils and vegetable oil–based margarine is still sometimes made, though it has gradually given way to the advice to consume more monounsaturated fats such as those found in olive oil.  Today, omega–3 fatty acid supplements like fish oil have largely received the approval of mainstream and “alternative” medical practitioners alike.  As a whole, however, such imprecise recommendations have largely failed to improve public health, and are instead likely to be causing unique and unprecedented health disturbances.  Numerous controlled and epidemiological studies show that, even in surprisingly low amounts, the omega–6 fatty acid, linoleic acid may be a powerful contributor to heart disease, cancer, and obesity.  From the research, it’s reasonable to conclude that the optimal dose of linoleic acid for adult humans is near or below 2% of calories.  At this intake of linoleic acid, the omega–6–to–omega–3 fatty acid ratio of the diet will automatically be lowered, meaning that only minute amounts of omega–3 fats will suffice to properly balance the production of linoleic acid–derived inflammatory eicosanoids.  Low overall intakes of PUFA (polyunsaturated fatty acids, omega–3 and omega–6) will also result in less harmful oxidative damage to these lipids in vivo.

Because even a small change in the fatty acid composition of the diet can have a profound biological impact, health–conscious people will be well served to calculate the amount, and relative ratios of certain fatty acids in their diet.  Though the concepts of omega–6 and omega–3 “essential fatty acids” are widely bandied about in food and supplement marketing, the overwhelming majority of people (even those who take fatty acid supplements) have no idea what amount of these fatty acids they’re taking in, or what amounts (and ratios) are likely to be needed for optimal health.

Judging by the research, it’s likely that the first fundamental guiding principle of healthy fat intake is to reduce linoleic acid consumption to as low a level as is reasonably possible.

Excess Linoleic Acid and Heart Disease

Though historically hypothesized to reduce the risk of cardiovascular disease by lowering serum cholesterol and triglyceride levels, vegetable oils rich in linoleic acid have often proven harmful when incorporated into the diet as a replacement for the more–saturated (and less chemically–reactive) animal fats.  In the 1960’s, a two–year study of individuals with existing heart disease investigated the use of corn oil (containing ~59% linoleic acid) as a replacement for animal fat.  In contrast to expectations at the time, the corn oil–users fared worse than those eating a standard diet.  The study found that the percentage of corn–oil users remaining alive and free of heart attack at the end of two years was 52%.  In the control group eating their regular diet, this number was 75%:

Study Link – Corn oil in the treatment of ischaemic heart disease.

Quote from the above study:

The patients receiving the key treatment (corn oil) fared worse than those in the other two groups: two years from the start of treatment infarction or death had occurred in one quarter more of the corn–oil than of the control group… It is concluded that under the circumstances of this trial corn oil cannot be recommended as a treatment of ischaemic heart disease. It is most unlikely to be beneficial, and it is possibly harmful.

Numerous studies in the scientific literature show that corn oil may contribute to heart disease and cancer, but it’s especially interesting to note that one group in the above study replaced animal fat with olive oil – an oil widely promoted for its health benefits.  The percentage of this group remaining alive and free of heart attack after two years was 57% — a result remarkably similar to that of corn oil, and far below the 75% in the control group.  Olive oil contains far less linoleic acid than corn oil (~10%), and does contain some protective polyphenols, but this study suggests that it’s incorporation into the diet in high amounts (or at the expense of animal–based lipids) may not necessarily reduce the rate of heart attack or mortality.

Such research may be particularly meaningful, as many health–conscious people today avoid industrial vegetable oils and opt for olive oil for home–cooking uses.  This is generally a beneficial trend, but it may not necessarily be enough to reduce heart disease risk in the Western world.

The scientific literature on the role of certain fats in heath and disease can often seem contradictory – many studies show olive oil, for example to have a beneficial impact on markers of health, levels of disease, or mortality.  Other studies (like the one above), show the opposite.  Similarly contradictory findings can be found for many sources of fats including fish oils, and saturated fats from meat or dairy.  Clearly, there’s a level of complexity which is largely being ignored by public health authorities in their determinations of what constitute “healthy” and “unhealthy” fats.

Though it’s rarely stated explicitly, the most important factor in engineering a healthy fat intake is that the overall amount of PUFA in the diet be kept low.  It’s probably also important that the omega–6–to–omega–3 ratio of our diet be lowered to one mimicking traditional diets.  It’s uncertain exactly what ratio is optimal, but this is a secondary issue, as lowering the overall PUFA intake will automatically lower the omega–6–to–omega–3 ratio to a more balanced level.  Keeping these factors in mind helps to explain some of the seemingly contradictory findings in the scientific literature relating to dietary fat.

Olive oil is a part of traditional and healthy diets in the Mediterranean region, but unlike the American diet, these diets are also low in other sources of omega–6 linoleic acid.  The fish consumed in the Mediterranean region is also likely to contribute small, but meaningful amounts of omega–3 fatty acids to the diet, thus lowering the omega–6–to–omega–3 ratio.  In other words, in our culture, it’s still entirely possible for both the overall level of linoleic acid, and the omega–6–to–omega–3 ratio of the diet to remain dangerously elevated despite the regular use of olive oil.

The Mediterranean Diet

Beginning in the late 1950s, researcher Ancel Keys began a large–scale study of dietary patterns in relation to cardiovascular disease.  More than 12,000 men of Finland, Greece, Italy, Japan, Holland, the United States, and Yugoslavia were studied in what was called The Seven Countries Study.  Ultimately, men of Finland and the United States had the highest rates of heart disease, whereas men from Mediterranean countries and Japan had the lowest.

Interpreting the results of this study led many researchers to advocate a Mediterranean–style diet with particular emphasis on foods like olive oil, fish, and red wine.  Of course, the average American’s conception of the Mediterranean Diet is often quite different than the health–promoting diet actually consumed in traditional Mediterranean cultures.  The true Mediterranean diet is a varied mixture of nutrient–rich and minimally–processed foods, and while some of these foods may have become accepted into American culinary culture, it’s naïve to think that these foods, alone, will confer the benefits of the overall Mediterranean diet.  Case in point, the widespread use of olive oil among health–conscious Americans is certainly a beneficial trend relative to the use of many other types of industrial vegetable oils, but it can hardly be expected to act as the sort of magical cardio–protective elixir it’s often made out to be.  We find a similar scenario with the currently–fashionable use of fish oil supplements.

Often, when meaningful research such as the Seven Countries Study is distilled through the filter of the popular media, the only messages that survive are messages geared towards selling products (buy olive oil, buy fish oil, buy red wine, buy resveratrol pills, etc.). The benefits of the Mediterranean diet, however, are likely to stem from a wide variety of nutrient–rich foods.  More importantly, what the Mediterranean diet lacks may be equally as important as what it contains.

If the actual Mediterranean diet (and not just isolated aspects of it), does reduce heart disease risk, it’s important to investigate which aspects of the diet are most responsible.  Recent controlled studies (where diets were purposefully manipulated to test the effects) have shed even more light on the issue.  One such study is the Lyon Diet Heart Study – one of the most successful dietary interventions ever conducted in terms of reducing cardiovascular and overall mortality.

In the study which took place in Lyon, France, 605 men and women with pre–existing heart disease were instructed to follow either a control diet similar to the one advocated by the American Heart Association (i.e., < 30% fat, < 10% saturated fat) or a “Mediterranean” diet defined as “low in total fat and saturated and omega–6 fatty acids, but rich in omega–3 fatty acids, oleic acid, fiber, antioxidants, vegetable proteins, and vitamins of the B group.”

The effects of consuming the Mediterranean diet were so favorable, that what was to be a five–year study was halted after 27 months (when an intervention is so clearly effective, it’s deemed unethical to continue it for the benefit of the control group not receiving the treatment, or in this case, diet).   

Article Link – Dietary Prevention of Coronary Heart Disease.  The Lyon Diet Heart Study.

Quote from the above study:

The initial report was published in Lancet in 1994 after the study was terminated by its Scientific and Ethics Committee at 27 months mean follow–up time of what had been planned as a 5–year study, because the benefits in the experimental group at that time were so favorable.

Study Link – Mediterranean Diet, Traditional Risk Factors, and the Rate of Cardiovascular Complications After Myocardial Infarction Final Report of the Lyon Diet Heart Study.

All told, the specifically–constructed Mediterranean diet was associated with a 76% reduction in cardiovascular deaths, and a 70% reduction in overall mortality.

As relates specifically to lipids, the experimental diet in the above study was characterized by the use of olive oil and a canola oil–based margarine to replace butter.  Participants in this study did, therefore consume more monounsaturated oleic acid (from olive oil) and a slightly higher amount of omega–3s (from canola oil). However, it’s notable that they also consumed significantly less linoleic acid than the control group.

The graphic below shows that the linoleic acid content of the Mediterranean diet was 3.6% of calories – significantly less than the 5.3% in the control group. As we shall see, many of the detrimental effects of linoleic acid may begin to manifest when this fatty acid comprises above 4% of the diet.

In addition to olive oil consumption, the Mediterranean diet is also characterized by fish (and therefore, omega–3 fatty acid) consumption.  The omega–3 linolenic acid content of the experimental diet, at 0.84% was slightly higher than the 0.29% of the control group.  This 0.84% translates into 1.8 grams of omega–3 per day in a 1,947 calorie–per–day Mediterranean diet – an amount of omega–3s easily obtainable on any diet of whole foods.  Despite marketing efforts to the contrary, this study does not provide evidence of the need for omega–3 supplementation – as such supplementation may increase the omega–3 percentage of the diet to historically unprecedented and potentially harmful levels. What it does provide is evidence for a diet low in linoleic acid – an environment in which trace amounts of dietary omega–3s are then able to function optimally.  This is the same principle at work in numerous healthy traditional diets, as we saw in the previous edition of the Integrated Supplements Newsletter.

Damage to PUFAs in Heart Disease

Why shouldn’t an excess of omega–6 fatty acids like those found in the modern American diet be “balanced out” with additional omega–3s as is often advocated by the sellers of omega–3 supplements?  The reason has to do with the chemical instability of both omega–6 and omega–3 fatty acids.  We’ll delve into this topic in greater detail in subsequent Integrated Supplements Newsletters, but for now, we’ll look at how the chemical instability of polyunsaturated oils has major implications for heart disease.

The ability of polyunsaturated fats to increase heart disease risk is easier to understand with a bit of knowledge of the chemical structure of fatty acids.  In molecules of saturated fatty acids, each carbon atom is attached to as many hydrogen atoms as its chemical nature can support.  In other words, the carbon atoms are “saturated” with hydrogen atoms.  By contrast, unsaturated fatty acids contain double–carbon bonds in their structure.  When these double bonds are formed, hydrogen atoms are eliminated, so the carbon atoms aren’t saturated with hydrogen as they are in saturated fatty acids.  As their names suggest, monounsaturated fatty acids contain one double bond whereas polyunsaturated fatty acids contain more than one double bond.  Each double bond in a fatty acid’s structure is chemically reactive; and though this chemical reactivity gives unsaturated fats important biological functions, it also makes them prone to damage when spontaneously reacting with other substances such oxygen.

Generally, the greater the amount of unsaturated lipids in the diet (and therefore body’s tissues), the more fragile and easily damaged all tissues of the body become.  This is one reason why excess PUFA consumption has implications for heart disease and all other age–related disorders.

Heart disease mortality in the U.S. reached its peak between 1950 and 1975 – a time in which saturated and animal fat consumption decreased, at the same time unsaturated vegetable fat consumption increased significantly.  Vegetable oil proponents (and purveyors) likely over–emphasized the ability of vegetable oils to lower serum cholesterol.  Not only is this effect short–lived, but serum cholesterol is a remarkably poor indicator of cardiovascular risk to begin with.  A far more important indicator of cardiovascular risk may be the tendency of cholesterol–carrying lipoproteins to oxidize.

As their name suggests, lipoproteins are proteins which contain lipid structures.  They often serve to transport fat soluble lipids such as cholesterol through the watery environment of the blood.  Fats in the diet directly influence the lipid composition of lipoproteins, and the ingestion of lipids which are prone to oxidative damage (i.e., PUFAs) create lipoproteins which are prone to oxidative damage as well.

Oxidized low density lipoprotein (oxLDL) has been shown to attract immune cells, called macrophages, to the vascular intima.  These macrophages engulf oxidized (and only oxidized) products of LDL , which leads to the production of foam cells and the eventual development of atherosclerotic plaque characteristic of heart disease. Where polyunsaturated fatty acids of the omega–6 and omega–3 class are both inherently prone to spontaneous oxidation due to the double bonds in their structure, the consumption of each is associated with increased levels of oxidized LDL :

Study Link – Dietary polyunsaturates and peroxidation of low density lipoprotein.

Quote from the above study:

Omega–6 polyunsaturated fatty acids enhance the susceptibility of low density lipoprotein to oxidation compared with monoenes [monounsaturated fatty acids]. Most studies on omega–3 fatty acids also exhibit increased peroxidation of low density lipoprotein, although these data are more conflicting.

In studies where saturated fat was replaced with canola oil and sunflower oil (including low–trans–fat margarine made from these oils), levels of oxidized LDL and another cardiovascular disease risk marker, lipoprotein(a), both increased – even though the diet was high in antioxidants:

Study Link – Changes in Dietary Fat Intake Alter Plasma Levels of Oxidized Low–Density Lipoprotein and Lipoprotein(a).

Quote from the above study:

In conclusion, we found that a diet traditionally considered to be anti–atherogenic (low in saturated fat and high in polyunsaturated fat and naturally occurring antioxidants) increased plasma levels of circulating oxidized LDL and Lp(a).

In the above study, the dietary changes made were not extreme.  Compared to baseline intakes, the two study groups decreased their saturated fat intake from 15% to between 9.5% and 11% of overall calories.  The two study groups also increased their polyunsaturated fat intake from 6% to between 7% and 9.5% of overall calories.

In the Mediterranean diet of the Lyon Diet Heart study, omega–3 lipids from canola oil were added to the diet as they were in the above study.  However, unlike the above study, the overall PUFA intake in the Lyon Diet Heart Study was under 5% of calories.  In the above study, the overall PUFA intake was between 7% and 9.5% of calories.  The Lyon Diet Heart Study was associated with reductions in cardiovascular and overall mortality, yet the above study found increased markers of cardiovascular risk.  Together, these studies provide evidence that increasing the PUFA intake of the diet (from either omega–6s or omega–3s) is likely to have negative consequences once a certain threshold is crossed.

Note: It’s important to note that the harmful effects of polyunsaturated oils in the above study were probably not due to trans fats, as the study specifically indicates that low–trans–fat oils were chosen.  Trans fats are created when unsaturated oils are chemically stabilized (as by hydrogenation) to give liquid oils different physical characteristics (i.e., the ability to be spread, as in margarine, or the ability to withstand cooking temperatures as in vegetable shortening).  With the recent backlash against trans fats, many consumer products are currently promoted on the basis that they are trans fat–free, but the toxicity and metabolic destruction caused by the unsaturated oils isn’t necessarily a function of trans fats.  It’s the chemically–reactive double bond in the structure of unsaturated fatty acids which is largely responsible for their toxicity.  As such, even fresh, “unrefined,” or “cold–pressed” sources of polyunsaturated fatty acids are liable to cause damage when consumed in excess.  When the diet contains a high amount of polyunsaturated fats, there is simply no practical way to avoid the spontaneous oxidative damage these lipids undergo in the human body – even in the presence of an antioxidant–rich diet.

Excess Linoleic Acid and Cancer

Though excess linoleic acid is likely to play a role in the development of heart disease, a more major concern may be the fatty acid’s ability to cause or support the development of cancer.

Multi–year studies in which animal fats were replaced with unsaturated oils showed some benefit with regard to cardiovascular mortality, but no benefit with regard to overall mortality.  This is likely to be because groups consuming polyunsaturated oils experienced a greater incidence of fatal cancer:

Study Link – Incidence of cancer in men on a diet high in polyunsaturated fat.

Quote from the above study:

…total mortality was similar in the two groups: 178 controls v. 174 experimentals, demonstrating an excess of non–atherosclerotic deaths in the experimental group.  This was accounted for by a greater incidence of fatal carcinomas in the experimental group.

Many animal studies clearly show that linoleic acid increases cancer risk.  In the following study, even 5% of calories as linoleic acid increased the development of chemically–induced colon cancer in rats:

Study Link – Effect of Dietary Unsaturated and Saturated Fats on Azoxymethane–induced Colon Carcinogenesis in Rats.

Quote from the above study:

The rats were fed two types of semipurified diets consisting of 5% linoleic acid or 4.7% stearic acid plus 0.3% essential fatty acid as dietary fats. The rats were treated with azoxymethane (7.4 mg/kg body weight) s.c. once a week for 11 weeks and sacrificed 15 weeks after the last injection of the carcinogen. The rats fed unsaturated fat diet demonstrated a significantly higher incidence of colon tumors [100%], more tumors per rat [2.68 ± 1.60 (S.D.)], and greater malignant differentiation histologically than did those fed saturated fat diet [76%, 1.79 ± 1.59, respectively].

And similarly:

Study Link – The essential fatty acid requirement for azoxymethane–induced intestinal carcinogenesis in rats.

Quote from the above study:

Large bowel tumor incidence showed a dependence on the essential fatty acid content of the diet.

In the following study, human breast cancer cells implanted into mice grew and metastasized to a greater extent when mice were fed a diet containing 12% linoleic acid versus a diet containing 2% linoleic acid:

Study Link – Effects of Linoleic Acid on the Growth and Metastasis of Two Human Breast Cancer Cell Lines in Nude Mice and the Invasive Capacity of These Cell Lines in Vitro.

Quote from the above study:

…the mean weight of mammary fat pad MDA –MB–231 cell tumors in 12% LA–fed mice was significantly higher (6.7 ± 1.4 g) than that of the mice fed 2% LA; also, it was higher than that of MDA–MB–435 cell tumors in the 12% LA–fed mice (3.6 ± 0.1 g) or the 2% LA–fed mice (3.3 ± 0.1 g) (each P < 0.001). Mice fed the 12% LA diet had a higher incidence of grossly visible MDA–MB–435 cell pulmonary metastatic nodules than those fed the 2% LA diet (67% versus 33%; P < 0.02), more metastatic lesions (5.7 ± 1.6 versus 2.3 ± 0.8; P < 0.05), and greater total volumes (62.0 ± 25.9 versus 24.8 ± 9.0 mm3; P < 0.02) per mouse.

Studies in rats have found that the maximal cancer–promoting dose of linoleic acid was 4.4% of the diet by weight, which amounts to approximately  8% of the diet when measured as a percentage of calories:

Study Link – Requirement of essential fatty acid for mammary tumorigenesis in the rat.

Quote from the above study:

Mammary tumorigenesis was very sensitive to linoleate intake and increased proportionately in the range of 0.5 to 4.4% of dietary linoleate. Regression analysis indicated that a breakpoint occurred at 4.4%, beyond which there was a very poor linear relationship, suggesting the possibility of a plateau. From the intersection of the regression lines in both the upper and lower ranges, the level of linoleate required to elicit the maximal tumorigenic response was estimated to be around 4%.

In an animal study which may have particular relevance for human nutrition, the following rat study found that when corn oil exceeded 3% of the diet, any subsequent increase in total fat intake caused tumors to develop more quickly.  When corn oil comprised less than 3% of the diet, however, the development of tumors was slowed, and there was a decrease in the overall incidence of tumor development:

Study Link – Dietary lipid effects on the growth, membrane composition, and prolactin–binding capacity of rat mammary tumors.

Quote from the above study:

Our results indicated that 1) when the polyunsaturated lipid component (corn oil) of the diet exceeded 3%, it was the quantitative level of total lipid, rather than the level of polyunsaturated lipid alone, that best correlated with the observed reduction in tumor latent period; 2) when the polyunsaturated lipid content of the diet fell below 3%, there was a decrease in tumor incidence and an increase in the mean latent period.

Remember that the amount of linoleic acid in the average American diet is approximately 9% of calories.  From the above studies, it’s clear that the dose of linoleic acid which has repeatedly been shown to maximize cancer development in laboratory animals is significantly less than the dose of linoleic acid consumed in the typical American diet.

In animal studies of cancer like those above, cancer cells or cancer–causing chemicals are injected, and the diet can be meticulously controlled to examine the effects of different types of diets on the subsequent development of cancer.  For ethical reasons, of course, human studies can’t involve the induction of cancer.  This is why human studies of cancer must rely on epidemiological data – population data which, in the realm of nutritional science, examines how populations generally eat, and relates this to their overall incidence of cancer or other disorders.  Hypotheses are then formed about the association between nutrient status and the development of disease.

Some studies have shown evidence that omega–6 linoleic acid is associated with cancer in humans.  The following study even found that the relatively stable fats from dairy were protective against prostate cancer in smokers:

Study Link – (n–6) PUFA Increase and Dairy Foods Decrease Prostate Cancer Risk in Heavy Smokers.

But although many animal studies clearly show that linoleic acid increases cancer incidence, human studies are far more equivocal.  In human studies, overall fat intake is more closely associated with cancer incidence than is linoleic acid intake per se.  But, from the  rodent studies above, we can see that as little as 3–5% of dietary calories as linoleic acid is sufficient to increase cancer incidence, whereas 2% did not.  In industrialized human populations, however, it’s rare to find any significant number of people not consuming at least 3–5% of their daily calories from linoleic acid.  In humans, as in the rat study previously mentoned, it’s likely that once a certain threshold of linoleic acid is reached in the diet, any subsequent increase in fat intake increases cancer risk.

Using the diet of traditional cultures (for whom cancer incidence is low) as a guide, we may want to construct our diet to contain ~2% linoleic acid.  All evidence suggests that this dose easily prevents omega–6 deficiency, and lower doses than this are quite difficult to achieve on any whole–food diet.

From the accumulated research, we can see clear evidence that unprecedented intakes of polyunsaturated fats in industrialized nations may predispose us to increased incidence of heart disease and cancer.  Yet the related disorders of industrialization, obesity and diabetes, may also owe much to our uniquely high polyunsaturated fat intake.

Multigenerational Effects of Excess PUFA in Obesity

Long–term studies in which unsaturated fats replaced saturated fats in the diet clearly show that the fatty acid composition of the body’s tissues changes commensurately.  Logically, a greater amount of chemically–unstable and pro–inflammatory lipids in the body’s tissues can set the stage for major metabolic disruption.  The following study is one of the few in the scientific literature which investigated the long–term (up to five years) effects of replacing saturated fats with polyunsaturated fats:

Study Link – Composition of lipids in human serum and adipose tissue during prolonged feeding of a diet high in unsaturated fat.

In the above study, elderly men consuming increased amounts of PUFA exhibited serum lipids (i.e., triglycerides and lipoproteins) in which linoleic acid was incorporated commensurately with dietary intake (thus predisposing these blood lipids to increased oxidation as seen earlier).  By the end of five years, the linoleic acid content of adipose tissue had risen from 11% at the start of the study to 32% – in essence, building a nearly limitless storehouse of this inflammatory lipid.  The high–PUFA group was shown to gain weight compared to those eating the normal diet (those eating the normal diet actually lost weight).  While there’s reason to believe that their higher PUFA intake inhibited metabolism somewhat, the degree of weight gain in the high–PUFA group wasn’t remarkably pronounced.  There are several additional factors to consider, however, when investigating the role of polyunsaturated lipids in causing weight gain.

This study was conducted on elderly men, and was published in 1966 – the men in this study were born, and experienced their formative years, before the massive influx of PUFA into the American food supply.  It’s quite likely that a high–PUFA intake during childhood may fundamentally alter metabolic rate and increase the propensity to gain fat in the long–term.

As evidence, It’s helpful to investigate what happens when animals are fed high–PUFA, or high omega–6 diets in the long–term – including their formative years when adipocyte number (and subsequent risk of obesity) is largely determined.

Studies have found that different dietary lipids can influence the rate of weight gain, even independent of caloric intake.  Rats fed beef tallow (a source of saturated and relatively stable fats) exhibited less weight gain than those fed either olive oil or safflower oil.  All groups were also fed omega–3 fats from linseed (flaxseed) oil, and only in the rats fed beef tallow was the incorporation of these omega–3s into tissue phospholipids not inhibited.  This is further evidence that linoleic acid intake must be kept low in order for omega–3s to exert their beneficial effects:

Study Link – Dietary Lipid Profile Is a Determinant of Tissue Phospholipid Fatty Acid Composition and Rate of Weight Gain in Rats.

Quote from the above study:

Despite isocaloric feeding, weight gain was lower (P < 0.001) in rats fed the more highly saturated ET–L diet (69 ±8 g) than in those fed either the high (n–9) fatty acid OL–L diet (93 ±2 g) or the high (n–6) fatty acid SAF–L diet (108 ±4 g).

In adulthood, fat cells can expand to hold more lipids, but the overall number of fat cells remains largely constant.  It’s during gestation and early childhood that the quantity of the body’s fat cells is largely determined.  Linoleic acid appears to stimulate the production of fat cells at this critical time in development, and animals exposed to large amounts of linoleic acid during gestation and lactation appear to be particularly prone to obesity:

Study Link – Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern?

Quote from the above study:

During the pregnancy–lactation period, mother mice were fed either a high–fat diet rich in linoleic acid, a precursor of arachidonic acid (LO diet), or the same isocaloric diet enriched in linoleic acid and alpha–linolenic acid (LO/LL diet). Body weight from weaning onwards, fat mass, epididymal fat pad weight, and adipocyte size at 8 weeks of age were higher with LO diet than with LO/LL diet. In contrast, prostacyclin receptor–deficient mice fed either diet were similar in this respect, indicating that the prostacyclin signaling contributes to adipose tissue development. These results raise the issue of the high content of linoleic acid of i) ingested lipids during pregnancy and lactation, and ii) formula milk and infant foods in relation to the epidemic of childhood obesity.

Similar evidence from animal studies suggests that the obesity–inducing effects of omega–6–rich oils may even increase across generations.  Animals fed vegetable oils produce offspring which are more apt to have both larger and more numerous fat cells and greater fat mass, even with no change in caloric intake.  Several generations of such feeding has been shown to result in offspring exhibiting marked obesity.  If even a similar phenomenon occurs in humans, this would go a long way towards explaining the rapidly increasing rate of obesity (especially childhood obesity) found in recent decades:

Study Link – A Western–like fat diet is sufficient to induce a gradual enhancement in fat mass over generations.

Quote from the above study:

Offspring showed, over four generations, a gradual enhancement in fat mass due to combined hyperplasia and hypertrophy with no change in food intake.

Study Link – Fatty acid composition as an early determinant of childhood obesity.

Quote from the above study:

…changes over decades in the fatty acid composition of dietary fats observed in breast milk and formula milk, i.e. a high increase in [linoleic acid] with slight or no change in [linolenic acid], may be responsible, at least in part, of the dramatic increase in the prevalence of childhood overweight and obesity.

Researchers involved in the above studies have thus postulated that our unique fatty acid intake may have much to do with dramatic increases in the prevalence and degree of obesity in industrialized countries.  The role of linoleic acid as a precursor to various inflammatory and proliferative signaling molecules has been noted, as has the historical over–estimation of the true human linoleic acid requirement:

Study Link – An emerging risk factor for obesity: does disequilibrium of polyunsaturated fatty acid metabolism contribute to excessive adipose tissue development?

Quote from the above study:

Recent human and animal studies suggest that by altering rates of adipocyte differentiation and proliferation, differences in the composition of dietary fat may also contribute to adipose tissue development. At least in rodent models, the relative intake of n–6 to n–3 PUFA is clearly emerging as a new factor in this development …One factor potentially contributing to oversight about the apparent role of dietary n–6 PUFA (especially excess dietary linoleate) in adipose tissue development is the historical overestimation of linoleate requirements and the enthusiasm for higher intake of 'essential fatty acids'. More research is needed to address whether disequilibration of dietary PUFA intake contributes to the risk of obesity in humans.

In the next edition of the Integrated Supplements Newsletter, we’ll examine more ways in which an excess of linoleic acid and other polyunsaturated fats may cause major metabolic disruption.  We’ll see how a diet containing low levels of polyunsaturated fats may be particularly beneficial for various health concerns, and we’ll examine practical aspects of analyzing and constructing a low–PUFA diet.

April 27, 2011

Whey Protein Enhances Muscle and Liver Glycogen Storage – Implications For Muscle Growth and Exercise Recovery.

WorkoutCurl Even in academic circles, dietary protein is often simplistically viewed as a mere source of amino acid “building blocks” for the body’s tissues and enzymes.  Decades’ worth of research clearly shows, however, that certain food proteins and peptides exert remarkable biological effects independent of their role in forming the structural material of tissues and enzymes.

Dairy proteins – and whey proteins in particular – happen to be among the richest sources of such bioactive peptides.  In previous Integrated Supplements Blog articles, for example, we’ve examined how the potent antioxidant activity of whey’s cysteine-containing peptides may be of unique benefit in conditions characterized by oxidative stress such as diabetes:

Select Studies on Whey Protein - Whey Protein, Blood Sugar, and Oxidative Stress

We’ve seen how the iron-binding properties of whey’s lactoferrin peptide may protect against iron-induced oxidative damage:

Select Studies on Whey Protein - Whey Protein Protects Against The Toxic Effects Of Iron

And, we’ve seen how the whey peptide called glycomacropeptide may suppress appetite, ultimately leading to reduced caloric intake:

Study Finds Whey Protein Containing Glycomacropeptide Leads To Reduced Calorie Consumption

As it turns out, even the muscle-building properties of whey protein aren’t solely due to protein’s role as a structural component of muscle tissue.  Whey protein may have the unique ability to facilitate the uptake and storage of carbohydrate in the body’s cells – thus creating the optimal environment for exercise recovery and muscle growth.

Muscle and Liver Glycogen – Keys to Exercise Performance, Recovery, and Muscle Building

Glycogen is the storage form of carbohydrate found in the body’s cells.  When energy demands are taxed – as they are in intense exercise – levels of muscle glycogen and the “emergency reserve” of liver glycogen become drained.  In this scenario, not only does performance suffer (glycogen depletion is thought to be a major factor in the fatigue of endurance athletes, for example), but recovery from training is hindered as well.  This is why the muscle-building effects of weight training are often hindered by inadequate nutrition.  In other words, no matter how much protein is consumed, muscle protein synthesis (i.e., muscle growth) simply cannot occur optimally until glycogen stores are replenished.

In fact, monitoring the level of liver glycogen may be a fundamental way in which the body gauges a fed state (i.e., a metabolic environment suitable for growth and repair).  When liver glycogen is low, the body may elicit the adrenaline-driven “fight-or-flight” response which converts structural (e.g., muscle) proteins into fuel sources – obviously, not the ideal situation for muscle growth. 

Note – the role of liver glycogen as a signal of the fed state is outlined in our article:

A Diet For Long-Term Weight Control And Optimal Health - Part 2 - The True Role of Sugar in Weight Gain, Diabetes, and Metabolic Syndrome

Whey Protein Increases Glycogen Levels

Recent research has shown that whey protein may be unique among protein sources in facilitating the uptake and storage of muscle and liver glycogen.

Human studies have shown that mixtures of whey and casein protein combined with carbohydrates led to significantly greater rates of glycogen storage relative to either carbohydrate or protein alone:

Study Link - Carbohydrate-protein complex increases the rate of muscle glycogen storage after exercise.

Quote from the above study:

The rate of muscle glycogen storage during the CHO-PRO treatment [35.5 +/- 3.3 (SE) mumol.g protein-1.h-1] was significantly faster than during the CHO treatment (25.6 +/- 2.3 mumol.g protein-1.h-1), which was significantly faster than during the PRO treatment (7.6 +/- 1.4 mumol.g protein-1.h-1). The results suggest that postexercise muscle glycogen storage can be enhanced with a carbohydrate-protein supplement as a result of the interaction of carbohydrate and protein on insulin secretion.

Subsequent animal studies have found that whey protein (more so than casein) is uniquely responsible for increasing glycogen levels after exercise.

Study Link - Dietary whey protein increases liver and skeletal muscle glycogen levels in exercise-trained rats.

Quote from the above study:

Total glycogen synthase activity in the skeletal muscle in the whey protein group was significantly higher than that in the casein group. The present study is the first to demonstrate that a diet based on whey protein may increase glycogen content in liver and skeletal muscle of exercise-trained rats. 

In all, it seems that whey protein along with a source of carbohydrates (including some fructose) – consumed either before or after workouts – is the ideal way to maximize the muscle-building effects of exercise.

Ideally, the whey protein chosen will contain the full spectrum of whey’s bioactive peptides, be all-natural, and free of residual amounts of cholesterol – as is Integrated Supplements CFM® Whey Protein Isolate.

Related Articles:

Building The Perfect Workout Drink With Whey Protein Isolate


April 10, 2008

Select Studies on Whey Protein - Whey Protein, Blood Sugar, and Oxidative Stress

Blood_sugar72In keeping with our recent theme of oxidative stress and aging, it seems that yet another disorder in which oxidative stress plays a particularly major and multi-faceted role is diabetes.

It’s important to clear up any misconceptions right from the beginning – diabetes is not simply a disease of altered carbohydrate and sugar metabolism as many people think. As research accumulates, it’s becoming well-recognized that diabetes, although it obviously involves faulty blood sugar regulation, would be more precisely classified as fundamentally a disease of oxidative stress.

In other words, oxidative stress is now thought to be the primary underlying cause of faulty blood sugar regulation in diabetes. When we reduce our levels of oxidative stress, our blood sugar naturally tends to normalize.

Study Link - Diabetes, oxidative stress, and antioxidants: a review.

Increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of both types of diabetes mellitus.

Diabetes Is Deadly

With how frighteningly common diabetes has become, it’s important for us to recognize how profoundly dangerous and life threatening diabetes can be. Left uncorrected, a chronically elevated level of blood sugar will eventually damage virtually every organ system and function of the body. In diabetes, the cellular damage characteristic of oxidative stress is known to ultimately manifest as extensive damage to the tissues of:

The eyes, (often resulting in blindness)

The blood vessels (often resulting in heart disease, and even sexual dysfunction)

The kidneys (called diabetic nephropathy, often requiring dialysis or a kidney transplant)


Foot ulcers (caused by nerve damage called diabetic neuropathy – often requiring amputation)

With the extensive damage diabetes can cause, finding safe and effective ways of reducing our burden of oxidative stress should be a first priority for any health-conscious person looking to avoid the ravages of the disease.

Not coincidentally, research is beginning to indicate that reducing oxidative stress via stimulating the production of glutathione may be one of the most important keys to healthy blood sugar metabolism:

Study Link - Meal cysteine improves postprandial glucose control in rats fed a high-sucrose meal

Dietary cysteine alleviates sucrose-induced oxidative stress and insulin resistance

Diets that promote oxidative stress favor impairment in glucose homeostasis. In this context, increasing the cysteine intake may be beneficial by maintaining glutathione status. . . Of great interest was the observation that all beneficial effects of cysteine supplementation were duplicated by the consumption of a cysteine-rich protein. These data show that increasing the cysteine intake limits [sugar]-induced impairment of glucose homeostasis and suggest that these effects are mediated by a reduction in oxidative stress.

In the above studies, whey protein was able to improve glucose control, and reduce oxidative stress in rats given high-sugar diets.

And of course, as we’ve shown you before, Integrated Supplements CFM® Whey Protein Isolate is among the richest sources of glutathione-boosting compounds including cysteine and glutamylcysteine.

By itself, it’s certainly premature to say that whey protein will be able to treat or prevent diabetes (remember, supplements by themselves should never be expected to treat, cure, or prevent any disease), but as part of a healthy diet and lifestyle, whey protein isolate may very well be a sound nutritional choice for anyone looking to support a healthy blood sugar through the production of glutathione.

Other Factors

As we’ve showed you in recent editions of the Integrated Supplements Newsletter and blog, other major dietary factors contributing to oxidative stress include excessive amounts of unsaturated fats, oxidized cholesterol, and iron.

Those looking for a comprehensive approach to reducing oxidative stress, may want to read the following articles and Blog posts to get up to speed.


Rancid Fats and Oxidative Stress - Strategies To Reverse Aging - Part 1

Combating Oxidative Stress - Strategies to Reverse Aging - Part 2

The Anti-Aging Diet Part 1 - Can Some Foods Accelerate Aging?

The Anti-Aging Diet Part 2 - The Dark Side of Iron

The Anti-Aging Diet Part 3 - Solving The Puzzle of Iron

Blog Posts:

Select Studies on Whey Protein - Whey Protein Protects Against The Toxic Effects Of Iron

Oxidative Stress And Exercise - Too Much of a "Good Thing"

How To Combat The REAL Risk Factor For Heart Disease And Aging

Studies Find Antioxidants Harmful. Well, Sort Of.

And, of course, stay tuned here for more.


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