By Benjamin V. Treadwell, Ph.D.

Many people, including some medical doctors, advise against supplementing our diets with vitamins, minerals, and other micronutrients. The most common reason given? We can obtain all the nutrients our bodies require from healthy eating.



Is this true? Or is supplementing the key to maintaining sufficient levels of vitamins and nutrients for a balanced metabolism and optimum health? A large group of medical/health professionals has come to this conclusion. Let's take a closer look at one essential nutrient, biotin, as an example of how and why.



Biotin Basics

Our bodies cannot make biotin, the more common name for vitamin B-7. It serves key functions in the production of energy in our cells, including metabolizing glucose, amino acids and fat. (See Juvenon Health Journal Volume 3 Number 10, "B for Biotin.") More recent research supports a role for biotin in regulating gene expression as well.



The micronutrient biotin is present, at varying concentrations, in cow's milk, liver, other meats, fish and many vegetables, fruits and grains. Cooked eggs are also a good source of this nutrient.



The recommended daily allowance (RDA) for biotin is 300 micrograms (mcg). Even though many multivitamins on the market contain less per dose, biotin has actually been shown to be safe at amounts much higher than the RDA. In fact, the upper safe limit remains to be established.



How do you know if your cells aren't getting enough biotin? A rash can be an early warning sign. Almost 10 years ago, it was also part of what led scientists at Juvenon to better understand biotin uptake.



Decade of Discoveries

Pilot studies during the development of the Juvenon Cellular Health Supplement yielded primarily positive feedback (more energy, sharper mind, shinier hair…). But there were a very few people (less than 1 in 1,000) who reported a skin rash, a metallic/salty taste or losing their normal sense of taste.



The Juvenon scientists were somewhat puzzled. The two primary nutrients in the formula -- acetyl-L-carnitine and alpha lipoic acid -- had shown no adverse effects, even at much higher than the supplement's recommended dose.



One of the investigators, however, remembered previous studies that might apply. An expert in the field of biotin research had conducted an experiment that demonstrated lower biotin levels in the tissues of some animals fed large amounts of lipoic acid.



Later work had shown that lipoic acid, biotin and another B-vitamin, pantothenic acid (B5) share structural similarities and the same Multivitamin Transporter (MTV). The MTV moves the nutrients of more than one vitamin from the blood into the cell to perform their functions.



The Juvenon researchers theorized the MTVs of the few individuals reporting side effects might not function efficiently. This small group remained side-effect-free until Juvenon elevated their metabolism. The Cellular Health Supplement provided more lipoic acid, increasing the need for pantothenic acid and biotin.



Pantothenic acid is present at high levels in many foods and most multivitamins (5x RDA). But biotin, from food or multivitamins (low RDA), is not as readily available. If the MTV were not functioning efficiently and the levels of the three nutrients were not balanced, more of one nutrient would be absorbed into the cell at the expense of another.



So, conditions like a rash or loss of taste might actually be a warning of an under-performing MTV that could result in a biotin imbalance.



Biotin Balancing

Based on this research and biotin's safety record, the solution seemed to be adding the vitamin to the Cellular Health formula. The adjustment resulted in a dramatic decrease in reports of side effects: from one in 1,000 users to less than one in 7,000.



The "less than one" led the Juvenon scientists to another important discovery. Suspecting that low biotin might still be producing the symptoms, they recommended that this smaller minority take 5 milligrams (mg) of biotin (17x RDA), along with the Cellular Health Supplement, per day. Over 70% of those following this protocol reported becoming side-effect-free.



The conclusion from these results? Biotin requirements for maximum health vary from person to person, perhaps determined by how well their MTVs function, a genetic predisposition, or both. The case studies that follow seem to support this conclusion.



More Please

In a recent Juvenon Cellular Health clinical trial (designed to evaluate its benefits for human cognition), a female participant experienced loss of taste after a few weeks. A research team documented her condition and were the first to report how this "unexplained loss of taste" was resolved.



Confirming that this development had been previously reported and successfully reversed, the team initially recommended the same protocol, using the 5 mg biotin dose. Surprisingly, this approach produced little change in the subject's symptoms. The investigators suggested increasing the daily dosage to 10 mg (33x RDA). After a few days, the woman regained her normal sense of taste.



Who Needs More and Why?

Did this response to the 10mg dose demonstrate a more individualized (and perhaps pharmacological) need for biotin? The investigators examined another case to find out.



A male patient, unconnected to Juvenon, awoke from abdominal surgery with no sense of taste. Like the first case study subject, he was asked to begin by taking 5 mg of biotin per day and showed no apparent positive response after several days.



Unlike the female patient, however, increasing the daily dosage to 10 mg also had no effect. The researchers continued to give incrementally larger doses to the male participant, eventually reaching 20 mg per day (67 times RDA). It took this mega-dose to fully restore his sense of taste.



Beyond Biotin

The two case studies seem to support the concepts of variable MVT efficiency from one person to another and differences in individual needs for/responses to biotin. Perhaps more importantly, this research suggests that requirements for other nutrients, and the need for supplementing, will vary.



Factors like gene composition, diet, weight, general health, level of stress and age could account for the variations. Speaking of age, studies have also shown a general need for more nutrients as we get older. (The case study subjects were 67 and 60 years old, respectively.) Higher intake compensates for age-associated decreases in absorption from the digestive tract and uptake into the body's cells and tissues (older, inefficient nutrient transporters).



We may require higher concentrations for one more reason. Recent studies are uncovering new tasks performed by other nutrients, similar to biotin's broader function with loss of taste. In view of these findings, a healthy diet alone (fruits, vegetables, whole grains and legumes), although important, may simply not be sufficient, particularly as we age.



In other words, taking supplements (with the guidance of a health professional, of course) seems to be the best option for protecting and promoting optimum health.

By Benjamin V. Treadwell, Ph.D.

It's likely that anyone who pays even passing attention to his or her health is aware that antioxidants are generally good for us. But what are they, really? How do antioxidants work? Are some better than others?

What Are Antioxidants?

Before we get to the "anti" part of the story, let's begin with the oxidants that the "antis" fight. The sun is a source of oxidants familiar to all. Its effects on manufactured products are well known. Colors fade in clothing, plastics, and on painted surfaces. The rubber tires on your car harden and then crack. The sun essentially takes the life out of the products exposed to its rays.

This happens because sun's ultraviolet rays disrupt the chemical bonds that hold together materials such as rubber and plastics. Electrons in pairs characterize these bonds. The sun's energy agitates the electrons and splits off some of them, leaving disrupted or broken bonds with, figuratively speaking, jagged ends characterized by a single unpaired electron. The unglued or broken bond with its single unpaired electron is an oxidant. And it doesn't like the single life. It aggressively pursues a mate, another electron to pair-up with. The result is an attack on a chemical bond in the vicinity of the ruptured bond. The single electron ends up with a mate, but only by breaking up an existing pair, and thereby propagating another oxidant, or free radical. This series of events unfolds in chain-reaction fashion until the attacked material is completely oxidized (bleached and weakened fabric, or cracked rubber tire).

In the case of paint, rubber and fabrics, chemists have figured out ways to prevent, or at least inhibit oxidation by adding specific antioxidant compounds to the materials during their manufacture. These compounds safeguard the material through their greater susceptibility to oxidation than that of the materials they are protecting. When they are oxidized, their chemical structure stabilizes the unpaired electron. Thus they prevent and/or terminate the oxidant-induced chain of reactions and protect the material in which they are imbedded.

What About Human Cells?

Living tissue requires protection from environmental oxidants (the sun, smoke, pesticides, drugs etc.), as well as oxidants produced as by-products of normal metabolism. However, oxidants, including free radicals, are necessary for numerous reactions involved in cellular energy production and survival. Since the oxidation reactions necessary for normal cell health are tightly confined to specific cellular machinery known as enzymes, the antioxidants normally present in the cell cannot breach their domain. For this reason it is difficult (but not impossible) to overdose on most essential antioxidants.

Approximately 1-2% of the oxygen taken in through the lungs and used by the body to produce energy is released from the enzyme confines as nasty free radicals. This amounts to a whopping 20 billion molecules of free radicals produced by each cell per day. These molecules are the targets for the antioxidants that our bodies need to maintain cellular health.

Fighting the Oxidants

To disarm the oxidants, our bodies use antioxidants that are either produced by our tissues or absorbed from the foods we eat. They divert the attack of free radicals from vital cellular components to the more oxidant-prone antioxidant. They, too, form free radicals when oxidized, but the odd reactive electron is dispersed over the specialized structure of the antioxidant, thus stabilizing it.

Scientists previously thought the organism excreted usurped (oxidized) antioxidants. Researchers have shown, however, that biological antioxidants are recyclable, unlike those added to synthetic materials such as paints and plastics. Work performed in the laboratories of Dr. Lester Packer (a member of Juvenon's Scientific Advisory Board) and others has demonstrated the existence of a rechargeable antioxidant system utilized by our cells.

Which Antioxidants Are Best?

Two general types of antioxidants work together to protect the cells and tissues of our bodies. One type protects the aqueous (watery) portion of the tissues and the other the hydrophobic, or lipid (fatty) component. The aqueous environment is protected by vitamin C, and at least two additional antioxidants produced by tissues, glutathione and thioredoxin. Cell membranes are protected by the lipid-soluble antioxidants, including vitamin E, and the ubiquinols (CoQ10). Another antioxidant, alpha lipoic acid, is unique in that it can enter and protect both lipid and water environments.

When vitamins C and E react with and neutralize a free radical, the oxidized or spent vitamins are converted back to the reduced or recharged, active form. Vitamin C can donate electrons to oxidized vitamin E and convert the E back to its active state, leaving vitamin C oxidized. Vitamin C, in turn, can be recharged after reacting with glutathione or the more potent antioxidant, alpha lipoic acid.

The most versatile antioxidant in the cell is alpha lipoic acid. It is one of the more potent antioxidants, owing to its property of being the most easily oxidized. Alpha lipoic acid is the foundation of an antioxidant network involved in the conversion of the spent or oxidized forms of four different cellular antioxidants back to their active protective forms. The obvious questions, then, are how lipoic acid is regenerated and whether this process ever ends.



The answer lies in the unique property of lipoic acid, its solubility in both water and lipid. Lipoic acid can be converted from its oxidized state to its reduced state with the aid of a mitochondrial enzyme (the organelle within the cell where energy is produced). Unlike vitamins C and E, the cell has machinery specifically designed for the regeneration of reduced lipoic acid. Therefore, lipoic acid can itself react with and neutralize free radicals in addition to recycling vitamins C and E (as well as CoQ10, glutathione and thioredoxin). This is critical, since each antioxidant has a unique function. The conclusion, then, is that all of these antioxidants are required for optimal cellular health.

Without vitamin E, we essentially turn rancid. Vitamin E is fat-soluble, that is, able to penetrate the fatty areas of our tissues. As it does so, it neutralizes toxic oxidants and protects oxidant-sensitive membranes. Thus vitamin E is justifiably known as an antioxidant, and for helping to prevent age-associated increases in oxidative insults to our bodies.

The Eight Forms of Vitamin E

In reality, vitamin E comes in eight different forms, all of which are derived from plants. The eight E's are divided into two classes:

• The tocopherols consist of 4 types of vitamin E, alpha, beta, gamma, and delta. The features distinguishing each are slight chemical differences (location and number of methyl groups) on its core structure.
• The tocotrienols are virtually identical to the tocopherols in structure, except for the presence of 3 unsaturated bonds (hence trienol). Alpha, beta, gamma and delta tocotrienols are more permeable to cell membranes because of their unsaturated bonds. This chemical difference imparts certain advantages over the less permeable tocopherols.

The most potent antioxidant of the group is alpha tocopherol. For reasons still unknown, this form of E represents the bulk of vitamin E present in our serum. This is puzzling, since the plants we normally consume contain much more gamma tocopherol. Scientists originally speculated that our bodies require high serum levels of alpha tocopherol and have developed mechanisms to retain it. Thus, multi-vitamins almost always contain alpha tocopherol.

It is becoming more evident, however, that all forms of E are important and that they serve very different functions. Laboratory experiments have indicated that gamma and alpha tocopherol may complement one another with respect to antioxidant protection. Alpha tocopherol is most effective at neutralizing oxygen-based free radicals, whereas gamma tocopherol does best with nitrogen-based free radicals. Both types of radicals are destructive to our bodies.

The vitamin E offered on the market is either man-made or isolated from plants. Man-made (or synthetic) vitamin E is designated on the bottle's label as DL alpha tocopherol. The D and L are isomers or mirror images of each other. Only the D form is representative of the natural vitamin E alpha tocopherol. There is considerable controversy as to whether the L form interferes with the natural D form in the body. Some researchers believe it may be toxic.

Natural vitamin E is usually labeled D alpha tocopherol but almost always contains all 4 tocopherols. Typically, the bottle's label mentions only D alpha tocopherol because of the expense the manufacturer would incur to assay for the presence and quantity of the other three. The 4 tocopherols are derived from soybean oil or, less commonly, wheat germ. The 4 tocotrienols are usually prepared from extracts of palm oil or rice bran.

Vitamin E deficiency is not common, but it can occur with poor nutrition and/or a problem with absorption of fats. The RDA for vitamin E is 30 International Units (IU) per day for DL and 22 IU/day for D alpha tocopherol. A diet totally devoid of fats can result in a deficiency of E, since some fat is required for absorption from the intestines.

Fragile red blood cells are a common characteristic of E deficiency. Blood cell membranes, normally protected by E, tend to oxidize and rupture easily. Recent studies indicate vitamin E may help in slowing cognitive decline in Alzheimer's patients, and it may even lower blood pressure and cholesterol levels. Significant evidence also supports the vitamin as important for protecting tissues from the destructive action of oxidants and consequent disease, including heart disease, cataracts, cancer, neurological disorders and disorders of the muscular system. The incidence of these diseases increases with age. Thus it is important to obtain enough E to attenuate the age-associated destructive process.

Vitamin E is more than an antioxidant. Growing evidence supports specific roles for the different forms of vitamin E. For example, recent research demonstrates gamma tocopherol to be capable of blocking the activity of an enzyme involved in producing cellular mediators of inflammation (prostaglandins), which can lead to disease. Other tocopherols, including the more popular alpha, are largely ineffective in this context.

Alpha tocotrienol has now been shown in cell culture experiments to protect cells of the nervous system from the degenerative action created by the overproduction of the neurotransmitter, glutamate. This chemical, better known as monosodium glutamate, is used as a food enhancer and is infamous for its reputation as the agent responsible for the Chinese restaurant syndrome (bad headaches, etc.) in those who consume too much of it. Normally, an excess of this neurotransmitter activates a neurotoxic enzyme (12-LOX). Tocotrienol, in very small amounts, stops this toxic enzyme in its tracks, thus potentially protecting the nervous tissue.

The unique behavior of the different forms of vitamin E helps explain the advice of nutritionists to consume a variety of fruits, vegetables, legumes and grains. All are good sources of the various forms of vitamin E. Grains should preferably be non-refined. The tocotrienols, as well as other micronutrients, are present in the rice bran, which is lost in processing. People on low-fat diets, such as vegans, are often deficient in vitamin E and should consider taking supplements.

How much E should one take, if any? The upper safe limit for D alpha tocopherol is 1,500 IU/day, according to The Institute of Medicine. The major danger in taking high levels of E is its capacity to inhibit the adherence of platelets to the walls of blood vessels. This is positive for cardiovascular health in those with over-active clotting, but too much E can cause bleeding, especially for people taking other anticoagulants, such as aspirin or coumadin. If you are inclined to take vitamin E, 400 IU/day of natural vitamin E is a reasonable target. However, it is advisable to consult with your physician before taking this supplement.

Finally, the E vitamins function as antioxidants only in their reduced, non-oxidized state. In a subsequent newsletter we will describe how the cells of the body maintain these antioxidants in their reduced or active state. We will also describe how the versatile antioxidant, alpha lipoic acid, functions to recycle these and other antioxidants to maintain cellular health as we age.

Substantial progress has been made in understanding the bio- chemistry of the mitochondria - the organelles that power our cells. Similarly, mitochondrial decay is broadly recognized as playing a central role in the aging process. However, much less is known about effective nutritional approaches to maintain and promote mitochondrial health.

A recent literature review in Canada has evaluated the effects of a wide variety of substances that are reported to produce positive effects on the mitochondria. These include coenzyme Q₁₀; other antioxidants, such as ascorbic acid, vitamin E, and lipoic acid; niacin; creatine; carnitine, and some others. For further information, click here.

This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.

Alpha lipoic acid (ALA) is a vitamin-like nutrient that is essential for life. The conversion of food to energy within our cells derives predominantly from a series of reactions within the mitochondria, commonly referred to as the Krebs Cycle. Alpha Lipoic Acid acts like a catalytic converter for the reactions that involve two key enzyme complexes, without which the Cycle would shut down and the cell would die. (For more information visit the following articles Alpha Lipoic Acid: A Marvelous Nutrient, and The Two Faces of Alpha Lipoic Acid.)

Although this conversion of food to energy is its primary function, recent studies have shown that Alpha Lipoic Acid may also be effective in treating many chronic health problems.

Cell culture and animal research, along with human clinical trials and anecdotal evidence, seem to support Alpha Lipoic Acid's therapeutic value for migraine headache, macular degeneration, obesity, inflammation, cataracts, multiple sclerosis, neurodegenerative, cardiovascular and liver disease, and, in particular, type II diabetes.

ALA The Cell Protector

Pain, numbness, tingling, burning sensations.. .the exact mechanism by which Alpha Lipoic Acid lessens these diabetic symptoms is not yet known. However, results from recent cell culture and animal studies appear to provide some exciting clues.

A study examining the effects of Alpha Lipoic Acid on preventing the death of liver cells, after exposure to a death-promoting inflammatory substance produced by the cell (TNF alpha), demonstrated a new function for Alpha Lipoic Acid: the ability to bind to a specific area (tyrosine kinase domain) of the insulin receptor, which results in its activation. Once activated, the receptor initiates a series of reactions forming a biochemical pathway (PI3-K/Akt pathway) in the cell that acts to counter the TNF alpha-induced death pathway.

The investigators also noted that the PI3-K/Akt pathway, although primary, was not the only cell-saving mechanism. Their results indicated that the antioxidant property associated with Alpha Lipoic Acid (ALA) plays some role in preventing cellular death as well. Moreover, only ALA, and not other antioxidants, binds to the insulin receptor and activates the life-saving PI3-K/Akt pathway.

Less Cellular Stress

These results provide valuable insight into how ALA may function to improve the symptoms of diabetic neuropathies and increase insulin receptor sensitivity.

Animal studies of tissue under diabetic conditions have also demonstrated how cellular stress is produced by increased oxidative stress. Similar to what happened in the liver cell study, this stress promotes inflammation and the production of inflammatory substances like TNF alpha. The end-result is damage to nerve tissues and eventual death of some nervous system cells.

Translation: The painful condition of the peripheral nervous system experienced by diabetic patients may be partially caused by this inflammation-induced damage. ALA may neutralize the inflammatory pathway via binding to the insulin receptor which activates the PI3-K/Akt, or pro-survival, pathway.

As to increased insulin sensitivity and its glucose regulating benefits, this, too, seems to be a result of ALA's ability to support insulin in activating the receptor. You might say that ALA converts a rusty non-compliant insulin receptor to a hair-trigger receptor that is more easily set-off, i.e., activated, in response to insulin.

ALA and Us

Recent human clinical trials seem to support cell culture and animal study findings. Patients with certain nervous system pathologies associated with type II diabetes have experienced significant improvement from taking ALA in oral doses (600 mg/day). Clinical trials also indicate that ALA does improve insulin sensitivity.

Whether the actual mechanisms responsible for the positive effects in humans are explained by the results obtained from animal and cell culture studies remains to be determined. However, it is clear from these and other studies on ALA that additional research on this vitamin-like compound is warranted.

By Benjamin V. Treadwell, Ph.D.

Vitamins have taken several significant hits lately for not delivering their purported health benefits. In fact, there are claims that, under specific conditions, some vitamins can actually have a negative effect on health. In contrast, experts have also recently become aware that the current recommended dietary amounts of some vitamins are far below what is needed for maximum health. Who is responsible for those recommendations and how will they change?

Initially, vitamin D was believed to help prevent the inadequate bone mineralization that progressed to the disease known as rickets in children and osteoporosis in adults. Consequently, the RDA for vitamin D was set to prevent bone-mineralization-associated diseases.

Research, however, has identified this vitamin’s contribution to numerous other biological functions, including a potential role in preventing breast and prostate cancer, tuberculosis, autoimmune diseases, and other disorders unrelated to bone mineralization. (For a review of new vitamin D findings, visit the following articles see Vitamin D - Recent Provocative Discoveries, Vitamin D - A Hormone with New Health Benefits, and Vitamin D — A Vitamin In Need of Revision.) Furthermore, there are more vitamin D receptors whose functions have yet to be discovered, in organs such as the brain.

In other words, the current recommended dose of 400 IU appears to be far short of what many require for maximum health, especially the elderly and those with pigmented skin and/or minimal exposure to sunlight. As a result, the government is scrambling to establish a new, significantly higher RDA. The maximum safe dosage may also be increased by a factor of at least 5 to 10 times the current recommended daily intake.

Another Story: Vitamin K

In 1943, Danish biochemist Carl Dam shared a Nobel Prize for his work on discovering a substance required for the clotting of blood: vitamin K. Taking its name from “koagulation,” Danish for coagulation, vitamin K functions as a cofactor for an enzyme (gamma glutamylcarboxylase) involved in modifying specific amino acid residues in several proteins to convert them from inactive to active blood-coagulating proteins.

People who lack sufficient amounts of vitamin K have a prolonged clotting time that can result in severe bleeding problems or hemorrhage. The recommended daily intake of vitamin K was initially estimated to be between 90 and 120 micrograms/day, the amount required for normal clotting time. It turns out that this amount is fairly easy to obtain from a diet rich in green, leafy vegetables (spinach, broccoli, lettuce). Bacteria residing in our intestines produce an even more potent form of vitamin K, vitamin K2, to help supplement what is supplied by diet.

These bone-specific proteins function in a way analogous to the steel reinforcement rods that give concrete its tensile strength. This is especially important in post-menopausal women and the aged, who have an increased rate of bone loss and increased incidence of osteoporosis and fractures.

As an even more effective method of increasing bone formation and strength, new data supports taking vitamin K, vitamin D and calcium in combination. The bottom line, to further our steel and concrete analogy: vitamin D and calcium help to promote the formation of "cement" in bone, while vitamin K may help promote the production of the bone-strengthening "reinforcing rods."

Blood Thinners and Bone Loss

Data from patients taking the blood thinner Coumadin® (aka warfarin) over long periods of time also seems to identify vitamin K as an important factor for bone formation. Coumadin, often used to treat an abnormally high tendency to form blood clots, effectively interferes with the normal process of recycling vitamin K from an inactive oxidized state to an active reduced state. The net result of this interference is that active vitamin K is less available as a cofactor to initiate blood clot formation.

Although Coumadin may help prevent stroke and other clot-related pathologies, it is also associated with a significantly higher incidence of osteoporosis (loss of bone density) than in age-matched people not taking the drug. Even more alarming, however, are recent results from animal studies showing that inhibiting vitamin K with Coumadin can promote the development of calcified plaques in blood vessels.

The implication is that atherosclerosis may, in part, be associated with low levels of vitamin K. In fact, the arterial plaque in the Coumadin-treated animals could be reduced or even eliminated by feeding the animals high doses of vitamin K2. Whether this applies to humans has yet to be determined.

What we do know is that people with atherosclerosis as well as osteoporosis have protein markers in their blood indicative of low levels of vitamin K. Furthermore, as we age, these same markers increase along with the incidence of osteoporosis and atherosclerosis. Consequently, should there be an age-associated increase in daily vitamin K intake?

Enough K Today

Except for Coumadin patients, there is no evidence that taking vitamin K in higher doses – even those far exceeding the RDA -- is dangerous to our health. However, unless a higher dose is recommended by a qualified health professional, the vitamin K from a healthy diet and multi-vitamin supplements should be sufficient for most people. Until more research is completed on higher doses for the prevention of certain diseases as described above, a nutritious diet with lots of green leafy vegetables may be the best method for obtaining a sufficient amount of this vitamin.

American and Japanese physicians, from a number of prestigious institutions specializing in critical care, pediatrics and geriatrics, have summarized recent work that demonstrates the broad range of biological activities associated with vitamin K.

The investigators point out the surprising evidence implicating vitamin K deficiency as potentially associated with a host of diseases including osteoporosis, atherosclerosis, osteoarthritis and liver cancer. They underscore the finding that many individuals who go on to develop these diseases appear to have normal vitamin K status as judged by normal hemostatic or blood-clotting activities.

The accumulated information from studies on vitamin K and its diverse activities suggests that this vitamin should be more intensely investigated. The current studies clearly indicate that some individuals, especially the elderly, may be deficient in this vitamin and could benefit from increased intake of vitamin K.

To read the abstract, click here.

"Pleiotropic actions of vitamin K: protector of bone health and beyond?"

Nutrition, Volume 22, Issue 7-8, Pages 845-852.

This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.

Cholesterol! The word strikes fear into the hearts of many Americans. Popular press and TV have dumbed down the basics of cholesterol:

• High total cholesterol is associated with heart attack and stroke.
• LDL (low density lipoprotein) Cholesterol is bad.
• HDL (high density lipoprotein) Cholesterol is good.

Healthy Cholesterol Levles Aren't Quite That Simple

There is in fact only one kind of cholesterol. Whether obtained from the diet or synthesized by the liver, it is immediately bound to specific carrier substances, lipoproteins, and transported via the blood stream to the 60 trillion cells of the body. LDL is the major lipoprotein responsible for the transport of cholesterol TO the cells of the body. HDL, in contrast, takes cholesterol FROM the cells of the body and transports it back to the liver, where it is sequestered, or metabolized and secreted in the intestine as bile.

Our bodies require a certain amount of cholesterol for numerous cellular functions, including cell membrane integrity, absorption of nutrients such as fat-soluble vitamins, and synthesis of vitamin D and sex hormones. Too much of it can hurt us, however. Research has demonstrated an association between elevated LDL and atherosclerosis, a disease of the arteries causing heart attack and stroke.

How does this work? When the LDL-cholesterol combination (technically, LDLc) is present in the blood at a high level, it diffuses across the endothelial cells that line the interiors of blood vessels and is deposited just underneath these cells. This leaves a pool of LDL within the wall of the blood vessel. LDL is susceptible to attack by common cellular oxidants, which in effect turn it rancid. When LDL is present in the blood at normal healthy amounts, this does not occur, as there are substances, such as HDL and cellular antioxidants, to protect it from oxidation.

When the blood level of LDL Cholesterol is too high, large amounts of LDL transfer across the vessel wall, the antioxidant protection is overwhelmed, and LDL is oxidized (turns rancid). Now it becomes toxic to the cell and surrounding tissue. The process is aggravated by hypertension (high blood pressure), a condition characterized by elevated vascular pressure that can excessively stretch vessels and stimulate the oxidation of LDL.

Since the liver has the capacity to make cholesterol, we really don't need much of it from the foods we eat. In general, western industrialized man has too much LDL, largely as a result of sedentary lifestyles, and a diet high in substances that promote cholesterol synthesis, such as saturated fat, and trans fats. More than 90 million American adults - about 50% - have unhealthy blood-cholesterol levels.

What can you do to avoid being one of them? Recently, new standards have been suggested for the desired level of HDL (>40mg/deciliter), LDL (<100mg/dl) and total cholesterol (<200 mg/dl). As we age, these figures go in the wrong direction. Total cholesterol and LDL go up; HDL goes down. Most people can correct these markers of health to optimal or near optimal levels with minimum effort and cost. This is one area of healthcare that has real solutions. Various approaches are available to either control these precursors of poor health or help maintain levels that are already within the normal range.

Diet and Lifestyle. Diet does have an effect, but the intensity of it varies with age, genetic constitution and physical condition. The diet should include about 25-30% of total calories from fat. Less than 10% of these calories should come from saturated fats (which raise LDL), and none from trans fats (which raise LDL and lower HDL). A diet high in fruits and vegetables (7 servings/day), nuts and fiber has been demonstrated to promote a healthy lipid profile.

Lowering total cholesterol by diet and keeping your total daily intake of cholesterol to less than 300mg/day almost always improves the ratio of HDL/LDL. It stimulates the synthesis of LDL receptors in liver cells, thus decreasing the circulating level of the lousy cholesterol. Avoiding a sedentary lifestyle and maintaining a regular exercise routine can significantly improve the level of HDL.

Drugs. OK, you did all that and your cholesterol level, although improved, remains in the red zone, so now what? Numerous ads on TV and elsewhere promote cholesterol-lowering prescription drugs, but many of us are aware of documented side effects from these drugs. On the other hand these drugs, commonly referred to as statin drugs, do work. They lower cholesterol by as much as 45-50% and raise HDL, while lowering LDL and another circulating neutral fat, triglyceride. The bottom line is they have been shown to work, and they decrease mortality from atherosclerosis.

Supplements. Dietary supplements can help improve and or maintain cholesterol levels. One example is a plant-derived substance commonly known as policosanol. Niacin (vitamin B3), in large doses (>1gm/day), has a significant effect on lowering triglycerides, and raising HDL, especially when used in combination with one of the statin drugs or policosanol. Any decision to try these dietary supplements should be taken under a health professional’s supervision, since these products, like the statin drugs, may have side effects.

Another approach to help maintain cholesterol levels that are already within the normal range is to supplement with antioxidants, since the body's natural inflammation response involves oxidants. The potent antioxidant alpha lipoic acid may help by acting directly to neutralize oxidants and indirectly by increasing levels of two key antioxidants, vitamin C and glutathione, in the cells lining the vessel walls. Lipoic acid also enhances synthesis of the chemical messenger, nitric oxide, which in turn protects the function of these cells and promotes vascular relaxation.

Whichever approach you choose, the important thing for healthy aging is to get your cholesterol under control and keep it there.

This month we highlight once again a study of the powerful antioxidant alpha lipoic acid. Among the general population, double-blind, placebo-controlled clinical trials, with human subjects, are perhaps the most widely known form of healthcare testing. Studies in laboratory animals are even more extensively used by pre-clinical scientists. To understand fundamental biochemistry, however, scientists often use cell cultures.

S cientists at Vanderbilt University School of Medicine examined the antioxidant effects of alpha lipoic acid in cultured human endothelial cells (which line our blood vessels). They found that alpha lipoic acid enhances both the antioxidant defenses and the function of endothelial cells. For details on how alpha lipoic acid protects the cells lining the arteries to prevent inflammation, click here.

This Research Update column highlights articles related to recent scientific inquiry into the process of human aging. It is not intended to promote any specific ingredient, regimen, or use and should not be construed as evidence of the safety, effectiveness, or intended uses of the Juvenon product. The Juvenon label should be consulted for intended uses and appropriate directions for use of the product.

By Benjamin V. Treadwell, Ph.D.

We wash our hands, scrub the floors, sanitize our surroundings, and cook our foods, sometimes obsessive-compulsively, to destroy those dirty, nasty microorganisms we know as bacteria or bugs. But are all bugs bad for our health? Or have some evolved in a symbiotic way?

100 Trillion Microbes

They are on our skin and in our mouths. In fact, the microbes outnumber the cells comprising the tissues and organs of our body, and contain a hundred times more genetic information than what’s in our genetic profile. And the bulk of them thrive within our digestive system.

The gut is teaming with microbes that, under normal circumstances, do not produce disease. In fact, the genes contained within the numerous different species of intestinal bugs code for enzymes that are capable of digesting a variety of food materials, such as normally indigestible plant polysaccharides.

Digestive Bug-organ

These digestive system microbes have evolved with man’s predecessors, functioning in a symbiotic way to help protect them from starvation. This was a fantastic advantage for early man for at least two important reasons. First, man was not limited to those foods his genetic makeup was competent at converting to energy and, second, man did not have to carry within his genome the extra genetic garbage to produce the enzymes the bugs furnish.

This large community of genetically diverse bugs functioned as an extra organ, as it continues to function today. A free gift to man in a way, our "bug-organ" does, however, need to be supplied with the proper nutrients to maintain a healthy balance or ratio between its microbe species.

Firmicutes and Bacteroidetes

The gut microbes, for the most part, belong to two of the 70 known divisions of bacteria: the Firmicutes and the Bacteroidetes, each of which contains thousands of different species. The ratio between these two divisions of organisms has been recently demonstrated to vary with an individual’s weight.

The lean individual’s gut bacteria has a ratio of about 40% Bacteroidetes to 60% Firmicutes. With weight gain, edging toward the obese condition, Bacteroidetes decrease to 20% while Firmicutes increase to 80%. With weight loss, the ratio reverts back to the lean condition. So, a laboratory test of the Bacteroidetes-Firmicutes ratio in intestinal bacteria can determine whether a person is overweight. (Of course, it would be far simpler to step onto a bathroom scale).

Diet and the Bacterial Ratio

Why does the bacterial ratio change with an individual’s weight and what does that mean in terms of our health? The investigation is just beginning. (See this month’s Research Update.) There is no question that eating to excess is a major contributor to the obese condition and its associated health risks. However, it now appears that obesity itself also contributes to an increase in fat storage via a pronounced change in the ratio of bacteria.

Early man was never obese, but did eat excessively under those rare conditions when food was plentiful. He needed to ingest and store as many nutrients as possible during those intermittent times of food excess, and a change in the bacterial ratio to favor increased fat/energy storage was an added advantage.

Historic periods of food scarcity contrast sharply with modern Western diets of copious amounts of calorie-rich processed foods with little non-digestible fiber. Consequently the change in bacterial ratio with weight gain, and the associated storage of food-derived energy as fat, has become a health hazard rather than an advantage.

More Bug-organ Basics

It is not yet known why a change in this bacterial ratio predisposes one to increased fat storage. One reasonable speculation is that the gut microbial organ automatically alters the residing bacterial types in response to increased food intake so as to increase maximum absorption, which was vital for ancient man’s survival. However, in today’s industrialized world there is constant exposure to excess junk food (Western-style food), confusing the microbial gut organ into believing it must work to convert all of it to digestible components to be stored as fat.

Although the bacterial residents of our intestines seem to play a role in excessive fat storage, they also provide numerous health benefits. For example, many of the vitamins we need to survive are produced from our diet by intestinal bacteria, albeit at a low level.

On the other hand, a change in the composition of the species of bacteria residing in our intestines, by ingestion of a pathogenic bacterial species, diet or the use of antibiotics, can result in disease. Furthermore, the experts involved in this research are likely to discover additional critical relationships between the gut microbiota and our health and longevity.

In short, these microorganisms, their health and their healthy ratio are vital to our health. Maintaining a nutritious diet and avoiding excess caloric intake - especially high-sugar and processed foods as well as refined grains and saturated fats - will help promote a healthy intestinal microbial community and its many benefits.

By Benjamin V. Treadwell, Ph.D.

Can life span be extended? The optimist answers with a resounding yes, the pessimist an equally intense no, and the realist with "let’s see more data." Over the years, numerous theories have been put forth about the mechanisms involved in the aging process. As described in this month's issue, evidence suggests that a new hypothesis on the mechanisms of aging appears to explain more pieces of the puzzle, but a truly unifying principle remains elusive.

A fresh hypothesis on aging was recently stated by Lloyd Demetrius, a mathematician/ biologist at Harvard. In general, species with higher metabolic rates have the shortest life spans. Demetrius’s hypothesis holds that it is not the stresses of life, such as oxidative stress produced by free radicals, or the relative metabolic rates, that are important in determining life span. He believes the more important issue is metabolic stability, which is defined as the capacity of the networks of cellular metabolic pathways to continue to run smoothly, even during times of stress. This hypothesis has the appearance of a unification theory, since it encompasses other theories of aging rather than opposing them.

Longevity and Metabolic Stability: The Connection

Metabolic stability is dependent on several factors, including capacity to repair damaged cellular machinery, and the innate robustness of individual cellular components, such as enzymes. It also depends on integration of networks of metabolic pathways and their capacity to readjust under varying conditions of stress to maintain a stable steady-state metabolism - like shifting into lower gear on a hill to maintain steady speed. The cell contains numerous biochemical pathways that must be in sync with one another to maintain a constant concentration of metabolites for optimum cellular health. So metabolic stability is the ability of the cell to maintain its cool, even during times of stress.

All Animals Age, but at Different Rates

The metabolic stability hypothesis states that animals with low metabolic stability have short life spans. The mouse, with a 2-3 year life span, is often cited as an example. Compared to humans, with a maximum life span of 120 years, the mouse is 40 times more metabolically unstable. This theory goes on to predict that any method that promotes metabolic stability should have a much greater effect on the mouse, relative to the more metabolically stable human. One established method to increase life span in the mouse is caloric restriction (CR). Of interest, and in support of this theory, is experimental evidence showing that caloric restriction does in fact tend to stabilize metabolic pathways. For example, the insulin signaling pathway for glucose metabolism, and the pathway involved in the production of energy, readjust to a healthy steady-state and generate fewer toxic by-products in animals maintained on a food-restricted diet. The animals are healthier in virtually all respects, experiencing less cancer, vascular disease and other age-associated disorders. The hypothesis predicts that in the more metabolically stable human, CR will have very little effect on longevity, provided the subject is not obese or experiencing diseases associated with excess food intake (heart disease, diabetes, etc.).

Aging and the Accumulation of Cellular Garbage

Ample evidence demonstrates a correlation between the age of a cell and the amount of damaged cellular components it contains. The older the cell, the more stability-impairing garbage it contains. Most of the cellular garbage is the product of damage to cellular constituents (proteins, lipids, RNA/DNA), caused mostly by free radicals released during metabolism, especially during the production of energy in the mitochondria. The radicals react with and distort the active conformation of these cell constituents (supportive of the Free Radical Theory of Aging). In general, the higher metabolic rate of an organism (the metabolic rate of the mouse/gram is 7 times the rate of man), the greater the production of free radicals (supportive of the Metabolic Rate Theory of Aging).

Support for the metabolic stability hypothesis can be appreciated when examining a major flaw in the metabolic rate theory of aging. For example, the bat (a mammal) has a high metabolic rate that is similar to the short-lived shrew, yet it can have a life span as long as 35 years as compared to only 2-3 years for the shrew. Birds also appear to break the rules with respect to metabolic rate. The humming bird has an enormously high metabolic rate yet its life span can be 15 years.

The metabolic stability hypothesis would explain the long life span of the bird and the bat as a consequence of an extraordinary capacity of one or more of their metabolic pathways to maintain metabolic homeostasis, or a steady state. In other words, they rapidly readjust to keep metabolites at a steady constant level, or to use the auto analogy, smooth down-shifting to make it up that hill with constant speed.

An Example of a Metabolic Stabilizer

Although cellular garbage accumulates with age, cells also have anti-garbage defenses. The most important are two cellular machines, the proteosome and the lysosome. The former removes damaged cellular proteins, and the latter largely eliminates oxidized and damaged cellular structures, such as the mitochondria. Caloric restriction has been demonstrated to improve the efficiency of at least one machine, the proteosome. In effect, caloric restriction prevents the accumulation of garbage, thus helping to stabilize cellular metabolism.

Is Metabolic Stability the Answer?

The hypothesis does help explain many aspects of aging, but it too appears to have flaws. For example, experimental evidence supports a gradual decrease in metabolic stability with age. Our cells don’t respond to environmental stresses as well when we age, and as a consequence damage accumulates more rapidly than it did in our youth. So it appears that a steady decrease in metabolic stability occurs with time. Thus the metabolic stabilizer, caloric restriction, may prove to have enormous effects on human health and longevity.

Can Metabolic Stability Be Improved by Lifestyle or Diet?

The hypothesis does not preclude the use of possible methods to increase life span. Demetrius is an optimist at heart! For example, enzymes - proteins with catalytic activity that constitute the metabolic pathways - are notoriously less stable in the absence of metabolites they specifically act on. So by adding enough of the enzyme-specific metabolite (such as taking a supplement containing it), one could stabilize the enzyme, and in effect increase metabolic stability. Furthermore, obesity, the product of an unhealthy diet and/or lifestyle, clearly affects metabolic stability negatively. Restricting the amount of calories one consumes, at least after mid-life when metabolic stability may begin to sharply decline, may have a significant effect on attenuating or perhaps reversing this decline. Exercise, as with caloric restriction, also should improve metabolic stability. Current research in our laboratories is directed toward discovering agents that pep-up our cellular anti-oxidant defense systems, which dramatically decline with age. This too should help promote metabolic stability, and a long healthy life span.