By Benjamin V. Treadwell, Ph.D.

Where did I place the car keys? Deterioration in mental function with age occurs throughout the animal kingdom, but the degree of this deterioration varies between individuals of a species. There are some smart old mice as well as some smart old people. Why do we have this decline, and why do some have a sharper decline in mental function than others?

A recent study suggests some potential answers to this question. Post-mortem examination of the brains of elderly people with a neurodegenerative condition, as compared to the brains of elderly persons who had no such condition, demonstrated a significant increase in mutations in genes contained in a particular cellular structure responsible for energy production, the mitochondria. Specific types of mutations, those in the region involved in switching the gene on and off, were two-thirds more common in persons with a neurodegenerative condition.

The central nervous system, which includes the brain and spinal cord, requires more energy than any other tissue of the body, including muscle tissue (except during strenuous exercise). In fact, every day our brains require the equivalent of a quarter-pound of sugar to be converted into the chemical form of energy, ATP. If there is a deficit in ATP stores, the health of the brain deteriorates. Why? One reason is that structural components of the brain deteriorate with age. They must be disassembled and replaced, much like the components of an engine have to be periodically replaced to maintain a smooth-running machine. In fact, the youthful brain, compared to an older one, has more energy, and greater capacity to prevent damage to cellular structures, as well as to replace those that do get damaged. These and other activities performed by the brain take work, and ATP is the source of energy to run the cellular machinery.

The manifestation of a brain that is deficient in stores of energy (ATP) is impaired mental function - where did I place my keys? Parts of the body that require the highest amounts of energy, brain and muscle tissues, are in fact the most susceptible to deterioration during an energy failure. Therefore, it should be no surprise these two tissues are most affected by the aging process.

That brings us back to the original question, the connection between gene mutations in our mitochondria and the aging process. The mitochondria are the cell’s dynamos involved in converting food to the form of energy the cell can use, ATP. So anything that affects their function will affect ATP production. The mitochondria, like the cell’s nucleus, contain genes. (In a way, they are a cell within a cell). The genes of the mitochondria are switched on when the cell requires more energy. More ATP is then produced. A healthy, clear-thinking brain is the consequence. If one or more of the genes of the mitochondria are mutated, the ATP-production switch will not be turned on, and an ATP deficit will occur - where did I place my keys?

The above description of age-associated mental decline is supportive of the major theory of aging, the mitochondrial theory of aging. Briefly, this theory proposes that symptoms of aging are the result of an accumulation of mutations to the genes of the mitochondria. Furthermore, the theory goes on to state that the source of the toxic substances that cause these mutations is the mitochondria. The toxic substances are oxidants or free radicals released during the production of energy.

Impairment of energy production or mitochondrial efficiency actually increases the production of toxic free radicals. So a mutated mitochondrial gene not only impairs energy production, but this in turn adds to th e problem, namely an increase in the rate of toxic free-radical production. Secondly, the brain contains cells referred to as post-mitotic cells, because once the organ reaches maturity, its cells no longer divide (undergo mitosis). We are stuck with them for life. So if defects in the cell, including the mitochondrial defects, cannot be repaired, we are stuck with them too.

Multiple factors probably explain why some people have earlier decline in mental function. For example, gene profile has a profound effect on mental health. Some individuals may have genes that are more effective in producing potent antioxidant defense systems than others. A second factor is environmental. People exposed to environmental toxins, such as cigarette smoke and toxic chemicals, and/or who maintain a poor diet, are at a higher risk for early mental decline.

What, if anything, can be done to help prevent or slow down the process of mitochondrial deterioration?

Recent work from the laboratory of Bruce Ames, Chairman of the Juvenon Scientific Advisory Board, at the University of California, Berkeley, not yet published, provides additional insights pertinent to this story. Researchers fed aged rats a compound, acetyl-L-carnitine, for 4 weeks and examined the tissues of the brain for markers of aging. This compound, normally present in the mitochondria, but at lower levels as we age, was selected for this study as it was previously shown to improve mitochondrial function in aged rats.

One area of the brain known to be involved in spatial memory, the hippocampus, has been previously demonstrated to accumulate numerous age-associated oxidation products. As expected, the oxidized products were present in increased quantities in the old animals Ames was studying. The oxidation products include oxidized proteins, lipids, and - more relevant to today’s topic - oxidized or mutated DNA. Examination of the brains of aged rats maintained on a diet containing acetyl-L-carnitine for 4 weeks revealed a significant decrease in the quantity of oxidized protein, lipid and more importantly, DNA. These results suggest that this compound may be of value in helping to maintain healthy brain tissue as we age, and thus mitigating age-associated decline in mental acuity.

Much more work is required before one can extrapolate these results to humans. Nevertheless, a number of earlier studies with humans have suggested a role for acetyl-L-carnitine as an agent that helps maintain healthy nervous system tissue.

By Benjamin V. Treadwell, Ph.D.

Most of us know someone who had healthy habits but nevertheless came down with one of the dreaded diseases of aging, such as cancer or Alzheimer's. We all wonder what we can do to improve our chances against these scourges.

The generic answer is familiar to everyone: eat right, exercise, and live right (meaning, don't smoke, drink in moderation, be safe, stay active, etc.). Let's take a deeper look at eating right.

Eating Right and a Healthy Diet Isn't Everything

Eating right has to do with providing nutrition to our bodies and, at the most basic level, to our cells. The challenge of defining a diet to provide that nutrition has spawned an unending stream of recommendations, ranging from serious scientific studies to fad diets.

The simple truth is that no recipe for optimal diet is applicable to all people. Because of genetic differences and age-related changes in body chemistry, requirements vary from one individual to another. We have all known people who seem to have iron stomachs, and others who have ultra-sensitive digestive systems and react to a variety of foods. These variations are a manifestation of the composition of our bodies at the molecular level.

Some individuals with certain gene mutations or variations (gene polymorphisms) require several-fold greater amounts of particular nutrients than most people, in order to achieve normal cellular function. It is now becoming apparent that even our appetites are to some extent under genetic regulation. A hormone-like substance known as ghrelin, produced by the stomach, stimulates hunger and is balanced by another fat cell-produced hormone, leptin, that tells us when we have had enough to eat. It is now known that in some people this balance is upset, and the ghrelin dominates.

Nutritional requirements also vary from one time of life to another. As we age, our ability to absorb nutrients declines, and we need to ingest more of certain nutrients in order to provide a sufficient amount for optimum cellular health. This forms the basis for the necessity to supplement with nutrients for maximum health as we age.

In spite of the above-mentioned variations, the vast majority of us can have a significant effect on our health by eating right.

It has been known for some time that the people who live around the Mediterranean lead some of the longest, healthiest lives in the world. A recent publication in the medical journal Lancet reports that the secret to these peoples' health is probably their diet, which consists of high consumption of fish, fruits, vegetables, nuts, and olive oil, with fewer than 10% of calories derived from saturated fat. This is supportive of the theory that saturated fats are detrimental, and mono and poly-unsaturated fats, like olive oil and the omega 3 fats found in fish oil, are beneficial. (The authors also note that these people incorporate into their daily routine a high level of physical activity.)

A study of more than 400 men and women over four years found that people who eat a Mediterranean-style diet are 50 to 70 percent less likely to suffer repeat heart attacks. These findings were published in the journal of the American Heart Association.

It is important to emphasize that the carbohydrates in the Mediterranean diet are largely from whole grain rather than the refined grain products we commonly use in the American diet. The whole grain carbohydrates are slowly metabolized to glucose during digestion and therefore do not promote a spike in insulin release. In contrast, the refined carbohydrates are almost immediately converted to glucose. A high blood-glucose level is toxic and promotes serious disease states, such as diabetes, heart disease and perhaps even neurodegenerative diseases such as Alzheimer's disease.

But as we age, eating right is not enough.

Each person is genetically unique. Because of this inherent variation, we have different sensitivities and require different amounts and types of nutrients for health. In addition to genetic uniqueness, our requirement for particular nutrients varies with age. In general, the older we become, the more susceptible we are to all forms of disease. There is evidence that absorption of nutrients at the macro level, from the intestines, as well as at the micro level, cellular uptake and utilization, is much less efficient as we age.

While a balanced diet is fundamental, growing numbers of nutrition scientists believe we need to supplement our diet with at least a multiple vitamin. Support for the beneficial effects from taking supplements, at least for some, is becoming more apparent as exemplified by a recent observational study showing surprising positive effects from large doses of vitamins C and E. Briefly, the results showed a remarkable decrease (44%) in the rate of development of Alzheimer's disease in those on long-term high dose vitamin E (more than 400IU/day) and vitamin C (more than 500mg/day).

As discussed in prior issues of this newsletter, Professor Bruce Ames of the University of California -Berkeley has demonstrated, with laboratory experiments, the benefits of supplementation with alpha lipoic acid and acetyl-L-carnitine. Prof. Ames's current work is demonstrating a boost in the longevity of cells in culture when they are given high levels of vitamins, especially the B vitamins, as well as antioxidant vitamins.

Previous to these experiments, it was assumed that the standard nutrient medium used by scientists throughout the world contained nutrients at optimum quantities. Prof. Ames's finding is significant in light of similar assumptions that the recommended daily allowance (RDA) of vitamins is all we need for maximum health. This notion is currently being challenged, and it is clear that major changes in RDA will be coming in the future. Supplementing our diets as we age, to ensure adequate cellular nutrition, may become standard practice in the future.

By Benjamin V. Treadwell, Ph.D.

The importance of the nutrient alpha lipoic acid on cellular health was described in some detail in a previous Juvenon Health Journal The Two Faces of Alpha Lipoic Acid . Today’s article begins with a brief summary of the previous publication and then provides significant new information on the effects alpha lipoic acid cellular metabolism.

Alpha Lipoic Acid and Cellular Energy Production

Alpha lipoic acid is an essential nutrient that functions as a cofactor in the catalytic conversion of food-derived metabolites to energy. While the cells of our body synthesize lipoic acid, we also obtain it from the foods we eat. Evidence indicates we require both sources to supply healthy quantities to our cells. As we age, however, this amount may be insufficient for maximum cellular health, since absorption from foods may decline and cellular synthesis may be less efficient.

Lipoic acid has been demonstrated to be a potent antioxidant in several ways. First, it can scavenge toxic free radicals directly. Second, because it is soluble in fat and water, it can insert itself in membranes as well as in the cell’s water compartments. Thus, lipoic acid can protect virtually all the cell from oxidants. Third, it is well known that various antioxidants with different properties are required to protect the cell. Lipoic acid has been shown to function as the ultimate reducing (activating) agent in converting several additional antioxidants to their reduced and active forms. These include vitamins C and E, ubiquinone (Coenzyme Q10), and the important cellular antioxidant, glutathione. Finally, lipoic acid has been demonstrated in cell culture and animal experiments to have the capacity to activate a family of genes (called phase II genes), which are critical in the removal of toxic cellular substances. There are over 200 of these cell-protective genes. They are important in keeping our cells free from toxins produced during cellular metabolism as well as those obtained from prescribed drugs and environmental toxins.

By Benjamin V. Treadwell, Ph.D.

We have all heard the words, "life is a balancing act." The phrase usually applies to mixing work, play and other activities to achieve a healthy mental-physical state. It turns out that the health of our body at the biochemical level is also a balancing act that involves numerous metabolic pathways interacting and communicating with each other within the cells of our tissues and organs. As with the adage, "too much work makes Jack a dull boy," it is also true that too much exposure to certain external factors, such as toxins, carcinogens (smoking, etc.) or even food, can create a metabolic imbalance. This metabolic imbalance, if not corrected, will lead to some form of disease.

What causes a metabolic imbalance?

Let's take a look at what happens when we eat. When food is metabolized, some of it is converted to the sugar-fuel glucose. Glucose is transported into the blood stream, and is detected by a sensor in the pancreas, which in turn secretes the hormone insulin. Insulin is transported through the blood stream to various tissues of the body including muscle, fat, and liver. The cells in these tissues also have sensors for insulin, which in turn latch onto the circulating insulin. The interaction between insulin and its receptor activates a switch embedded in the cell's membrane that turns on numerous signaling mechanisms in the cell. The cell then takes up the nutrient glucose, and either converts it to energy, or stores it in the form of fat. This is an example of a metabolic pathway (see Figure below).

By Benjamin V. Treadwell, Ph.D.

A healthy, potent immune system is important in disease prevention. We cannot survive without it, and its health is increasingly important as we age. Observers dating back to the ancient Greek physician Galen (A.D. 180), as well as the 19th century father of pathology, Virchow, noted the relationship between inflammation (presence of immune cells) and cancer. In other words, they saw that cancer cells and the surrounding tissues appeared inflamed and contained inflammatory cells. In the 20th Century scientists came to understand that immune cells are present in a cancerous area to do just what one would expect of them: kill cancer cells.

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.