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Promoting Mitochondrial Health Nutrients That Optimize Cellular Energy

February 2005

By Dale Kiefer

R-Alpha-Lipoic Acid: Potent Antioxidant and More

Acetyl-L-carnitine and lipoic acid could be considered the “dynamic duo” of anti-aging chemicals. Like acetyl-L-carnitine, lipoic acid is a natural mitochondrial metabolite with potent antioxidant properties.5,31 The “R-” form is the most biologically potent form of lipoic acid,32 and numerous studies have paired it with acetyl-L-carnitine to determine the two compounds’ synergistic effects on mitochondrial function. All have shown benefits ranging from improvements in memory to increased physical activity levels, improved mitochondrial structure, positive changes in age-related hearing and vision loss, and decreased oxidative damage.5,21,22,23,24

Studies have shown that lipoic acid improves endothelial and heart function, which are important factors influencing cardiovascular health.32-35 Given that aging is the single largest risk factor for cardiovascular disease, and that such diseases are the leading cause of death among people over the age of 65, lipoic acid would appear to be indispensable to anyone of advanced years who wishes to maintain optimal health.33

Like acetyl-L-carnitine, lipoic acid readily crosses the blood-brain barrier, enabling it to benefit neurons and body cells alike. Although it penetrates cell and mitochondrial membranes, it also benefits the extracellular matrix after conversion in the body to a still more potent antioxidant, R-dihydro-lipoic acid. This multitasking molecule possesses the rare ability to function as an antioxidant in both water- and fat-soluble tissues,36 and it is considered an especially potent protector of brain function. As one research team commented, “In-vitro, animal, and preliminary human studies indicate that alpha-lipoate may be effective in numerous neurodegenerative disorders.”37

Multiple sclerosis: axon demyelination in the central nervous system. Demyelination slows or blocks the normal transmission of nerve impulses, leading to the sensory, motor, and autonomic symptoms that characterize this disease.

Indeed, exciting new research conducted at Italy’s National Cancer Research Institute indicates that lipoic acid may play a role in preventing or reversing the course of neurological disorders such as multiple sclerosis, which involves demyelination, or the destruction of the fatty sheath that insulates neurons.38 Researchers discovered that oral lipoic acid, given before induction of the disease in an animal model, significantly slowed the onset of demyelination. By contrast, destruction of myelin sheathing in brain cells progressed rapidly among control animals that did not receive lipoic acid.38

In the study’s second phase, scientists administered lipoic acid only after the disease had been induced. Although oral alpha-lipoate failed to halt the disease’s progression, intraperitoneal infusion of lipoic acid significantly curtailed disease progression. (Intraperitoneal means within or administered through the peritoneum, a thin, transparent membrane that lines the walls of the abdominal or peritoneal cavity and encloses abdominal organs such as the stomach and intestines.) The benefit was achieved, researchers noted, independently of lipoic acid’s antioxidant activity. In other words, lipoic acid’s benefits are not limited to its potent antioxidant activity alone.38

While lipoic acid is a potent antioxidant, it also regenerates the antioxidant capacity of other important antioxidants, such as vitamins C and E. In addition, it boosts levels of the body’s important natural antioxidant, glutathione—an especially significant trick. Glutathione is universally recognized as a crucial player in overall health and immunity, but direct supplementation with glutathione offers limited benefit, since it is poorly absorbed when taken orally.36,37 Alpha-lipoic acid (50% R-lipoic acid), on the other hand, is readily absorbed and disseminated throughout the body, and is well tolerated and safe at clinically useful doses of up to 600 mg per day.39-41

Lipoic acid’s benefits are numerous. It has been used as a treatment for diabetic neuropathy in Europe for more than 40 years. According to a recently published meta-analysis of double-blind, placebo-controlled studies of patients with diabetic neuropathy, a painful and often debilitating condition: “…treatment with alpha-lipoic acid (600 mg/day i.v.) over 3 weeks is safe and significantly improves... symptoms... to a clinically meaningful degree.”39 Additionally, lipoic acid improves glycemic control among type II diabetics, according to recent research on standard and slow-release forms.34,40,42,43 Its combined blood-sugar-lowering and antioxidant effects are believed to account for lipoic acid’s multiple benefits.43

Carnosine: Putting the Brakes on Glycation

Aging is a multifactorial process, so fighting back requires a multi-pronged strategy. An invaluable weapon in this battle, carnosine is a dipeptide (two linked amino acids) that occurs naturally in cells. Carnosine is a natural antioxidant and free radical scavenger, but it also tackles another important underlying cause of aging: glycation.

Glycation occurs when protein or DNA molecules chemically bond, or cross-link, with sugar molecules. Eventually the sugars are further modified, forming advanced glycation end products that ultimately cross-link with adjacent proteins, rendering tissue increasingly stiff and inflexible.44 Advanced glycation end products are resistant to the body’s routine efforts to remove damaged proteins.

This gradual process plays out in the mirror as we age. Collagen and elastin in the skin lose their suppleness, causing wrinkles to develop, among other changes. However, the damage inflicted by advanced glycation end products does not stop there. Glycation reduces protein flexibility and functionality. It is the culprit behind cataracts, and it plays a role in numerous other degenerative processes, including arthritis, erectile dysfunction, atherosclerosis, kidney disease, and complications of diabetes.45-49

Even worse, advanced glycation end products trigger inflammatory reactions. In the brain, they have been shown to prompt certain cells to generate free radicals and immune system factors, such as chemokines, cytokines, and adhesion molecules, which are ultimately toxic to neurons.50 Many scientists believe that advanced glycation end products play a key role in the development of cognitive decline and Alzheimer’s disease. Advanced glycation end products are thought to oxidize tau proteins, which then form the neurofibrillary tangles associated with Alzheimer’s disease.51

Fortunately, there is a way to put the brakes on all this glycation damage. Although skeletal muscle levels of carnosine drop by 63% from age 10 to age 70,52 it is possible to augment falling supplies with oral supplementation. Doing so slows or even reverses some of glycation’s effects.49,53-55 For instance, when added to living cells growing in culture, carnosine extends the cells’ life span. When added to decrepit aged cells, it rejuvenates them.49,54,56

Carnosine’s benefits stem from a variety of helpful properties, including its antioxidant capacity. However, it appears to reverse glycation by directly reacting with carbonyl groups that consist of an oxygen atom joined by a double bond with a carbon atom. Alone, these chemical entities are called carbon monoxide. During glycation and oxidation, carbon monoxide attaches to proteins, seriously damaging them and playing an important role in the pathology of advanced glycation end products. Carnosine evidently reacts with these carbonyl groups, altering the defective proteins to which they are attached. This change renders them susceptible to removal by means of ordinary cellular processes.57 Carnosine is nature’s multipurpose age-fighter: it scavenges free radicals that cause oxidative damage, inactivates reactive aldehydes and lipid peroxidation products, inhibits glycation, and acts as an endogenous neuroprotective agent.58,59

Diabetes: An Impending Pandemic

According to the American Diabetes Association, diabetes affects about 17 million Americans. Some medical professionals believe this figure may vastly underestimate the true scope of the pandemic. An additional 16-20 million are suspected of having a precursor condition known as pre-diabetes. The legions of people at risk of developing serious diabetic complications swell alarmingly when pre-diabetic patients are included. Taken together, known diabetics and pre-diabetics—collectively described as having “glucose-handling” difficulties— represent a shockingly large percentage of the US population.60

Patients with glucose-handling difficulties are at increased risk of developing life-threatening conditions ranging from heart disease and stroke to blindness, nerve damage, depression, and kidney disease. New evidence suggests that diabetes also takes a toll on the brain, subtly eroding patients’ memory and cognition.61,62 These dire secondary complications are the result of excess glucose in the bloodstream, a condition known as hyperglycemia. Although insulin and other medications are used to regulate blood glucose levels as much as possible, damage eventually accumulates. Oscillations in glucose levels are inevitable, even for the most diligent patient.

Benfotiamine Tames Excess Blood Sugar

Until recently, physicians could do little to prevent the dire complications of chronic hyperglycemia. Fortunately, this situation is changing. Exciting research indicates that a nutritional supplement called benfotiamine can block three of the four major metabolic pathways leading to tissue damage. Although it was synthesized in a Japanese laboratory nearly 50 years ago, benfotiamine is only now gaining recognition as a powerful supplement capable of preventing destructive aging effects in the hyperglycemic and alcoholic populations.

Benfotiamine is a slightly altered form of vitamin B1 (thiamine). The alteration renders the vitamin fat soluble, enabling it to access areas of the body that water-soluble thiamine cannot penetrate. This is crucial for controlling potential hyperglycemia-induced damage. Although the problems associated with hyperglycemia are myriad, they all stem from the root problem of glucose flooding into vascular cells and overwhelming their metabolic machinery.

One of the body’s proteins, an enzyme called transketolase, blocks the absorption of too much glucose. To do its work, however, transketolase, like many enzymes, requires a co-factor. In this case, it needs assistance from thiamine. Unfortunately, thiamine is water soluble, which makes it less available to cells. Experiments have shown that transketolase’s effects are only marginally boosted by the addition of thiamine to cell cultures bathed in excess glucose.63

Used for more than a decade in Germany to successfully treat nerve pain in diabetics, benfotiamine is considerably more available to the body than thiamine. A landmark study, published recently in the medical journal Nature Medicine, found that benfotiamine increases transketolase activity in cell cultures by an astounding 300%. By comparison, when added to cell cultures, thiamine raises transketolase activity a mere 20%. Benfotiamine’s robust activation of transketolase was sufficient to block three of the four major metabolic pathways leading to blood vessel damage. Additionally, benfotiamine blocked activation of the pro-inflammatory transcription factor nuclear factor-kappa beta.63

Nuclear factor-kappa beta has been implicated in inflammation, tumor formation, and macular degeneration, as well as retinal disease in diabetics.64,65 It regulates cellular proliferation and suicide. Blocking nuclear factor-kappa beta has been shown to improve the prognosis of arthritis patients.66 These findings suggest still more benefits of benfotiamine therapy.