Researchers say they have now identified the mechanism of action of lipoic acid, a remarkable compound that in animal experiments appears to slow down the process of aging, improve blood flow, enhance immune function and perform many other functions.

The findings, discussed at the “Diet and Optimum Health” conference sponsored by The Linus Pauling Institute at Oregon State University, shed light on how this micronutrient might perform such a wide range of beneficial functions.

“The evidence suggests that lipoic acid is actually a low-level stressor that turns on the basic cellular defenses of the body, including some of those that naturally decline with age,” said Tory Hagen, an LPI researcher and associate professor of biochemistry and biophysics at OSU. “In particular, it tends to restore levels of glutathione, a protective antioxidant and detoxification compound, to those of a young animal. It also acts as a strong anti-inflammatory agent, which is relevant to many degenerative diseases.”

Researchers at LPI are studying vitamins, dietary approaches and micronutrients that may be implicated in the aging or degenerative disease process, and say that lipoic acid appears to be one of those with the most compelling promise. It’s normally found at low levels in green leafy vegetables, but can also be taken as a supplement.

According to Hagen, research on the natural processes of aging, and steps that could slow it or improve health until near the end of life, are of growing importance.

“We’re coming into the middle of an aging epidemic in the country,” he said. “In a short time more than 70 million Americans will be over 65. This is partly because of the Baby Boom, but also people are living longer, being saved with antibiotics and other medical treatments. In any case, it will be an unprecedented number of elderly people in this nation.”

The goal of LPI research, Hagen said, is to address issues of “healthspan,” not just lifespan – meaning the ability to live a long life with comparatively good health and vigor, free of degenerative disease, until very near death. The best mechanisms to accomplish that, scientists say, have everything to do with diet, exercise, healthy lifestyle habits and micronutrient intake.

At the moment, Hagen said, that’s not the way things appear to be headed – diabetes is skyrocketing, about 50 percent of people over 65 have high blood pressure, heart disease often leads to permanent disability, and almost half of the elderly people in America have malnutrition that is easily preventable.

No single intervention can address all of these issues, Hagen said, but one that scientists keep coming back to is lipoic acid.

“Our studies have shown that mice supplemented with lipoic acid have a cognitive ability, behavior, and genetic expression of almost 100 detoxification and antioxidant genes that are comparable to that of young animals,” Hagen said. “They aren’t just living longer, they are living better – and that’s the goal we’re after.”

What the OSU researchers now believe is that the role of lipoic acid is not so much a direct one to benefit cells, but rather an indirect aid that “kick starts” declining function in cells and helps them recover the functions that came more easily and naturally in young animals.

In various effects, lipoic acid appears to help restore a cellular “signaling” process that tends to break down in older blood vessels. It reduces mitochondrial decay in cells, which is closely linked to the symptoms of aging. With age, glutathione levels naturally decline, making older animals more susceptible to both free radicals and other environmental toxins – but lipoic acid can restore glutathione function to near normal. And the expression and function of other genes seems to come back to life.

“We never really expected such a surprising range of benefits from one compound,” Hagen said. “This is really unprecedented, and we’re pretty excited about it.”

Furthermore, with the emergence of Lipoic Acid Palladium Complex (LAPd), even more excitement has been generated. LAPd is a complexed compound, partially comprised of lipoic acid, which maintains its water and fat solubility and yet has been shown in testing to have the oxygen-absorbing capability four times that of regular lipoic acid. Not only does lipoic acid palladium complex quench and protect from free radicals but it actually can shuttle this energy source back to the cells for cellular energy production. In our modern age of recycling we have the ideal molecule to protect our cells and then give back to them at the same time. What this could mean for protecting and preventing aging and degenerative disease could be tremendous.

The Lipoic Acid Palladium Complex compound has already shown to be supportive for cancer patients in case studies and outcome-based studies. It is also being used in a study for hypertension protection, based upon the protective effect it provided to animals in which strokes were induced. LAPd offered almost 100% protection when blood flow was restored from reperfusion radicals. Additionally, in cell line studies for various types of cancer cells it has shown to trigger apoptosis by the very same means through which it supports cells. This compound by utilization of its electron donor can support the production of oxygen radical generation that will benefit normal cells and yet be damaging to cancer cells. Ongoing research will continue to show the many benefits of this compound and its ability to support overall well-being as well as prevention and treatment of degenerative diseases.

Many other presentations were made at the conference on the role of diet, lifestyle and micronutrients in health and degenerative disease, including cancer, heart disease, neurological diseases and aging. The conference is organized every two years by OSU’s Linus Pauling Institute, and attracts leading experts from around the world in these research fields.

Frank Antonawich, Ph.D.

Over fifty years ago, most scientific and medical therapeutic approaches focused on cellular metabolism. With the advent of genetics a concentrated shift toward genomics, and subsequently proteomics (protein profiles), dominated the therapeutic stage. The area of metabolism (metabolomics) is now being revisited as an attractive target.

One such regulatory approach is via the manipulation of cellular energy. Cellular energy is synonymous with metabolic power. As we age there is a decrease in metabolism, furthermore, numerous disease states involve metabolic dysfunction (i.e. ischemia/stroke, cancer). As we all know, the major power plant of the cell is the mitochondria. It utilizes high energy intermediates (NADH and FADH) to donate electrons and drive the production of ATP, our functional energy source. Can we alter metabolic fitness by providing an alternative electron source?

WHAT IS POLY-MVA?

Poly-MVA is a dietary supplement that contains a patented lipoic acid palladium complex (LAPd). LAPd is a composed of the element palladium irreversibly bound to the antioxidant lipoic acid in a trimer about thiamine (B1). The name Poly-MVA was coined by Dr. Albert Sanchez since Poly-MVA is composed of minerals, vitamins, and amino acids (MVA). In addition to the LAPd, the proprietary formulation contains riboflavin, cyanocobalamin, formyl-methionine and acetyl-cysteine. Dr. Sanchez became its principle proponent in his search for non-invasive support/treatment for cancer patients, following his wife’s tragic battle with colon cancer.

The lipoic acid palladium complex family of compounds was discovered by Dr. Merrill Garnett. While Dr. Garnett was formally trained as a dentist, this was followed by substantial graduate work in biochemistry and electrochemistry, followed by over 40 years of scientific bench work. His inquiry and screening into thousands of organo-metallic compounds, led to the discovery of the non-toxic LAPd chemotherapeutic agent. The principles that led to this finding in the early 90s still drive Dr. Garnett’s principle laboratory interests today; that ultra-low frequency electrical currents are at the heart of all physiological processes and determine such events as the polarization, charge and folding of enzymes, nucleic acids and membrane phospholipids. He believes that the regulation of charge transfer may form the basis of several new methods of medicinal management.

Q & A

I am frequently contacted at my laboratory, on the radio, or approached at conferences with common questions regarding Poly-MVA.

• A number of people are under the impression that Poly-MVA is merely a cocktail of palladium, alpha-lipoic acid, thiamine, riboflavin, cyanocobalamin, formylmethionine and acetyl-cysteine. There is no free lipoic acid or palladium in Poly-MVA; it is bound irreversibly with thiamine. Therefore, comparisons to free palladium or lipoic acid are irrelevant. This was done by Dr. Garnett to create a metallic polymer that is both fat and water soluble. Furthermore, it is prepared in a unique fashion so it does not metabolize, dissociate, and liberate the metal, which could accumulate in tissues and eventually become toxic like most chemotherapeutics.

• Is Poly-MVA safe? LAPd has undergone extensive toxicology study (Calvert Laboratories, Inc; Pharmakon USA, Inc.). The toxicology was conducted both intravenously and orally with LAPd. Mice were administered doses of 5,000 mg/kg (a typical human dose is 20 mg/kg). No deaths or signs of organ damage occurred in the test animals. It was concluded that the LD50 of LAPd exceeds 5,000 mg/kg. The Ames test was conducted by the same independent lab and demonstrated not to cause any mutations. LAPd was also studied for its effectiveness in halting the growth of glioblastoma cells in vivo. Tumors were allowed to establish and mice were divided into 8 groups of 10. Four groups were given daily intravenous (IV) doses LAPd or placebo; four groups were given intraperitoneal doses of .05, 1.0 or 2.0 mg per mouse for a total of four weeks and tumor volume was measured throughout the study. Compared to the controls who received no LAPd, mice receiving the test material orally or intravenously at 0.5, 1.0 or 2.0 mg had a significantly reduced growth of the glioblastoma (50% or greater reduction in tumor size).

• Palladium is a precious metal and quite expensive. Why was it used? Dr. Garnett discovered during his electrochemistry studies that DNA (and other biological cellular entities) has select electrical frequencies that it resonates at. After testing thousands of chemicals, Dr. Garnett found that only a limited few metals shared the same resonance frequencies with DNA. This characteristic facilitates electron flow between them. This is analogous to the propulsive energy provided to a surfer by a wave. If the surfer is in “sync” with the wave he can ride it all the way in to the beach. However, if he or she isn’t, they will crown right over the top of the wave. Palladium is important since this is the only one that Dr. Garnett could “cook” with the lipoic acid and thiamine to form this irreversible crystal polymer.

• Why are the other components added to the dietary supplement? Most people feel the other components are added without regard to the LAPd complex, but this is not true. Any molecule that transfers electrons has the ability to generate heat. In very early studies, patient temperatures elevated. The proprietary blend in Poly-MVA is not inert, but plays a role in buffering the temperature alterations.

• Is Poly-MVA just a super free radical scavenger? This was my initial thought after my first transient global ischemia experiments with the lipoic acid palladium complex in Poly-MVA. However, the LAPd complex is a liquid crystal polymer. There is extensive data supporting the dramatic redox potential of polymers versus monomolecular structures, such as vitamins. Any redox molecule can certainly absorb electrons, but it also donates them. Dr. Garnett’s electrochemistry papers demonstrate LAPd’s significant redox potential versus its monomolecular competition. After my initial ischemia research findings, I sent some Poly-MVA to Brunswick Labs, Inc. (Wareham, MA) for an ORAC analysis. An ORAC assay measures the oxygen radical absorbance capacity of a compound as compared to Trolox (vitamin E). The table below demonstrates the potent antioxidant capacity of Poly-MVA (expressed as Trolox equivalent per gram):

Vitamin A = 1.6 (2,800)
Vitamin C = 1.12 (1,890)
Vitamin E = 1.0 (1,700)
Melatonin = 2.04 (3,468)
Lipoic Acid = 1.4 (2,400)
Poly-MVA = 5.65 (9,605)

• Why is this supplement often credited or associated with providing energy? While Poly-MVA does indeed have the ability to be a highly effective free radical scavenger, its ability to donate electrons to the mitochondria of the cell is critical to explaining its dramatic benefits. Anecdotal clinical evidence of the reports of additional energy led to my early hypotheses regarding its possible benefits in stroke and ischemia. Following an interruption of blood flow to any tissue, in my particular case it is the brain, there is deprivation of oxygen and glucose. Providing an alternative energy source can maintain the integrity of the electron transport chain within the mitochondria. The LAPd complex was demonstrated,
by Dr. Garnett, to shuttle electrons to oxidized DNA, however, this energy flow does not appear to proceed directly to DNA. By conducting a competition assay with lipoic acid, which works at complex I of the mitochondria as a cofactor as
pyruvate is converted to acetyl CoA, one can attenuate the beneficial effects. This is critical since mitochondrial health is a major concern during myocardial and cerebral ischemia. By providing this alternative energy source, the electron
transport chain components do not readily dissociate (coenzyme Q-10 = ubiquinone; cytochrome C). In a normal cell this would obviously provide a boost, but serve as a supplement to an ischemic cell.

• Can Poly-MVA be taken with other vitamins and free radical scavengers? Since lipoic acid palladium complex is a highly efficient redox molecule, normal daily recommended values of vitamins have not been of consequence in our laboratory studies. However, excessive doses of anti-oxidants may attenuate Poly-MVA’s benefits. As mentioned above, administration of alpha lipoic acid in our competition assay hindered the redox benefits of Poly-MVA. However, alpha lipoic acid alone only offers a fraction of the ischemic protection offered by the polymer.

MECHANISMS OF ACTION

Poly-MVA’s proposed mechanisms of action directly related to its structural formulation. Dr. Garnett’s complex is a liquid crystal polymer and provide a unified redox. Redox polymers more efficiently accept charge, and therefore serve as potent
anti-oxidants. Furthermore, they can also donate charge and serve as alternative energy sources. This electron transfer appears to be the key to its physiological effectiveness. When glucose enters a cell it is broken down under anaerobic conditions (absence of oxygen) into pyruvate. Pyruvate subsequently enters the mitochondria, via complex I, and is quickly oxidized, in the presence of alpha-lipoic acid, to acetyl-CoA. In aerobic respiration, acetyl-CoA is then channeled into the Krebs/Citric Acid Cycle to create the reduced form of nicotinamide adenine dinucleotide (NADH). NADH donates its electron to the electron transport chain to drive the phosphorylation of adenosine triphosphate (ATP). The energy needs of the body are supplied by splitting ATP into adenosine diphosphate (ADP) and a free phosphate molecule.

Studies have demonstrated that LAPd provides electrons to DNA (to replace the electrons lost in normal cells as a result of the oxidative damage associated with radiation and chemotherapy) via the mitochondria. This electron transfer will provide an additional energy source to normal cells. However, cancer cells are metabolically challenged, as well as, function in a hypoxic environment. Since excess electrons have less oxygen to accept them in the cancer cell, a local generation of free radicals occurs at the mitochondrial membrane. This activates apoptosis by facilitating the release of cytochrome C from the inner mitochondrial membrane, allowing the formation of an apoptotic complex in the cytoplasm. This complex, results in the subsequent activation of the caspase cascade of enzymes that destroy the malignant cells. Given that healthy
cells are richly oxygenated, LAPd is nontoxic to them and they actually benefit from the energy boost.

Recent findings have focused on the role of  Poly-MVA and a malignant cell’s ability to physiologically adapt to a hypoxic environment. These physiological changes are mediated by a molecule called HIF-1 (hypoxia inducible factor-1), which increases in hypoxic conditions to promote an increases in: Vascular Endothelial Growth Factor (VEGF) - a promoter of angiogenesis; Glucose Transport 1 (GLUT1) and glycolytic enzymes – critical components in anaerobic respiration; and Erythropoietin (EPO) – responsible for the differentiation of red blood cells).  Poly-MVA appears to decrease the
production of HIF-1 thus restricting the ability of the cells to adapt to its environment and subsequently making it more vulnerable to the apoptotic cell death discussed above.