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Promoting Mitochondrial Health Nutrients That Optimize Cellular Energy

February 2005

By Dale Kiefer

Cell structure. Illustration of the ultrastructure of a typical cell. Components of this cell are in three dimensions and color coded. At center, the nucleus (pink) has a nucleolus (brown) containing the DNA genetic material. Closely associated with the nucleus is endoplasmic reticulum (ER, purple), a membrane system in the cytoplasm studded with ribosomes (red dots, sites of protein synthesis). Golgi bodies (yellow membranes) package products from the ER into spherical lysosomes (orange). Above the nucleus, two centrioles made of microtubules play a role in cell division. Mitochondria (green) store energy for the cell. The cytoplasm (blue) is bordered by a white cell membrane.

Mitochondria, the powerhouses in each human cell, have the crucial job of generating energy for use throughout the body. With advancing age and cumulative free radical attack, however, mitochondria can become less efficient, leading to degenerative changes associated with aging.

Maintaining healthy mitochondrial function is critically important in preventing disease and promoting longevity. Nutrients such as coenzyme Q10, acetyl-L-carnitine, and alpha-lipoic acid help optimize mitochondrial health. Other nutritional remedies—including carnosine, benfotiamine, and rhodiola—complement the actions of CoQ10, acetyl-L-carnitine, and alpha-lipoic acid in promoting a healthy and energetic lifestyle.

Mitochondria populate the interiors of our cells. These little organelles follow a different drummer when implementing orders from DNA. Unlike other components of the cell, mitochondria have their own DNA.

The mitochondria are genetically exact copies traceable far back into the mists of time. Because human mitochondrial DNA descends through the female alone, it is useful for tracking evolution. In fact, some scientists believe current mitochondrial DNA traces back to a single female known as “Mitochondrial Eve” that eventually climbed all the way up the evolutionary ladder to modern humans.

The Mitochondrial Theory of Aging

Mitochondria literally means “thread granules,” a name evidently inspired by the stubby rod-like shape of these organelles. Scattered throughout the jelly-like cytoplasm within our cells, mitochondria range in number from the hundreds to thousands per cell. They generate energy in the form of ATP (adenosine triphosphate)—a molecule that humans literally could not live without. They do so, however, at a price. According to the mitochondrial theory of aging, free electrons are generated as a byproduct of aerobic respiration, which is the chain of ATP-producing chemical reactions that occur within the mitochondria. These electrons convert oxygen to a highly reactive form, which in turn creates still more reactive oxygen species, capable of ravaging proteins and lipids while wreaking havoc with DNA over time. Progressive respiratory chain dysfunction ensues. Damage accumulates slowly, eventually leading to the degenerative changes associated with aging.1-3

Preserving youthful mitochondrial function therefore is of paramount importance to prolonging life span. Fortunately, modern science, often guided by ancient wisdom, is rapidly discovering an ever-increasing arsenal of chemicals and nutrients capable of slowing or reversing many of the degenerative changes constantly occurring within our mitochondria. Nutritional supplements such as acetyl-L-carnitine and lipoic acid have been shown to improve mitochondrial function, protect brain cells, and restore flagging energy.4-8

Electron micrograph of
mitochondrial DNA (red).

An acetyl-L-carnitine derivative—acetyl-L-carnitine arginyl amide— has been shown to stimulate brain cells, prompting them to grow new connections to other neurons. This remarkable property suggests an important potential role for this nutrient in combating degeneration of the central nerve system, such as that which occurs because of “normal” senescence. This beneficial derivative of the mitochondrial metabolite acetyl-L-carnitine also protects brain cells from the toxic effects of aggregated amyloid beta peptide. This is especially significant, because amyloid beta is an insoluble protein fragment that forms plaques and induces cell death in the brains of patients with Alzheimer’s disease.9,10

Carnosine prevents age-related damage known as glycation, which is responsible for the development of unsightly wrinkles, the corneal opacity of cataracts, and some complications of diabetes, among other things. Natural plant flavonoids such as luteolin favorably modulate immunity and protect against further damage from free radicals.11 Still others, such as benfotiamine and the herb Rhodiola rosea, work in a variety of ways to boost energy, increase endurance, and prevent age-associated changes in cellular processes and structures.

L-Carnitine Metabolites Protect Brain Health

Acetyl-L-carnitine and acetyl-L-carnitine arginate (arginyl amide) may be two of the most potent anti-aging compounds available today. In combination with lipoic acid, they represent the cutting edge of anti-senescence science. Beyond their ability to neutralize damaging free radicals, they act to directly improve brain health through a variety of mechanisms.12

Acetyl-L-carnitine is the ester of a naturally occurring compound, L-carnitine, which serves as an important co-factor in the oxidation of fatty acids within neuronal mitochondria to release energy.

L-carnitine deficiencies are associated with a number of serious disorders of the central nervous system.

Conversely, supplementation with L-carnitine metabolites, such as acetyl-L-carnitine and acetyl-L-carnitine arginate, has been shown to improve various brain health parameters. As one researcher recently noted, “... esters such as acetyl-L-carnitine... possess unique neuroprotective, neuromodulatory, and neurotrophic properties which may play an important role in counteracting various disease processes.”12

For instance, animal research shows that acetyl-L-carnitine reverses age-related declines in receptors present on the surface of nerve cells in the brain. Studies of Alzheimer’s sufferers have reported improvements in memory compared to patients receiving inactive placebo.13 Other studies have investigated the effectiveness of adding acetyl-L-carnitine to standard pharmaceutical treatments for Alzheimer’s disease.

In a recent Italian study, two grams of acetyl-L-carnitine per day were given orally for three months to early-stage Alzheimer’s patients who had failed to respond to treatment with standard acetylcholin-esterase inhibitor drugs, such as Aricept® (donepezil) and Exelon® (rivastigmine). Response rates, as determined by a variety of functional and behavioral parameters, improved to 38% with the acetylcholinesterase inhibitor drugs alone and to 50% with the addition of acetyl-L-carnitine.14 An earlier double-blind, placebo-controlled study from Stanford University concluded, “acetyl-L-carnitine slows the progression of Alz-heimer’s disease in younger subjects... ”15

More recently, researchers at Imperial College University in London conducted a statistical meta-analysis of published studies that had examined the effects of acetyl-L-carnitine supplementation versus placebo for the treatment of Alzheimer’s symptoms or the disease’s precursor condition, mild cognitive impairment. The analysis considered only double-blind, placebo-controlled studies—considered the scientific “gold standard”—of at least three months’ duration. Doses ranged from one and a half to three grams of acetyl-L-carnitine taken daily. “Meta-analysis showed a significant advantage for [acetyl-L-carnitine] compared to placebo,” the researchers concluded. Beneficial effects were noted by both clinical assessments and psychometric tests, and effects were evident at the time of the first assessment. Moreover, the improvements increased over time. The researchers also noted that acetyl-L-carnitine was well tolerated in all studies.16

Other Anti-Aging Effects Reported

Acetyl-L-carnitine’s benefits are not limited to Alzheimer’s patients. In studies of laboratory animals, acetyl-L-carnitine supplementation has demonstrated many dramatic benefits. Aging rats that were fed acetyl-L-carnitine experienced marked increases in levels of tissue carnitine, and significant improvements in age-associated changes in brain lipid composition.17,18 In other animal studies, researchers have reported other dramatic effects, including remarkable increases in physical activity among aging rats fed acetyl-L-carnitine,19,20 improvements in memory,4,21 reversal of age-associated hearing loss,22 and improvements in age-associated glycation of (eye) lens proteins.23

Electron microscopy has shown actual changes in brain mitochondrial structure following acetyl-L-carnitine supplementation.4 Some researchers suggest that acetyl-L-carnitine improves heart function due to its ability to enhance mitochondrial activity. Hard-working cardiac cells that require abundant energy are particularly susceptible to mitochondrial decline.24

In a cleverly designed study, researchers at the FDA’s National Center for Toxicological Research showed recently that supplementation with L-carnitine, the precursor to acetyl-L-carnitine, prevents experimentally induced mitochondrial dysfunction in laboratory animals.25 On the other side of the globe, Japanese researchers investigated acetyl-L-carnitine’s role in fatigue. In an experiment on human subjects, the researchers determined that serum acetyl-L-carnitine levels are significantly lower among patients with chronic fatigue syndrome than among normal control subjects. The scientists speculated that acetyl-L-carnitine plays an important role in the biosynthesis of neurotransmitters, and that this pathway may be reduced in the brains of chronic fatigue patients.26

Acetyl-L-carnitine’s importance to neurotransmitter (brain messenger chemical) production may also underlie the finding that acetyl-L-carnitine supplementation alleviates depression among the elderly.27 Neurotransmitters such as norepinephrine and serotonin are known to play an important role in the regulation of mood, and modern antidepressant drugs operate by increasing the availability of these important brain chemicals.28,29

Acetyl-L-Carnitine Arginate: Unique Benefits

Acetyl-L-carnitine arginate (arginyl amide) exhibits several beneficial properties, especially in the aging brain. Its activities differ from, but also complement, those of acetyl-L-carnitine.

For example, acetyl-L-carnitine arginate appears to mimic the effects of nerve growth factor, a protein that plays a crucial role in the development and maintenance of the nervous system. In the central nervous system (comprising the brain and spinal cord), nerve growth factor supports the survival of neurons in areas of the brain associated with emotion, such as the hippocampus, and in the forebrain, which is associated with cognition, emotion, and important body functions.10

As laboratory rats age, they experience a significant loss of neurons and neuronal activity in these areas. These losses are associated with the degeneration of various physiological functions, and are usually accompanied by deteriorating performance on memory tests. One of the causes of this degeneration may be a reduction in neurotrophic factors, which are supporting factors involved in the nutrition or maintenance of neural tissues, such as nerve growth factor. Since acetyl-L-carnitine has been shown to reverse some of these deficits, Italian researchers reasoned that acetyl-L-carnitine arginate might also improve brain function among aging animals.

To test this hypothesis, they added acetyl-L-carnitine arginyl amide to rat brain cells growing in tissue culture. After ensuring the absence of any native trophic factors, they added acetyl-L-carnitine arginate. The brain cells sprouted new connections—tentative new tendrils of axons and dendrites—known as neurites. The researchers concluded that acetyl-L-carnitine arginate stimulated this remarkable growth by acting directly on receptors for nerve growth factor that are located on the surface of nerve cells.10 This groundbreaking research was later expanded on by researchers at the University of Texas, who experimented on tissue cultures derived from human brain cortex. Their results indicated that acetyl-L-carnitine arginyl amide is indeed neurotrophic.30

Acetyl-L-carnitine arginate’s ability to stimulate new growth by neurons is extraordinarily significant. Brain nerve cells, unlike other cells in the body, are generally incapable of repairing themselves. The discovery that acetyl-L-carnitine arginyl amide stimulates new neurite outgrowth suggests an exciting potential treatment for diseases involving neuronal degeneration, such as Alzheimer’s disease and Parkinson’s disease.

Yet another research team demonstrated that acetyl-L-carnitine arginate protects brain cells from the toxic effects of amyloid beta, the peptide that is believed to trigger cell death when it aggregates in the brains of Alzheimer’s sufferers. Using brain cells in culture, the scientists demonstrated that acetyl-L-carnitine arginyl amide “... was able to rescue neurons from [amyloid beta]-induced neuro-toxicity.”9