Chronic fatigue, aging, mitochondrial function and nutritional supplements

Townsend Letter for Doctors and Patients,  July, 2003  by Garth L. Nicolson

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Abstract

Intractable fatigue is the most common complaint of patients seeking medical care, and in most patients it is a chronic condition that is not reversed by sleep or rest. Although fatigue is a complex phenomenon, it has been defined recently as a multi-component sensation. It is related to aging, decreased mitochondrial function and loss in the ability of mitochondria in cells to produce high-energy molecules for cellular functions. Also, it is known that oxidative damage to mitochondria, mainly from Reactive Oxygen Species or ROS, resulting in modifications in mitochondrial lipids, proteins and DNA, is related to aging. Certain natural dietary products and supplements can reduce oxidative damage and replace high energy molecules or restore mitochondrial function. Recent clinical trials have shown the benefit of dietary supplements in restoring mitochondrial function and reducing fatigue. In aging subjects mitochondrial function was restored to levels found in young adults in consort with reductions in fatigue , suggesting the anti-aging and antifatigue benefits of protecting mitochondria and cells from oxidative and other molecular damage, by lipid replacement and antioxidant use.

What is Fatigue?

The most common complaint of patients seeking medical care from general medical practitioners is fatigue or loss of energy, and in fact, chronic fatigue (intractable fatigue lasting more than 6 months and not reversed by sleep) is reported by approximately one quarter of all patients seeking medical care. (1,2) Many medical conditions are associated with chronic fatigue, such as respiratory, coronary, skeletal-muscular and bowel conditions as well as various cancers and infections, (3,4) and chronic fatigue is often an important secondary condition in many clinical diagnoses. Loss of energy and the symptom of fatigue often precede and are usually related to clinical diagnoses, and this may be the most important reason that it is so commonly reported by patients seeking medical care. (5)

Fatigue has been in the medical literature for hundreds of years in many forms and indicated by several different historical terms, but it has been only recently that fatigue has been defined and attempts made to determine the extent of fatigue and its possible causes. Although we now know much more about fatigue, its universal definition remains to be determined. It is thought to be a multidimensional sensation with many possible causes. (1,2) Most patients understand fatigue as a loss of energy and inability to perform even simple tasks without exertion.

Recently Piper et al. (4) described fatigue as a multi-component sensation with behavioral (interference with normal activities), affective (how fatigue is described), sensory (feelings associated with fatigue) and cognitive (mood, memory and thinking) components. They also designed a simple measurement tool for assessing fatigue that combined multiple fatigue-associated elements into an overall fatigue score. (4,5) We have successfully used this validated instrument in clinical studies on aging subjects to determine their fatigue responses to various dietary supplements. (6,7)

Fatigue at the Cellular Level -- Role of Mitochondria

At the cellular level fatigue is involved with cellular energy systems that for the most part are found in the mitochondria. Mitochondria are specialized semiautonomous cellular organelles with their own lipid membranes, enzymes and DNA genetic information, and they degrade and convert sugars and lipids to energy that is stored in high-energy molecules (ATP, NADH, etc.) using oxygen and a system called the mitochondrial electron transport chain. The electron transport chain is responsible for oxidative phosphorylation, the principal source of high-energy molecules in every cell. Although mitochondria appear to be semi-autonomous, separate units within our cells; in fact, they are completely dependent functionally on many proteins and enzymes that are made by other parts of the cell and encoded by nuclear DNA.

Without the proper functioning of mitochondria, our cells must depend on anaerobic sources of metabolism to produce high-energy molecules from starches and sugars, resulting in the production of lactic acid as a byproduct of sugar metabolism. Everyone at one time or another, has noticed what happens when we over-exert physically and cannot provide enough oxygen for our mitochondria, and our cells must resort to sources such as anaerobic metabolism to produce high-energy molecules such as ATP for our muscles. Eventually our muscles cramp due to the build-up of lactic acid and other metabolites. Thus our mitochondria are our most important sources of high-energy molecules for building and maintaining cellular functions in an oxygen environment.

Oxidative Damage to Mitochondria and Aging

Damage to cellular mitochondria can impair the abilities of cells to produce high-energy molecules, and this occurs naturally with aging, mainly by the buildup of oxidative damage to mitochondrial molecules. During aging the production of Reactive Oxygen Species or ROS, made up of oxidative and free radical molecules, such as nitric oxide, oxygen and hydroxide radicals and other oxidative molecules, can cause oxidative stress and cellular damage, resulting in oxidation of lipids, proteins (enzymes) and DNA in cells. Once oxidized, these cellular molecules can be deactivated or structurally and functionally changed. Major targets of cellular ROS damage are mitochondria and nuclei, mainly their phospholipid/protein membranes and DNA, (8-11) resulting in damage to membrane lipids and protein enzymes and deletion or modification of DNA.