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Journal of Chronic Fatigue Syndrome 2006; 13(1)

 

Lipid Replacement and Antioxidant Nutritional Therapy

for Restoring

Mitochondrial Function and Reducing Fatigue in

Chronic Fatigue Syndrome and other Fatiguing Illnesses*

 

Garth L. Nicolson, Ph.D. and Rita Ellithorpe, M.D.

The Institute for Molecular Medicine, Huntington Beach, California, USA

 

 

ABSTRACT.

Evidence in the literature indicates that diminished

mitochondrial function through loss of efficiency in the electron

transport chain caused by oxidation occurs during aging and in fatiguing

illnesses. Lipid Replacement Therapy (LRT) administered as a nutritional

supplement with antioxidants can prevent oxidative membrane damage, and

LRT can be used to restore mitochondrial and other cellular membrane

functions via delivery of undamaged replacement lipids to cellular

organelles. Recent clinical trials using patients with chronic fatigue

have shown the benefit of LRT plus antioxidants in restoring

mitochondrial electron transport function and reducing moderate to

severe chronic fatigue. These studies indicate the benefits of LRT plus

antioxidants in reducing fatigue and preventing loss of mitochondrial

function, most likely by protecting mitochondrial and other cellular

membranes from oxidative and other damage and removing damaged lipids by

lipid replacement. In one clinical study we determined if mitochondrial

function is reduced in subjects with mild to severe chronic fatigue, and

if this can be reversed with NTFactor®, a nutritional supplement that

replaces damaged cellular lipids. Using the Piper Fatigue Scale there

was a significant time-dependent reduction in overall fatigue in

moderately or severely fatigued subjects while on the dietary supplement

for 4-8 weeks. Analysis of mitochrondrial function indicated that four

and eight weeks of the dietary supplement in moderately or severely

fatigued subjects significantly increased mitochondrial function.

Similarly, chronic fatigue syndrome patients administered antioxidants

plus LRT also show reductions in fatigue. The results indicate that LRT

plus antioxidants can significantly reduce moderate to severe chronic

fatigue and restore mitochondrial function. Dietary use of unoxidized

membrane lipids plus antioxidants is recommended for patients with

moderate to severe chronic fatigue.

 

KEYWORDS. lipids, antioxidants, therapy, dietary supplement, fatigue,

mitochondria, chronic fatigue syndrome

 

Address correspondence to: Prof. Garth L. Nicolson, Department of

Molecular Pathology, The Institute for Molecular Medicine, 16371 Gothard

St. H, Huntington Beach, California 92647, Tel: +1-714-596-6636,

Email: gnicolson, Website: www.immed.org ;

Fax: +1-714-596-3791.

 

*The authors have no financial interest in the products discussed in

this contribution.

 

 

INTRODUCTION

 

One of the most important changes in tissues and cells that occurs

during aging and chronic degenerative disease is accumulated oxidative

damage due to cellular reactive oxygen species (ROS). ROS are oxidative

and free radical oxygen- and nitrogen-containing molecules, such as

nitric oxide, oxygen and hydroxide radicals and other molecules [1].

Critical targets of ROS are the genetic apparatus and cellular membranes

[1,2], and in the latter case oxidation can affect lipid fluidity,

permeability and membrane function [3,4]. Similar changes occur in

fatiguing illnesses, such as chronic fatigue syndrome (CFS), where

patients show increased susceptibility to oxidative stress and

peroxidation [5,6]. One of the most important changes caused by

accumulated ROS damage during aging and in fatigue is loss of electron

transport function, and this appears to be directly related to

mitochondrial membrane lipid peroxidation [1], which can induce

permeability changes in mitochondria and loss of transmembrane potential

and oxidative phosphorylation [1,2].

 

We will concentrate this brief review on recent clinical trials that

have shown the effectiveness of lipid replacement therapy (LRT) plus

antioxidants in the treatment of certain clinical disorders and

conditions, such as chronic fatigue [7]. LRT is not just the dietary

substitution of certain lipids with proposed health benefits; it is the

actual replacement of damaged cellular lipids with undamaged lipids to

ensure proper structure and function of cellular structures, mainly

cellular and organelle membranes [7]. Damage to membrane lipids can

impair fluidity, electrical properties, enzymatic activities and

transport functions of cellular and organelle membranes [1-6].

During LRT lipids must be protected from oxidative and other damage, and

this is also necessary during storage as well as during ingestion,

digestion, and absorption in vivo. LRT must result in delivery of high

concentrations of unoxidized, undamaged membrane lipids in order to

reverse the damage and restore function to oxidized cellular membranes.

Combined with antioxidant supplements, LTR has proven to be an effective

method to prevent ROS-associated changes in certain cellular activities

and functions and for use in the treatment of certain clinical conditions

[7].

 

HEALTH BENEFITS OF LIPID SUPPLEMENTS

 

Mixtures of lipids introduced as dietary supplements have been used to

improve general health [8,9], and they have also been used as an adjunct

therapy in the treatment of various clinical conditions, for example,

the use of n-3 fatty acids in cardiovascular diseases and inflammatory

disorders [9-12]. Although not every clinical study has found health

benefits from lipid dietary supplementation [13], most studies have

documented the value of dietary supplements that favor certain types of

lipids over others, such as when n-3 polyunsaturated fatty acids (mainly

fish- or flaxseed-derived) are favored relative to n-6 lipids [8-12].

Cellular lipids are in dynamic equilibrium in the body, and this is why

LRT is possible [7]. Orally ingested lipids diffuse to the gut

epithelium and are bound and eventually transported into the blood and

lymph using specific carrier alipoproteins and also by nonspecific

partitioning and diffusion mechanisms [14,15]. Within minutes, lipid

molecules are transported from gut epithelial cells to endothelial

cells, then excreted into and transported in the circulation bound to

lipoproteins and blood cells where they are generally protected from

oxidation [16,17]. Once in the circulation, specific lipoprotein

carriers and red blood cells protect lipids throughout their passage and

eventual deposition onto specific cell membrane receptors where they can

be taken into cells via endosomes and by diffusion [17]. After binding

to specific cell surface receptors that bring the lipids into cells,

lipid transporters in the cytoplasm deliver specific lipids to cell

organelles where they are taken in by specific transport proteins,

partitioning, and diffusion [18]. The concentration gradients that exist

from the gut during the digestion of lipids to their absorption by gut

epithelial cells and their transfer to blood and then tissues are

important in driving lipids into cells. Similarly, damaged lipids can be

removed by a similar reverse process that may be driven by lipid

transfer proteins and by enzymes that recognize and degrade damaged

lipids and remove them [18].

 

CHRONIC FATIGUE AND OXIDATIVE DAMAGE TO MITOCHONDRIA

 

Intractable or chronic fatigue lasting more than 6 months that is not

reversed by sleep is the most common complaint of patients seeking

medical care [19,20]. It is also an important secondary condition in

many clinical diagnoses and occurs naturally during aging [19,20]. The

phenomenon of fatigue has only recently been defined as a

multidimensional sensation, and attempts have been made to determine the

extent of fatigue and its possible causes [21-23]. Most patients

understand fatigue as a loss of energy and inability to perform even

simple tasks without exertion. Many medical conditions are associated

with fatigue, including respiratory, coronary, musculoskeletal, and

bowel conditions as well as infections and cancer [7,20-23].

Fatigue is related to cellular energy systems found primarily in the

cells' mitochondria. Damage to mitochondrial components, mainly by ROS

oxidation, can impair their ability to produce high-energy molecules

such as ATP and NADH. This occurs naturally with aging and during

chronic illnesses, where the production of ROS can cause oxidative

stress and cellular damage, resulting in oxidation of lipids, proteins

and DNA [24,25]. When oxidized, these molecules are structurally and

sometimes functionally changed. Important targets of ROS damage are

mitochondria, mainly their phospholipid-containing membranes, and

cellular and mitochondrial DNA [1,24,25].

 

Excess ROS production throughout our lifetimes can result in accumulation of

mitochondrial and nuclear damage [1,24-26]. Opposed to this, cellular

free-radical scavenging enzymes neutralize excess ROS and repair the enzymes

that

reverse ROS-mediated damage [25,26]. Although some ROS production is important

in

triggering cell proliferation, gene expression and destruction of invading

microbes [27,28], with aging ROS damage accumulates [1,24-26]. When this occurs,

antioxidant enzymes and enzyme repair mechanisms along with biosynthesis

cannot restore or replace enough ROS-damaged molecules[1,24,28-30]. Disease and

infection can result in oxidative damage that exceeds the abilities of cellular

systems to repair and replace damaged molecules [6,24,27], and this is also the

situation in fatiguing illnesses [5,6].

 

In CFS patients there is evidence of oxidative damage to DNA and lipids

[reviewed in 5,6] as well as the presence of blood markers, such as

methemoglobin, that are indicative of excess oxidative stress [31].

Fulle et al. [32] found oxidative damage in the DNA and membrane lipids

from muscle biopsy samples obtained from CFS patients. They also found

increases in antioxidant enzymes, such as glutathione peroxidase, and

suggested that this was an attempt to compensate for excess oxidative

stress in CFS. Pall [33] has proposed that CFS patients have sustained

elevated levels of the RNS peroxynitrite due to excess nitric oxide and that

this results in lipid peroxidation and loss of mitochondrial function as well

as changes in cytokine levels that exert a positive feedback on nitric oxide

production. In addition to mitochondrial membranes, mitochondrial enzymes, such

as succinic dehydrogenase and cis-aconitase, are inactivated by

peroxynitrite, and this could also contribute to loss of mitochrondrial function

[34,35].

Also, cellular molecules that could counteract the excess oxidative capacity of

ROS/RNS, such as glutathione and cysteine, have been found in lower levels in

CFS patients [36].

 

PREVENTING ROS/RNS-MEDIATED DAMAGE WITH ANTIOXIDANTS

 

Reversal of damage of cellular and mitochondrial membranes as well as

DNA are important in preventing loss of cellular energy [5,29,30,37].

This can be accomplished, in part, by neutralizing ROS/RNS with various

antioxidants or increasing free-radical scavenging systems that

neutralize ROS/RNS. Thus dietary antioxidants and some accessory

molecules, such as zinc and certain vitamins, are important in

maintaining antioxidant and free-radical scavenging systems [reviewed in

5]. In addition to zinc and vitamins, there are at least 40

micronutrients required in the human diet [38], and aging increases the

need to supplement these to prevent age-associated damage to

mitochondria and other cellular elements. Antioxidant use alone,

however, may not be sufficient to maintain cellular components free of

ROS damage. Therefore, LRT is important in replacing ROS-damaged

membrane lipids [7].

 

In animal studies dietary antioxidant supplementation has partially

reversed the age-related declines in cellular antioxidants and

mitochondrial enzyme activities and prevented mitochondria from most

age-associated functional decline. For example, in rodents fed diets

supplemented with antioxidants the antioxidants were found to inhibit

the progression of certain age-associated changes in cerebral

mitochondrial electron transport chain enzyme activities [39,40]. Thus

animal studies have shown that antioxidants can partially prevent

age-associated changes in mitochondrial function. However, antioxidants

alone cannot completely eliminate ROS damage to mitochondria, and this

is why LRT is an important addition to antioxidant dietary

supplementation [7].

 

Dietary antioxidants may also modify the pathogenic processes of certain

diseases [5,7,33,41]. For example, antioxidant administration has been

shown to have certain neuroprotective effects [42]. The dietary use of

antioxidants has been shown to prevent age-associated mitochondrial

dysfunction and damage, inhibit the age-associated decline in immune and

other functions and prolong the lifespan of laboratory animals [5,7,42-44].

 

PRECLINICAL STUDIES USING LIPID REPLACEMENT THERAPY

 

LTR replaces damaged cellular and mitochondrial membrane phospholipids

and other lipids that are essential structural and functional components

of all biological membranes [7]. One such LRT dietary supplement is

NTFactor®, and this supplement has been used successfully in animal and

clinical lipid replacement studies [45,46]. NTFactor's encapsulated

lipids are protected from oxidation in the gut and can be absorbed and

transported into tissues without undue damage. NTFactor® contains a

variety of components, including phospholipids, glycophospholipids and

other lipids, nutrients, probiotics, vitamins, minerals and plant

extracts (Table 1).

 

NTFactor® has also been used for studies in laboratory animals. In aged

rodents, Seidman et al. [47] found that NTFactor® prevented hearing loss

associated with aging and shifted the threshold hearing from 35-40 dB in

control aged animals to 13-17 dB in the treatment group (P<0.005). They

also found that NTFactor® preserved cochlear mitochondrial function as

measured in a Rhodamine-123 transport assay [48], increasing

mitochondrial function by 34%. NTFactor® also prevented aging-related

mitochondrial DNA deletions found in the cochlear [47]. Thus LRT was

successful in preventing age-associated hearing loss and mitochondrial

damage in rodents.

 

CLINICAL STUDIES USING LIPID REPLACEMENT THERAPY

 

LRT has been successfully used in clinical studies to reduce fatigue and

protect cellular and mitochondrial membranes from damage by ROS/RNS

[45,46]. For example, NTFactor® has been used in a vitamin and mineral

mixture (Propax®) in cancer patients to reduce the effects of cancer

therapy, such as chemotherapy-induced fatigue, nausea, vomiting and

other side effects associated with chemotherapy [49]. This

double-blinded, cross-over, placebo-controlled, randomized trial on

cancer patients receiving chemotherapy Propax® supplementation showed

LRT improvement from fatigue, nausea, diarrhea, impaired taste,

constipation, insomnia and other quality of life indicators [49].

Following cross-over to the Propax® supplement, patients reported rapid

improvement in nausea, impaired taste, tiredness, appetite, sick feeling

and other quality of life indicators [49].

 

Propax® containing NTFactor® has been used in a dietary LRT study with

severe chronic fatigued patients to reduce their fatigue [45]. Using the

Piper Fatigue Scale [23] we found that fatigue was reduced approximately

40.5% (P<0.0001), from severe to moderate fatigue, after eight weeks of

supplementation with Propax® containing NTFactor® (Table 2). Recently

we examine the effects of NTFactor® on fatigue in moderately and mildly

fatigued subjects and to determine if their mitochondrial function, as

measured by the transport and reduction of Rhodamine-123 and fatigue

scores, improved with administration of NTFactor® [46]. Use of NTFactor®

for 8 or 12 weeks resulted in a 33% or 35.5% reduction in fatigue,

respectively (P<0.001) (Table 2) [46]. In this clinical trial there was

good correspondence between reductions in fatigue and gains in

mitochondrial function. After only 8 weeks of LRT with NTFactor®,

mitochondrial function was significantly improved (P<0.001), and after

12 weeks of NTFactor® supplementation, mitochondrial function was found

to be similar to that of young healthy adults [46]. After 12 weeks of

supplement use, subjects discontinued the supplement for an additional

12 weeks, and their fatigue and mitochondrial function were again

measured. After the 12-week wash-out period fatigue and mitochondrial

function were intermediate between the initial starting values and those

found after eight or 12 weeks on supplement, indicating that continued

dietary LTR is probably required to show improvements in mitochondrial

function and maintain lower fatigue scores [46]. The results indicate

that in moderately to severely fatigued subjects dietary LRT can

significantly improve and even restore mitochondrial function and

significantly improve fatigue. Using the Piper Fatigue Scale our

unpublished data on a small number of CFS (and/or Fibromyalgia Syndrome)

patients indicates that LRT plus antioxidants for 8 weeks reduces

moderate to severe fatigue by 43.1% (Table 2).

 

SUMMARY

 

When mitochondrial function is impaired, such as during moderate to

severe fatigue, the net energy available to cells is limited to the

Krebs Cycle and anaerobic metabolism. There are a number of conditions

and substances that can impair mitochondrial function, but peroxidation

and damage of mitochondrial membrane lipids are probably among the most

important effects [35,39,50]. Mitochondrial function appears to be

directly related to fatigue, and when patients experience moderate to

severe fatigue their mitochondrial function is inevitably impaired.

Fatigue is a complex phenomenon determined by several factors, including

psychological health [22,23], but at the biochemical level fatigue is

related to the metabolic energy available to tissues and cells, mainly

through mitochondrial electron transport. Thus the integrity of

mitochondrial membranes is critical to cell function and energy

metabolism. When mitochondrial membrane lipids are damaged by oxidation,

they must be repaired or replaced in order to maintain the production of

cellular energy to alleviate fatigue. During aging and in many diseases,

including fatiguing illnesses, ROS/RNS-mediated accumulation of oxidized

mitochondrial lipid occurs. The failure to repair or replace these

damaged molecules at a rate that exceeds their damage results in

impaired mitochondrial function.

 

Mitochondrial membrane damage and subsequent dysfunction by ROS/RNS can

also lead to an increased rate of mitochondrial DNA modifications

(especially mutations and deletions). The mitochondrial theory of aging

proposes that the development of chronic degenerative diseases is the

result, in part, of accumulated oxidative damage to mitochondrial

membranes and DNA over time [29,30,41,43].

 

The damage to mitochondrial membranes and DNA seems to also be involved in

the etiology of age-associated degenerative diseases [41,51]. Restoration of

mitochondrial membrane integrity, fluidity and other properties are essential

for the optimal functioning of the electron transport chain.

The ability to control membrane lipid peroxidation and DNA damage will

likely play an important role in attenuating the development of

age-related degenerative diseases [41,43,52].

 

Dietary LRT plus antioxidants has proven to be a valuable tool in maintaining

mitochondrial function and preventing fatigue, and it should be an important

part of treatment strategies for CFS and other fatiguing illnesses [7].

 

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TABLE 1. Components of NTFactor®, a dietary LRT supplement [7].

 

NT Factor® is a nutrient complex that is extracted and prepared using a

proprietary process that protects lipids from oxidation. In addition,

nutrients, vitamins and probiotic microorganisms are added to the

preparation. It contains the following ingredients:

 

Glycophospholipids: polyunsaturated phosphatidylcholine, other

polyunsaturated phosphatidyl lipids, glycolipids and other lipids such

as cardiolipin and sterol lipids.

 

Probiotics: Bifido bacterium, Lactobacillus acidophilus and

Lactobacillus bacillus in a freeze-dried, microencapsulated form with

appropriate growth nutrients.

 

Food Supplements, Vitamins and Growth Media:

 

bacterial growth factors to support probiotic growth, including defatted rice

bran, arginine, beet root fiber extract, black strap molasses, glycine,

magnesium sulfate, para-amino-benzoate, leek extract, pantethine (bifidus growth

factor), taurine, garlic extract, calcium borogluconate, artichoke extract,

potassium citrate, calcium sulfate, spirulina, bromelain, natural

vitamin E, calcium ascorbate, alpha-lipoic acid, oligosaccharides,

vitamin B-6, niacinamide, riboflavin, inositol, niacin, calcium

pantothenate, thiamin, vitamin B-12, folic acid, chromium picolinate.

 

NTFactor® is a registered trademark of Nutritional Therapeutics, Inc.,

P.O. Box 5963, Hauppauge, NY 11788 (Tel: +1-800-982-9158),

Website: www.propax.com

 

 

TABLE 2. Effects of NTFactor®, a dietary LRT supplement, on Piper

Fatigue Scale scores.

 

_______________

AverageTime on Piper Fatigue Scale

Subjects/patients N age NTFactor® fatigue reduction (%) Reference

_______________

 

Chronic fatigue 34 50.3 8 wks 40.5** 45

 

 

Chronic fatigue 20 68.9 12 wks 35.5* 46

 

CFS (and/or FMS‡) 15 44.8 8 wks 43.1* --

_______________

 

**P<0.0001, *P<0.001 compared to data without supplement

‡ Fibromyalgia Syndrome, 5/15

 

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