Oxygen Free Radicals and Aging: Part II
In case you missed Part I of this three-part series, we reviewed the major theories of aging, including: the rate of living theory; the somatic mutation theory; the neuroendocrine theory; the glycation theory; the crosslinking theory; and the free radical theory. The free radical theory of aging, which holds that aging is due to damage to DNA and molecular membranes by highly reactive molecules known as free radicals, is especially appealing for many reasons. First, it provides a unifying mechanism for the different theories; second, it can be experimentally verified; third, it suggests a number of parameters that can be evaluated to determine the progress of aging and the success of anti-aging therapies; and finally, it is a mechanism that can be altered by appropriate antioxidant therapies. Sources of free radicals were also discussed, which included both exogenous (outside the body) and endogenous (inside the body) sources. Some of these exogenous sources include air pollution and cigarette smoke. It’s obvious that it’s impossible to avoid contact with these reactive molecules.
Fortunately, the body is naturally equipped with antioxidant defense systems to detoxify these dangerous agents. Unfortunately, the body’s defense system becomes less effective as we get older, leading to the accumulation of oxidative damage and the development of chronic degenerative diseases like arthritis, hypertension, atherosclerosis, diabetes, cancer and diseases of the central nervous system such as stroke, Alzheimer’s disease and Parkinson’s disease. Depletion of antioxidants can thus lead to a variety of chronic diseases. The relationship between oxidative damage and aging is a double-edged sword. On one hand, oxidative damage to DNA, lipids, proteins and other macromolecules appears to be a major contributing factor to aging,1 while at the same time, this oxidative damage accumulates with aging (Fig. 1), despite attempts by an individual’s cellular machinery to repair it.7,8
For example, blood levels of glutathione, the major cellular antioxidant in the body, decline with age.1,2 Low glutathione levels are associated with a higher incidence of diseases in the elderly.3 In fact, blood glutathione concentrations may become recognized not only as a predictor of susceptibility to disease, but also as a marker of biological age.
Oxidation and
Disease Progression
In this article, we’re going to discuss the specific contributions that
damaging free radical reactions make in promoting the onset and progression of
the chronic degenerative diseases of aging. We’ll discuss the role of free
radicals (oxidants) in the development of each of these diseases, and provide a
strong rationale for using antioxidant supplements for disease prevention and
treatment. Indeed, a great deal of evidence regarding the role of free radicals
in aging and its related diseases has been derived from studies in which
antioxidant supplements have been used to successfully treat or prevent these
diseases. Many of these studies will be reviewed in Part III of this series.
Cancer
Free radicals are involved in both the process of aging and the development of
cancer.4 They attack many cellular targets including membranes, proteins and
nucleic acids,5 and cause structural damage to the cellular DNA. These
structural changes manifest as point mutations and chromosomal alterations in
cancer-related genes.5 Consequently, elderly people are predisposed to the
development of cancer. Fortunately, certain antioxidant supplements like
vitamins C and E, can prevent much oxidative damage to DNA and thus reduce the
ability of the oxidants to induce cancer.7
Cardiovascular
Disease
One of the most significant discoveries in modern cardiovascular disease
research was the discovery of how free radical activity contributes to
cardiovascular disease.4,7 These discoveries were made using two different
approaches. One approach, using epidemiological studies, showed that
cardiovascular disease is associated with low plasma concentrations of
antioxidant vitamins.7 The other approach, using experimental studies, provided
strong evidence that free radicals oxidize low density lipoprotein (LDL) — the
bad form of cholesterol. The modified LDL molecules are then easily taken up by
white blood cells called macrophages (phagocytes) to form foam cells and plaques
in the cardiovascular wall,4,7 causing a hardening and narrowing of the blood
vessels which impairs blood flow and deprives the heart of oxygen and nutrients.
Also, what is known as reperfusion (reoxygenation) injury is caused by
inadequate supplies of intracellular antioxidants! Reperfusion injury is the
damage to cells which occurs following restoration of the blood and oxygen
supply to the heart after a period of ischemia (inadequate blood supply).
Antioxidants are able to prevent or reduce the severity of this type of tissue
damage.4
Diseases of the
Central Nervous System
Oxidative damage has been implicated in brain aging as well as several
degenerative diseases of the central nervous system (CNS). A number of
mechanisms have been identified which explain the causative role played by free
radicals in the neurodegenerative diseases. First, oxidants may activate an
enzyme of nerve cells (poly ADP-ribose synthetase) and cause an increase in the
intracellular calcium ion concentrations, which is injurious to neurons.12
Second, reoxygenation of brain cells following a period of ischemia contributes
to oxidant injury of the CNS, as already mentioned in the case of cardiovascular
disease. Third, certain areas of the brain, e.g., the globus, pallidus and
substantia nigra often contain high amounts of iron. Excess iron enhances
oxidative reactions and consequent injury to the neurons.12 It is therefore not
surprising that antioxidant supplements have been successfully used to improve
the functioning of the brain both in people who are aging normally, as well as
patients suffering from neurodegenerative diseases such as stroke and
Alzheimer’s and Parkinson’s diseases.
I. Strokes
Free radical-produced damage due to ischemia-reperfusion in the brain has
been implicated as a major cause of strokes.12 Antioxidant supplements appear to
be of benefit in the prevention and reduction of strokes.12,13 And, to top it
off, recent clinical studies indicate that surgical therapy (i.e., carotid
endarterectory) is actually worse than no therapy in many cases.
II. Alzheimer's
Disease
Alzheimer’s disease (AD) is the tragic brain-robbing disease of aging. It can
be recognized by the progressive loss of memory and other aspects of cognitive
functioning. Its characteristic pathological features include tangles of nerve
fibers, senile plaques (which contain aluminum, iron, and calcium) and the loss
of brain cells.9 Oxidative damage has been implicated in AD, for a number of
reasons. First, the brain has the highest oxygen consumption rate of any organ
in the body, high concentrations of easily-oxidizable lipids, and a relative
deficiency of antioxidant enzymes (compared to other tissues).9 Second, iron,
which plays an important role in free radical generation, has been found in high
concentrations in the brain in AD.9 Third, antioxidant supplementation often
improves memory performance in aged individuals.10
III. Parkinson's
Disease
The hallmark of Parkinson’s disease is degeneration of a portion of the brain
called the substantia nigra — the portion of the brain that produces the
stimulatory neurotransmitters epinephrine (adrenaline) and norepinephrine (noradrenaline).
There are two mechanisms that have been proposed as possible causes of this
neuronal damage.11 The first is that increased production of oxidants causes
damage to this vital portion of the brain (the substantia nigra) through
iron-dependent free radical reactions. It has been shown that the iron content
of the substantia nigra is often elevated, while ferritin, the iron-binding
protein is often decreased in Parkinson’s disease. Again, the resulting
increase in free iron ions enhances iron-dependent lipid peroxidation and damage
to nerve cells.12 A second mechanism is impaired neuronal mitochondrial
function, which leads to failure of energy production and adverse changes in the
metabolism of nerve cells.
There are several mutually supporting links between these two mechanisms.11 As previously noted, mitochondria are a critical target for damage by free radicals.4,7,11 Also, mitochondrial damage may cause a further increase in generation of free radicals.11 Another link between the two mechanisms (i.e., oxidative damage to mitochondria vs free-radical induced damage to neuronal metabolism) is glutathione. Patients with Parkinson’s disease tend to have low levels of this powerful intra-cellular antioxidant in their brains, resulting in higher levels of free radical activity.11 These two mechanisms both contribute to neuronal damage through alterations in glutathione levels.11
A variety of antioxidant vitamins and drugs are helpful for patients with this disease, especially Vitamin E and deprenyl (in particular Discovery Liquid Deprenyl, available from International Anti-Aging Systems — an overseas pharmacy where this and many other European anti-aging drugs can be ordered without a prescription — our operators can supply their number)(WD). I believe that one of the most beneficial nutrients for Parkinson’s disease is N-acetyl cysteine (NAC). NAC boosts glutathione production, and should be of tremendous benefit to Parkinson’s patients, in doses ranging from 600-1200 mg per day.
Inflammatory
Diseases
Arthritis and inflammatory diseases of the large intestine, such as ulcerative
colitis and Crohn’s disease, are conditions in which oxidative damage has also
been implicated.4,14 While there is agreement that free radicals play a role in
the pathogenesis of inflammatory disease, the mechanism(s) involved is still a
matter of intense research. One plausible mechanism of oxidant mediated injury
involves tissue protein oxidation, otherwise referred to as protein
carbonylation. It has been been proposed that inflammatory bowel disease (IBD)
may arise from the oxidation of proteins in the intestinal mucosa cells which
thereby disrupt the critical enzyme systems that are important for the
maintenance of mucosal integrity or ion transport, both of which are impaired in
IBD.15 Antioxidant supplements have helped many people who suffer from a variety
of inflammatory diseases.4,7,15
Diabetes
Diabetes is a multi-systemic disease caused by a defect in glucose metabolism.
Abnormally high blood sugar levels are a major clinical feature of the disease,
which is usually followed by accelerated onset and progression of
atherosclerosis and other diseases. In type 2 diabetes, oxidative damage has
been implicated in both the development of the disease as well as its many
complications. Oxidants inhibit glucose metabolism in the glycolytic pathway and
at the level of oxidative phosphorylation, thereby causing a sugar overload in
the blood. The medical term for high blood sugar levels is hyperglycemia.
Increased blood sugar levels cause auto-oxidation of glucose and glycation of
proteins which have been implicated in the development of diabetic
complications.16 It is therefore not surprising that antioxidant supplements —
particularly vitamins C and E, and lipoic acid — have been found to be
beneficial to patients suffering from diabetes.16 This subject was covered
extensively in previous reviews by this author (see Nutritional News volume 10:
6 and 7, 1997).
Vision
I. Cataracts
Oxidative damage to the lens of the eye, which collects and focuses light on the
retina, plays a major role in the formation of cataracts.7,17 With age, the
constituents of the lens are damaged by oxidants causing opaque precipitations
that are referred to as senile cataracts.17 A variety of antioxidant supplements
have been shown to provide protection against the development of cataracts7,17
— especially, lipoic acid — a key player in the prevention of cataracts.
II. Macular
Degeneration
Macular degeneration is a leading cause of blindness in the elderly. It is one
condition which ophthalmologists used to stand by and helplessly watch as their
patients’ vision failed. Now, they are finding that combinations of
antioxidant and carotenoids have demonstrated the ability to halt or delay the
progression of this dreaded condition.
Many studies have been performed with multi-nutrient protocols to treat ARMD and
cataracts. For example, Dr. E.N. Crary of Smyrna, Georgia published a study in
1987 in the Southern Medical Journal titled “Antioxidant Treatment of Macular
Degeneration of the Aging and Macular Edema in Diabetic Retinopathy.” In this
study, Dr. Crary used 250 mcg of selenium, 15,000 units of beta carotene, 500 mg
of vitamin C and 400 units of vitamin E for a period of 7 to 12 years. He
treated over 500 patients and found that the treatments either halted or
improved degenerative macular changes in 60% of the patients with age-related
macular degeneration.
Summary
It is apparent, as outlined above, that free radical (oxidative) damage plays a
significant role in the process of aging as well as in the development of a
broad spectrum of age-associated diseases. Specific supplements and their
dosages for preventing and minimizing the effects of these diseases will be
reviewed in part III of this series.
Highly recommended
source of nutrients and supplements. 
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