Free Radicals and Antioxidants
Superoxide Dismutase
Superoxide is a highly reative free radical species, which can cause very profound damage to cells. Superoxide is the anion O2−.[1] with one unpaired and therefore reactive electron. Superoxide is a very toxic substance. It's toxicity is in fact used beneficially by the immune system to destroy invading microorganisms. Phagocytes (white blood cells) engulf invading organisms, such as bacteria and use superoxide to oxidise them. The superoxide is produced in these immune cells by the enzyme NADPH oxidase. A deficiency of this enzyme results in the immunodeficiency syndrome known as chronic granulomatous disease, a syndrome characterised by extreme susceptibility to infection.
Superoxide is also produced in the mitochondria of the cells as a bi-product of the process of aerobic respiration. Mitochondria are the centres for respiration and are often referred to as the powerhouses of the cells, without which a cell cannot function. In mitochondria the superoxide is produced notably by complex I and complex III. This free radical is also produced by several other enzymes, an example of which is xanthine oxidase (involved in the formation of uric acid).
Mechanism of action
The toxic affects of superoxide result from its ability to inactivate iron-sulphur containing enzymes. These enzymes are essential in a large number of metabolic reactions. Once these enzymes are deactivated, iron is free to undergo a process known as fenton chemistry (see below):
Fe2+ + H2O2 Fe3+ + OH. + OH-
This results in the generation of the highly reactive free radical known as Hydroxyl.
In its HO2 form, Superoxide also initiates the peroxidation of polyunsaturated fatty acids and when superoxide reacts with carbonyl compounds and halogenated carbons it can create toxic peroxy radicals.
Definition of Superoxide Dismutase
One of the most important free radical scavengers in the human body is the enzyme superoxide dismutase (SOD). This enzyme catalyzes the dismutation of superoxide into oxygen and hydrogen peroxide. Its function is to defend the cells of the body against molecular damage from oxygen. Nearly all cells and cellular organisms use SOD to eliminate superoxide. One of the exceptions is Lactobacillus plantarum and related lactobacilli. These bacteria use a different mechanism for eliminating superoxide.
Structure of Superoxide Dismutase
The role of Superoxide dismutase in the cells
SOD is located in two places with the cells. The Mitochondria and the cytoplasm. The SOD that resides in the mitochondria contains manganese and has the formula MnSod. Mitochondrial SOD is transcribed in the nucleus, but has a targeting sequence that localises it to the matrix of the mitochondria. The cytoplasmic SOD contains copper and zinc with the formula CuZnSod. SOD is coded for in genes located on chromosomes 4, 6 and 24.
When cellular superoxide dismutase comes into contact with superoxide, the SOD a reaction takes place, which results in the production of hydrogen peroxide. For each two superoxides that are encountered by the SOD, one hydrogen peroxide (H2O2) is created. Hydrogen peroxide does however pose a great danger to the cell as it transforms easily into the highly reactive hydroxyl radical. A process involving the Fenton chemistry (described previously). Luckily, there does exist an efficient mechanism for dealing with the hydrogen peroxide. The enzyme Catalase is produced by the rough endoplasmic reticulum and is concentrated in peroxisomes surrounding the mitochondria (as well as being present in lower concentrations throughout the cell). The catalase reacts with the hydrogen peroxide to produce water and oxygen.
There is also another mechanism for neutralising the hydrogen peroxide and thus preventing it from forming hydroxyl radicals. The selenium containing enzyme Glutathione peroxidise reduces H2O2 by transferring the energy of the reactive peroxides to a small protein called glutathione (a protein containing sulphur). The selenium contained in this enzyme is where a key reaction takes place. A reaction that transfers electrons from the peroxide to the glutathione.
Reaction
A typical reaction of an SOD protein containing copper (and zinc) looks like this:
Cu2+-SOD + O2- → Cu1+-SOD + O2
Cu1+-SOD + O2- + 2H+ → Cu2+-SOD + H2O2.
In this reaction the oxidation state of the copper changes between +1 and +2.
Mark S D'Arcy
Selenium
Selenium (Se) plays important roles in many essential chemical reactions in the brain and in cells throughout the body. Regarding the processes involved in cellular degradation and aging, Selenium is essential for the effective elimination of hydrogen peroxide from the cells. Selenium eliminates hydrogen peroxide from the cells and thus prevents it from undergoing a process involving Fenton chemistry which can form the highly reactive hydroxyl radicals. Selenium does this as a part of the free radical scavenging enzyme Glutathione peroxidise.
Definition of Selenium
Selenium is an essential trace element. It is an integral part of enzymes, which are critical for control of the numerous chemical reactions involved in brain and body functions. Selenium has a variety of functions. The main one is its role as an antioxidant in the enzyme selenium-glutathione-peroxidase. This enzyme neutralizes hydrogen peroxide, which is produced by some cell processes and would otherwise damage cell membranes.
Selenium also seems to stimulate antibody formation in response to vaccines. It also may provide protection from the toxic effects of heavy metals and other substances.
Selenium may assist in the synthesis of protein, in growth and development, and in fertility, especially in men. It has been shown to improve the production of sperm and sperm motility. http://www.nlm.nih.gov/medlineplus/ency/article/002414.htm
Sources of Selenium
- Red meat
- Fish such as Tuna and Cod
- Shellfish
- Garlic
- Chicken and Turkey
- Eggs
- Sometimes vegetables (if grown in selenium rich soil)
- Certain nuts, including Brazil and Walnuts
- Cheese
- Long grained brown rice
- Oatmeal
Recommended Daily intake of Selenium
|
Age |
Males and Females |
|
1-3 |
20 |
|
4-8 |
30 |
|
9-13 |
40 |
|
14-18 |
55 |
|
19+ |
55 |
Effects of reduced levels of Selenium
Selenium is an essential trace mineral, however at levels of over 1200 mcg (inorganic Se) or 3500 mcg (organic Se) it can be toxic. There is some evidence suggesting that selenium by itself does not cause illness. Instead it is theorised that a deficiency of selenium makes the body more susceptable to illnesses caused by a variety of infections agents and nutritional or biochemical deficiencies.
Three diseases have been linked with a deficiency in selenium. these are:
- In selenium deficient children Keshan disease can occur. This results in an enlarged heart together with a general degradation in the functioning of this organ. This disease was first identified in China in the 1930’s and is still seen in rural areas of China where the soil is particularly deficient in selenium
- Myxedematous Endemic Cretinism. The result of this condition is mental retardation
- Kashin-Beck disease. This results in osteoarthropathy (a disease affecting the joints and bones)
Effects of too much Selenium
Overdosing on selenium can result in a condition called Selenosis. The symptoms of this disease include gastrointestinal damage, garlic smelling breath, low grade nerve damage, fatigue, irritability and hair loss. Overdosing on selenium is however rare and is usually associated with such things as industrial accidents resulting in environmental contamination or (as in one American case) an excessively high level of selenium produced in a dietary supplement. 400 micrograms per day is generally considered the maximum safe dosage of selenium to take.
Anti-aging and general benefits of Selenium
A number of studies involving selenium have shown that it may help to protect against such wide-ranging conditions as cancer, heart disease and arthritis. Below is a summary of the research so far:
Selenium and cancer
A study released by the Division of Nutritional Sciences, Cornell University, Ithaca, New York involved 1312 patients who had a history of basal/squamous cell carcinomas of the skin. These patients were recruited between 1983-1990 and were assigned randomly into two groups. One group was given a daily oral supplement of selenium-enriched yeast (200 micrograms), the other group was given a low-selenium yeast placebo. The study was conducted in a double-blind manner and plasma selenium concentrations were determined at intervals of 6-12 months. Any illnesses reported by the patients were recorded, together with any development of cancers or deaths.
Selenium intake did not seem to affect significantly the recurrence of basal/squamous cell carcinomas of the skin. High selenium plasma concentrations did however correlate with a reduction in the incidence of other cancers, including prostate cancer, lung cancer and colorectal cancer. There was also a reduced rate of mortality in patients who had been taking the selenium supplements compared with those who had recieved the placebo.
For further information on this study, visit Cornell Selenium study
Selenium and heart disease
There have been a number of population studies that have shown links between low intakes of antioxidants (including selenium) and an increased incidence of heart disease. It has also been theorised that increased levels of free radicals in the body contribute to heart disease. Basically cholesterol is transported in the bloodstream from the liver to the tissues of the body in the form of Lipoproteins. Low density lipoproteins (LDL's) can become oxidised and seem to play a part in the development of atherosclerosis, a condition were the arteries and medium-sized blood vessels become clogged and harden. This can lead to heart attacks, strokes as well as kidney and eye problems. Note that High density lipoproteins (HDL's) deposit cholesterol in liver were it is then excreted from the body.
It has been postulated that selenium may help to prevent the oxidation of LDL and thus reduce the chances of developing heart disease.
Selenium and arthritis
Our immune systems produce free radicals in order to destroy invading microorganisms and also to break down damaged tissue. Unfortunately however, these same free radicals can also cause damage to healthy cells and tissues. Rheumatoid arthritis is a painful chronic condition that results in swelling, stiffness and a loss of functionality of the joints. A number of surveys including one conducted by the Social Insurance Institution, Helsinki, Finland have shown that sufferers of rheumatoid arthritis have reduced blood levels of selenium. Although research is still inconclusive, it may be possible that selenium supplements may help to eleviate some symptoms of this condition by neutralising free radicals.
For more details of how selenium plays a role in scavenging free radicals in cells and tissues, see Glutathione peroxidase
Mark S D'Arcy
Vitamin E
Definition of Vitamin E
The most active form of vitamin E, a-tocopherol, is a 6-hydroxychroman derivative with methyl groups in position 2,5,7, and 8 and a phytyl side chain attached at carbon 2. There are 8 known forms of vitamin E: a-,b-,g-, and d-tocopherols contain saturated phytol side chains and a-, b-, g-, and d-tocotrienols have 3 double bonds in the side chain.
Molecular structure of Vitamin E
It seems that d-tocotrienol is the earliest member of the group to be formed in plants, methylation leading to the other tocotrienols and hydrogenation producing the respective tocopherols. Natural a-tocopherol, termed d-a-tocopherol, may be described chemically as 2R-(4'R,8'R)-5,7,8-trimethyltocol, the term tocol being the name for the 2-ring structure basic to all vitamin E compounds.
The term "Vitamin E" should be used for all tocopherol and tocotrienol derivatives exhibiting the biological activity of d-a-tocopherol. The term "tocopherol" should be used for all methyl tocols. Since tocotrienols have some vitamin E activity, "tocopherol" is not synonymous with "vitamin E". http://www.cyberlipid.org/vite/vite0001.htm
Sources of Vitamin E
Note that vitamin E cannot be manufactured in the human body and is it is therefore essential that we include foods in our diets that contain this vitamin. Primarily, vitamin E can be found in the following foodstuffs:
- Oils such as wheat germ oil, palm oil, sunflower, soybean, canola and olive
- Nuts
- Sunflower seeds
- seabuckthorn berries
- Whole grains
- The leaves of green vegetables
- Milk
- Fish
General functions of Vitamin E
Vitamin E is the primary fat-soluble antioxidant. It is found notably in cellular membranes. This fat-soluble vitamin acts as an antioxidant and may have life prolonging affects (although this is still debatable) due to its free radical scavenging ability in lipid membranes, such as those of the cells.
Effects of reduced levels of Vitamin E
The affects of greatly reduced levels of vitamin E/dietary fatty acids is associated with an increase in lipid peroxidation in fatty tissues. There are not really any obvious symptoms of vitamin E deficiency initially as this vitamin is not essential for or involved in any enzmatic reactions. This is why vitamin E is often considered more of an antioxidant, than an actual vitamin. Prolongued absence of this antioxidant from the diet however (over several decades) has been linked to such diseases as cancer and atherosclerosis (heart disease).
Effects of too much Vitamin E
If an individual overdoses on vitamin E, then they may experience the following symptoms:
- Fatigue
- Weakness
- Headache
- Flatulence
- Diarrhoea
- Blurred vision
- Nausea
Vitamin E as an antioxidant
In lipid structures, it has been shown that vitamin E acts to neutralise peroxide free radicals. When vitamin E does this it becomes itself a radical, using vitamin C to once again return to its antioxidant state. One theory suggests that vitamin E may protect against cardiovascular disease by preventing LDL (Low density lipoprotein) oxidation from HDL (High density lipoprotein) – this is the process by which the arteries, including notably the coronary arteries become clogged with a fatty plaque.
One study (De la Fuente, M. et al 1998) was conducted of 30 elderly woman. 10 of these woman were considered healthy, 10 suffered from depression and 10 had been diagnosed with heart disease. All of the participants took daily doses of 1000 mg of vitamin C, together with 200 mg of vitamin E for 16 weeks. The results showed that the serum MDA levels (used to measure lipid peroxidation – damage to membranes by free radicals) dropped by 40% in the healthy woman, 65% in the woman who had been suffering from depression and by 60% in the woman with heart disease.
Vitamin E and cancer
Vitamin E has been shown to stimulate the immune system. This may result in the prevention of certain cancers due to a more competant immune sytem destroying cancerous cells at an early stage. Vitamin E also has been shown to inhibit the conversion of nitrates into nitrosamines in the stomach. These nitrates can be ingested in pickled, cured or smoked foods. Nitrosamines are STRONG tumour promotors.
Vitamin E and Athletic performance
General experimentation has not yielded results pointing towards a link between the ingestion of antioxidants and the enhancement of athletic performance. This is however with the notable exception of Vitamin E. A placebo controlled study conducted on mountaineers at altitude showed that those participants who supplemented their diet with vitamin E demonstrated less free radical damage and a reduced decline in their anaerobic threshold than did the control group. These results are not conclusive, but do point towards the benefits to physical performance of ingesting vitamin E.
To comment on vitamin E as as antioxidant or it's role in health and aging, click on this link Discussion
Mark S D'Arcy
Vitamin C
Vitmain C has for many decades been hailed as the ‘wonder pill.’ It has been suggested that it greatly strengthens the immune system, speeds up the healing process – and yes, slows down the process of aging through its anti-oxidant properties. So how does vitamin C operate in the human body? How is it absorved, matabolised and most importantly in this site – does it play any role in retarding the processes associated with aging??? The purpose of the next few pages is to examine those questions in detail and hopefully to provide some enlightening answers.
Definition of Vitamin C
The term vitamin C was coined to collectively apply to any substances that exhibit antiscorbutic properties (antiscorbutic literally means prevention of scurvy). Vitamin C can be divided into two distinct forms, together with their salts. These are
L-ascorbic acid. Usually simply referred to as ascorbic acid
L-dehydroascorbic acid
Note that ascorbic acid is the primary dietary form of Vitamin C.
In many texts, the terms ascorbic acid and ascorbate are used interchangeably. Both forms of the vitamin are basically derived from hexose and are similar in structure to the six-carbon sugar glucose.
The molecular structure of vitamin C
Absorption and Transportation of Vitamin C
One of the things that is unusual about Vitamin C is that only a few species of animals actually require it in their diet. Man, other primates, the red-vented barbul, the guinea pig and Passeriform birds, the Coho salmon, rainbow trout and various insects, together with a few other animals, all need to take this vitamin into their body in its raw form. The majority of other species of animals and plants possess the ability to synthesise this vitamin themselves from glucose or other forms of sugar. This synthesis of vitamin C from glucose is accomplished by using the enzyme L-gulano-gamma-lactone oxidase. This is the final enzyme that takes part in converting glucose to vitamin C and is not present in any vitamin C requiring animals.
In doses of 30 miligrams per day or less, nearly all dietary vitamin C is absorbed through the lumen of the small intestine into the enterocytes (a type of epiphelial cell of the small and large intestine). In doses up to 500 miligrams, this absorption is facilitated via a sodium-dependent active transport mechanism. For doses above 500 miligrams, absorption of vitamin C starts to occur via diffusion.
The primary ascorbic acid intestinal transporter is sodium-dependant vitamin C transporter 1 (abbreviated to SVCT1). SVCT1 also transports ascorbic acid into Liver and Kidney cells. Sodium-dependant vitamin C transporter 2 (SVCT2) seems to help to transport vitamin C into the aqueous humor of the eye.
Dehydroascorbic acid is taken up by the enterocytes via glucose channels. Some ascorbic acid may also be taken up by the enterocytes of the intestinal lumen after first being converted to dehydroascorbic acid by a process of oxidation. Once inside the enterocytes, dehydroascorbic acid (DHA) is reduced back to ascorbic acid by the reduced glutathione enzyme. Once converted back to ascorbic acid, the vitamin C then leaves the enterocytes and enters the portal circulation, then the systemic circulation. From this point the vitamin C is transported by the circulatory system throughout the body.
The highest concentrations of ascorbic acid can be found in the adrenal glands, pituitary gland, the white blood cells and the brain. To enter the tissues of the brain, the ascorbic acid must first cross the blood-brain barrier. Something that it cannot accomplish alone. To cross this barrier, the ascorbic acid is first converted to Dehydroascorbic acid (DHA) by a process of oxidation. Glucose transporter 1 (GLUT1) then comes into play and transports the DHA across the blood-brain barrier by a process of facilitative diffusion. GLUT1 transports the DHA into then out of the endothelial cells that line the surface of the blood-brain barrier. The DHA is then reduced back to ascorbic acid. It then remains in the tissues of the brain as there is no further mechanism to convert the ascorbic acid back into DHA and GLUT1 can only carry the ascorbic acid in its oxidised form.
Note that the GLUT1 mechanism is also used to transport ascorbic acid into the Neutrophils.
Metabolism of ascorbic acid
Large doses of ascorbic acid result in a reduced rate of absorption. This is why the vitamin should be taken in smaller doses throughout the day, rather than in single large doses. Any unabsorbed ascorbic acid will leave the body in the faeces. Once taken into the body, the ascorbic acid can be converted into several metabolites. These include Dehydroascorbic acid, diketogulonate, threonic acid, oxalic acid, ascorbate-2-sulfate and L-xylose. Any access ascorbic acid or its associated metabolites are extracted by the kidneys and are then excreted in the urine.
General functions of Vitamin C
Effects of reduced levels of Vitamin C
The major syndrome that lack of vitamin C in the diet will result in is Scurvy. This is a very encompassing syndrome, resulting in the sufferer presenting a number of different symptoms. These include:
- Petechiae – Small multiple hemorrhages of the blood vessels beneath the surface layer of the skin.
- Follicular hyperkeratosis – Increase in the concentration of Keratin in the follicles.
- Perifollicular hemorrhages
- Impaired wound Healing
- Inflamed and bleeding gums
- Coiled hairs
- Ecchymosis – A bleeding into the skin or bruising. This differs from Petechiae only in size.
- Arthralgia – Pain in the joints.
- Muscle weakness
- Fatigue
- Myalgia – Muscular pain
- Anemia
- Depression
- Increased susceptibility to infections
- Pulmonary and Kidney problems
- Joint effusions
- Diarrhea
- Anorexia
- Dry eyes and mouth (Sjögren's syndrome)
- Coma and Death!!!!!
Effects of too much Vitamin C
A lot of talk is made about overdosing on vitamins and whilst keeping a firm eye on ones dietary intake is very important for a variety of foodstuffs (including many of the fat-soluble vitamins) concerning yourself about overdosing on Vitamin C should not overly occupy your mind. Ascorbic acid is basically non-toxic. It is a water-soluble vitamin and therefore any access amounts that enter the system are simply excreted.
You should be careful however not to go ridiculously overboard with your Vitamin C intake. A daily dosage of 200 milligrams is just about enough to saturate plasma and lymphocyte levels. The recommended daily intake of Vitamin C in adult non-smokers is 90 mg for men and 75 mg for woman. For smoking adults the RDA's are a little higher - 125 mg per day for a man and 110 mg for a woman. If an individual takes in more than about 200 mg of Vitamin C per day, then temporary conditions such as stomach aches and diarrhoea may result.
Anti-aging effects of Vitamin C
A study was conducted by the London School of Hygiene and Tropical Medicine on the affects of differing levels of Vitamin C in older people. The study involved 1214 individuals aged between 75 and 84 and was followed up over a 4 year period. Samples of vitamin C (ascorbate), vitamin E, vitamin A (retinol) and beta-carotene were taken and detailed questionnaires of dietary habits were also completed by the participants of the study.
The research showed that ascorbate concentrations in the subjects decreased markedly over the course of the study. This indicates that Vitamin C levels naturally reduce as we age. More significantly, the subjects with the highest concentrations of ascorbate (greater than 66 micromol/L) had on average half the risk of dying over the 4 year period compared with those with the lowest levels (less than 17 micromol/L). Also significant here was the fact that the levels of the other tested antioxidants did not seem to correlate with mortality.
For further information on how vitamin C levels in the elderly affect longevity visit http://www.medscape.com/viewarticle/464048
Vitamin C and Cancer
There is a famous study conducted by the researchers Linus Pauling and Ewan Cameron that was published in the early 1970’s. This study compared 100 advanced cancer patients who were treated daily with 10, 000 milligrams of vitamin C with 1000 patients treated by other doctors, whose records were taken from the same hospital. This study showed that the patients treated with the vitamin C survived three to four times longer than those who did not receive this treatment.
This sounds very definite, which is why even today this study is often quoted when trying to push the virtues of vitamin C. Unfortunately however, the story does not end there. The study was not performed in the conventional manner. Usually in this type of study two groups are chosen randomly and treated using pre-defined protocols to give statistically accurate results. In this study however guesses where made on how the control group was treated based on other doctors records. In fact other studies conducted in later years showed no correlation between vitamin C intake and the survival rates of cancer patients. For example the 1978 Mayo Clinic study that was conducted using double-blind methodology and using the same doctors to monitor patients who were given vitamin C and those given a placebo showed that Vitamin C intake had no affect on the survival rate of cancer patients.
In conclusion, vitamin C as a treatment for cancer has so far not been proven.
Vitamin C as an antioxidant
There has recently been some debate as to the status of vitamin C as an antioxidant. One study reported in Nature showed that in some situations this vitamin can function as a pro-oxidant. However most research currently shows vitamin C as a substance that benefits health generally whilst functioning as an antioxidant. It has been found that vitamin C as an aqueous antioxidant can function to scavenge aqueous peroxyl radicals before they have a change to damage lipids (such as those present in cellular membranes and the membranes of Mitochondria).
To comment on vitamin C as as antioxidant or it's role in health and aging, click on this link Discussion
Mark S D'Arcy
Vitamin A
Vitamin A is not taken into the human body in a form that it can be utilised effectively in. It is instead taken into the body in precursor forms and is then converted into Retinol and then to either Retinoic acid or Retinal. It is these forms of vitamin A that are then used by the body. The antioxidant properties of vitamin A have been widely publicised, as to have the damaging affects of overdosing on this vitamin. I will now begin the discussion of vitamin A as an antioxidant with a couple of definitions.
Definition of Retinol
Retinol is the dietary form of vitamin A and can be defined as a fat-soluble antioxidant. It is important in both bone growth and also in vision. We ingest vitamin A in two forms. In plants such as carrots and spinach, vitamin A is absorbed in the form of compounds known as carotenoids (precursors of vitamin A known as Provitamin A). From animals, we obtain vitamin A in the shape of retinoids (retinol, retinal and retinoic acid). Vitamin A activity is always measured in relation to retinol. Retinol can either be reversibly oxidized to retinal or irreversibly oxidized to retinoic acid.
The Molecular structure of Retinol
Definition of Carotene
Carotene is an orange photosynthetic pigment known as a terpene. It is a dimer of vitamin A and can be found in several forms, including α and β-carotene. These two forms of carotene are sometimes known as provitamin A carotenoids. Excess carotene is stored in the liver and in subcutaneous fat and unlike retinol, it is non-toxic. The α and β-carotene is converted to retinol when it is needed by the tissues of the body. Note that this is done primarily by the tissues of the intestines and the lungs.
One thing to mention here is that of the approximately 600 carotenoids that have so far been identified in nature, 90% of them have been found not to be precursors of vitamin A. Many of them have however been found to be powerful antioxidants.
Absorption and transportation of retinol
Retinoids are absorbed through the intestines and are then incorporated into structures known as chylomicrons (note that as vitamin A is a fat soluble vitamin, it must be ingested with fat for it to be absorbed correctly). These chylomicrons first incorporate the retinoids in their ester form. They then mediate the transportation of this form of vitamin A to the liver, where it is stored in the hepatocytes (liver cells) until it is required. When the retinol is needed by the body, it is de-esterified and released in its alcohol form into the blood stream. Retinol then binds to retinol binding protein (present in the blood stream) and is transported in this form to the target tissues. Note that retinol binding protein synthesis is dependant on zinc. Once this compound reaches the target cells a complex known as cellular retinoic acid binding protein then stores and transports the retinoic acid intracellularly.
General functions of Vitamin A in the body
Vitamin A (80% of which is found in the liver) plays a part in a number of processes in the human body. Some effects of vitamin A are positive, but in some cases they can be negative (see below). Note that the requirement for retinol in adult humans is between 500 and 1000 micrograms per day.
General Effects of vitamin A on the body
- In the form of retinal, vitamin A plays an important role in vision. In the retina of the eye, retinal is attached to opsin, resulting in the formation of rhodopsin. Rhodopsin reacts with light, which then causes an amplifying chain of events, leading eventually to cGMP production and a signalling via the optic nerve. Normal vision is therefore dependent on an adequate supply of vitamin A
- In the cells themselves, vitamin A is important as a transcription factor. Cellular binding proteins form a complex with vitamin A and then bind to DNA. This triggers the transcription of important growth factors. This mechanism is particularly important in epithelial cells, where this hormone-like process is the primary controller of cell differentiation, growth and shape
- Vitamin A has been found to offer some protection against chemical induced lipid peroxidation in the heart
Effects of reduced levels of vitamin A
- Nyctalopia (night blindness) can occur if retinal is not made available to the eye for the formation of rhodopsin
- Keratinization of epithelial cells resulting in a condition called follicular hyperkeratosis can result from vitamin A deficiency
- Increased risk of infection
- Impaired wound healing
- Abnormal skeletal development in children
- Vitamin A deficiency has also been observed to result in oxidative damage to the mitochondria in the livers of rats
Note that a deficiency in vitamin E may lead to a reduction of the availability of retinol as retinol then becomes more susceptible to oxidation. A deficiency in either zinc, protein or iron can also result in the symptoms of retinol deficiency due to the negative affects on retinol plasma transportation and the release of retinol from the cells of the liver.
Effects of too much vitamin A
- In severe cases of vitamin A toxicity, a patient may exhibit hydrocephalus (an increase in the amount of cerebrospinal fluid in the brain)
- Vomiting
- Tiredness
- Constipation
- Headaches
- Hair loss
- Brittle nails
- Bone pain
- Note that if a mother ingests too much vitamin A during pregnancy, then the foetus may develop abnormally
When provided as a supplement, the maximum safe level of retinol ingestion is 3, 000 micrograms per day. Note that the consumption of high doses of carotinoids does not have the same toxic effects as the consumption of high doses of retinol. This is due to the fact that the efficiency of carotinoid absorption decreases with increasing doses. Also the rate of conversion into a more toxic form of vitamin A is too slow to contribute massively to overall vitamin A toxicity.
Anti-aging effects of Vitamin A
Vitamin A has been associated with many beneficial affects in the human body (as discussed previously). Most of the protective affects of vitamin A are however to do with the part that it plays in such processes as immunity, bone growth, reproduction and cell differentiation. All very important functions. Pro vitamin A substances such as the carotenoids have however been shown to have very potent anti-oxidant and possibly anti-aging affects.
Beta carotene more specifically is a particularly potent anti-oxidant. Just a single molecule of beta carotene can neutralise up to 1000 free radicals. Beta carotene has also been shown through experimentation to offer some protection against such conditions as heart disease and cancer. This is perhaps due to its free radical scavenging activities. By mopping up free radicals, it could after all reduce the accumulative damage to cell membranes and DNA. Although Beta carotene does also stimulate the immune system, which may also help to explain its general affects on health.
A number of population studies have shown that lower dietary levels of beta carotene can increase the risk of developing cancer later in life, particularly lung cancer! Other cancers have also been associated (although evidence is less strong) with reduced levels of beta carotene. These include breast, prostate, colorectal, ovarian and cervical cancers.
One notable study was conducted by The Western Electric Company in the US. This study monitored the dietary intake of a number of nutrients amongst approximately 1, 500 men through the 1950’s. In this study, it was shown that the men who had higher intakes of beta carotene had correspondingly lower rates of cancer and cardiovascular disease.
One other study worthy of mention involves more than 120, 000 female US nurses. This study has shown that woman who take in higher levels of beta carotene show a significantly lower risk of cardiovascular disease.
All in all Vitamin A has been shown to be very beneficial in the correct amounts and the Pro Vitamin caroteniods (particularly beta carotene) have been shown to be very conducive to a healthy life in a number of seperate studies. These substances may in fact help to retard the aging processes by a combination of mopping up free radicals and by bolstering up the immune system!
To comment on vitamin A as as antioxidant or it's role in health and aging, click on this link Discussion
Mark S D'Arcy
Antioxidants
This section of the website is devoted to the subject of Antioxidants. A subject that is far more complex than most people are initially aware of. Antioxidants are an extremely hot topic. A topic, which is it seems forever being written about in both the scientific and the popular press. The role of antioxidants has been publicised as the key to the fountain of youth by every dietician and health guru out there. This is mainly due to a number of positive studies, which were conducted primarily with Vitamin A (Retinol or Carotene), Vitamin C and Vitamin E. Not to mention research into the intracellular antioxidants Glutathione Peroxidase, Superoxide Dismutase and Catalase.
A great deal of the observed affects of antioxidants in vitro have however been difficult to reproduce in vivo. Despite this however, antioxidants remain extremely important in longevity research. This is because, despite a number of non-conclusive results from experimentation with antioxidants, they have nonetheless been proven to be the primary mechanism for mopping up the highly damaging free radicals that are produced as a by-product of cellular metabolism. These Free radicals (as discussed in other sections of this site) attack the organs and tissues of the body at a cellular and molecular level. This includes attacking and oxidising the DNA of the chromosomes and the mitochondrial DNA (mtDNA).
In the sub-sections of this area of the site, I intend to outline the antioxidants that are the major players in the prevention of free radical accumulation and damage. I will begin each sub-section with a definition of the antioxidant being discussed and its mechanisms of action. I will then outline some of the current research and experimentation that involves that antioxidant.
So now, as in other areas of the site, let’s throw forward a definition.
Definition of an Antioxidant
Antioxidant – substance that inhibits oxidation or inhibits reactions promoted by oxygen or peroxides.
More specifically, an antioxidant is a chemical that prevents the oxidation of other chemicals. In biological systems, the normal processes of oxidation (plus a minor contribution from ionizing radiation) produce highly reactive free radicals. These can readily react with and damage other molecules: in some cases the body uses this to fight infection. In other cases, the damage may be to the body’s own cells. The presence of extremely easily oxidisable compounds in the system can “mop up” free radicals before they damage other essential molecules. http://dictionary.laborlawtalk.com/antioxidant
Mark S D'Arcy
Free Radical damage to Cells
A lot is spoken and written about free radicals and their aging affects on cells, tissues and organisms. This is a very public discussion, which has resulted in the popularity of antioxidants as a food supplement (something that I discuss further in other sections of this site). Some of what has become common knowledge on the subject is simply hearsay and a lot more is guesswork. I will attempt in this section of the site to outline exactly what a free radical is and how exactly it affects the aging and longevity of a cell and ultimately the organism to which the cell belongs.
Definition of a Radical
In chemistry, radicals (often referred to as free radicals) are atomic or molecular species with unpaired electrons on an otherwise open shell configuration. These unpaired electrons are usually highly reactive, so radicals are likely to take part in chemical reactions. Radicals play an important role in combustion, atmospheric chemistry, polymerization, plasma chemistry, biochemistry, and many other chemical processes, including human physiology. For example, superoxide and nitric oxide regulate many biological processes, such as controlling vascular tone. "Radical" and "Free Radical" are frequently used interchangeably, however a radical may be trapped within a solvent cage or be otherwise bound. http://en.wikipedia.org/wiki/Radical_(chemistry)
Basic Free Radical Terminology
Before outlining exactly how a Free Radical goes about damaging cellular organelles, proteins and DNA, I need to first define the three distinct processes that free radical reactions tend to be grouped into.
- Initiation Reactions. An Initiation reaction is one in which the net number of free radicals increases. This may involve the creation of free radicals from a stable species or it may involve the creation of free radicals by means of a reaction between a free radical and a stable species.
- Propagation Reactions. A Propagation reaction is one in which the overall number of free radicals stays the same as it previously was.
- Termination Reactions. Finally a Termination reaction is one in which there is a net decrease in the overall number of free radicals. This commonly occurs when two free radicals combine, resulting in the formation of a more stable species. An example would be 2Cl·→ Cl2 (note that the dot after the 2Cl is the means of denoting free radicals in a chemical reaction).
Benefits of Free radicals
Free radicals are mainly discussed in relation to the detrimental effects that they have on cells and organisms. In biology, free radicals do however have their uses. Without them in fact there would be all sorts of problems. Free radicals for example are used by the cells for several important reasons:
- In the cellular organelle known as the lysosome, free radicals are used to break down other cellular organelles that have become damaged.
- Lysosomes also use free radicals to cause cell suicide or Apoptosis by breaking down all cellular components.
- Lysosomes also use there free radicals to destroy bacteria, which have become engulfed by the white blood cells that are known as Neutrophils.
- In phagocytes (cells that engulf material and bacteria) superoxide is produced in great quantities by the enzyme NADPH oxidase. This free radical is then used to destroy the material and pathogens that the cell has injested.
- They may also play a part in some cell signalling processes.
Drawbacks of Free Radicals
What is probably of interest to the reader here are the damaging affects of free radicals. These are after all involved in a number of conditions, including that of aging itself. The two most relevant oxygen-centred free radicals are the hydroxyl (OH) and superoxide (HO2) radicals. Superoxide is produced by the enzyme NADPH oxidase and also as a by-product of mitochondrial respiration. Hydroxyl can be produced due to the affects of superoxide.
Basically superoxide has the ability to inactivate iron-sulphur cluster containing enzymes, which are essential in a large variety of metabolic pathways. This results in the release of free iron into the cell. Fe2+ iron is a reducing agent and can react with hydrogen peroxide (H2O2) to produce hydroxyl. Together with other free radicals, their many effects on the body are:
- To cause diseases such as cancer by damaging the DNA of certain genes. These mutations can gradually cause a cells behaviour to change and for it to eventually become malignant.
- Atherosclerosis (one major disease of the aged) is also thought to be attributed to free radical induced oxidation of a variety of chemicals that make up the body.
- Parkinson’s and Alzheimer’s disease have also been linked to damage induced by free radicals.
- Finally the multiple affects of aging, from damage to DNA, RNA, proteins, to arterial and general tissue damage, not to mention damage to cell membranes, have all been linked to free radicals.
Free radicals are produced during the cells natural process of respiration (utilisation of our cells energy). A cell uses the energy that we gather from our food to manufacture a molecule called Adenosine Triphosphate (ATP) from Adenosine Monophosphate (AMP) and Adenosine Diphosphate (ADP). This ATP molecule is then broken back down to AMP and ADP to make its energy available for all sorts of intracellular processes. During the process of respiration free radicals are generated. These radicals by definition are molecules which lack a full complement of paired electrons. They therefore are prone to stealing electrons from other molecules. Molecules which have a weaker hold of their own paired electrons.
This process obviously damages the donor molecule and also as a result of the oxidised molecule losing its full compliment of electrons, causes it also to become a free radical. This process goes on and if it were left unchecked, would soon result in massive damage to the cell.
Free radicals have a particularly damaging affect on the unsaturated lipid molecules that make up the cell membranes. Lipid peroxidation is the hardening of cellular membranes and is one consequence of free radical damage. As you can imagine, if a cell wall becomes hardened, then it will make it difficult or sometimes impossible for that cell to be able to absorb nutrients, receive signals from the cells that surround it or to perform a variety of other functions that are dependent on the fluidity of the cell membrane.
The primary site of free radical damage is the DNA of the cellular organelle known as the mitochondria. It is in the mitochondria that oxidative cellular respiration takes place. These organelles are therefore exposed to a great deal of free radical activity and consequently suffer the most damage. The main problem is that the DNA that we find in mitochondria (mitochondrial DNA or mtDNA) does not benefit from the DNA repair mechanisms that are present in the nucleus of the cell and which help to minimise the free radical damage to nuclear DNA. Mitochondria therefore gradually become more and more damaged and therefore are less able to produce the energy that the cell needs to function. This eventually results in a cell shutting down or dying.
To summarise.
Free radicals are generated naturally in the body as a normal part of respiration and cellular metabolism. They offer some benefits to the organism, however their production also causes a lot of damage and may ultimately result in the aging and eventual death of the cell. In the section of the site on Antioxidants, I outline the mechanisms that are used to mange free radicals and to ultimately transform them into more stable species that no longer have the ability to damage the cell.
Mark S D'Arcy