Antioxidants and Aging

Oxygen is a poison! A startling statement, but a true one. It is, of course, also a vital necessity for us and most living creatures. This presents both a paradox and a challenge since we are obliged to live with its presence despite it posing a major threat to our lives. Our processes of metabolism in the presence of oxygen lead to the production of extremely hostile and damaging entities, molecules or fragments of molecules, which contain unpaired electrons – namely the free radicals that I have already mentioned.


Drs Elmer Cranton and James Frackelton describe them, in an article entitled ‘Free Radical Pathology in Age Related Diseases’ published in The Journal of Holistic Medicine (1984 6(1)) as follows: ‘Every free radical has an unpaired electron in an outer orbit, causing it to be highly unstable and to react almost instantaneously with any substance in its vicinity. These reactions often cause a cascade of new free radicals in a multiplying (chain-reaction) effect.’ It is such free radical activity which allows high level radiation to damage and kill, as the rays (gamma, X, ultraviolet, cosmic etc.) knock electrons out of orbiting pairs, thus producing free radicals.


Radiation is one extreme of the range of this phenomenon, although some scientists describe the damage free radicals cause to cells in everyday life as ‘continuous internal radiation’. Surprisingly perhaps, a good deal of free radical activity is produced by the body itself for specific purposes (killing bacteria
for example and in detoxification processes). This phenomenon can therefore be considered to be ‘controlled internal radiation’. Oxygen in its everyday form is an amazing substance which can either generate free radicals or can help to switch them off. As Cranton and Frackelton explain it:

A liter of normal atmospheric air on a sunny day will contain over one billion hydroxyl free radicals, whereas oxygen at normal physiological concentrations in living tissues neutralizes more free radicals than it produces. When oxygen levels are reduced (low), as occurs in ischemic tissues (lacking good blood supply and therefore poorly oxygenated) oxygen becomes a net contributor of free radical damage.


Some oxygen processes are more likely to produce large quantities of free radicals than others, and it is when there is either too much or too little oxygen present in a metabolic reaction that the worst situations arise. Evolutionary processes have fortunately helped to ensure that we can survive in an oxygen environment through the provision of an army of substances which protect us, with healthy body cells producing and/or using over a dozen antioxidant control substances.


What free radicals do

If cellular damage is a cause of ageing, and if we can slow down that damage, it makes sense to think that ageing can be retarded. For example, when free radical activity is taking place, damage to cells occurs, protein synthesis becomes impaired, proteins become cross-linked and tangled, tissues become less pliable, arteries incur damage leading to atherosclerosis, genetic material (DNA/RNA) is damaged leading to possible cancer development and to inefficient repair processes, age pigments accumulate which literally drown the cells in lipofuscin, preventing them from functioning, and in general all the signs and indications of ageing are promoted, whether this is stiffness, poor circulation or wrinkles (cross-linkage), not to mention diseases such as atherosclerosis, arthritis, cancer and, it is now believed, Alzheimer’s disease.


Professor Alan Hipkiss, of King’s College, University of
London, writing in Human Ageing and Later Life (edited by Anthony Warnes and published by Edward Arnold, London, 1989) tells us that free radicals are also responsible for the damage which occurs in cataracts due to cross-linkage of proteins, and he says: ‘Oxygen free radicals can also damage DNA which, if it is not repaired, could give rise to altered, mutant proteins.’


Some free radical activity is actually essential for good healthy functioning. For example, when certain of our immune functions are operating, say when white blood cells are attacking and deactivating invading micro-organisms (bacteria, viruses, fungi etc.) they generate free radicals in order to do their job. It should not be surprising to discover, therefore, that in the face of the flood of free radicals produced both by normal metabolism and other functions of the body, as well as those received from outside the body (radiation, low level radiation, cigarette smoke, environmental pollution, alcohol and many other ‘contributors’) our bodies have, of necessity, had to find ways of coping.


Can ageing due to free radicals be slowed down?

Professor Hipkiss is not sure. He says:

Ageing may be inevitable in complex organisms; indeed it is surprising that we live so long given the multiplicity of insults to which our cells are continuously subjected. Only homoeostatic mechanisms (self-repairing, self-balancing, including antioxidant functions) enable our survival. Maybe, if we wish either to live longer or to resist the ravages of time, we should design further homoeostatic systems to repair our repair systems.


Doctors Cranton and Frackelton dramatically underline the importance of dealing with free radicals:

When free radicals in living tissues exceed safe levels, the result is cell destruction, malignant mutation, tumor growth, damage to enzymes and inflammations, which manifest clinically as age-related, chronic degenerative diseases. Each uncontrolled free radical has the potential to multiply a
million-fold. But, when functioning properly, our antioxidant systems suppress excessive free radical reactions.


They point out that the life expectancy of mammals (such as ourselves) is in direct proportion to the free radical control enzymes, like superoxide dismutase. The use of antioxidant and dietary restriction approaches would seem to be able to boost and enhance antioxidant activity, given the evidence accumulated to date. We are literally repairing the repair system (or allowing it to repair itself) when we fast or modify what is eaten in the manner suggested by Drs Weindruch and Walford’s experiments. The question seems not only to be whether such repairs influence life expectancy rather than health, but also what are the best ways of achieving this end?


Since Dr Denham Harman of the University of Nebraska first proposed that free radicals were the keys to ageing, as far back as the mid-1950s, the study of ageing has spent much time examining the possibilities of slowing down both free radical damage and ageing. Recently, however, although the theory still looks accurate in many respects, some doubts have begun to be cast on just how antioxidant activity at cellular level can be achieved. Our self-produced defense against free radicals comes in the form of substances which literally sacrifice themselves so that the rogue free radical molecules are mopped up, thus preventing their ability to latch onto electrons in healthy tissues, and damaging or altering them in the process.


Amazing substances

Our bodies have evolved defensive substances such as the enzyme catalyst which can deactivate hydrogen peroxide (bleach), one of the substances our immune system uses in its own attacks on unwelcome, invading, micro-organisms. Catalase and other antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase, are also present as defenders of body tissues against oxidative processes. These enzymes are dependent upon a number of trace elements and vitamins (mainly of the B-complex group) for their function, including copper, zinc and manganese (for SOD), selenium (for glutathione peroxidase) and iron (for catalase).


There are also non-enzyme free radical deactivators, some of which are literally consumed in their battle against radicals, including beta carotene (the precursor of vitamin A),vitamins E and C, amino acids glutathione, methionine and cysteine, and the mineral selenium which is symbiotically active with vitamin E.


A surprise defender

One of the more surprising antioxidants, which we produce in our own cells, is cholesterol. This substance helps protect the cell membrane against free radical damage, as well as itself being a precursor of vitamin D. Vitamin D is formed by the body, from cholesterol in the skin, in response to radiation from sunlight (ultraviolet light). When too much vitamin D is formed in some tissues this attracts the deposition of calcium into cells in the region, in turn interfering with normal cell transportation functions and energy production.


The health benefits which have been seen as a result of reducing cholesterol in the diet seem to be a result of a coincidental reduction in fat intake, which reduces free radical potential (fats peroxidize easily under free radical attack.) However, use of drugs which reduce cholesterol levels in the blood (nine-tenths of which is self-produced rather than result of the food we eat) have had a history of side-effects, mainly because of the failure to recognize the protection cholesterol gives us as an antioxidant.


Another extremely powerful antioxidant, universally present in the system, is uric acid, which, although toxic in excess, is easily metabolized by the body if adequate nutritional levels of vitamin C are present.


What about ageing?

Now, since we know that antioxidants can slow down or switch off free radical activity, should it not be the case that ageing automatically slowed down when these are supplied in increased quantities? Weindruch and Walford are not sure, saying that feeding antioxidants to animals has so far failed to demonstrate increase in life span (this statement has been challenged, see below They suggest that the ‘excuses’ which believers in oxidant nutrition offer for this failure are that the antioxidants given to the experimental animals may not be able to penetrate he sites of free radical activity in the cells, or that the body adjusts its own production of natural antioxidants downwards when these are supplemented in the diet, so that no net gain is seenin antioxidant activity (and therefore no improvement in terms of lessened damage or life expectancy). The second ‘excuse’ come at least partially accurate. As mentioned previously, we come equipped with a wide array of self-repair and protection mechanisms including an assortment of antioxidant enzymes which quench free radicals.


Evidence

Richard Cutler of the National Institute of Aging in the US , studied more than 20 species, including rats and humans. In cases those that live longest have the highest and most active levels of antioxidant enzymes which literally soak up free radical activity (remember a squeeze of lemon juice on a browning apple, rust-proofing metal?). However, some studies show that when antioxidants such as vitamin A are provided, cells respond by reducing their own production of antioxidants, allowing the same amount of free radical activity to continue. This does not stand as absolute proof that antioxidant methods are not going to work, but certainly puts a question mark on just how this can best be achieved, and I tackle this later in the book.


One argument against free radical damage being a major cause ageing is based on the fact that the ageing process seems to a well-organized progression, whereas the damage cause by e radicals appears more chaotic and random. So, although it might well be that most if not all the major diseases of old age have roots which link them to free radical damage, this does not necessarily connect ageing itself to the activity of free radicals, only to poor health.


Genetics again

There is also the argument that when a certain degree of damage has taken place on a cellular level, a preprogrammed, genetically based process might be called into play, a sort of ‘self-destruct button’ having been pressed. Just when this happens will depend upon the degree of damage caused by free radicals (or other factors), which are themselves to a large extent the product of the rate at which metabolic activity is going on, which takes us back to the ‘thrifty’ and ‘burner’ types described by Weindruch and Walford.


As I explain in Chapter 9, there is much evidence to support the importance, in the delaying of ageing, of lowering internal temperature levels, which naturally enough means slowing down metabolic processes. When metabolic processes are slower, free radical activity slows down, and ageing is delayed. Once again we see the interconnection between one aspect of the picture with another – slow metabolism, leading to less free radical damage, leading to less cellular damage and disease, leading to lesser likelihood of programmed obsolescence via the genes being triggered.


The idea that a genetic programme exists which decides that enough is enough, and that ageing should be accelerated is not completely fanciful, as it fits into some of the evolutionary concepts which I have previously talked about. It is quite certain that antioxidant techniques can lead to a reduction in oxidation damage caused by free radicals, resulting in improved health (both in animals and humans). It is also reasonably certain that youthful qualities can be generated by such an approach, but what remains very unclear is whether this would have any noticeable impact on life expectancy.


Can anti-free radical approaches lengthen life?

Over the years, three approaches to ‘using’ the understanding of free radical activity for promotion of life extension have been suggested:


  1. Employment (in the diet) of free radical deactivators (antioxidants) such as vitamins A, C, E, and B6; minerals zinc and selenium; amino acids cysteine, methionine and glutathione, as well as enzymes such as SOD and catalase (which are now known to survive the bodys digestion process and to be able to increase tissue levels when supplemented in certain forms, such as freeze-dried wheat grass juice). Some (e.g. Pearson and Shaw) also recommend the use of artificial substances such as BHT in this quest (see below).


  2. Reduction in the diet, as far as is possible, of foods and substances which add to the free radical burden, including polyunsaturated fats and metals such as copper. A logical extension of this sort of tactic would be to avoid wherever possible exposure to environmental pollution, whether in the workplace or at home, as well as curbing lifestyle habits which might add to the burden (smoking and alcohol consumption, for example).


  3. Dietary restriction, which reduces metabolic rate, and therefore free radical activity, as well as actually increasing the presence of some of the most important antioxidants. Some experts suggest that one of the main reasons why dietary restriction actually increases life span is its effect on free radicals.


Some of these approaches might seem to be more health
enhancing than life span extending, but it is almost impossible to distinguish which is which. It seems, therefore, that there is no good reason for not trying to include all three elements of this approach, and I deal with this in greater detail in the section on strategies.


Antioxidants and life span increase

Durk Pearson and Sandy Shaw (in their book Life Extension)
quote the work of Dr Denham Harman, who looked at increasing
life span by using artificial antioxidants such as BHT (butylated
hydroxy-toluene) a substance frequently used as a food additive
to protect against spoilage (commonly by free radical activity).
BHT was shown by Dr Harman to increase the life spans of mice,
initially in those which normally had a short life span due to the
spontaneous development of cancer. Critics of this type of evidence for life extension by use of antioxidants suggest that it is only the prevention of cancer which lengthened’ the lives of these animals, which in any case did not exceed the norm for the species. Dr Harman has subsequently also produced evidence of life extension in normally long-lived, non-tumour generating mice, using BHT.


A variety of other experiments on mice, chickens and other creatures hint at life span being extended by use of antioxidant nutrition. For example, a report from the Department of Biochemistry, University of Louisville School of Medicine (Proceedings of Society of Experimental Biology and Medicine (1986 183(1):81-5) by Drs J. Richie, B. Mills and C. Lang showed that the use of a powerful artificial antioxidant nordihydroguaiaretic acid (NDGA) could increase the life spans of insects by between 42 and 64 per cent. NDGA was either added to the medium in which larvae developed or to adult mosquito diets (involving different ages and sexes). Young adults and active larvae were the best responders. The researchers make the point that this evidence is important since it demonstrates life extension without dietary restriction.


Why mosquitoes, and do results such as this mean anything in human terms?

Insects have a short life expectancy, and experiments can be conducted which do not have to be spread over many months or years (even mice experiments on life extension take years). They do have implications for humans since, as has been demonstrated by so many researchers into dietary restriction, the effects are found in ALL species tested to date. If life extension is achieved in mosquitoes using dietary restriction, and if it is also achieved using antioxidant nutrition, we can read into this the implication that it would probably help us as well.


Pearson and Shaw quote numerous studies which support the idea of antioxidant supplementation helping health and longevity, however much of this seems (as in the report on the mosquitoes) to involve synthetic substances. For example, they
quote studies by Dr Harman involving mice in which senile changes were prevented by use of synthetic antioxidants such as Santoquin, commonly used as a stabilizer in commercial chicken feed, and found to have an unexpected bonus in that it seems to keep chickens laying longer by slowing their ageing processes. As well as retarding the senile changes, this substance also increased the life spans of the mice by between 30 and 45 per cent – equivalent, Pearson and Shaw tell us, to a human life span of 100 years. What that really amounts to is not life extension (since our true life expectancy is around 120) but a definite improvement on our present average life span.


This artificial antioxidant acts, according to Pearson and Shaw, ‘in all metabolic functions’ exactly like vitamin E, one of the most powerful of all antioxidants. It is tempting to ask why vitamin E is not therefore used in chicken feed? One answer might be that there is no patent on vitamin E and therefore there would be little commercial advantage to the company producing and marketing this feed additive, since anyone else could simply copy the product. A less cynical answer might be that when the body receives a quantity of an antioxidant which it should be producing for itself, there may occur an automatic reduction in its own production, leaving a no-gain situation in terms of potential for deactivating free radicals (as seen in the supplementation of vitamin A).


Could it be that the body does not recognize the artificial antioxidants as readily as it might recognize materials which are part of its normal everyday economy, such as vitamins A and E? And that it then continues to manufacture its own antioxidants which work alongside the artificial ones to keep free radical activity low?


Weindruch and Walford’s views

When animals are placed on dietary restriction programmes there seems to be a ‘selective’ improvement in levels of certain antioxidants and not of others. For example, no change is seen in levels of production of superoxide dismutase or glutathione peroxidase, two of our most potent free radical fighters, when restricted diets are followed. However, there is a significant
increase in levels of catalase with dietary restriction, especially in the liver and kidneys, and interestingly one of the signs of ageing is a marked lessening of catalase activity in these organs. Weindruch and Walford have now clearly demonstrated that an average of 50 per cent improvement in catalase activity occurs during dietary restriction. They caution that, in their opinion, other systems and effects divorced from free radical activity theories are the main factors in ageing. However, it remains clear that dietary restriction influences important aspects of the body’s ability to cope with free radicals, and it is hard to see how this cannot but be significant, bearing in mind the importance of the damage free radicals can cause.


In the section on strategies I give guidelines for modifying or preventing free radical activity. This will involve diet, supplementation of specific nutrients, moderation of lifestyle habits and exercise, as well as other methods such as chelation therapy which have been found to have marked and beneficial effects on free radical activity.


What about natural vitamins?

I said early in this chapter that supplementation of artificial antioxidants seems to offer cell protection and some life extension potential. I also mentioned that when some nutrients are supplemented, such as pro-vitamin A (beta carotene) the tissues may be induced to synthesize or produce lower levels of other antioxidants, thus leaving the overall level of free radical fighters much the same as before supplementation. There is, however, much evidence that disappointing results such as this are not universal, even when the supplemented vitamins and other nutrients are not synthetic.


Background

Professor B. Ames of the Department of Chemistry, University of California, Berkeley, has stated that there exists a growing amount of evidence which shows that ageing, cancer, heart disease and other degenerative diseases are mainly due
damage caused to cells by lipid peroxidation, including their DNA (Science (1983 221:1256-64)). Such peroxidation is, as we know, caused by free radicals which in turn are generated by a variety of factors including dietary fats, heavy metals (lead, cadmium) radiation, heavy exercise, increased metabolic rate, infectious or inflammatory processes and others, including deficiencies of antioxidants.


As Elmer Cranton MD states Journal of Holistic Medicine (1984 6(1):6-31)): ‘Research in senility, dementia, brain ischaemia, stroke, and spinal cord injury provides a wealth of evidence incriminating free radicals as a cause of nervous system disease, and also provides a rationale for treatment.’ He points out that the central nervous system not only contains the highest concentrations of fat of any organ, but that in good health it also contains vitamin C in concentrations 100 times greater than that found in most other tissues and organs of the body.


The concentrations of antioxidants in our tissues is, along with the level of free radicals active in those tissues, a key determining factor of length of life (as well, of course, as the level of health). An important function of vitamin C is protection of the central nervous system from peroxidative damage caused by free radical activity on fatty tissues.


Can antioxidants in the diet increase protection from free radicals?


  1. Dr E. Calebrese and colleagues examined the protective effect of vitamin E supplementation against exposure to ozone (commonly present in polluted air) which degrades to form hydrogen peroxide (bleach) one of the most potent of all free radical producers. In this study, 12 adult human volunteers were supplemented daily with 600iu of vitamin E for a month. Samples of their blood – taken before the study started, and after two weeks and then after four weeks of supplementation – were exposed to varying levels of ozone in order to test the amount of damage taking place to cells, with and without different degrees of supplemented vitamin E in the donors of the blood. When blood is exposed to ozone it forms a damage by-product called methaemoglobin. This byproduct was found in far lower levels during the second and fourth weeks of vitamin E supplementation, especially at the highest exposure to ozone.


  2. Much research confirms that as red blood cells reach the end of their useful life (as they age in fact) ‘markers’ appear on their surface (called ‘senescent cell antigens’) which alert defense mechanism cells (immunoglobulin-G auto-antibodies) to target them for removal from the circulatory system. A study was conducted in which red blood cells taken from vitamin E deficient rats were examined in relation to this whole phenomenon. The results showed that vitamin E deficiency caused premature ageing of the red blood cells and that this led to binding with the cells of the antibodies. The cells of vitamin E deficient animals – of all ages – were seen to behave in the same way as the red blood cells of old animals on normal diets. The researchers said: ‘Results of the experiments indicate that erythrocytes (red blood cells) from vitamin E deficient rats age prematurely, indicating that oxidation accelerates cellular ageing.’


  3. Dr A. Blackett, of the General Infirmary, University of Leeds, has studied the relationship between vitamin E levels and the accumulation of lipofuscin (the fat/protein substance-‘age pigment – associated with ageing) in mice Journal of Gerontology (1981 36:529-33)). Half the mice were supplemented with vitamin E and half were not, and it was found that the levels of vitamin E in the tissues of the supplemented animals rose by 400 per cent over the length of the study (two years) and that the supplemented mice had lower levels of lipofuscin throughout their lives. By the time they were 28 months old they had levels which were similar to non supplemented mice aged 23 months. If accumulation of age pigments is an indication of the rate of ageing, then this is clear evidence that the process is slowed by antioxidant supplementation. Unfortunately the study did not show any consistent increase in life span for the supplemented mice despite their ability to stay young longer. One argument against expecting any life extension for supplemented mice is that other factors, such as the content of their overall diet and levels of other antioxidants, were unchanged. Clearly, altering
    just one factor, as in this example of supplementing one antioxidant, while having health enhancing benefits, does not necessarily prolong life.


  4. A Japanese experiment involving rats showed that vitamin E deficient diets produced a faster rate of lipofuscin accumulation in cells than a diet with adequate vitamin E. Not only did the deficient animals age faster but when exposed to additional fatty toxins their aortas showed signs of tissue damage. This experiment, therefore, showed what is already widely assumed in human terms, that lipid peroxidation can be directly linked, not only to ageing, but also to the illnesses of ageing such as arterial damage, unless adequate antioxidants such as vitamin E are present (S. Hirai et al, Proceedings of the International Conference of Lipid Peroxides in Biological Medicine, Academic Press, New York, 1982).


  5. A Russian study involving rabbits showed what happened when they were fed a diet deficient in vitamins C and E as well as co-enzyme Q10 (all of these are powerful antioxidants present in a good balanced diet). All the rabbits on the deficient diet showed signs of advanced premature ageing within 50 to 100 days, suggesting (or rather confirming) a major contribution to the ageing process from free radical activity (O. Voskresenskii et al, ‘Chronic polyantioxidant insufficiency as a model for ageing’ Dokl. Akad. Nauk. USSR (1983) 268:470-3


  6. The activity of the important antioxidant enzyme glutathione peroxidase was found to be extremely poor in duckling tissues where selenium deficiency existed. In these same ducklings supplementation of vitamin E had no effect on improving glutathione peroxidase activity. This Chinese study teaches us several important things, including the strong link between vitamin E and selenium, in which a symbiotic relationship exists, both antioxidants being more powerful in their work when the other is present. However, when one is absent (as is common in parts of China where levels of selenium in the soil are particularly low, leading to a very high incidence of cancer and heart disease) vitamin E on its own cannot make up for selenium deficiency (G. Xu et al, British Journal of Nutrition (1983) 50:437-44).


  7. Doctors Porta, Joun and Nitta of the University of Hawaii at
    Manoa, Honolulu, studied the health and life span effects on rats of six different diets containing various types and levels of fats and antioxidants, with no dietary (calorie) restriction involved. The researchers make the very important point that while no overall life extension pattern was observed, whatever the diet, ‘the 50 per cent survival time of rats fed on safflower oil with high vitamin E supplementation was significantly longer than in all other groups’. This indicates that this particular group of animals stayed healthy and young longer than other groups who were receiving saturated fats (e.g. coconut oil) and low, or no, vitamin E supplementation (Henkel Corporation, Minnesota, Vitamin E Abstracts (1980) page 61).


  8. But does life span actually increase in animals on antioxidants? In research conducted at Charles University, Czechoslovakia, mice were studied for the effects on life span of a diet rich in sunflower oil (polyunsaturated oil) or on the same diet with vitamin E also being supplemented. Those mice recieving additional vitamin E ‘showed a slight prolongation of maximum life span’. Here we see evidence of some extension of life, using just one nutritional alteration, vitamin E supplementation, although the degree of extension of life was regarded as slight (M. Ledvina et al, Experimental Gerontology (1980) 15:67-71).


Conclusions

There can be very little doubt that antioxidants in the diet offer protection from many of the diseases of ageing, as well as from many of the signs of ageing (those which are caused by free radicals at any rate). There is, however, only limited evidence that antioxidants on their own have very much to offer towards actual life extension, although it would be folly to avoid supplementing to some extent as part of a natural life extension approach. Guidelines for their safe use are given in Chapter 14.


The recurrent theme of earlier chapters comes to the fore again, that dietary restriction is the key to the puzzle of natural life extension. Use of dietary restriction achieves antioxidant effects by two extremely important methods. It reduces free activity due to its effect of lowering rates of metabolic activity, and it enhances some of the antioxidant activity vital to life, notably the functional activity of catalase. As will be explained in Chapter 13, there exist other methods which can alter free radical activity, including the controversial method of chelation therapy, in which an artificial amino acid (EDTA) is infused into the system to leach out heavy metals which are thought to play such a large part in triggering free radical activity.


The subject of the next chapter is the connection between the lowering of core (inner body) temperature and reduced metabolic activity and its implications in the quest for increased life span.


Body Temperature and Life Extension

Leon Chaitow ND DO MRO Written by Leon Chaitow ND DO MRO

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