Antioxidants, Neurodegeneration, and Cancer

Research article. Interesting but lacking depth. Good balance on the issue of antioxidant supplementation.

The study can be downloaded here.

Article:
The role of antioxidant supplement in immune system, neoplastic, and
neurodegenerative disorders: a point of view for an assessment of the
risk/benefit profile
Authors:
Daria Brambilla, Cesare Mancuso,Mariagrazia Rita Scuderi,Paolo Bosco,Giuseppina Cantarella, Laurence Lempereur, Giulia Di Benedetto, Salvatore Pezzino, Renato Bernardini,
Journal: Nutrition Journal 2008, 7:29 doi:10.1186/1475-2891-7-29
Location: Life\Nutrition\title
Date obtained: 3/10/2008
Date Read: 19/10/2008
Date to Review:
Web Page:
Printed:
Notes:
Abstract
This review will discuss some issues related to the risk/benefit profile of the use of dietary antioxidants. Thus, recent progress regarding the potential benefit of dietary antioxidants in the treatment of chronic diseases with a special focus on immune system and neurodegenerative disorders will be discussed here. It is well established that reactive oxygen species (ROS) play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes and cancer. Among the physiological defense system of the cell, the relevance of antioxidant molecules, such as glutathione and vitamins is quite well established. Recently, the interest of researchers has, for example, been conveyed on antioxidant enzyme systems, such as the heme oxygenase/biliverdin reductase system, which appears modulated by dietary antioxidant molecules, including polyphenols and beta-carotene. These systems possibly counteract oxidative damage very efficiently and finally modulate the activity of oxidative phenomena occurring, for instance, during pathophysiological processes. Although evidence shows that antioxidant treatment results in cytoprotection, the potential clinical benefit deriving from both nutritional and supplemental antioxidants is still under wide debate. In this line, the inappropriate assumption of some lipophylic vitamins has been associated with increased incidence of cancer rather than with beneficial effects.
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However, several clinical studies demonstrated that not only malnutrition, but also the excess of certain nutrients (e.g. iron, alphatocopherol, beta-carotene, ascorbic acid) may set into motion oxidation phenomena and, therefore, cell injury [8,9]. Thus, it is of relevance that prior to considering introducing antioxidant therapy into mainstream medicine, significant advances in basic cell biology, pharmacology and clinical bioanalysis will be required.
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Heme oxygenase is a microsomal enzyme which metabolizes heme into ferrous iron, carbon monoxide and biliverdin (BV); the latter is then reduced by BVR into bilirubin (BR), a molecule endowed with strong antioxidant and antinitrosative activities [11-14]. Interestingly, all these protective factors act in a concerted way, enhancing the antioxidant defense system of the cell. When the balance between ROS/RNS and antioxidants turns in favor of the former, oxidative/nitrosative stress occurs.
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Extracellularly generated ROS can diffuse through anion channels into the cytoplasm; the resulting variation in the cell redox state leads to modulation of an array of transcription factors (eg. NF-kB, AP-1), protein kinases (e.g. AKT, JNK, p38), and receptor activated MAP kinases involved in apoptosis [17, 24,25,26]
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However, not only immune cell produce ROS necessary for the microbicidal activity, but they are also sensitive to external ROS, due to their high polyunsaturated fatty acids (PUFA) content. Immune cells are atypical, as compared with other somatic cells, in that they contain high levels of antioxidant vitamins, presumably providing protection against lipid peroxidation and immunosuppression, both of which are well known risks posed by high PUFA content [38].
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Intriguingly, the combined treatment with wheat germ and vitamin C profoundly inhibited metastasis formation in various tumor models of different origin (Lewis lung carcinoma, B16 melanoma and human colon carcinoma xenografts [HCR25]) [61].
61. Hidvégi M, Ráso E, Tömösközi-Farkas R, Paku S, Lapis K, Szende B: Effect of Avemar
and Avemar + vitamin C on tumor growth and metastasis in experimental animals.
Anticancer Res 1998, 18(4A): 2353-2358.
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Heme oxygenase-1, the inducible isoform of HO, is a key protein in the cell stress response and its up-regulation is a common event during pro-inflammatory conditions [11,69-72]. Recent work clearly demonstrated that regulatory T cells overexpress HO-1 and release CO under pro-oxidant conditions. Carbon monoxide may inhibit the proliferation of effector T cells, thus reducing the immune response and prevent autoimmunity and/or graft reaction [73,74]. Dietary antioxidants, in particular polyphenols, has been shown to increase HO-1 expression in different in vitro systems [3,75,76] and the potential use of this natural substances to regulate immune response should be carefully addressed.
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Other studies report that combination of vitamin A and other antioxidants, significantly increases mortality related to neoplastic diseases. [91]. According to these studies, selenium would be the only element displaying beneficial effects, as it has been shown that it reduces total cancer incidence, an apparently sex-related effect, as it is predominant among males, rather than in females [89].
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Due to their scarce bioavailability, only a negligible amount of polyphenols reaches brain tissue and the concentrations achieved are much lower than those efficacious in vitro [3]. As far as NSAIDs, ad hoc designed clinical trials with a large number of patients, clearly demonstrated that these drugs do not have any significant effect in slowing cognitive decline in patients suffering from mild-to-moderate AD [120,121].
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It is noteworthy to underlie that as for all drugs, antioxidants may give important side effects if not correctly used or in combination with other drugs. Vitamin A, E and â-carotene for instance, have been shown to have pro-oxidant effects at higher doses or under certain conditions [39].
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Exercise and Brain Aging

There is now abundant research pointing to the beneficial effects of aerobic exercise on cerebral health. This recent study finds that taking up exercise can improve cognition and cerebral health. There is a striking relationship between cardiovascular and cerebral health. The reason for this is obvious: the brain consumes approximately 20% of our oxygen intake, so maintaining maximal blood supply to the brain is critical. One of the reasons Ginkgo Biloba works is because it reduces platelet activating factor, thereby improving cerebral circulation.

Exercise and do it often. You don't have to run marathons, in fact intense exercise can do more harm than good. Light exercise is okay but it is important to push yourself, just going for a casual walk is good but going for a brisk walk is much better.

Exercise effects on cognitive and neural plasticity in older adults
Kirk Erickson and Arthur F Kramer
British Journal of Sports Medicine (2008).
The abstract:

Older adults frequently experience cognitive deficits accompanied by deterioration of brain tissue and function in a number of cortical and subcortical regions. Because of this common finding and the increasing aging population in many countries throughout the world, there is an increasing interest in assessing the possibility that partaking in or changing certain lifestyles could prevent or reverse cognitive and neural decay in older adults. In this review we critically evaluate and summarize the cross-sectional and longitudinal studies that assess the impact of aerobic exercise and fitness on cognitive performance, brain volume, and brain function in older adults with and without dementia. We argue that six-months of moderate levels of aerobic activity are sufficient to produce significant improvements in cognitive function with the most dramatic effects occurring on measures of executive control. These improvements are accompanied by altered brain activity measures and increases in prefrontal and temporal grey matter volume that translate into a more efficient and effective neural system.

Low antioxidant status and high sunlight exposure = Retinal Degeneration

I don't know if the below is a true statement because I have never heard it before but it does highlight why even blue light is damaging to vision. Lesson: obtain sunnies with blue light filtering capacity. Take it as high risk that by the time you reach 70 there is a distinct possibility you have some degree of cataract formation and retinal degeneration. The key is to contain the progress of these conditions as much as possible. That can be done but even with the best of care some of us are going to need cataract surgery and may develop AMD. Genes! In particular, a diet specifically addressing the oxidative balance in your blood is very important.

Most importantly control cholesterol, I have seen enough research to indicate that high cholesterol, particularly the small LDL variant (vLDL), readily penetrates the Retinal Pigment Epithelium and thus sets off unwanted cascades of nasties.

http://www.sciencedaily.com/releases/2008/10/081013171431.htm

... The eye is particularly vulnerable to the damaging effects of sunlight. Ultraviolet radiation is absorbed by the lens, but visible or “blue” light penetrates to the retina so allowing us to see. Protection against the harmful effects of blue light is provided by the antioxidant vitamins C and E, the carotenoids (lutein and zeaxanthin) which filter blue light, and zinc. --------

The Aging Brain

This study from the Neurobiology of Aging highlights the significance of white matter in the aging process of the brain. The news item can be read here. White matter is the extensive sheath that surrounds the long and not so long axons of nerve cells. The presence of white matter markedly improves the speed at which signals can traverse through long axons. The process of myelination is long and we can in our late 20's or even early 30's before this process is completed.



Myelin creation is not a one off event, it is subject to continual degradation and renewal. The cells that produce myeline are called oligodendrocytes, a type of glial cell. Unfortunately oligodendrocyte cells demonstrate some particular vulnerabilities to insult. In those with Multiple Sclerosis, a common autoimmune condition, the immune processes responds to various "danger signals" emitted by oligodendrocytes and this can establish an ongoing destruction of these cells and myelin production. The initial triggers for this condition remain unknown but there are a number of strategies that Multiple Sclerosis sufferers can undertake which may alleviate the progress of the condition.

As we age the balance between myelin degradation and renewal falls out of kilter, the result being that we start losing the myelin covering. Of interest is the association between dementias and changes in white matter, it may even be the case that in some individuals the destruction of myelin is so extensive as to initiate a series of inflammatory processes that in turn induce dementias.

There is an important lesson here. The brain controls the body, maximising cerebral health is critical to maintaining good health as we age.

Lipofuscin And Aging

Lipofuscin is the deposition of waste products in the cell that are not degraded. The critical factor seems to be rate at which proteins and lipids are degraded by the various "house keeping" functions in the cell. In these days the emphasis on the dynamics of aging is typically excessive oxidation events and lipofuscin receives little attention. Lipofuscin is something that needs to be addressed because as lipofuscin deposits increase the cell becomes increasingly unable to do its job.

In the graphic below I have extracted a table from a very old study. It highlights the huge increase in lipofuscin aggregation with age. They used acetyl l carnitine has a therapeutic intervention and the results were quite good but only at very high dosages. Other and much more recent research has found that acetyl l carnitine can also play an important role in preventing Age Related Macular Degeneration (AMD). In those studies they created a compound called Phototrop, a combination of acetyl L carnitine, omega 3 fatty acids, and co-enzyme Q10.

Word of warning: you should always use alpha lipoic acid with ALC because ALC increases mitochondrial function and mitochondria are the key region where oxidants are formed.

The table below is from

Japan J Pharmacol, 38, 365-71(1988)

Another worrying study concerning mobile phones

There are now a number of studies pointing to the dangers of mobile phones. Of particular concern is the widespread and frequent use of mobile phones amongst teenagers. This study reveals a disturbing quality about the microwave radiation emitted from mobile phones: the markers of oxidative stress, MDA(malondialdehyde) and XO(xanthine oxidase) remain up to 40 days after exposure to the microwave radiation in a rat model. One factor causing this sustained expression of inflammatory markers was the persistent reduction in catalase, a key antioxidant pathway in our cells.

Previous research has found increased risk of brain tumours in the young. While the telecommunications industry strenously denies any danger from using mobile phones increasing research is painting a very different picture. Some authorities have even claimed that the widespread use of mobile phones is paving the way for an epidemic of brain tumours.

Thanks to Dr. Lefever for forwarding this study to me.

The full study can be downloaded here.

Electric Eels and Electronic Implants

This study from Nature Nanotechnology is fascinating. They claim to have found a way to model the cells in electric eels that create electricity so that artificial cells can be used to power medical implant devices.

The news item can be read here.

Financial Risk Taking and Testosterone

Previous studies have found that the higher one's position in the social ladder, the higher the Testosterone levels tend to be. In light of this study then it is not surprising that we find ourselves in this current financial predicament because financiers, for reasons which escape this humble mind, earn extraordinarily high incomes. Think about it, there are any other number of professions that should be paid more because the people in these professions have much greater responsibility and experience much greater stress than those in the finance industry. Those poor souls can't go running home to mama(the Central Banks) when they stuff up, they go broke. Financiers go running to mama and expect a handout for being naughty boys. This has to stop and I hope this crisis makes everyone take a long hard look at the financial industry.

Here is a news release on the study.

The Future of Global Warming

It has always been my belief that we will never sufficiently reduce carbon dioxide output to address global warming. The simple fact is that we must find ways to capture existing CO2 AND reduce carbon dioxide output. This technology is amongst many currently under investigation.

Supplements for Osteoarthitis - Conflicting Results Again

I've seen this a number of times with various over the counter supplements. Some studies paint a good picture, others show equivocal results, and other studies claim the supplement is a dud. There is far too much hype concerning the purported value of all those supplements out there but the research is indicating that some supplements can be of great value not only in addressing specific pathologies but also general health. For example, Juvenon (see picture on the right) is a supplement compound backed up by credible research. While I haven't tried juvenon itself I have tried to the two components of it. It took a while for the effects to kick in but it definitely worked.

Osteoarthritis is a very common condition and many alternative therapists advocate the use of the supplements glucosamine and chondroitin sulfate. Studies have been mixed but mostly negative. This latest study suggests a mild favourable effect for glucosamine.

How does the consumer know what to do in these circumstances? Here are some guidelines:

1. Look for reliable well conducted clinical trials on the supplement. If these don't exist then be very careful. Typically I will never advocate the use of a compound that has not been subject to clinical trials.
2. NEVER trust the sellers of a product to provide reliable information. NEVER NEVER NEVER.
3. Ask others who have used the supplement for their impression of it. This may help but remember individual responses to various drugs and supplements vary so widely that there is no guarantee what works for one person will work for you. This, incidentally, is also true of clinical trials. That something has worked in a clinical trial is no guarantee it will work for you. Remember, clinical trials are statistically based and hence the results apply to the treatment group, the results may not even be applicable to individuals within the treatment group.
4. As long as you are convinced the supplement is safe and even in the absence of clinical trials there is no harm in giving it a go. It may just work for you even work clinical trials make low claims to efficacy or even state no efficacy. I appreciate this sounds contradictory but we are individuals and sometimes, even if by placebo effect, people do find benefits in supplements that have no scientific support for their use.