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Study of Role of some Molecules in Prevention of Cancers and Degenerative Diseases, Retardation of Aging and Prolonging Life
By Premendra Priyadarshi FRCP1

Death and old age have horrified human minds since earliest days. Much of human institutional effort has been directed directly or indirectly towards increasing human lifespan (and providing a better quality of life for the aged), whether by prevention of crime, maintenance of traffic rules, establishing of hospitals or erection of temples or churches in the past when God alone was capable of helping man out from diseases and natural calamities. Growth of preventive medicine, immunization, better nutrition and recent awareness about metabolic consequences of over-eating, sedentary life, stress and obesityand how to control them by yoga, regular exercise, regulated diet and anti-oxidants etc. have gone a long way in improving human survival and quality of life. Improvement in survival has to be associated with freedom from diseases especially the degenerative diseases which are usually side-effects of longer survival. As our life expectancy increases, we now feel more concerned to have a disease-free, independent existence in the old age. In the last few years, ginkgo, Co-enenzyme Q, rapamycin, resveratrol, brahmi and many other substances have been tested for their beneficial effects for prevention and treatment of aging related degenerative conditions. Many of these have been found to prolong life significantly. Ginkgo biloba, called Balkuwari in Hindi, is a tree whose nut and bark have been used in Indian medicine and Chinese Buddhist medicine for thousands of years. Its common English name Maidens Hair is just a literal translation of its Hindi name (bal=hair; kuwari= maiden). It improves memory, improves dementia and slows down the progression of Alzheimers disease (Ernst and Pittler, 1999). It is helpful in multi-infarct dementia or dementia caused by cerebral infarcts (Kanowski 1996). A recent external study i.e. study by neutral examiners also approved of its efficacy in dementia of various origins (Bronthoft 2008). Although Gingko has been found to improve memory, retard
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The article was published in the Nov 2009 issue of the Eternal India journal, published by the India First Foundation, 5 Hailey Road, New Delhi. Author Email: priyadarshi101@hotmail.com

brain degeneration and slow the progression of dementia, it is toxic in over dose, and is not recommended without medical supervision. Sirolimus, also known as rapamycin, is an immunosuppressant drug used to prevent organ transplant rejection, especially in patients with kidney transplants. In structure, it is a macrolide antibiotic (like erythromycin). It was first discovered as a product of the bacterium Streptomyces, and was used as an anti-fungal agent. But soon it was found that it had strong immunosuppressive effects, and therefore its use as anti-fungal antibiotic was abandoned. Now it is used only for its immuno-suppressive effect which is required to prevent rejection of transplanted organ by recipients body. It was only recently noted that it prolongs life and prevents many degenerative diseases. Although it has been shown to prolong life of mice, it cannot be licensed for use in humans for this purpose, simply because of its unacceptable immuno-suppressive effects. But it is likely that some of its derived molecules may be discovered in future which would not have immuno-suppressive effects or other side effects, but would be capable of prolonging life. Resveratrol seems to be the most promising of these newer agents and without any side-effect. Its story begins with detection of the French Paradox. THE FRENCH PARADOX Irish physician Samuel Black observed in 1819 that although the French consumed highest amount of fats among the white people, they had relatively lower incidence of heart disease and that they had longer lifespan. This phenomenon was termed the French Paradox by Surge Renaud in 1992. Many speculations were made how the French avoided coronary artery (heart) diseases in spite of consuming so much of fat, especially the saturated fats. Lastly, it was proposed that this was possibly because of highest consumption of red wine by the French. It has been known for long that moderate amount of alcohol intake is associated with slight reduction in cardiovascular mortality, possibly because of anti-clotting effects of alcohol on the platelets. But the degree of protection by red wine observed in the French people was far more than that which could be produced by drinking similar amounts of other forms of alcohol like whisky. Hence it was concluded that the red wine had something more than alcohol in it. It was later found that red wine contained very high amounts of resveratrol.

RESVERATROL Resveratrol was isolated in 1940. It is widely distributed in plant kingdom. It is found in skin of grapes, peanuts, raspberries and pine. It is produced by plant cells in response to stress like attack by fungus, bacteria or lack of nutrients and exposure to ultraviolet rays. The red and the white grapes have nearly the same amounts of resveratrol in them. But while making white wine the skin is peeled off, that reduces the resveratrol content of white wine. Thus red wine contains twenty times greater concentration of this substance as compared to white wine. Resveratrol, a polyphenol, is known to protect against cardiovascular diseases, cancers and degenerative diseases of brain and many other organs. It is known to have anti-aging effects in numerous organisms, and prolongs life (Aggarwal and Shishodia 2005). A large number of effects of aging are caused by oxidative damage to the cells. Many of the biological substances used as food have anti-oxidant properties and are helpful in retarding degenerative diseases and harmful effects of aging. Beta-carotene and carotenoids (which derive their names from carrot) found in tomato, papaya and carrot, as well as vitamin C found in most of the fruits (except dry-fruits) are good anti-oxidants. Jang et al (2003) experimentally demonstrated that resveratrol does have excellent anti-oxidant properties, and is good at stopping or slowing down degenerative diseases. In mice, resveratrol was shown to protect from some forms of cancers (Jang et al 1997). Following this research, worldwide interest surged in this molecule and a large number of experiments and trials followed. It was tried in a large number of diseases and degenerative conditions. It was found that resveratrol may prevent cancers to some extent. It was found that resveratrol has beneficial effects if used as a chemo-preventive agent for breast cancer (Lu, 1999; Bhat, 2001). Since then a large number of studies have shown that resveratrol is helpful in breast cancer. Pozo-Guisado (2002) found that resveratrol could produce cancer cell specific alterations in cell-cycle thereby helping in stopping cancer growth. They also found that this substance promoted death of cancer cells (apoptosis). It has been further noted that resveratrol could prevent skin cancer (Aziz 2005; Raul 2006). Ding et al (2002) found that it could inhibit proliferation of pancreatic cancer cells and could lead to death of such cancer cells.

Bianchini and Vinino (2003) found that resveratrol inhibits the metabolic activation of carcinogens (chemical substances which cause cancer), has

antioxidant and anti-inflammatory properties, decreases cell proliferation and induces apoptosis (death of cancer cells) in animal studies. Yu et al (2003) found that resveratrol given in a dose of 10-15 mg per kilogram of rats body weight, was able to shrink the size of liver cancer tissue, transplanted to a mouse. They found that resveratrol could inhibit certain cell cycle proteins, which cause cellular proliferation in cancers. Mitchell (1999) found that resveratrol could modulate the prostatic cancer cells and thereby inhibit their growth.

The inhibition was dose dependant. It, thus, prevents cancer-cell formation and growth and also destroys them. It has been further found that it prevents all the stages of cancer formation, proliferation and dissemination within body (Bishayee, 2009). Alzheimer's disease is an irreversible, progressive degenerative brain disease that slowly destroys memory and thinking skills. Lindsay (2002) noted that use of nonsteroidal anti-inflammatory drugs, wine consumption, coffee consumption, and regular physical activity were associated with a reduced risk of Alzheimers disease. Marambaud et al (2005) showed that resveratrol helped in clearing amyloid-betapeptides from brain indicating that it could benefit the Alzheimers patients. Anekonda (2006) found that this substance had an enormous potential in treating and preventing the Alzheimers disease. Recently Vingtdeux et al (2008) noted, Several epidemiological studies indicate that moderate consumption of red wine is associated with a lower incidence of dementia and Alzheimer's disease. Red wine is enriched in antioxidant polyphenols with potential neuroprotective activities. Despite scepticism concerning the bioavailability of these polyphenols, in vivo data have clearly demonstrated the neuroprotective properties of the naturally occurring polyphenol resveratrol in rodent models for stress and diseases. Furthermore, recent work in cell cultures and animal models has shed light on the molecular mechanisms potentially involved in the beneficial effects of resveratrol intake against the neurodegenerative process in Alzheimer's disease. It was experimentally shown that resveratrol could increase the life-span of Saccharomyces, a microscopic fungus (Howitz et al, 2003). Resveratrol treatment extended life of the fruit flies and worms under experimental conditions (Wood et al. 2004). High calorie diet has been regularly shown to be associated with shorter live-span in man and animals. It was found that

resveritrol somehow neutralized the effects of high calorie diet in these organisms. In 2006, Italian scientists fed a fish (Nothobranchius) on high doses of resveritrol. It was found that the average life-span of the fishes increased by 56% (Valenzano et al. 2006). Further research showed that addition of resveratrol to the diet of mice fed on very high amounts of fat protected the coronary arteries of these mice from blockage (Baur, 2006; Barger, 2008). Resvratrol has been shown to experimentally prevent some types of cancers in animal studies (Athar et al. 2006). Gastritis, acidity and peptic ulcer are extremely common conditions in India and all of these are associated with Helicobacter pylori infection. Mahady et al (2003) found that this bacterium was killed by resveratrol under standard laboratory conditions. This may be the reason that jamun, berries and such rural and wild fruits are found to have curative effect for gastritis and other acidity related symptoms, and are use as household treatment for a large number of bowel upsets in rural India. In diabetic rats, resveratrol was shown to protect the brain and spinal cord from damaging effects of diabetes. Treatment with this drug led to increased levels of glutathione in the central nervous system. Glutathione protects body cells from oxidative damage (Ates, 2007). Diabetic patients often develop peripheral neuropathy in which they may have severe nerve pain. Resveratrol was tried on mice which had been rendered diabetic experimentally. There was significant improvement in neuropathic pain in these mice. The researchers found that an injection with resveratrol significantly and dosedependently attenuated thermal hyperalgesia, decreased the serum level of tumour necrosis factor-alpha and whole brain nitric oxide release. They concluded that resveratrol holds a potential in attenuating diabetic neuropathic pain (Sharma et al, 2007). Resveratrol has anti-inflammatory effects against COX mediated inflammations, and prevents angiogenesis. Thus it prevents microvascular complications of diabetes and hypertension (Brakenhielm et al, 2006). It has been claimed that resveratrol does help in losing weight to some extent. Resveratrol was shown to expedite nerve function recovery in spinal cord damage and stroke in experimental animals. Human experiments are in the early stage, but it is likely that resveratrol may prove to be a molecule which can not only prolong life and delay aging of man but also prevent many of the degenerative diseases and processes associated with high calorie food, sedentary life-style and stress: the banes of modern civilization. Being a natural ingredient of many fruits and vegetables, it may be

marketed for over the counter sales, as it may not have any serious side effect which is usually feared in case of synthetic molecules. In India dark wine (by the name drakshasava) has been used for health promotion, retardation of aging and for treatment of a large number of disorders in the Ayurvedic medicine. It is possible that quite a few beneficial effects of drakshasava may be because of resveratrol content in it. Conclusion: It thus becomes obvious by reviewing the recent scientific literature about resveratrol, that it has enormous potential for prevention of human diseases and also to some extent their amelioration. It is found in the skin of fruits. Hence the fruits which are usually eaten with their skin intact should be encouraged in our diets. Such fruits like guava, ber, jamun (Indian plum), makoy, black currant, etc have traditionally formed part of Indian rural diet, especially during puja and festivals. It may be recommended on the basis of available evidence that apart from them, grapes, berries and peanuts should be taken on a regular basis, while keeping in mind not to exceed ones daily calorie allowance. Peanuts have a fairly high fat content, and therefore their calorie content may become unacceptably high if eaten in good amounts, especially by the obese persons. Those who drink alcoholic drinks should rather take red wine. It helps in many ways as discussed above. Moreover red wine contains about ten to twelve percent alcohol, while whisky, gin, vodka and rum contain forty percent alcohol. Thus the high alcohol content of the latter not only produces gastritis, pancreatitis, neuropathy, brain damage and liver damage, but also often causes sociological problems and criminal behaviour. Because whisky is five to ten times cheaper than red wine on the basis of alcohol-unit price there is a greater addicting potential in whisky. As red wine is more expensive, there is a lesser tendency to alcohol abuse and excessive drinking among those who drink red wine. Moreover red wine cannot be made by illicit hooch makers and therefore there is nil chance of dying from poisonous alcohol or hooch. It has been recently found that spurious duplicate of even the best and most expensive of the brands of whisky are produced by alcohol mafia. This risk does not exist with any brand of red wine. Thus while maintaining that alcohol intake is commonly hazardous socially as well as health-wise, red wine can be considered both safe and good for health if compared to any other form of alcohol. However it has to be appreciated that alcohol significantly increases incidence of gastritis, neuropathy and many

cancers. Bagnardi et al (2001) reviewed 117,000 case reports of cancers and alcohol, and concluded in the British Journal of Cancer that among alcohol consumers, Strong trends in risk were observed for cancers of the oral cavity and pharynx, oesophagus and larynx. Less strong direct relations were observed for cancers of the stomach, colon and rectum, liver, breast and ovary. For all these diseases, significant increased risks were found also for ethanol intake of 25g per day. There is another problem with red wine. Many of the people who suffer from features of metabolic syndrome (like obesity and non-insulin dependent diabetes) also have high uric acid. Red wine causes uric acid levels to rise in susceptible individuals but not in all people. Hence Uric acid should be monitored half yearly especially in those who have possibility of metabolic syndrome. Therefore red wine will not be recommended to be initiated to any one for these benefits. However consumption of grapes and berries in good amounts and peanuts in small amounts can be recommended.

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