Anti-Aging Pill, The

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Anti-Aging Pill, The

by: Bill Sardi

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The Quest for an Anti-Aging Pill: 2005 In Review
There are no guarantees that extraordinary longevity can be achieved, but given the amazing developments in the science of anti-aging, the question increasingly is not whether life expectancy in the United States at birth will increase from the current 77 years to 100 or even 120 years, but when. -Donald B. Louria MD, New Jersey Medical School, Journal American Geriatrics Society 53: S317, 2005 Here are some of the news headlines involving the topic of anti-aging this past year: Professor sued over opinion of anti-aging group Chicago Tribune June 22, 2005
Florida woman sues over anti-aging product. Knight Ridder June 17, 2005
Is a longevity vaccine on the way? -Forbes Magazine August 8, 2005
Were extending lives, but at what price? -Boston Globe Sept. 26, 2005
Well, the professor that was sued was S. Jay Olshansky of the University of Illinois who claimed that the American Academy of Anti-Aging Medicine (A4M) is a peddler of baseless ideas about how to reverse the aging process. Dare I add anything more here and get sued by A4M? The Florida woman sued Estee Lauder because its skin care products didnt live up to its claim of having youth inducing benefits. The youth vaccine was a premature announcement made to grab headlines. It was based upon a paper published in Science magazine that showed the Klotho gene produces a hormone (a protein) that prolongs life in mice. Nobody captured the publics attention better than Ray Kurzweil, the prolific inventor, who appeared on John McLaughlins One on One TV interview program to promote his new book, Live Long Enough to Live Forever. The Science Behind Radical Life Extension. Dr. Terry Grossman is co-author. Kurzweil didnt have much to say. He is swallowing over 100 pills a day in hopes of slowing aging. His approach appears to be rather unfocused. Providing a more practical vein of evidence, the November issue of National Geographic heralded its cover story, The Secrets of Living Longer, and went on a photographic journey to places where humans live extra long, like Sardinia, Okinawa, and Loma Linda, California. There certainly are pockets of human populations that live extra long. But why? The offered answers were the red wine, limited calorie and vegetarian diets. The July 2005 issue of Science Magazine asked How much can human life span be extended? No one has an agreed-upon answer yet. Though Jeanne Calment of France did, and lived 122 years, the oldest in modern records. Also, the Japanese now report over 1 million people aged 90 or older, and a record 23,000 centenarians out of a population of 127 million. [Associated Press June, 2005] For comparison, according to American Demographics magazine, there are 1.5 million Americans over the age of 90 and roughly 30,000 of these are over the age of 100, out of a population of nearly 290 million. Forbes Magazine tackled the issue of age extension in its November 14, 2005 issue entitled Want to live forever? Donald Ingram of the National Institute on Aging, quoted in the Forbes report, said that increasing the maximum human life span by 25 to 30 years is possible. But Thomas Perls of Boston University disagreed, saying it is pure science fiction to say we can change the rate of aging in an organism as complex as ours. Again, tell that to Jeanne Calment. What will an anti-aging pill cost? Regardless of the debates over anti-aging strategies, the average American now lives 12 years longer than in 1950. So that caused the Rand Corporation think-tank to mull over which future life-prolonging technologies would add the greatest cost to the Medicare program. If someone comes up with a new pill, say to prevent aging, that could break the bank in ways that we didnt foresee, said Dana Goldman of Rand. [USA Today Oct. 24, 2005 ] Cancer vaccines, Alzheimers drugs, pacemakers made Rands list, but for the first time an anti-aging pill was also listed, as if to presume there will be such a development. The Rand report calculated such a pill would cost $1 a day and add 10 years to life and would be the lowest cost of all promising new technologies. But gaining approval for an anti-aging pill will be elusive. Showing that a drug prevents aging in people is proving almost impossible, said a report in Nature Medicine. [Nature Medicine March 2005] Providing a group of people with an anti-aging pill and another group a placebo and waiting to see which group lives longer is a vexing and costly undertaking. Instead of attempting to prove the impossible, Harvard researcher David Sinclair is steering his resveratrol pill, labeled as an anti-aging molecule in 2003, toward approval as an anti-diabetic drug. Sirtris Pharmaceuticals is the developer. In March of 2005 philanthropist Paul F. Glenn announced he had committed $5 million for research on the biological mechanisms of aging. The money will establish the Paul F. Glenn Laboratories at Harvard. In the same month, Sirtris announced it had secured $27 million in new financing. However, resveratrol pills appeared to have competition from Protandim, a pill heralded in June of 2005 as a booster of superoxide dismutase, an inborn antioxidant enzyme. Utilizing five botanical extracts, including milk thistle, turmeric and green tea, Protandim received considerable attention in the news media, and then appeared to fade from view. Calorie restriction confirmed The one unequivocal approach to life extension, calorie restriction, continued to be confirmed, though not without contention. Calorie restricted animals consume 34% less oxygen. [American Journal Physiological Endocrinological Metabolism May 10, 2005] Edward Masoro called calorie restriction a hormetic process (a little bit of biological stress causes the body to upregulate defenses). [Mechanisms Ageing Development 2005] In July, researchers in Britain published a report stating that calorie restriction doesnt work by deprivation of calories per se, but by reduction of dietary yeast or sugar, according to their study with fruit flies. [PLOS Biology July 2005] Other researchers claim the use of non-optimal rearing condition skews the fruit-fly research involving calorie restriction. [Ageing Research Reviews 4: 409, 2005] By July 2005 researchers John Phelan and Michael Rose were claiming calorie restriction works in lower organisms, but not very well in humans. They predict only a 7% gain in human life span by restriction of calories. [Ageing Research Reviews 4: 339, July 23, 2005] Calorie restriction mimetics George S. Roth, of GeroScience Inc., says most humans are not likely to opt for depriving themselves of food to live longer and that calorie restriction mimetics, ways to achieve the benefits of calorie restriction without eating less, are likely to be more popular. [Journal American Geriatrics Society 53: S280, 2005] David Sinclair of Harvard updated all the current evidence regarding caloric restriction and longevity regulation in a paper published in Mechanisms of Ageing and Development. [Mechanisms Ageing Development 126: 987, Sept. 2005] Evidence points to small molecules that can mimic the effects of food deprivation. Not without contention However, scientific progress towards an anti-aging pill certainly has its interruptions. By November of 2005 researchers at the University of Southern California reported that the removal of the Sir2 gene (akin to the human Sirtuin 1 gene) from yeast cells brought about much longer survival than activation of the gene. [Cell 123:655-67, Nov. 18, 2005] Two years ago David Sinclair at Harvard Medical School reported that resveratrol, a red wine molecule, prolongs the life of yeast cells via its ability to up-regulate Sir2 gene-controlled proteins. Not to worry yet, as epidemiological data indicates both calorie restriction (Okinawa) and its molecular mimic (France, Sardinia, red wine resveratrol) works in humans. Researchers also report that de-alcoholized red wine, but not alcohol itself, protects against DNA damage in humans. [Mutation Research Mutation Research 591:290-301, December 2005] If there was one worrisome drawback regarding resveratrol, it was that it inactivates the p53 tumor suppressor gene. But that was only demonstrated in a lab dish and in June 2005 researchers at the Salk Institute showed that such data is not relevant to living, breathing organisms. [Proceedings National Academy Sciences 102:10188-93, July 2005] Genetic medicine Modern medicine probably does not realize the direction it is headed towards. Researchers in Italy talk of ways of silencing disease genes by the use of the Sirtuin 1 gene, that causing bundles of chromatin (genetic material) to literally curl up so they cannot express proteins (in essence, they would be like a computer file that is locked and cannot be read). The researchers describe small molecules, like resveratrol, that can accomplish this. [Trends Pharmacological Sciences 26: 94, 2005] The sequencing of the human genome, and the development of gene targeted anti-cancer drugs, like Iressa, Gleevec, Erbitux, has ushered in a whole net era of genetic medicine. But the problem is, only 1% of human disease is caused by single-gene disorders, and these are the rare diseases. Simon Frantz, the news editor for Nature Reviews Drug Discovery, says what is needed are drugs that target many genes at one time. This would represent a giant U-turn for drug development. [Natures 437: 942, Oct. 13, 2005] Riccardo Ghidoni and Paola Signorelli of the University of Milan indicate small molecules found in nature, such as resveratrol, target whole pathways and sets of intracellular events rather than a single gene enzyme, as do many synthetic drugs. This offers a less specific but perhaps more effective strategy for cancer therapy in inducing combinations of effects. [Journal Nutritional Biochemistry 16: 449, 2005] Resveratrol speaks volumes The many scientific reports involving resveratrol in 2005 are too voluminous to cite here. But suffice to say, resveratrol was found to clean up beta amyloid plaque in the brain [Journal Biological Chemistry 280: 37377, 2005], inhibit the replication of the flu virus [Journal Infectious Diseases May 15, 2005], inhibit the production of hypoxia inducible factor-1, which causes tumor cells to cease using oxygen for cell energy [Molecular Cancer Therapeutics 4: 1465, Oct. 2005], suppresses the development of arterial plaque regardless of circulating cholesterol levels [International Journal Molecular Medicine 16: 533, Oct. 2005], enhances the healing of heart tissues following a heart attack [Journal Molecular Cellular Cardiology 39: 833, 2005], reduces spinal cord injury when used prophylactically in animals prior to aneurysm surgery [Annals Thoracic Surgery 90: 2242-49, 2005], inhibits rejection of organ transplants [World Journal Gastroenterology 11: 4745, August 2005], and inhibits bone loss in animals whose ovaries have been removed [Journal Medicinal Food 8: 14, March 2005].
Is resveratrol bioavailable? A bigger issue that arose in 2005 involving resveratrol was the question of its bioavailability. Research report after research report claimed resveratrol is not bioavailable. [Molecular Nutrition Food Research 49: 49: 495-504, 2005] One report said the oral bioavailability of resveratrol is almost zero due to rapid and extensive metabolism (glucuronidation in the liver). [Molecular Nutrition Food Research 49: 472, May, 2005] Pharmaceutical companies are supposedly attempting to overcome this obstacle by developing new technology. Yet the problem appears to be imagined, even contrived. The metabolic process of glucuronidation in the liver actually appears to protect resveratrol from degradation, extending its half life and maintaining its biological properties. [Biochemistry Journal 374 (Pt 1):157-63, 2003] Researchers state that these observations raise the possibility that glucuronidation of resveratrol may have a role in detoxification, disposition, and prolongation of the effectiveness of resveratrol in humans. [Journal Pharmaceutical Science 93:24482457, 2004] Oral doses of resveratrol have been found in organs beyond the intestines, liver and kidneys. For example, Italian researchers have shown that resveratrol from red wine exerts significant cardiac bioavailability in rodents. [Drugs Experimental Clinical Research 24: 51-55, 1998] Other researchers conclude that resveratrol is bioavailable following oral administration and remains mostly in an intact form. The results also suggest a wide range of target organs for cancer chemoprevention by wine polyphenols in humans. [Life Science 72: 2219-33, 2003] Since glucuronidation and subsequent production of a releasing enzyme (glucuronidase) at the site of tumors, inflammation and infection, has been described as a drug delivery system, it appears disingenuous to claim resveratrol is not bioavailable as a dietary supplement. [Current Pharmaceutical Design 8: 1391, 2002] Resveratrol stability A larger issue appears to be the stability of resveratrol as a drug or dietary supplement. It is subject to photo-induced isomerization upon exposure to light, and further degradation by oxygen and heat, which can alter it from its more active trans resveratrol form to its lesser active cis resveratrol form. [Journal Agriculture Food Chemistry 44: 1253-57] Only a few published reports even bring up this topic. [Neurosignals 14:61-70, 2005] It is interesting that efforts have been made to produce a red wine resveratrol pill by freeze-drying wine solids. While freeze-drying preserves about 68% of the grape skin molecules, it doesnt appear to preserve resveratrol. [Life Sciences 74: 1159, 2004] The November report in Forbes Magazine about anti-aging strategies described four approaches to longevity: (1) activation of the Sirtuin 1 gene; (2) elevation of HDL good cholesterol; (3) control of insulin resistance and (4) regulation of growth hormones (insulin growth factor). Remarkably, Forbes editors are unaware that resveratrol addresses all four of these factors. Resveratrol was even the subject of an entire scientific text this year (Resveratrol In Health and Disease -CRC Press 2005). The question is, does the scientific and medical community intend to withhold public notification of resveratrols potential until it becomes a drug? It took quite a battle before a federal agency finally permitted Willamette Valley Vineyards to label that its wine contains resveratrol. Technically, the FDA considers resveratrol a drug and dietary supplements labeled to contain resveratrol are in violation and should be labeled as red wine extracts. While public demand for red wine resveratrol is low, various startup companies began marketing resveratrol pills in 2005 with claims that they stop aging. When tested by HPLC, some of these products (Revatrol, MuscadinePlus- Nutragon) yielded less than a milligram of resveratrol per recommended dose.

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