full
image
#d9d9d9
http://warddeanmd.com/wp-content/themes/smartbox/
http://warddeanmd.com/
#26ade4
style1

Resveratrol: Anti-Aging Review

Clinical and Anti-Aging Benefits of Resveratrol

By Ward Dean, M.D.

Resveratrol (3,5,4’-trihydroxy-trans-stilbene) (Fig. 1) is a compound found in the skins of red fruits, grapes, seeds, berries (especially, mulberries), peanuts, red wine, various herbs, and propolis (a natural honeybee product). Resveratrol occurs in two forms — cis and trans resveratrol — but it is the trans isomer that is biologically active. This article reviews resveratrol’s history, mechanisms, dosage and broad range of clinical uses and anti-aging potential.

The Resveratrol Story

Resveratrol was first identified in the early 1980s as the principal active ingredient in the dried roots of Polygonum cuspidatum. As a traditional Japanese and Chinese medicine, Polygonum extracts have been used to treat a wide range of afflictions, including fungal infections, various skin inflammations, and liver and cardiovascular diseases.1

In the early 1990s, scientists were attempting to unravel the “French paradox”—i.e., the surprisingly low incidence of cardiovascular disease observed in France among people consuming a rich, high-fat diet.2 Researchers proposed that the “paradox” may be due to the routine consumption by the French of resveratrol-rich red wine.

Studies that subsequently compared alcohol consumption to the risk of death from coronary heart disease (CHD) revealed that those with the lowest risk drank red wine, while those who preferred other alcoholic beverages had the highest risk.3 Scientists also discovered that when healthy subjects were given pure alcohol or red wine for 15 days, pure alcohol increased platelet aggregation (a cause of heart attack and stroke-producing blood clots); however, red wine decreased platelet aggregation while elevating HDL-cholesterol (“good” cholesterol).
As scientists began to appreciate the cardiovascular benefits conferred by red wine polyphenols—especially, resveratrol—a blockbuster article in the prestigious journal Science electrified the scientific community with the finding that “Resveratrol inhibits cellular events associated with tumor initiation, promotion and progression.” In other words, resveratrol blocks all three mechanisms of cancer formation!4 But resveratrol’s effects don’t stop there.


Mechanisms and Potential Clinical Uses of Resveratrol

 

Cardio-Protective Effects

  • Resveratrol has been shown to protect the cardiovascular system by multiple mechanisms. Among these are:
  • protecting against ischemia-reperfusion injury (see next paragraph)
  • promoting vasorelaxation (i.e., protect against vasospasm)
  • protecting and maintaining the smooth, single cell-thick lining of the arteries (endothelium), which produces substances that influence arterial dilation
  • inhibiting the oxidation of low-density lipoprotein (LDL)5,6
  • suppressing platelet aggregation.7


“Ischemia-reperfusion injury” refers to the extensive damage to tissues when blood flow is restored following a temporary loss of circulation. Such a situation occurs due to spasm of an artery, or temporary blockage of blood flow by a thrombus (blood clot), followed by resumption of blood flow.

The ischemia-reperfusion mechanism is the cause of extensive tissue damage in strokes, transient ischemic attacks (TIAs—mini strokes) and heart attacks. Resveratrol has been demonstrated to protect against ischemia-reperfusion injury not only in the heart,5,8 but also in the ovaries9 and spine.10

In these studies, resveratrol administration resulted in a number of beneficial effects, including:

  • decreased cardiac arrhythmias
  • reduced cardiac infarct size
  • increased NO (nitric oxide) release
  • decreased plasma levels of lactate dehydrogenase (LDH) and creatine kinase (CK) (indicators of tissue damage)
  • decreased levels of malondial-dehyde and xanthine oxidase (indicators of oxidative stress)
  • increased glutathione (a protective antioxidant).


Anti-Cancer

Cancer is one of the leading causes of death in the United States, second only to heart disease. The prognosis for patients with metastatic carcinoma of the lung, colon, breast, or prostate undergoing conventional therapeutic and surgical approaches remains dismal.

An ideal natural anti-cancer substance should have certain properties: little or no toxic effects in normal and healthy cells; high efficacy against multiple sites; capability of oral consumption; known mechanism of action; and low cost.11 Resveratrol appears to meet all these criteria.

 

In Vitro (Cellular) Studies

Following the previously mentioned discovery of resveratrol’s ability to block all three stages of carcinogenesis, a number of cellular (in vitro) and animal (in vivo) studies were conducted to evaluate resveratrol’s anti-cancer effects on a number of tumor types. Resveratrol’s cancer fighting effects include the ability to inhibit cell proliferation and induce necrosis (cell death) and apoptosis (“cell suicide” of abnormal cells). These anti-cancer effects of resveratrol were confirmed in in vitro studies in virtually every type of human cancer on which it was tested, including:

  • breast12,13
  • cervix14
  • ovary15
  • esophagus16
  • prostate17-19
  • lung20-21
  • neuroblastoma (NB) (an aggressive childhood cancer of the peripheral nervous system)22
  • melanoma (a highly virulent form of skin cancer)23,24
  • leukemia.25

In addition, resveratrol sensitizes cancer cells to enhance the effects of anti-cancer drugs, making them more effective against the target cells while reducing their toxic side effects to healthy cells.26

In Vivo (Animal) Studies

Skin Cancer: In Taiwan, a team of Chinese scientists demonstrated that resveratrol-fed mice treated topically with an agent known to cause skin cancer caused a delay in tumor formation, with fewer tumors per mouse compared to control animals.27

Hepatoma:One of the most virulent forms of cancer is that of the liver. In Asia, hepatoma is among the most common of abdominal tumors, although it is rarely found as a primary tumor in the U.S. Scientists in Japan and China treated rats implanted with hepatoma cells with resveratrol. Resveratrol, by itself, suppressed tumor growth and reduced metastases in two studies.6,28 When used in conjunction with the anti-cancer drug 5-FU, resveratrol enhanced the efficacy of the drug and reduced its toxicity.29

Glioma: In animals implanted subcutaneously with gliomas (a type of brain tumor), resveratrol exerted significant antitumor effects, including slower tumor growth rate, longer animal survival time, and higher animal survival rate. The scientists concluded that resveratrol should be considered a possible treatment strategy for gliomas.30

Endocrine Normalizer

Resveratrol also acts as an estrogen receptor sensitizer (i.e., estrogen receptor agonist).31,32 This means that resveratrol will help maintain normal levels of estrogen, and that what estrogen is available will work more efficiently, with fewer estrogenic side effects.

Thus, resveratrol may have anti-aging effects, in conformance with the neuroendocrine theory of aging. (Please see the many articles on the neuroendocrine theory in previous issues of Vitamin Research News, and on the VRP website, www.vrp.com.)
In addition, scientists at the City of Hope in Duarte, California, recently provided evidence that resveratrol is also a potent aromatase inhibitor.33,34 Aromatase is the enzyme that converts testosterone to estrogen. Men who supplement their regimens with testosterone or testosterone precursors to normalize hormone levels (as well as bodybuilders who use testosterone and anabolic steroids) risk their testosterone also elevating their estrogen levels.

One effective way to prevent testosterone from elevating estrogen levels is to use the highly effective (and very expensive) prescription drug, Arimidex®, in a dose of about 1 mg two times per week. However, resveratrol may offer a far less expensive, natural solution to the problem of estrogen excess in men, as well as for women who require aromatase inhibitors in the treatment of cancer.

Other Potential Mechanisms / Clinical Uses

In addition to its unparalleled potential as a cardioprotectant and anti-cancer agent, resveratrol has a number of other beneficial effects including:

  • anti-inflammatory35,36
  • anti-infective against fungi37 and viruses (herpes simplex)38
  • neuroprotective,39-43 including protection from noise-induced hearing loss.44

Anti-Aging / Life-Extension Potential of Resveratrol

Caloric restriction has been shown repeatedly to be one of the most effective means of slowing the rate of aging and extending lifespan. Severely reducing food intake of laboratory mice can increase their lifespan to the human equivalent of 162 years. Experiments demonstrate similar gains in maximum lifespan in virtually every organism in which caloric restriction has been tested. Nevertheless, despite the potential increase in lifespan that could be gained with caloric restriction, few humans willingly choose to live in a constant state of semi-starvation for even a few days, let alone 162 years.

Although the mechanism for the anti-aging effect of caloric restriction has remained elusive, scientists recently identified a class of regulatory “longevity genes”—that are shared by almost all living organisms—which they believe may be at least partially responsible for the effect of caloric restriction. These genes function to enhance survival during times of stress, such as during drought or famine, and have been designated as sirtuins (derived from the term silent information regulator proteins). Once triggered by environmental cues, the longevity genes “switch on” and induce defensive changes at the cellular level, such as slowing metabolism and enhancing cellular respiration to help the body adapt.45

The human sirtuin, SIRT-1, for example, has been shown to suppress the p53 enzyme system that helps to inhibit tumor growth and trigger cell death (apoptosis). By suppressing p53 activity, SIRT-1 prevents premature aging and apoptosis that is induced when cellular DNA is damaged or stressed, thus giving cells an opportunity to repair the damage. A second sirtuin found in yeast, SIR2, has also been shown to become activated when placed under stress. SIR2 increases DNA stability and speeds cellular repairs, while increasing total cell lifespan.46

Intrigued by the positive health benefits of caloric restriction, a research team from Harvard University began to search for other methods of modulating sirtuin activity without resorting to starvation. The researchers discovered that several plant metabolites acted as sirtuin-activating compounds (STACs), and that the most potent activator of sirtuins was resveratrol.

To test the ability of resveratrol to activate sirtuins in living creatures, the Harvard researchers selected yeast, a single-celled organism that is closely related to animals, including humans. The research team hypothesized that if resveratrol was effective in triggering sirtuin production, it would closely reflect the protein’s role in lifespan extension, at least for yeast. Their study found that even small doses of resveratrol helped yeast cells live as much as 60 to 80 percent longer, as measured by the number of generations. Yeast treated with resveratrol lived for an average of 38 generations, as compared to only 19 generations for untreated yeast47 (Fig. 2).
Resveratrol

Additional experiments with human cells found that resveratrol enabled 30 percent of the treated human cells to survive gamma radiation compared to 10 percent of untreated cells. In the paper, the Harvard researchers also report that preliminary experiments with flies and worms are encouraging, and mouse studies are in the works.

One of the major impediments to faster progress in anti-aging research is the time required to prove that a substance has life-prolonging effects. Consequently, one of the major goals of biomedical gerontology is to develop a set of biomarkers that can be used to measure biological age to determine—in a reasonably short period—whether a substance has an age-retarding effect. Recently, two research teams have developed such biomarkers—one by scientists in Austria48 for use in the same yeast strain used by the Harvard research team described above, and another by researchers at the University of Connecticut for use in anti-aging studies with fruit flies.49 Interestingly, both of these research teams used their biomarkers to evaluate the anti-aging effects of resveratrol, and both confirmed that resveratrol was an effective anti-aging substance (at least, in yeast and fruit flies).

Bioavailability/Dosage/Safety

Resveratrol appears to be effective in the prevention and treatment of cancer in cells and experimental animals, and as a life-extending substance in yeast and fruit flies.
These findings raise two important questions: Does resveratrol work in humans; and what dose is required to obtain optimal benefits? Unfortunately, the only human studies available are the epidemiological studies showing cardiovascular benefits from consuming red wine. Scientists recently calculated that benefits could be obtained by as little as 1.25 mg of resveratrol per day (based on wine containing about 5 mg of resveratrol per liter, with an average intake of moderate wine drinkers of about 250 ml per day).50

In a recent review article,51 researchers attempted to determine an equivalent human dosage to reproduce the apparent cancer “chemopreventive” benefits of resveratrol observed in in vitro and in vivo animal studies. The authors pointed out that most animal studies used what would be considered “massive” human doses, ranging from 10 to 500 mg/kg per day. That would equate directly to a daily human dose of about 700 to 35,000 mg per day! However animal doses can rarely be directly extrapolated to humans, due to differences in physiology and metabolic rates. Three more recent papers demonstrated “extraordinary in vivo [anti-cancer] potency” of resveratrol in rats, using much lower doses, ranging from 200 mcg/kg per day to 2 mg/kg per day.52-54 That is a doable range of about 14 to 140 times the amount of resveratrol consumed by our “average” daily wine drinker (i.e., a calculated human therapeutic dose ranging from about 10 to 100 mg of resveratrol per day).

The next question, pending human clinical studies, is what amount — if any — is a toxic dose of resveratrol? In a study designed to specifically evaluate potential toxicity of resveratrol, scientists from the National Cancer Institute conducted a four-week study of trans-resveratrol in rats, administered via gavage feeding (i.e., through a tube, directly into the stomach) at doses of 300, 1,000 and 3,000 mg per day. The 300-mg-per-day dosage resulted in absolutely no side effects whatsoever. The 1,000-mg-per-day dosage resulted in slight weight loss in female rats and slight elevation in white blood count in the
male rats.

However, the 3,000 mg per day dosage resulted in significant clinical signs of toxicity, as well as reduced body weight and food consumption. Other abnormalities caused by the 3,000 mg “mega dose” included55:

  • elevated BUN (blood urea nitrogen)
  • elevated creatinine
  • elevated alkaline phosphatase
  • elevated alanine aminotransferase
  • elevated total bilirubin
  • elevated albumin
  • reduced hemoglobin
  • reduced hematocrit
  • reduced red cell counts
  • increased white cell counts
  • increased kidney weight
  • increased incidence and severity of nephropathy (kidney damage)


It should be noted that no studies of resveratrol have ever used the high dosages seen in this study—and that the specific purpose of this study was to determine whether resveratrol was toxic at any dose. This study confirms that resveratrol is clearly one of the safest anti-cancer substances known.

Conclusion

The more we learn about resveratrol and its wide-ranging benefits in life-threatening diseases, the better it looks in terms of its preventive and therapeutic benefits—and overwhelming record of safety. Although optimum dosages of resveratrol for humans have not been definitively determined, based on our present state of knowledge, reasonable dosages for humans appear to be in the range of 1 to 10 mg per day for preventive and anti-aging purposes, and 10 to 100 mg per day for therapeutic purposes, with the higher doses recommended as an adjunctive part of a comprehensive anti-cancer regimen.

Dr. Dean’s Criteria for Selecting Anti-Aging Nutrients for This Series

For this series of articles reviewing top anti-aging nutrients, Ward Dean, MD, has selected substances based on several criteria:

1. The mechanism by which the substance is believed to act. Most substances discussed are involved in one or more theories of aging (i.e., antioxidants/free radical theory; cross-linkage inhibitors/cross-linkage theory; hormone receptor sensitizers/neuroendocrine theory, etc).

2. The health-enhancing effect of the substance.

3. Whether the substance has shown the capability to reverse or restore a biomarker to a more youthful state.

4. Has the substance demonstrated the ability to extend the maximum lifespan of one or more experimental organisms?

5. Practical considerations: An individual’s “pill capacity”—how many capsules/tablets is a person willing to take? Cost and availability—for example, some substances are beyond the reach of many people due to high cost or other impediments (i.e., legal issues, availability, requirement for a prescription, etc.).
Based on these criteria, the series of articles presents what Dr. Dean considers to be the most effective anti-aging/life extending substances readily available today. The substances featured are presented in no particular order. The first article in the series focused on DHEA, published in the June 2004 issue; part 2, CoQ10, appeared in July; part 3, Melatonin, was featured in August; part 4, DMAE, was published in September; and part 5, Carnosine, appeared in October.

References:

1. Arichi H et al. Effects of stilbene components of the roots of Polygonum cuspidatum…on lipid metabolism. Chem Pharm Bull 1982, 30:1766-70.

2. Renaud S, de Lorgeril M. Wine, alcohol, platelets, and the French paradox for coronary heart disease. Lancet 1992, 339:1523-26.

3. Goldberg DM et al. Beyond alcohol: Beverage consumption and cardiovascular mortality. Clin Chim Acta 1995, 237:155-87.

4. Jang M, Cai E, Udeani G et al. Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997, 275:2118-220.

5. Bradamante S, Barenghi L, Villa A. Cardiovascular protective effects of resveratrol. Cardiovasc Drug Rev 2004, 22:(3),169-88.

6. Miura D, Miura Y, Yagasaki K. Hypolipidemic action of dietary resveratrol, a phytoalexin in grapes and red wine, in hepatoma-bearing rats. Life Sci 2003, 73(11):1393-400.

7. Pace-Asciak CR, Hahn S, Dimandis E et al. The red wine phenolics trans-resveratrol and quercetin block human platelet aggregation and eicosanoid synthesis: Implications for protection against coronary heart disease, Clin Chim Acta 1995, 235:207-19.

8. Hung LM, Su MJ, Chen JK. Resveratrol protects myocardial ischemia-reperfusion injury through both NO-dependent and NO-independent mechanisms. Free Radic Biol Med 2004, 36(6):774-81.

9. Hascalik S, Celik O, Turkoz Y, Hascalik M, Cigremis Y, Mizrak B, Yologlu S. Resveratrol, a red wine constituent polyphenol, protects from ischemia-reperfusion damage of the ovaries. Gynecol Obstet Invest 2004, 57:(4):218-23. Epub 2004 Feb 11.

10. Kiziltepe U, Turan NN, Han U, Ulus AT, Akar F. Resveratrol, a red wine polyphenol, protects spinal cord from ischemia-reperfusion injury. J Vasc Surg 2004, 40(1):138-45.

11. Aziz MH, Kumar R, Ahmad N. Cancer chemoprevention by resveratrol: in vitro and in vivo studies and the underlying mechanisms (review). Int J Oncol 2003, 23(1):17-28.

12. Laux MT, Aregullin M, Berry JP, Flanders JA, Rodriguez E. Identification of a p53-dependent pathway in the induction of apoptosis of human breast cancer cells by the natural product, resveratrol. J Altern Complement Med 2004, 10(2):235-9.

13. Kim YA, Choi BT, Lee YT, Park DI, Rhee SH, Park KY, Choi YH. Resveratrol inhibits cell proliferation and induces apoptosis of human breast carcinoma MCF-7 cells. Oncol Rep 2004, 11(2):441-6.

14. Battout S, Derradji H, Jacquet P, Ooms D, Michaux A, Mergeay M. Enhanced radiation-induced apoptosis of cancer cell lines after treatment with resveratrol. Int J Mol Med 2004, 13(6):895-902.

15. Opipari AW Jr, Tan L, Boitano, AE, Sorenson, DR, Aurora, A, Liu JR. Resveratrol-induced autophagocytosis in ovarian cancer cells. Cancer Res, 2004 64(2):696-703.

16. Zhou HB, Yan Y, Sun YN, Zhu JR. Resveratrol induces apoptosis in human esophageal carcinoma cells. World J Gastroenterol 2003, 9(3):408-11.

17. Scifo C, Cardile V, Russo A, Consoli R, Vancheri C, Capasso F, Vanella A, Renis M. Resveratrol and propolis as necrosis or apoptosis inducers in human prostate carcinoma cells. Oncol Res 2004, 14(9):415-26.

18. Kim YA, Rhee SH, Park KY, Choi YH. Antiprolifer-ative effect of resveratrol in human prostate carcinoma cells. J Med Food 2003, 6(4): 273-80.

19. Stewart JR, Artime MC, O’Brian C. Resveratrol: A candidate nutritional substance for prostate cancer prevention. J Nutr 2003, 133:2440S-2443S.

20. Kubota T, Uemura Y, Kobayashi M, Taguchi H., Combined effects of resveratrol and paclitaxel on lung cancer cells. Anticancer Res 2003, 23(5A):4039-46.

21. Revel A, Raanani H, Younglai E, Xu J, Rogers I, Han R, Savouret JF, Casper RF. Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects lung from DNA damage and apoptosis caused by benzo[a]pyrene. J Appl Toxicol 2003, 23(4):255-61.

22. Liontas A, Yeger H. Curcumin and resveratrol induce apoptosis and nuclear translocation and activation of p53 in human neuroblastoma. Anticancer Res 2004, 24(2B): 987-98.

23. Niles RM, McFarland M, Weimer MB, Redkar A, Fu YM, Meadows GG. Resveratrol is a potent inducer of apoptosis in human melanoma cells. Cancer Lett 2003, 190(2):157-63.

24. Fuggetta MP, D’Atri S, Lanzilli G, Tricarico M, Cannavo E, Zambruno G, Falchetti R, Ravagnan G. In vitro antitumour activity of resveratrol in human melanoma cells sensitive or resistant to temozolomide. Melanoma Res 2004 14(3):189-96.

25. Kang JH, Park YH, Choi SW, Yang EK, Lee WJ. Resveratrol derivatives potently induce apoptosis in human promyelocytic leukemia cells. Exp Mol Med 2003 35(6):467-74.

26. Cal C, Garban H, Jazirehi A, Yeh C, Mizutani Y, Bonavida B. Resveratrol and cancer: chemoprevention, apoptosis, and chemo-immunosensitizing activities. Curr Med Chem Anti-Canc Agents 2003, 3(2):77-93.

27. Fu ZD, Cao Y, Wang KF, Xu SF, Han R., [Chemopreventive effect of resveratrol to cancer]. Ai Zheng 2004, 23(8): 869-73.

28. Yu L, Sun ZJ, Wu SL, Pan CE. Effect of resveratrol on cell cycle proteins in murine transplantable liver cancer. World J Gastroenterol 2003, 9(10):2341-3.

29. Wu SL, Sun ZJ, Yu L, Meng KW, Qin XL, Pan CE. Effect of resveratrol and in combination with 5-FU on murine liver cancer. World J Gastroenterol 2004, 10(20):3048-52.

30. Tseng SH, Lin SM, Chen JC, Su YH, Huang HY, Chen CK, Lin PY, Chen Y. Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats. Clin Cancer Res 2004, 10(6):2190-202.

31. Gehm B, McAndrews J, Chien P, et al. Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Proc Natl Acad Sci 1997, 94:138-43.

32. Hao HD, He LR. Mechanisms of cardiovascular protection by resveratrol. J Med Food 2004, 7(3):290-8.

33. Eng ET, Ye J, Williams D, et al. Suppression of estrogen biosynthesis by procyanidin dimers in red wine and grape seeds. Cancer Res 2003, 63:(23)8516-22.

34. Eng ET, Williams D, Mandava U, et al. Anti-aromatase chemicals in red wine. Ann NY Acad Sci 2002, 963:239-46.

35. Donnelly LE, Newton R, Kennedy GE, Fenwick PS, Leung RH, Ito K, Russell RE, Barnes PJ. Anti-inflammatory effects of resveratrol in lung epithelial cells: molecular mechanisms. Am J Physiol Lung Cell Mol Physiol 2004, 287(4):L774-83. Epub 2004 Jun 04.

36. Culpitt SV, Rogers DF, Fenwick PS, Shah P, De Matos C, Russell RE, Barnes PJ, Donnelly LE. Inhibition by red wine extract, resveratrol, of cytokine release by alveolar macrophages in COPD. Thorax 2003, 58(11):942-6.

37. Roemer K, Mahyar-Roemer M. The basis for the chemopreventive action of resveratrol. Drugs Today (Barc) 2002, 38(8):571-80.

38. Docherty JJ, Smith JS, Fu MM, Stoner T, Booth T. Effect of topically applied resveratrol on cutaneous herpes simplex virus infections in hairless mice. Antiviral Res 2004, 61(1): 19-26.

39. Zhuang H, Kim YS, Koehler RC, Dore S. Potential mechanism by which resveratrol, a red wine constituent, protects neurons. Ann N Y Acad Sci 2003, 993:276-86.

40. Wang YJ, He F, Li XL. [Neuroprotection of resveratrol in experimental cerebral ischemia] Zhonghua Yi Xue Za Zhi 2003, 10;83(7):534-6.

41. Savaskan E, Olivieri G, Meier F, Seifritz E, Wirz-Justice A, Muller-Spahn F. Red wine ingredient resveratrol protects from beta-amyloid neurotoxicity. Gerontology 2003, 49(6):380-3.

42. Yang YB, Piao YJ. Effects of resveratrol on secondary damages after acute spinal cord injury in rats. Acta Pharmacol Sin 2003, 24(7):703-10.

43. Han YS, Zheng WH, Bastianetto S, Chabot JG, Quirion R. Neuroprotective effects of resveratrol against beta-amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C. Br J Pharmacol 2004, 141(6):997-1005.

44. Seidman M, Babu S, Tang W, Naem E, Quirk WS. Effects of resveratrol on acoustic trauma. Otolaryngol Head Neck Surg 2003, 129(5):463-70.

45. Ferguson LR. Role of plant polyphenols in genomic stability. Mutat Res 2001, 475:89-111.

46. Landryh J et al. The silencing protein SIR2 and its homologs are NAD-dependent protein deacetylases. Proc Natl Acad Sci USA 2000, 97:5807-5811.

47. Howitz KT, Bitterman KJ, Cohen HY, Lamming DW, Lavu S, Wood JG, Zipkin RE, Chung P, Kisielewski A, Zhang LL, Scherer B, Sinclair DA. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 2003, 425(6954):191-6. Epub 2003 Aug 24.

48. Jarolim S, Millen J, Heeren G, Laun P, Goldfarb DS, Breitenbach M. A novel assay for replicative lifespan in Saccharomyces cerevisiae. FEMS Yeast Res 2004, 5(2):169-77.

49. Bauer, JH, Goupil, S, Garber, GB, Helfand, SL. An accelerated assay for the identification of lifespan-extending interventions in Drosophila melanogaster. Proc Natl Acad Sci USA 2004, 101(35): 12980-5. Epub 2004 Aug 24.

50. Goldberg DM, Yan J, Soleas G. Absorption of three wine-related polyphenols in three different matrices by healthy subjects. Clin Biochem 2003, 36:79-87.

51. Gescher AJ, Steward WP. Relationship between mechanisms, bioavailability, and preclinical chemopreventive efficacy of resveratrol: A conundrum. Cancer Epidemiology, Biomarkers & Prevention 2003, 12: 953-957.

52.Tessitore L, Davit A, Sarotto I, Caderni G. Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21(CIP) expression. Carcinogenesis (Lond) 2002, 21:1619-1622.

53. Li Z, Hong T, Shimada Y, Komoto I, Kawabe A, et al. Suppression of N-nitrosomethylbenzylamine (NMBA)-induced esophageal tumorigenesis in F344 rats by resveratrol. Carcinogenesis (Lond.) 2002, 23:1531-1536.

54. Bannerjee S, Bueso-Ramos C, Aggarwal B. Suppression of 7, 12-dimethylbenz(a)anthracene-induced mammary carcinogenesis in rats by resveratrol: the role of nuclear factor KB, cyclooxygenase 2, and matrix metalloprotease 9. Cancer Res 2002, 62:4945-4954.

55. Crowell JA, Korytko PJ, Morrissey RL, Booth TD, Levine BS. Resveratrol Associated Renal Toxicity. Toxicol Sci 2004, Aug 25 [Epub ahead of print].

paged
Loading posts...
link_magnifier
#6E787E
on
fadeInUp
loading
#6E787E
off
Back