Life Extension Magazine February 2005
As We See It
A Revolutionary Concept Slowly Gains Recognition
By William Faloon
Deadly Role of Oxygen Radicals
Scientific American’s special issue provides abundant information on the destructive force of free radicals and how this relates to aging. The magazine described how oxygen radicals damage almost every critical component of cells, including DNA, proteins, and membranes.
Researchers interviewed by Scientific American describe how they were able to double the life span of insects by programming their genes to produce more natural antioxidants such as superoxide dismutase.14 They note that pigeons live 35 years, or about 12 times longer than rats of approximately the same weight—with the difference being that pigeons produce half as many free radicals as rodents do.
According to Scientific American, oxidants bombard the DNA inside our cells roughly 10,000 times each day, but many of the free radicals generated are intercepted and neutralized by antioxidants. They note, however, that free radical damage adds up over time and “the result just may be an older, frailer you.”
Encouragingly, researchers interviewed by Scientific American describe studies in which old rats looked and functioned like younger rats following oral administration of antioxidants.12 The researchers cautioned, however, that humans cannot expect the same benefits from most conventional supplements, as these do not supply the full spectrum of nutrients found in fruits and vegetables, and their nutrients may not be adequately disseminated throughout the body. Exceptions were nutrients like lipoic acid, which is uniquely able to boost antioxidant activity within the cell and protect against mitochondrial decay.
Critical Need to Keep Sugar Out
Of the various approaches to slowing aging, calorie restriction is considered the gold standard.15-31 The problem, of course, is that few people can adhere to a lifelong low-calorie diet.
Scientific American considered the beneficial bodily effects induced by calorie restriction, such as increased levels of the hormone DHEA and reduced blood levels of insulin and artery-clogging lipids.32-36 But one of the magazine’s most profound findings concerns calorie restriction’s effect of lowering glucose, which results in diminished cellular metabolic activity and fewer free radicals being generated.37 Scientific American produced a brilliant molecular drawing of how excess glucose may accelerate aging and how calorie-restriction mimetics could slow aging by blocking the ability of cells to use excess glucose.12
As members know, the Life Extension Foundation has been a pioneer in investigating compounds to mimic the beneficial effects of calorie restriction. Our research has uncovered the calorie restriction-mimicking effects of the drug metformin.38-42 Based on widely publicized findings about resveratrol, we are now seeking to ascertain whether this flavonoid can favorably alter genes that cause our bodies to degenerate with age.43-74
In reading Scientific American’s report on the broad-spectrum benefits of calorie restriction, the importance of keeping excess sugar out of one’s bloodstream becomes abundantly clear. People can now do this by taking relatively small amounts of super-soluble fiber before meals.
Reasons for Optimism
For those who think there is a limit to life span, Scientific American cites studies showing how the manipulation of genes in worms increased their life span to the human equivalent of 500 years.75-77 Scientific American goes on to point out how researchers can now make normal human cells live forever in a petri dish—something that scientists have long ridiculed as an impossibility.
If gene manipulation can be done in worms and human cell lines, how long will it be before it enables people to live for hundreds of healthy years? While pessimists reply “never” because human genomic structure is too complicated, groundbreaking research funded by Life Extension has already identified ways to measure the effects of anti-aging compounds on gene expression.78-81 This enables scientists to identify and validate ways to manipulate old cells to behave more like younger cells.
As the Life Extension Foundation enters its twenty-fifth year, the scientific community, the government, and even the news media are slowly recognizing that our concept of extending life is in fact technically feasible. This change in perception represents an enormous transformation in how humans view their role in the universe.
More Research Is Urgently Needed
As the New Year begins, we have reason to be optimistic about the prospect of living much longer than what is predicted by the mortality tables. We at Life Extension, however, are very much aware that time is not on our side. If our older members are to benefit from spectacular advances that may be only a few years away, the pace of scientific research must be accelerated.
The encouraging news is that new antioxidants have been discovered that significantly suppress damaging free radical and inflammatory reactions that are linked to underlying aging processes. These more potent antioxidants were introduced to Life Extension members less than two months ago, and several articles in this month’s issue elaborate on the science backing these enhanced formulations.
Every time you purchase a product designed to counteract age-related disease, you directly support our pioneering research. In 2004, the results of our work were published in several prestigious scientific journals, including the Proceedings of the National Academy of Sciences USA.82-84 Equally important to our research programs is that the proceeds from our supplement sales help us to educate greater numbers of people about the need to prioritize research that would lead to cures for today’s killer diseases, while at the same time discovering validated methods to eradicate biological aging.
Because of our intensive work last year, Life Extension members can now obtain superior formulations that are priced lower and require swallowing fewer capsules than before. At this time of year, long-time members traditionally stock up on a large supply of Life Extension products. The reason is simple: until the end of this month, prices on all supplements are discounted below the low prices members enjoy throughout the year.
For longer life,
1. Available at: http://www.nci.nih.gov/cancer_information/prevention. Accessed November 15, 2004.
2. Available at: http://www.nia.nih.gov/AboutNIA/StrategicPlan/ResearchGoalA/Subgoal1.htm. Accessed November 15, 2004.
3. Available at: http://www.ki.se/cmb/bmt/aging.pdf. Accessed November 15, 2004.
4. Corliss, R, Lemonick M. How to live to be 100. TIME. August 30, 2004:38-46.
5. Ljungquist B, Berg S, Lanke J, McClearn GE, Pedersen NL. The effect of genetic factors for longevity: a comparison of identical and fraternal twins in the Swedish Twin Registry. J.Gerontol A Biol Sci Med Sci. 1998 Dec;53(6):M441-6.
6. Iliadou A, Lichtenstein P, de Faire U, Pedersen NL. Variation in genetic and environmental influences in serum lipid and apolipoprotein levels across the life span in Swedish male and female twins. Am J Med Genet. 2001 Aug 22;102(1):48-58.
7. McLaughlin PJ and Weihrauch JL. Vitamin E content of foods. J Am Diet Assoc. 1979;75(6):647-65.
8. Schwenke DC. Does lack of tocopherols and tocotrienols put women at increased risk of breast cancer? J Nutr Biochem. 2002 Feb;13(1):2-20.
9. Heinonen M, Piironen V. The tocopherol, tocotrienol, and vitamin E content of the average Finnish diet. Int J Vitam Nutr Res. 1991;61(1):27-32.
10. Murphy SP, Subar AF, Block G. Vitamin E intakes and sources in the United States. Am J Clin Nutr. 1990 Sep;52(2):361-7.
11. Panfili G, Fratianni A, Irano M. Normal phase high-performance liquid chromatography method for the determination of tocopherols and tocotrienols in cereals. J Agric Food Chem. 2003 Aug 2;51(14):3940-4.
12. Available at: http://www.sciamdigital.com/browse.cfm?sequencenameCHAR=item&methodnameCHAR=resource_
13. Available at: http://www.un.org/NewLinks/older/99/older.htm. Accessed November 15, 2004.
14. Sohal RS, Toy PL, Allen RG. Relationship between life expectancy, endogenous antioxidants and products of oxygen free radical reactions in the housefly, Musca domestica. Mech Ageing Dev. 1986 Oct;36(1):71-7.
15. Cao SX, Dhahbi JM, Mote PL, Spindler SR. Genomic profiling of short- and long-term caloric restriction effects in the liver of aging mice. Proc Natl Acad Sci USA. 2001 Oct 11;98(19):10630-5.
16. Sohal RS, Agarwal S, Candas M, Forster MJ, Lal H. Effect of age and caloric restriction on DNA oxidative damage in different tissues of C57BL/6 mice. Mech Ageing Dev. 1994 Nov 20;76(2-3):215-24.
17. Walford RL and Spindler SR. The response to calorie restriction in mammals shows features also common to hibernation: a cross-adaptation hypothesis. J Gerontol A Biol Sci Med Sci. 1997 Aug;52(4):B179-83.
18. Weindruch R. Caloric restriction and aging. Sci Am. 1996 Feb;274(1):46-52.
19. Spindler SR. Calorie restriction enhances the expression of key metabolic enzymes associated with protein renewal during aging. Ann N Y Acad Sci. 2001 May;928:296-304.
20. Kayo T, Allison DB, Weindruch R, Prolla TA. Influences of aging and caloric restriction on the transcriptional profile of skeletal muscle from rhesus monkeys. Proc Natl Acad Sci U S A. 2001 Apr 24;98(9):5093-8.
21. Weindruch R. The retardation of aging by caloric restriction: studies in rodents and primates. Toxicol Pathol. 1996 Dec;24(6):742-5.
22. Aspnes LE, Lee CM, Weindruch R, Chung SS, Roecker EB, Aiken JM. Caloric restriction reduces fiber loss and mitochondrial abnormalities in aged rat muscle. Faseb J. 1997 Jul;11(7):573-81.
23. Fishbein L, ed. Biological Effects of Dietary Restriction. New York: Springer-Verlag;1991.
24. Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996 Aug 5;273(5271):59-63.
25. Weindruch R, Sohal RS. Seminars in medicine of the Beth Israel Deaconess Medical Center. Caloric intake and aging. N Engl J Med. 1997 Nov 2;337(14):986-94.
26. Weindruch R, Walford RL. Dietary restriction in mice beginning at one year of age: Effects on life span and spontaneous cancer incidence. Science. 1982 Apr;215(4538):1415-8.
27. Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging in mice by dietary restriction: longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986 May;116(4):641-54.
28. Roth GS, Lane MA, Ingram DK, et al. Biomarkers of caloric restriction may predict longevity in humans. Science. 2002 Jul 2;297(5582):811.
29. Bluher M, Khan BP, Kahn CR. Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003 Feb 24;299(5606):572-4.
30. Kenyon C. I want to live forever. New Scientist. 2003 Nov 18;180(2417):46.
31. Lane MA, Ingram DK, Ball SS, Roth GS. Dehydroepiandrosterone sulfate: a biomarker of primate aging slowed by calorie restriction. Clin Endocrinol Metab. 1997 Aug;82(7):2093-6.
32. Kemnitz JW, Roecker EB, Weindruch R, Elson DF, Baum ST, Bergman RN: Dietary restriction increases insulin sensitivity and lowers blood glucose in rhesus monkeys. Am J Physiol. 1994 May;266(4 Pt 1):E540-7.
33. Ramsey JJ, Colman RJ, Binkley NC, et al. Dietary restriction and aging in rhesus monkeys: the University of Wisconsin study. Exp Gerontol. 2000 Dec;35(9-10):1131-49.
34. Roth GS, Ingram DK, Black A, Lane MA. Effects of reduced energy intake on the biology of aging: the primate model. Eur J Clin Nutr. 2000 Jul;54 Suppl 3:S15-20.
35. Ingram DK, Anson RM, de Cabo R, et al. Development of calorie restriction mimetics as a prolongevity strategy Ann N Y Acad Sci. 2004 Jul;1019:412-23.
36. Deutsch JC, Santhosh-Kumar CR, Kolhouse JF. Efficacy of Metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1996 Feb 25;334(4):269-70.
37. Charles MA, Eschwege E. Prevention of type 2 diabetes: role of metformin. Drugs. 1999;58 Suppl.1:71-3.
38. Fontbonne A., Charles MA, Juhan-Vague I, et al. The effect of metformin on the metabolic abnormalities associated with upper body fat distribution. Results of the BIGPRO 1 trial. Diabetes Care. 1996 Oct;19(9):920-6.
39. Glueck CJ, Wang P, Fontaine R, Tracy T, Sieve-Smith L. Metformin induced resumption of normal menses in 39 of 43 (91%) previously amenorrheic women polycystic ovary syndrome. Metabolism. 1999 May;48(4):511-9.
40. Velazquez EM, Mendoza S, Hamer T, Sosa F, Glueck CJ. Metformin therapy in polycystic ovary syndrome reduces hyperinsulinemia, insulin resistance, hyperandrogenemia, and systolic blood pressure, while facilitating menstrual regulation and pregnancy. Metabolism. 1994 Jun;43(5):647-54.
41. Tadolini B, Juliano C, Piu L, Franconi F, Cabrini L. Resveratrol inhibition of lipid peroxidation. Free Radic Res. 2000 Aug;33(1):105-14.
42. Simonini G, Pignone A, Generini S, et al. Emerging potentials for an antioxidant therapy as a new approach to the treatment of systemic sclerosis. Toxicology. 2000 Dec 30;155(1-3):1-15.
43. Zou JG, Wang ZR, Huang YZ, Cao KJ, Wu JM. Effect of red wine and wine polyphenol resveratrol on endothelial function in hypercholesterolemic rabbits. Int J Mol Med. 2003 Apr;11(3):317-20.
44. Haider UG, Sorescu D, Griendling KK, Vollmar AM, Dirsch VM. Resveratrol increases serine 15-phosphorylated but transcriptionally impaired p53 and induces a reversible DNA replication block in serum-activated vascular smooth muscle cells. Mol Pharmacol. 2003 May;63(4):925-32.
45. Zbikowska HM, Olas B. Antioxidants with carcinostatic activity (resveratrol, vitamin E and selenium) in modulation of blood platelet adhesion. J Physiol Pharmacol. 2000 Oct;51(3):513-20.
46. Pace-Asciak CR, Hahn S, Diamandis EP, Soleas G, Goldberg DM. 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 Apr 31;235(2):207-19.
47. Burkitt MJ, Duncan J. Effects of trans-resveratrol on copper-dependent hydroxyl-radical formation and DNA damage: evidence for hydroxyl-radical scavenging and a novel, glutathione-sparing mechanism of action. Arch Biochem Biophys. 2000 Oct 15;381(2):253-63.
48. Jang JH, Surh YJ. Protective effect of resveratrol on beta-amyloid-induced oxidative PC12 cell death. Free Radic Biol Med. 2003 May 15;34(8):1100-10.
49. Chanvitayapongs S, Draczynska-Lusiak B, Sun AY. Amelioration of oxidative stress by antioxidants and resveratrol in PC12 cells. Neuroreport. 1997 May 14;8(6):1499-502.
50. Yang YB, Piao YJ. Effects of resveratrol on secondary damages after acute spinal cord injury in rats. Acta Pharmacol Sin. 2003 Aug;24(7):703-10.
51. Sinha K, Chaudhary G, Gupta YK. Protective effect of resveratrol against oxidative stress in middle cerebral artery occlusion model of stroke in rats. Life Sci. 2002 Jul 28;71(6):655-65.
52. Cal C, Garban H, Jazirehi A, Yeh C, Mizutani Y, Bonavida B. Resveratrol and cancer: chemoprevention, apoptosis, and chemoimmunosensitizing activities. Curr Med Chem Anti-Canc Agents. 2003 Apr;3(2):77-93.
53. Pervaiz S. Resveratrol–from the bottle to the bedside? Leuk Lymphoma. 2001 Mar;40(5-6):491-8.
54. Ding XZ, Adrian TE. Resveratrol inhibits proliferation and induces apoptosis in human pancreatic cancer cells. Pancreas. 2002 Dec;25(4):e71-6.
55. Gusman J, Malonne H, Atassi G. A reappraisal of the potential chemopreventive and chemotherapeutic properties of resveratrol. Carcinogenesis. 2001 Sep;22(8):1111-7.
56. Lu R, Serrero G. Resveratrol, a natural product derived from grape, exhibits anti-estrogenic activity and inhibits the growth of human breast cancer cells. J Cell Physiol. 1999 Jul;179(3):297-304.
57. Serrero G, Lu R. Effect of resveratrol on the expression of autocrine growth modulators in human breast cancer cells. Antioxid Redox Signal. 2001 Dec;3(6):969-79.
58. Mitchell SH, Zhu W, Young CY. Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Res. 1999 Dec 1;59(23):5892-5.
59. Narayanan BA, Narayanan NK, Stoner GD, Bullock BP. Interactive gene expression pattern in prostate cancer cells exposed to phenolic antioxidants. Life Sci. 2002 Apr 1;70(15):1821-39.
60. Wietzke JA, Welsh J. Phytoestrogen regulation of a vitamin D3 receptor promoter and 1.25-dihydroxyvitamin D3 actions in human breast cancer cells. J Steroid Biochem Mol Biol. 2003 Mar;84(2-3):149-57.
61. Ulsperger E, Hamilton G, Raderer M, et al. Resveratrol pretreatment desensitizes AHTO-7 human osteoblasts to growth stimulation in response to carcinoma cell supernatants. Int J Oncol. 1999 Dec;15(5):955-9.
62. Nakagawa H, Kiyozuka Y, Uemura Y, et al. Resveratrol inhibits human breast cancer cell growth and may mitigate the effect of linoleic acid, a potent breast cancer cell stimulator. J Cancer Res Clin Oncol. 2001 May;127(4):258-64.
63. 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 Jun;993:276-86.
64. Floreani M, Napoli E, Quintieri L, Palatini P. Oral administration of trans-resveratrol to guinea pigs increases cardiac DT-diaphorase and catalase activities, and protects isolated atria from menadione toxicity. Life Sci. 2003 Jun 2;72(24):2741-50.
65. Ferguson LR. Role of plant polyphenols in genomic stability. Mutat Res. 2001 May 18;475(1-2):89-111.
66. Casper RF, Quesne M, Rogers IM, et al. Resveratrol has antagonist activity on the aryl hydrocarbon receptor: implications for prevention of dioxin toxicity. Mol Pharmacol. 1999 Nov;56(4):784-90.
67. Hsieh TC, Burfeind P, Laud K, et al. Cell cycle effects and control of gene expression by resveratrol in human breast carcinoma cell lines with different metastatic potentials. Int J Oncol. 1999 Sep;15(2):245-52.
68. Torres-Lopez JE, Ortiz MI, Castaneda-Hernandez G, Alonso-Lopez R, Asomoza-Espinosa R, Granados-Soto V. Comparison of the antinociceptive effect of celecoxib, diclofenac and resveratrol in the formalin test. Life Sci. 2002 Mar 22;70(14):1669-76.
69. Mahady GB, Pendland SL, Chadwick LR. Resveratrol and red wine extracts inhibit the growth of CagA+ strains of Helicobacter pylori in vitro. Am J Gastroenterol. 2003 Jul;98(6):1440-1.
70. Yen GC, Duh PD, Lin CW. Effects of resveratrol and 4-hexylresorcinol on hydrogen peroxide-induced oxidative DNA damage in human lymphocytes. Free Radic Res. 2003 Jun;37(5):509-14.
71. Revel A, Raanani H, Younglai E, et al. Resveratrol, a natural aryl hydrocarbon receptor antagonist, protects lung from DNA damage and apoptosis caused by benzo[a]pyrene. J Appl Toxicol. 2003 Jul-Aug;23(4):255-61.
72. Adhami VM, Afaq F, Ahmad N. Suppression of ultraviolet B exposure-mediated activation of NF-kappaB in normal human keratinocytes by resveratrol. Neoplasia. 2003 Feb;5(1):74-82.
73. Tsang WY, Lemire BD. Mitochondrial genome content is regulated during nematode development. Biochem Biophys Res Commun. 2002 Mar 15;291(1):8-16.
74. Hill AA, Hunter CP, Tsung BT, Tucker-Kellogg G, Brown EL. Genomic analysis of Gene Expression in C. elegans. Science. 2000 Nov 27;290(5492):809-12.
75. Houthoofd K, Braeckman BP, Johnson TE, Vanfleteren JR. Extending life span in C. elegans. Science. 2004 Sep 27;305(5688):1238-9.
76. Bartke A, Coschigano K, Kopchick J, et al. Genes that prolong life: relationships of growth hormone and growth to aging and life span. J Gerontol A Biol Sci Med Sci. 2001 Sep;56(8):B340-9.
77. Brown-Borg HM, Borg KE, Meliska CJ, Bartke A. Dwarf mice and the ageing process. Nature. 1996 Dec 7;384(6604):33.
78. Flurkey K, Papaconstantiou J, Miller RA, Harrison DE. Life span extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci USA. 2001 Jul 5;98(12):6736-41.
79. Miller RA. Kleemeier Award Lecture: Are there genes for aging? J Gerontol A Biol Sci Med Sci. 1999 Aug;54(7):B297-307.
80. Lee CK, Allison DB, Brand J, Weindruch R, Prolla TA. Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts. Proc Natl Acad Sci USA. 2002 Dec 12; 99(23):14988-93.
81. Lee CK, Klopp RG, Weindruch R, Prolla TA. Gene expression profile of aging and its retardation by caloric restriction. Science. 1999 Sep 27;285(5432):1390-3.
82. Lee CK, Weindruch R, Prolla TA. Gene-expression profile of the aging brain in mice. Nat Genet. 2000 Aug;25(3):294-7.
83. Lane MA, Baer DJ, Rumpler WV, et al. Calorie restriction lowers body temperature in rhesus monkeys, consistent with a postulated anti-aging mechanism in rodents. Proc Natl Acad Sci USA. 1996 May 30;93(9):4159-64.
84. Available at: http://www.lef.org/featuredarticles/spindler_press_release01.html. Accessed November 15, 2004.