by Richard Weindruch and Stephen R. Spindler
The Diabetes Control and Complication Trial, a large prospective cohort study, has shown that higher mean blood glucose levels in non-diabetic humans correlate with a higher prevalence of diabetic retinopathy (damage to the retina), nephropathy (kidney damage) and neuropathy (damage to brain cells).
Caloric restriction in humans and experimental animals like mice, rats and monkeys ameliorates or eliminates all these aging and diabetic pathologies, perhaps just by lowering blood glucose levels. But, living with hunger probably will not be a widely practiced lifestyle. For these reasons, we will test two agents: aminoguanidine and alpha lipoic acid, which should reduce glycation damage during aging.
There are many data from animal studies showing that aminoguanidine inhibits the renal and vascular pathology found in diabetic animals. In aged rats, aminoguanidine protected against the accumulation of AGE and the decline in function of the cardiovascular system and kidney (Li, et al., 1996).
We will study the effects of aminoguanidine administered alone and in combination with alpha lipoic acid. Alpha lipoic acid also may reduce glycation damage as well as act as an antioxidant. This effect may arise from its ability to make muscle and fat tissues more sensitive to insulin, so blood glucose levels are lowered. (Stahl & Sies, 1996).
Why in combination? There are relatively few scientific studies of dietary supplementation with combinations of antioxidants, energy-enhancing agents, glycation inhibitors or hormones. Among the few such reports, there is evidence that multiple agents are able to work together to produce greater benefits than the separate agents alone. A good example is the studies discussed earlier showing that vitamins C and E are regenerated by a-lipoic acid, making them more potent.
There are also recent studies showing that vitamin C supplementation is necessary to restore the health benefits of beta-carotene in smokers, and that mixed forms of vitamin E are more effective than alpha-tocopherol alone.
The hormonal theory of aging will be tested with pregnenolone. Pregnenolone has been called the "mother" steroid hormone. It is produced from cholesterol in several steps, and subsequently serves as a precursor for the steroid hormone DHEA (dehydroepiandrosterone), and its more abundant sulfate ester, DHEA-S. These, then, serve as a precursor for other steroid hormones, including the estrogens and testosterone.
Both men and women suffer a precipitous drop in the levels of other steroid hormones, including DHEA and DHEA-S.
Perhaps not surprisingly, as men age they suffer a decrease in testosterone. Further, the secretion of growth hormone and the anabolic hormone insulin-like growth factor 1 (IGF-1) also decreases with age. During this same time, there is a progressive decline in protein synthesis, lean body mass, bone mass, and an increase in fat mass.
Because pregnenolone serves indirectly as the precursor to other steroids, we have chosen to study mice supplemented with pregnenolone. In doing so, we hope to maintain steroid hormones at higher levels in older animals. Since DHEA and DHEA-S increase levels of IGF-1 in both men and women, pregnenolone also may increase IGF-1.
There is increasingly good evidence that moderate supplementation of DHEA in elderly humans improves lean body mass, reduces heart disease, diabetes, memory loss, immune senescence, and other parameters negatively affected by aging. No large clinical trials have yet been completed. However, a recent DHEA study in mice did not result in lifespan extension. Perhaps pregnenalone will.
Albanes D: Energy balance, body size, and cancer. Crit. Rev. Oncol. Hematol. 10:283-303, 1990
Andersson S-O, Wolk A, Bergstrom R, Giovannucci E, Lindgren C, Baron J, Adami HO: Energy, nutrient intake and prostate cancer risk: a population-based case-control study in Sweden. Intl. J. Cancer 68:716-22, 1996.
Anonymous: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N. Engl. J. Med. 329:977-86, 1993.
Aspnes LE, Lee CM, Weindruch R, Chung SS, Roecker EB, Aiken JM: Caloric restriction reduces fiber loss and mitochondrial abnormalities in aged rat skeletal muscle. Faseb J. in press, 1997.
Baulieu EE: Dehydroepiandrosterone (DHEA): a fountain of youth? [editorial]. J. Clin. Endocrinol. Metab. 81:3147-51, 1996.
Baynes JW: Role of oxidative stress in development of complications in diabetes. Diabetes 40:405-412, 1991.
Beal MF, Henshaw, DR, Jenkins BG, Rosen BR, Schulz, JB. Coenzyme Q10 and nicotinamide block striatal lesions produced by the mitochondrial toxin malonate. Ann.Neurol. 36: 882-888, 1994.
Bellamy D: Long-term action of prednisolone phosphate on a strain of short-lived mice. Exp. Gerontol. 3:327-33, 1968.
Beyer RE An analysis of the role of coenzyme Q in free radical generation and as an antioxidant. Biochem.Cell Biol. 70:390-403, 1992.
Birkmayer W, Birkmayer JGD, Vrecko C, Paletta B, Reschenhofer E, Ott E. Nicotinamide adenine dinucleotide (NADH) as medication for Parkinson's disease - Experience with 415 patients, New Trends Clin. Neuropharmacol. 4:1:7-24, 1990.
Birt DF, Higgenbotham SM, Patil K, Pour P: Nutritional effects on the lifespan of Syrian hamsters. Age 5:11, 1982a.
Blackett AD, Hall DA: The effects of vitamin E on mouse fitness and survival. Gerontology 27:133-135, 1981.
Blot WJ, Li JY, Taylor PR, et al.: Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J. Natl. Cancer Inst. 85:1483-92, 1993. Bowman B. Acetyl-carnitine and Alzheimer's disease. Nutr. Rev. 50:142-144, 1992.
Cotzias GC, Miller ST, Tang LC, Papavasiliou PS, Wang YY: Levodopa, fertility and longevity. Science 196:549, 1977.
Dalderup LM, Visser W: Influence of extra sucrose in the daily food on the life-span of Wistar albino rats. Nature 222:1050-1052, 1969. Diplock AT: Antioxidants and disease prevention. Mol. Aspects Med. 15:293-376, 1994.
Diplock AT: The Leon Golberg Memorial Lecture. Antioxidants and disease prevention. Food Chem. Toxicol. 34:1013-20, 1996.
Drori D, Folman Y: Environmental effects on longevity in the male rat: exercise, mating, castration and restricted feeding. Exp. Gerontol. 11:25, 1976.
Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude JR, Rosselin G: Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia 19:205-10, 1980.
Everitt AV, Seedsman NJ, Jones F: The effects of hypophysectomy and continuous food restriction, begun at ages 70 and 400 days, on collagen aging, proteinuria, incidence of pathology and longevity in the male rat. Mech. Ageing Dev. 12:161, 1980.
Feldman DB, McConnell EE, Knapka JJ: Growth, kidney disease, and longevity of Syrian hamsters (Mesocricetus auratus) fed varying levels of protein. Lab. Animal Sci. 32:613-618, 1982.
Ferrari P, Weidmann P: Insulin, insulin sensitivity and hypertension. J. Hypertens. 8:491-500, 1990.
French CE, Ingram RH, Uram JA, Barron GP, Swift RW: The influence of dietary fat and carbohydrate on growth and longevity in rats. J. Nutr. 51:329, 1953.
Harman D: Free radical theory of aging: effect of free radical reaction inhibitors on the mortality rate of male LAF1 mice. J. Gerontol. 23:476, 1968.
Harris SB, Gunion MW, Rosenthal MJ, Walford RL: Serum glucose, glucose tolerance, corticosterone and free fatty acids during aging in energy restricted mice. Mech. Ageing Dev. 73:209- 21, 1994.
Hayes JD & Pulford DJ. The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit.Rev.Biochem.Mol.Biol. 30:445-600, 1995.
Hochschild R: Effect of dimethylaminoethyl p-chlorophenoxyacetate on the lifespan of male Swiss Webster albino mice. Exp. Gerontol. 8:177, 1973.
Holloszy JO, Smith EK, Vining M, Adams S: Effect of voluntary exercise on longevity of rats. J. Appl. Physiol. 59:826-831, 1985.
Iwasaki K, Gleiser CA, Masoro EJ, McMahan CA, E. S, Yu BP: Influence of the restriction of individual dietary components on longevity and age-related disease of Fischer rats: the fat component and the mineral component. J. Gerontol. Biol. Sci. 43:B13-B21, 1988b.
Iwasaki K, Gleiser CA, Masoro EJ, McMahan CA, Seo E, Yu BP: The influence of dietary protein source on longevity and age-related disease processes of Fischer rats. J. Gerontol. Biol. Sci. 43:B5-B12, 1988a.
Kagawa Y: Impact of westernization on the nutrition of Japanese: changes in physique, cancer, longevity, and centenarians. Prev.ÊMed. 7:205, 1978.
Kanter MM: Free radicals, exercise, and antioxidant supplementation [see comments]. Int.J.Sport.Nutr. 4:205-220, 1994.
Kaunitz H, Johnson RE: Influence of dietary fats on disease and longevity. In: A. Chavez, H. Bourges and S. Basta, eds. "Proc IXth Intl Congr Nutr (Book of Abstracts)." Basel: Karger; 1975:362-373.
Kehrer JP & Lund LG: Cellular reducing equivalents and oxidative stress. Free Radic.Biol.Med. 17:65-75, 1994.
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. 266:E540-7, 1994.
Kibler HHJ, H. D.: Temperature and longevity in male rats. J. Gerontol. 21:52, 1966.
Kohn RR: Effect of antioxidants on life span of C57BL mice. J. Gerontol. 26:378, 1971.
Koizumi A, Wada Y, Tsukada M, Hasegawa J: Low blood glucose levels and small islets of Langerhans in the pancreas of calorie-restricted mice. Age 12:93-96, 1989.
Koizumi A, Wada Y, Tuskada M, Kayo T, Naruse M, Horiuchi K, Mogi T, Yoshioka M, Sasaki M, Miyamaura Y, Abe T, Ohtomo K, Walford RL: A tumor preventive effect of dietary restriction is antagonized by a high housing temperature through deprivation of torpor. Mech. Ageing Dev. 92:67-82, 1996.
Kokkonen GC, Barrows CH: The effect of dietary vitamin, protein and intake levels on the life span of mice of different ages. Age 8:13-15, 1985.
LaBella FS, Vivian S: Effect of beta-aminopropionitrile or prednisolone on survival of male LAF/J mice. Exper. Gerontol. 10:185-8, 1975.
Lee AT, Cerami A: Role of glycation in aging. Ann. NY Acad. Sci. 663:63-70, 1992.
Li YM, Steffes M, Donnelly T, Liu C, Fuh H, Basgen J, Bucala R, Vlassara H: Prevention of cardiovascular and renal pathology of aging by the advancedglycation inhibitor aminoguanidine. Proc. Natl. Acad. Sci. U. S. A. 93:3902-7, 1996.
Ludwig FC, Elashoff RM: Mortality in syngeneic rat parabionts of different chronological age. Trans. N. Y. Acad. Sci. 34:582-7, 1972.
Masoro EJ, Compton C, Yu BP, Bertrand H: Temporal and compositional dietary restrictions modulate age-related changes in serum lipids. J. Nutr. 113:880-892, 1983.
Masoro EJ, Katz MS, McMahan CA: Evidence for the glycation theory of aging from the food-restricted rodent model. J. Gerontol. Biol. Sci. 44:B20-2, 1989.
Meydani SN, Wu D, Santos MS, Hayek MG: Antioxidants and immune response in aged persons: overview of present evidence. Am.J.Clin.Nutr. 62:1462S-1476S, 1995.
Mortensen SA: Perspectives on therapy of cardiovascular diseases with coenzyme Q10 (ubiquinone). Clin. Investig. 71:S116- S123, 1993.
Murtagh-Mark CM, Reiser KM, Harris RJ, McDonald RB: Source of dietary carbohydrate affects life span of Fischer 344 rats independent of caloric restriction. J. Gerontol. Biol. Sci. 50A:B148- 54, 1995.
Nakagawa I, Sasaki A, Kajimoto M, Fukuyama T, Suzuki T, Yamada E: Effect of protein nutrition on growth, longevity and incidence of lesions in the rat. J. Nutr. 104:1576-1583, 1974.
Nyce JW, Magee PN, Hard GC, Schwartz A: Inhibition of 1,2-dimethylhydrazine-induced colon tumorigenesis in Balb/c mice by dehydroepiandrosterone. Carcinogenesis 5:57, 1984.
Papavasiliou PS, Miller ST, Thal LJ, Nerder LJ, Houlihan G, Rao SN, Stevens JM: Age-related motor and catecholamine alterations in mice on levodopa supplemented diet. Life Sci. 28:2945, 1981.
Pierpaoli W, Regelson W: Pineal control of aging: Effect of melatonin and pineal grafting on aging mice. Proc. Natl. Acad. Sci. USA 91:787-91, 1994.
Reaven GM, Wright D, Mondon CE, Solomon R, Ho H, Reaven GM: Effect of age and diet on insulin secretion and insulin action in the rat. Diabetes 32:175-180, 1983.
Reiter RJ, Pablos MI, Agapito TT, Guerrero JM: Melatonin in the context of the free radical theory of aging. Ann.N.Y.Acad.Sci. 786:362-378, 1996.
Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC: Vitamin E consumption and the risk of coronary heart disease in men. New Eng. J. Med. 328:1450-6, 1993.
Robertson TG, Ray LA: Experimental studies on growth. XII. The influence of pituitary gland (anterior lobe) tissue, tethelin, egg lecithin, and cholesterol upon the duration of life of the white mouse. J. Biol. Chem. 37:427, 1919.
Ross MH: Nutrition and longevity in experimental animals. In: M. Winick, eds. "Nutrition and Aging." New York: Wiley; 1976:43-57.
Rossetti L, Giaccari A, DeFronzo RA: Glucose toxicity. Diabetes Care 13:610-30, 1990.
Schneider EL, Reed JD: Modulations of aging processes. In: C. E. Finch and E. L. Schneider, eds. "Handbook of the Biology of Aging," 2nd Ed. New York: Van Nostrand Reinhold; 1985b:45-76.
Schroeder HA, Mitchener M: Selenium and tellerium in rats: Effects on growth, survival and tumors. J. Nutr. 101:1531, 1971.
Shigenaga MK, Hagen TM, Ames BN: Oxidative damage and mitochondrial decay in aging. Proc.Natl.Acad.Sci. U.S.A. 91:10771- 10778, 1994.
Sies H, Stahl W: Vitamins E and C, beta-carotene, and other carotenoids as antioxidants. Am.J.Clin.Nutr. 62: 1315S-1321S, 1995.
Skolnick AA: Scientific verdict still out on DHEA [news]. JAMA 276:1365-7, 1996.
Smith MA, Taneda S, Richey PL, Miyata S, Yan SD, Stern D, Sayre LM, Monnier VM, Perry G: Advanced Maillard reaction end products are associated with Alzheimer disease pathology. Proc. Natl. Acad. Sci. U.S.A. 91:5710-4, 1994.
Sohal RS, Weindruch R: Oxidative stress, caloric restriction, and aging. Science 273:59-63, 1996.
Stahl W, Sies H: Uptake of lycopene and its geometrical isomers is greater from heat-processed than from unprocessed tomato juice in humans. J.Nutr. 122:2161-2166, 1992.
Stahl W, Sies H: Lycopene: a biologically important carotenoid for humans? Arch.Biochem.Biophys. 336:1-9, 1996.
Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC: Vitamin E consumption and the risk of coronary disease in women. New Eng. J. Med. 328:1444-9, 1993.
Steinmetz KA, Potter JD: Vegetables, fruit, and cancer prevention: a review. J. Amer. Diet. Assoc. 96:1027-39, 1996.
Stout RW: Insulin and atheroma. 20-yr perspective. Diabetes Care 13:631-54, 1990.
Talalay P, Fahey JW, Holtzclaw, WD, Prestera, T, Zhang Y: Chemoprotection against cancer by phase 2 enzyme induction. Toxicol.Lett. 82-83:173-179, 1995.
Van Liew JB, Davis PJ, Davis FB, Bernardis LL, Deziel MR, Marinucci LN, Kumar D: Effects of aging, diet, and sex on plasma glucose, fructosamine, and lipid concentrations in barrier-raised Fischer 344 rats. J. Gerontol. Biol. Sci. 48:B184-90, 1993.
Velthuis-te Wierik EJ, Westerterp KR, van den Berg H: Impact of a moderately energy-restricted diet on energy metabolism and body composition in non-obese men. Int. J. Obesity 19:318-24, 1995.
Verzar F: Note on the influence of prucaine (Novocain), para-aminobenzoic acid or dimethylethanolamine on the ageing of rats. Gerontologia 3:351, 1959.
Walford RL. "Maximum Life Span." New York: Norton; 1983.
Walford RL, Harris SB, Gunion MW: The calorically restricted low-fat nutrient dense diet in Biosphere 2 significantly lowers blood glucose, total leukocyte count, cholesterol, and blood pressure in humans. Proc. Natl. Acad. Sci. USA 89:11533-7, 1992.
Walford RL, Meredith PJ, Cheney KE: Immunoengineering: prospects for correction of age-related immunodeficiency status. In: T. Makinodan and E. Yunis, eds. "Immunology and Aging." New York: Plenum; 1977:183-201.
Weindruch R: Caloric restriction and aging. Sci. Am. 274(1):46- 52, 1996.
Weindruch R, McFeeters G, Walford RL: Food intake reduction and immunologic alterations in mice fed dehydroepiandrosterone. Exp. Gerontol. 19:297-304, 1984.
Weindruch R, Walford RL: Dietary restriction in mice beginning at one year of age: Effects on life-span and spontaneous cancer incidence. Science 215:1415-1418, 1982.
Weindruch R, Walford RL. "The Retardation of Aging and Disease by Dietary Restriction." Springfield, IL: C.C. Thomas; 1988. White RD, Wilson DM, Glosson JA, Madsen DC, Rowe WB, Goldberg DI: Toxicity evaluations of L-cysteine and Procysteine, a cysteine prodrug, given once intravenously to neonatal rats. Toxicol.Lett. 69:15-24, 1993.
Yen SS, Morales AJ, Khorram O: Replacement of DHEA in aging men and women. Potential remedial effects. Ann. N. Y. Acad. Sci. 774:128-42, 1995.
Ziyadeh FN, Cohen MP: Effects of glycated albumin on mesangial cells: Evidence for a role in diabetic nephropathy. Mol. Cell. Biochem. 125:19-25, 1993.