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Longevity Health and Wellness Protocol

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Recently developed molecular and genetic interventions have been successful in controlling aging and longevity. Even though these lines of investigation hold great potential, studies using CR in rodents and nonhuman primates continue to provide valuable information. Because the effects of CR on aging processes, age-associated diseases, and longevity could be universal across species, this nutritional paradigm would have similar eVects in humans. We believe that the genes or signal cascades altered by CR could be the principle target for generating novel mutant animal models that show suppressed aging processes and live longer. Moreover, CR mimetics, which are applicable in humans, may represent one strategy to modulate aging processes and longevity. Therefore, we emphasize the importance of dietary and calorie interventions and the interpretation of their eVects in aging research, particularly in rodents, to humans.


  • 1] Weindruch R, Walford RL. The retardation of aging and disease by dietary restriction. Springfield, IL: Charles C. Thomas, 1988.
  • 2] Yu BP. Modulation of aging processes by dietary restriction. Boca Raton, FL: CRC Press, 1994.
  • 3] Cheney KE, Liu RK, Smith GS, Meredith PJ, Mickey MR, Walford RL. The effect of dietary restriction of varying duration on survival, tumor patterns, immune function, and body temperature in B10C3F1 female mice. J Gerontol 1983; 38:420-430.
  • 4] Duffy PH, Leakey JE, Pipkin JL, Turturro A, Hart RW. The physiologic, neurologic, and behavioral effects of caloric restriction related to aging, disease, and environmental factors. Environ Res 1997; 73:242-248.
  • 5] Keenan KP, Smith PF, Hertzog P, Soper K, Ballam GC, Clark RL. The effects of overfeeding and dietary restriction on Sprague-Dawley rat survival and early pathology biomarkers of aging. Toxicol Pathol 1994; 22:300-315.
  • 6] Maeda H, Gleiser CA, Masoro EJ, Murata I, McMahan CA, Yu BP. Nutritional influences on aging of Fischer 344 rats: II. Pathology. J Gerontol 1985; 40:671-688.
  • 7] Iwasaki K, Gleiser CA, Masoro EJ, McMahan CA, Seo EJ, 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 1988; 43: B13-B21.
  • 8] Yu BP, Masoro EJ, McMahan CA. Nutritional influences on aging of Fischer 344 rats: I. Physical, metabolic, and longevity characteristics. J Gerontol 1985; 40:657-670.
  • 9] Iwasaki K, Gleiser CA, Masoro EJ, McMahan CA, Seo EJ, Yu BP. The influence of dietary protein source on longevity and age-related disease processes of Fischer rats. J Gerontol 1988; 43:B5-B12.
  • 10] Shimokawa I, Higami Y, Hubbard GB, McMahan CA, Masoro EJ, Yu BP. Diet and the suitability of the male Fischer 344 rat as a model for aging research. J Gerontol 1993; 48: B27-B32.
  • 11] 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; 116:641-654.
  • 12] Higami Y, Yu BP, Shimokawa I, Masoro EJ, Ikeda T. Duration of dietary restriction: An important determinant for the incidence and age of onset of leukemia in male F344 rats. J Gerontol 1994; 49:B239-B244.
  • 13] Masoro EJ. Caloric restriction and aging: An update. Exp Gerontol 2000; 35:299-305.
  • 14] Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science 1996; 273:59-63.
  • 15] Koubova J, Guarente L. How does calorie restriction work? Genes Dev 2003; 17:313-321.
  • 16] Ramsey JJ, Harper ME, Weindruch R. Restriction of energy intake, energy expenditure, and aging. Fre Rad Biol Med 2000; 29:946-968.
  • 17] Merry BJ. Molecular mechanisms linking calorie restriction and longevity. Int J Biochem Cell Biol 2002; 34:1340-1354.
  • 18] Holliday R. Food, reproduction and longevity: Is the extended life span of calorie-restricted animals an evolutionary adaptation? Bioessays 1989; 10:125-127.
  • 19] Masoro EJ, Austad SN. The evolution of the antiaging action of dietary restriction: A hypothesis. J Gerontol A Biol Sci Med Sci 1996; 51:B387-B391.
  • 20] Shimokawa I, Higami Y. Leptin signaling and aging: Insight from caloric restriction. Mech Ageing Dev 2001; 122:1511-1519.
  • 21] McCarter RJ, Palmer J. Energy metabolism and aging: A lifelong study of Fischer 344 rats. Am J Physiol 1992; 263:E448-E452.
  • 22] Sonntag WE, Xu X, Ingram RL, D'Costa A. Moderate caloric restriction alters the subcellular distribution of somatostatin mRNA and increases growth hormone pulse amplitude in aged animals. Neuroendocrinol. 1995; 61:601-608.
  • 23] Breese CR, Ingram RL, Sonntag WE. Influence of age and long-term dietary restriction on plasma insulin-like growth factor-1 (IGF-1), IGF-1 gene expression, and IGF-1 binding proteins. J Gerontol 1991; 46:B180-B187.
  • 24] Brown-Borg HM, Borg KE, Meliska CJ, Bartke A. Dwarf mice and the ageing process. Nature 1996; 384:33.
  • 25] Shimokawa I, Higami Y, Utsuyama M, et al. Life span extension by reduction in growth hormone-insulin-like growth factor-1 axis in a transgenic rat model. Am J Pathol 2002; 160:2259-2265.
  • 26] Bartke A, Wright JC, Mattison JA, Ingram DK, Miller RA, Roth GS. Extending the life span of long-lived mice. Nature 2001; 414:412.
  • 27] Shimokawa I, Higami Y, Tsuchiya T, et al. Life span extension by reduction of the growth hormone-insulin-like growth factor-1 axis: Relation to caloric restriction. FASE J 2003; 17:1108-1109.
  • 28] Masoro EJ, Compton C, Yu BP, Bertrand H. Temporal and compositional dietary restrictions modulate age-related changes in serum lipids. J Nutr 1983; 113:880-892.
  • 29] Wang ZQ, Bell-Farrow AD, Sonntag W, Cefalu WT. Effect of age and caloric restriction on insulin receptor binding and glucose transporter levels in aging rats. Exp Gerontol 1997; 32:671-684.
  • 30] Yamaza H, Komatsu T, Chiba T, et al. A transgenic dwarf rat model as a tool for the study of calorie restriction and aging. Exp Gerontol 2004; 39:269-272.
  • 31] Koizumi A, Tsukada M, Wada Y, Masuda H, Weindruch R. Mitotic activity in mice is suppressed by energy restriction-induced torpor. J Nutr 1992; 122:1446-1453.
  • 32] Koizumi A, Wada Y, Tuskada M, et al. A tumor preventive effect of dietary restriction is antagonized by a high housing temperature through deprivation of torpor. Mech Ageing Dev 1996; 92:67-82.
  • 33] Jin YH, Koizumi A. Decreased cellular proliferation by energy restriction is recovered by increasing housing temperature in rats. Mech Ageing Dev 1994; 75:59-67.
  • 34] Koizumi A, Tsukada M, Hirano S, Kamiyama S, Masuda H, Suzuki KT. Energy restriction that inhibits cellular proliferation by torpor can decrease susceptibility to spontaneous and asbestos-induced lung tumors in A/J mice. Lab Invest 1993; 68:728-739.
  • 35] McCarter RJ, McGee JR. Transient reduction of metabolic rate by food restriction. Am J Physiol 1989; 257:E175-E179.
  • 36] Dulloo AG, Girardier L. 24 hour energy expenditure several months after weight loss in the underfed rat: Evidence for a chronic increase in whole-body metabolic efficiency. Int J Obes Relat Metab Disord 1993; 17:115-123.
  • 37] Blanc S, Schoeller D, Kemnitz J, Weindruch R, et al. Energy expenditure of rhesus monkeys subjected to 11 years of dietary restriction. J Clin Endocrinol Metab 2003; 88:16-23.
  • 38] Herlihy JT, Stacy C, Bertrand HA. Long-term food restriction depresses serum thyroid hormone concentrations in the rat. Mech Ageing Dev 1990; 53:9-16.
  • 39] Snyder DL, Wostmann BS, Pollard M. Serum hormones in diet-restricted gnotobiotic and conventional Lobund-Wistar rats. J Gerontol 1988; 43:B168-B173.
  • 40] Herlihy JT, Thomas J, Bertrand H, Stacy C. The aging of the cardiovascular system: Modulation by dietary restriction. Ag Nutr 1992; 3:185-191.
  • 41] Kingsley TR, Nekvasil NP, Snyder DL. The influence of dietary restriction, germ-free status, and aging on adrenal catecholamines in Lobund-Wistar rats. J Gerontol 1991; 46: B135-B141.
  • 42] Duffy PH, Feuers RJ, Leakey JA, Nakamura K, Turturro A, Hart RW. Effect of chronic caloric restriction on physiological variables related to energy metabolism in the male Fischer 344 rat. Mech Ageing Dev 1989; 48:117-133.
  • 43] Barzilai N, Banerjee S, Hawkins M, Chen W, Rossetti L. Caloric restriction reverses hepatic insulin resistance in aging rats by decreasing visceral fat. J Clin Invest 1998; 101:1353-1361.
  • 44] Higami Y, Pugh TD, Page GP, Allison DB, Prolla TA, Weindruch R. Adipose tissue energy metabolism: Altered gene expression profile of mice subjected to long-term caloric restriction. FASE J 2004; 18:415-417.
  • 45] Schwartz MW, Woods SC, Porte D, Jr., Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature 2000; 404:661-671.
  • 46] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature 1994; 372:425-432.
  • 47] Ahima RS, Prabakaran D, Mantzoros C, et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996; 382:250-252.
  • 48] Bornstein SR. Is leptin a stress related peptide? Nat Med 1997; 3:937.
  • 49] Maffei M, Halaas J, Ravussin E, et al. Leptin levels in human and rodent: Measurement of plasma leptin and of RNA in obese and weight-reduced subjects. Nat Med 1995; 1:1155-1161.
  • 50] Shimokawa I, Higami Y. A role for leptin in the antiaging action of dietary restriction: A hypothesis. Aging Clin Exp Med 1999; 11:380-382.
  • 51] Kadowaki T, Hara K, Yamauchi T, Terauchi Y, Tobe K, Nagai R. Molecular mechanism of insulin resistance and obesity. Exp Biol Med 2003; 228:1111-1117.
  • 52] Fruebis J, Tsao TS, Javorschi S, et al. Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 2001; 98:2005-2010.
  • 53] Yamauchi T, Kamon J, Waki H, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001; 7:941-946.
  • 54] Yamauchi T, Kamon J, Minokoshi Y, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002; 8:1288-1295.
  • 55] Zhu M, Miura J, Lu LX, et al. Circulating adiponectin levels increase in rats on caloric restriction: The potential for insulin sensitization. Exp Gerontol 2004; 39:1049-1059.
  • 56] Sabatino F, Masoro EJ, McMahan CA, Kuhn RW. Assessment of the role of the glucocorticoid system in aging processes and in the action of food restriction. J Gerontol 1991; 46:B171-B179.
  • 57] Kalu DN, Hardin RH, Cockerham R, Yu BP. Aging and dietary modulation of rat skeleton and parathyroid hormone. Endocrinology 1984; 115:1239-1247.
  • 58] Merry BJ, Holehan AM. Onset of puberty and duration of fertility in rats fed a restricted diet. J Reprod Fertil 1979; 57:253-259.
  • 59] Hamilton GD, Bronson FH. Food restriction and reproductive development: Male and female mice and male rats. Am J Physiol 1986; 250:R370-R376.
  • 60] Bronson FH. Food-restricted, prepubertal, female rats: Rapid recovery of luteinizing hormone pulsing with excess food, and full recovery of pubertal development with gonadotropin-releasing hormone. Endocrinology 1986; 118:2483-2487.
  • 61] Howland BE. The influence of feed restriction and subsequent re-feeding on gonadotropin secretion and serum testosterone levels in male rats. J Reprod Fertil 1975; 44:429-436.
  • 62] Campbell GA, Kurcz M, Marshall S, Meites J. Effects of starvation in rats on serum levels of follicle stimulating hormone, luteinizing hormone, thyrotropin, growth hormone and prolactin; Response to LH-releasing hormone and thyrotropin-releasing hormone. Endocrinology 1977; 100:580-587.
  • 63] Glass AR, Swerdloff RS. Nutritional influences on sexual maturation in the rat. Fed Proc 1980; 39:2360-2364.
  • 64] Howland BE. Gonadotrophin levels in female rats subjected to restricted feed intake. J Reprod Fertil 1971; 27:467-470.
  • 65] Nelson JF, Gosden RG, Felicio LS. Effect of dietary restriction on estrous cyclicity and follicular reserves in aging C57BL/6J mice. Biol Reprod 1985; 32:515-522.
  • 66] Merry BJ, Holehan AM. Serum profiles of LH, FSH, testosterone and 5 alpha-DHT from 21 to 1000 days of age in ad libitum fed and dietary restricted rats. Exp Gerontol 1981; 16:431-444.
  • 67] Ingram DK, Cutler RG, Weindruch R, et al. Dietary restriction and aging: The initiation of a primate study. J Gerontol 1990; 45:B148-B163.
  • 68] Kemnitz JW, Weindruch R, Roecker EB, Crawford K, Kaufman PL, Ershler WB. Dietary restriction of adult male rhesus monkeys: Design, methodology, and preliminary findings from the first year of study. J Gerontol 1993; 48:B17-B26.
  • 69] Lane MA, Ingram DK, Cutler RG, Knapka JJ, Barnard DE, Roth GS. Dietary restriction in nonhuman primates: Progress report on the NIA study. Ann N Acad Sci 1992; 673:36-45.
  • 70] Black A, Tilmont EM, Handy AM, Ingram DK, Roth GS, Lane MA. Calorie restriction reduces the incidence of proliferative disease: Preliminary data from the NIA CR in nonhuman primate study. Gerontologist 2000; 40:5.
  • 71] Roth GS, Ingram DK, Lane MA. Calorie restriction in primates: Will it work and how will we know? J Am Geriatr Soc 1999; 47:896-903.
  • 72] Lane MA, Mattison J, Ingram DK, Roth GS. Caloric restriction and aging in primates: Relevance to humans and possible CR mimetics. Microsc Res Tech 2002; 59:335-338.
  • 73] Roth GS, Lane MA, Ingram DK, et al. Biomarkers of caloric restriction may predict longevity in humans. Science 2002; 297:811.
  • 74] Lane MA, Reznik A, Tilmont EM, et al. Aging and food restriction alter some indices of bone metabolism in male rhesus monkeys (Macaca mulatta). J Nutr 1995; 125:1600-1610.
  • 75] Lane MA, Ball SS, Ingram DK, et al. Diet restriction in rhesus monkeys lowers fasting and glucose-stimulated glucoregulatory endpoints. Am J Physiol 1995; 268:E941-E948.
  • 76] Lane MA, Baer DJ, Rumpler WV, et al. Dietary restriction lowers body temperature in rhesus monkeys consistent with a postulated anti-aging mechanism in rodents. Proc Nat Acad Sci USA 1996; 93:4159-4164.
  • 77] Lane MA, Ingram DK, Roth GS. Calorie restriction in nonhuman primates: Effects on diabetes and cardiovascular disease risk. Toxicol Sci 1999; 52:41-48.
  • 78] Kagawa Y. Impact of Westernization on the nutrition of Japanese: Changes in physique, cancer, longevity, and centenarians. Prev Med 1978; 7:205-217.
  • 79] Albanes D, Jones DY, Schatzkin A, Micozzi MS, Taylor PR. Adult stature and risk of cancer. Cancer Res 1988; 48:1658-1662.
  • 80] Albanes D. Energy balance, body size, and cancer. Crit Rev Oncol Hematol 1990; 10:283-303.
  • 81] 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 1992; 89:11533-11537.
  • 82] Velthuis-te Wierik EJ, van den Berg H, Schaafsma G, Hendriks HF, Brouwer A. Energy restriction, a useful intervention to retard human ageing? Results of a feasibility study. Eur J Clin Nutr 1994; 48:138-148.
  • 83] Nelson JF. Neuroendocrine involvement in the retardation of aging by dietary restriction: A hypothesis. In: Modulation of Aging Processes by Dietary Restriction. Boca Raton, FL: CRC Press, 1994: 37-55.
  • 84] Overton JM, Williams TD. Behavioral and physiologic responses to caloric restriction in mice. Physiol Behav 2004; 81:749-754.
  • 85] Overton JM, William TD, Chambers JB, Rashotte ME. Central leptin infusion attenuates the cardiovascular and metabolic effects of fasting in rats. Hypertension 2001; 37:663-669.
  • 86] Salway JG. Metabolism at a glance, second ed. OxfordK: Blackwell Science, 1999.
  • 87] Hashimoto T, Cook WS, Qi C, Yeldandi AV, Reddy JK, Rao MS. Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting. J Biol Chem 2000; 275:28918-28928.
  • 88] Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 1999; 103:1489-1498.
  • 89] Kroetz DL, Yook P, Costet P, Bianchi P, Pineau T. Peroxisome proliferator-activated receptor alpha controls the hepatic CYP4A induction adaptive response to starvation and diabetes. J Biol Chem 1998; 273:31581-31589.
  • 90] Rao MS, Reddy JK. Peroxisomal beta-oxidation and steatohepatitis. Semin Live Dis 2001; 21:43-55.
  • 91] Smith SA, Cawthorne MA, Simson DL. Glucose metabolism in the obese hyperglycaemic (C57B1/6 ob/ob) mouse: The effects of fasting on glucose turnover rates. Diabete Res 1986; 3:83-86.
  • 92] Lemberger T, Saladin R, Vazquez M, et al. Expression of the peroxisome proliferator-activated receptor alpha gene is stimulated by stress and follows a diurnal rhythm. J Biol Chem 1996; 271:1764-1769.


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Staying Young

Staying Young

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