Intermittent Fasting Dissociates Beneficial Effects of Dietary Restriction on Glucose Metabolism and Neuronal Resistance to Injury from Calorie Intake

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2003 May 2

PMID 12724520

Citations 280

Authors

R Michael Anson

Zhihong Guo

Rafael de Cabo

Titilola Iyun

Michelle Rios

Adrienne Hagepanos

Donald K Ingram

Mark A Lane

Mark P Mattson

Affiliations

Soon will be listed here.

Abstract

Dietary restriction has been shown to have several health benefits including increased insulin sensitivity, stress resistance, reduced morbidity, and increased life span. The mechanism remains unknown, but the need for a long-term reduction in caloric intake to achieve these benefits has been assumed. We report that when C57BL6 mice are maintained on an intermittent fasting (alternate-day fasting) dietary-restriction regimen their overall food intake is not decreased and their body weight is maintained. Nevertheless, intermittent fasting resulted in beneficial effects that met or exceeded those of caloric restriction including reduced serum glucose and insulin levels and increased resistance of neurons in the brain to excitotoxic stress. Intermittent fasting therefore has beneficial effects on glucose regulation and neuronal resistance to injury in these mice that are independent of caloric intake.

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References

Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech R . D-beta-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease. Proc Natl Acad Sci U S A. 2000; 97(10):5440-4. PMC: 25847. DOI: 10.1073/pnas.97.10.5440. View

Duan W, Guo Z, Mattson M . Brain-derived neurotrophic factor mediates an excitoprotective effect of dietary restriction in mice. J Neurochem. 2001; 76(2):619-26. DOI: 10.1046/j.1471-4159.2001.00071.x. View

Guo Z, Ersoz A, Butterfield D, Mattson M . Beneficial effects of dietary restriction on cerebral cortical synaptic terminals: preservation of glucose and glutamate transport and mitochondrial function after exposure to amyloid beta-peptide, iron, and 3-nitropropionic acid. J Neurochem. 2000; 75(1):314-20. DOI: 10.1046/j.1471-4159.2000.0750314.x. View

Kari F, Dunn S, French J, Barrett J . Roles for insulin-like growth factor-1 in mediating the anti-carcinogenic effects of caloric restriction. J Nutr Health Aging. 2000; 3(2):92-101. View

Anderson J, Konz E, Jenkins D . Health advantages and disadvantages of weight-reducing diets: a computer analysis and critical review. J Am Coll Nutr. 2000; 19(5):578-90. DOI: 10.1080/07315724.2000.10718955. View

Pan J, Rothman T, Behar K, Stein D, Hetherington H . Human brain beta-hydroxybutyrate and lactate increase in fasting-induced ketosis. J Cereb Blood Flow Metab. 2000; 20(10):1502-7. DOI: 10.1097/00004647-200010000-00012. View

Gilbert D, Pyzik P, Freeman J . The ketogenic diet: seizure control correlates better with serum beta-hydroxybutyrate than with urine ketones. J Child Neurol. 2001; 15(12):787-90. DOI: 10.1177/088307380001501203. View

Wolkow C . Life span: getting the signal from the nervous system. Trends Neurosci. 2002; 25(4):212-6. DOI: 10.1016/s0166-2236(02)02133-1. View

Hsieh C, Deford J, Flurkey K, Harrison D, Papaconstantinou J . Implications for the insulin signaling pathway in Snell dwarf mouse longevity: a similarity with the C. elegans longevity paradigm. Mech Ageing Dev. 2002; 123(9):1229-44. DOI: 10.1016/s0047-6374(02)00036-2. View

10.

Shimokawa I, Higami Y, Utsuyama M, Tuchiya T, Komatsu T, Chiba T . Life span extension by reduction in growth hormone-insulin-like growth factor-1 axis in a transgenic rat model. Am J Pathol. 2002; 160(6):2259-65. PMC: 1850833. DOI: 10.1016/S0002-9440(10)61173-X. View

11.

Mukherjee P, El-Abbadi M, Kasperzyk J, Ranes M, Seyfried T . Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model. Br J Cancer. 2002; 86(10):1615-21. PMC: 2746602. DOI: 10.1038/sj.bjc.6600298. View

12.

Bluher M, Kahn B, Kahn C . Extended longevity in mice lacking the insulin receptor in adipose tissue. Science. 2003; 299(5606):572-4. DOI: 10.1126/science.1078223. View

13.

Telfer Brunton W, PERCY-ROBB I . A rapid method for the measurement of plasma glucose concentration. Clin Chim Acta. 1976; 69(1):131-5. DOI: 10.1016/0009-8981(76)90483-6. View

14.

Fernandes G, Yunis E, Miranda M, Smith J, GOOD R . Nutritional inhibition of genetically determined renal disease and autoimmunity with prolongation of life in kdkd mice. Proc Natl Acad Sci U S A. 1978; 75(6):2888-92. PMC: 392670. DOI: 10.1073/pnas.75.6.2888. View

15.

MASORO E, Yu B, Bertrand H . Action of food restriction in delaying the aging process. Proc Natl Acad Sci U S A. 1982; 79(13):4239-41. PMC: 346614. DOI: 10.1073/pnas.79.13.4239. View

16.

HEICK H, Begin-Heick N . An improved double antibody radioimmunoassay for the determination of insulin in serum, plasma, and tissue incubation media. Can J Biochem. 1982; 60(10):962-6. DOI: 10.1139/o82-123. View

17.

GOODRICK C, Ingram D, Reynolds M, Freeman J, Cider N . Effects of intermittent feeding upon growth, activity, and lifespan in rats allowed voluntary exercise. Exp Aging Res. 1983; 9(3):203-9. DOI: 10.1080/03610738308258453. View

18.

Vazquez J, MORSE E, Adibi S . Effect of dietary fat, carbohydrate, and protein on branched-chain amino acid catabolism during caloric restriction. J Clin Invest. 1985; 76(2):737-43. PMC: 423891. DOI: 10.1172/JCI112029. View

19.

Kalant N, Stewart J, Kaplan R . Effect of diet restriction on glucose metabolism and insulin responsiveness in aging rats. Mech Ageing Dev. 1988; 46(1-3):89-104. DOI: 10.1016/0047-6374(88)90117-0. View

20.

SIEGEL I, Liu T, Nepomuceno N, Gleicher N . Effects of short-term dietary restriction on survival of mammary ascites tumor-bearing rats. Cancer Invest. 1988; 6(6):677-80. DOI: 10.3109/07357908809078034. View