Mech Ageing Dev 2000 May 18;115(1-2):61-71
Influence of short-term repeated fasting on the longevity of female (NZB x NZW)F1 mice.
Sogawa H, Kubo C.
Department of Psychosomatic Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, 812-8582, Fukuoka, Japan. sogawa@cephal.med.kyushu-u.ac.jp

Caloric restriction in rodents is well known to retard the rate of aging, increase mean and maximum life-spans, and inhibit the occurrence of many age-associated diseases. However, little is known about the influence of short-term repeated fasting on longevity. In this study, female (NZB x NZW)F1 mice were used to test the physiological effect of short-term repeated fasting (4 consecutive days, every 2 weeks). The results showed that fasting mice survived significantly longer than the full-fed mice, in spite of the fasting group having a heavier body weight than the control group. Mean survival times for fasting and control mice were 64.0+/-15.3 and 47.9+/-9.4 weeks, respectively. Short-term repeated fasting manipulation was also effective on the prolongation of life-span in autoimmune-prone mice.

Biomed Pharmacother 2000 Mar;54(2):74-9
Treatment of diabetes in patients with severe obesity.
Scheen AJ
Department of Medicine, CHU Sart Tilman (B35), Liege 1, Belgium.

ABSTRACT: Besides genetic predisposition, obesity is the most important risk factor for the development of diabetes mellitus, and weight reduction has been shown to markedly improve blood glucose control in obese subjects with type 2 diabetes. Therapeutic strategies for the obese diabetic patient include: 1) promoting weight loss through lifestyle modifications (hypocaloric diet and exercise) and anti-obesity drugs (orlistat, sibutramine, etc.); 2) improving blood glucose control, essentially through the reduction of insulin resistance (metformin, eventually thiazolidinediones) or insulin need (alpha-glucosidase inhibitors) and, at a later stage, the correction of defective insulin secretion (sulphonylureas, repaglinide) or low circulating insulin levels (exogenous insulin); and 3) treating common associated risk factors, such as arterial hypertension and dyslipidaemias, to improve cardiovascular prognosis. When morbid obesity is present, both restoring a good glycemic control and correcting associated risk factors can only be obtained through marked and sustained weight loss. This primary objective justifies more aggressive weight reduction programmes, including very low-calorie diets and bariatric surgery, but only within a multidisciplinary approach and in well-selected patients.

Epilepsia 2001 Nov;42(11):1371-8.
Caloric restriction inhibits seizure susceptibility in epileptic EL mice by reducing blood glucose.
Greene AE, Todorova MT, McGowan R, Seyfried TN.
Biology Department, Boston College, Chestnut Hill, Massachusetts 02167, USA.

Caloric restriction (CR) involves underfeeding and has long been recognized as a dietary therapy that improves health and increases longevity. In contrast to severe fasting or starvation, CR reduces total food intake without causing nutritional deficiencies. Although fasting has been recognized as an effective antiseizure therapy since the time of the ancient Greeks, the mechanism by which fasting inhibits seizures remains obscure. The influence of CR on seizure susceptibility was investigated at both juvenile (30 days) and adult (70 days) ages in the EL mouse, a genetic model of multifactorial idiopathic epilepsy. METHODS: The juvenile EL mice were separated into two groups and fed standard lab chow either ad libitum (control, n=18) or with a 15% CR diet (treated, n=17). The adult EL mice were separated into three groups; control (n=15), 15% CR (n=6), and 30% CR (n=3). Body weights, seizure susceptibility, and the levels of blood glucose and ketones (beta-hydroxybutyrate) were measured over a 10-week treatment period. Simple linear regression and multiple logistic regression were used to analyze the relations among seizures, glucose, and ketones. RESULTS: CR delayed the onset and reduced the incidence of seizures at both juvenile and adult ages and was devoid of adverse side effects. Furthermore, mild CR (15%) had a greater antiepileptogenic effect than the well-established high-fat ketogenic diet in the juvenile mice. The CR-induced changes in blood glucose levels were predictive of both blood ketone levels and seizure susceptibility. CONCLUSIONS: We propose that CR may reduce seizure susceptibility in EL mice by reducing brain glycolytic energy. Our preclinical findings suggest that CR may be an effective antiseizure dietary therapy for human seizure disorders.

Acta Derm Venereol 1983;63(5):397-403.
A fasting and vegetarian diet treatment trial on chronic inflammatory disorders.
Lithell H, Bruce A, Gustafsson IB, Hoglund NJ, Karlstrom B, Ljunghall K, Sjolin K, Venge P, Werner I, Vessby B.

Twenty patients with arthritis and various skin diseases were studied on a metabolic ward during a 2-week period of modified fast followed by a 3-week period of vegetarian diet. During fasting, arthralgia was less intense in many subjects. In some types of skin diseases (pustulosis palmaris et plantaris and atopic eczema) an improvement could be demonstrated during the fast. During the vegan diet, both signs and symptoms returned in most patients, with the exception of some patients with psoriasis who experienced an improvement. The concentrations of lactoferrin in serum reflect the turnover and activity of neutrophil leukocytes. When this protein was initially increased it fell to normal values in most cases. The improvement or impairment of signs and symptoms was related to the lactoferrin levels in serum.

J Nutr Health Aging 2000;4(3):182-186
Effects of Age and Dietary Restriction on Lifespan and Oxidative Stress of SAMP8 Mice with Learning and Memory impairments.
Choi J, Kim D
Faculty of Food Science and Biotechnology, Pukyong National University; 599-1 Daeyeon-Dong, Nam-Gu, Pusan 608-737, Korea.

This study was to evaluate the effect of dietary restriction (DR) on lifespan and oxidative stress of dementia mouse model SAMP8 with impaired learning and memory. SAMP8 female mice were fed either ad libitum (AL) or fed 60% of food intake of AL. Results showed that basal metabolic rates (BMR) were significantly lower (15 to 22%) in DR with increased median and maximum lifespans, suggesting feed and gross efficiencies were significantly lower in DR than in AL. Grading score of senescence resulted in a marked improvement about 2-fold by DR compared with AL. The amounts of lipofuscin at 12 months were significantly lowered 16% in DR than that of AL. Median and maximal lifespans significantly increased (28.5% and 16.4%, respectively) by DR, and also lowered superoxide radical about 15~45% in DR compared with AL at 4, 8 and 12 months of age. On the other hand, superoxide dismutase (SOD) activities were higher (about 15~30%) in DR than those in AL group of SAMP8 except for 4 months of age. Our results suggest that 40% calorie restricted SAMP8 can effectively suppress dementia-related abnormalities during aging.

Proc Natl Acad Sci U S A 2003 May 13;100(10):6216-20
Intermittent fasting dissociates beneficial effects of dietary restriction on glucose metabolism and neuronal resistance to injury from calorie intake.
Anson RM, Guo Z, De Cabo R, Iyun T, Rios M, Hagepanos A, Ingram DK, Lane MA, Mattson MP.
Laboratory of Neurosciences, Gerontology Research Center, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224.

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.

Carcinogenesis. 2002 May;23(5):817-22
Adult-onset calorie restriction and fasting delay spontaneous tumorigenesis in p53-deficient mice.
Berrigan D, Perkins SN, Haines DC, Hursting SD.
Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892-7105, USA.

Heterozygous p53-deficient (p53(+/-)) mice, a potential model for human Li-Fraumeni Syndrome, have one functional allele of the p53 tumor suppressor gene. These mice are prone to spontaneous neoplasms, most commonly sarcoma and lymphoma; the median time to death of p53+/- mice is 18 months. We have shown previously that juvenile-onset calorie restriction (CR) to 60% of ad libitum (AL) intake delays tumor development in young p53-null (-/-) mice by a p53-independent and insulin-like growth factor 1 (IGF-1)-related mechanism. To determine whether CR is effective when started in adult p53-deficient mice, and to compare chronic CR with an intermittent fasting regimen, male p53+/- mice (7-10 months old, 31-32 mice/group) were randomly assigned to the following regimens: (i) AL (AIN-76A diet), (ii) CR to 60% of AL intake or (iii) 1 day/week fast. Food availability on non-fasting days was controlled to prevent compensatory over feeding. Relative to the AL group, CR significantly delayed (P = 0.001) the onset of tumors in adult mice, whereas the 1 day/week fast caused a moderate delay (P = 0.039). Substantial variation in longevity and maximum body weight within treatments was not correlated with variation in growth characteristics of individual mice. In a separate group of p53+/- mice treated for 4 weeks (n = five mice per treatment), plasma IGF-1 levels in CR versus AL mice were reduced by 20% (P < 0.01) and leptin levels were reduced by 71% (P < 0.01); fasted mice had intermediate levels of leptin and IGF-1. Our findings that CR or a 1 day/week fast suppressed carcinogenesis-even when started late in life in mice predestined to develop tumors due to decreased p53 gene dosage-support efforts to identify suitable interventions influencing energy balance in humans as a tool for cancer prevention.

Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6659-63. Epub 2004 Apr 19
Long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans.
Fontana L, Meyer TE, Klein S, Holloszy JO.
Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.

Little is known regarding the long-term effects of caloric restriction (CR) on the risk for atherosclerosis. We evaluated the effect of CR on risk factors for atherosclerosis in individuals who are restricting food intake to slow aging. We studied 18 individuals who had been on CR for an average of 6 years and 18 age-matched healthy individuals on typical American diets. We measured serum lipids and lipoproteins, fasting plasma glucose and insulin, blood pressure (BP), high-sensitivity C-reactive protein (CRP), platelet-derived growth factor AB (PDGF-AB), body composition, and carotid artery intima-media thickness (IMT). The CR group were leaner than the comparison group (body mass index, 19.6 +/- 1.9 vs. 25.9 +/- 3.2 kg/m(2); percent body fat, 8.7 +/- 7% vs. 24 +/- 8%). Serum total cholesterol (Tchol), low-density lipoprotein cholesterol, ratio of Tchol to high-density lipoprotein cholesterol (HDL-C), triglycerides, fasting glucose, fasting insulin, CRP, PDFG-AB, and systolic and diastolic BP were all markedly lower, whereas HDL-C was higher, in the CR than in the American diet group. Medical records indicated that the CR group had serum lipid-lipoprotein and BP levels in the usual range for individuals on typical American diets, and similar to those of the comparison group, before they began CR. Carotid artery IMT was approximately 40% less in the CR group than in the comparison group. Based on a range of risk factors, it appears that long-term CR has a powerful protective effect against atherosclerosis. This interpretation is supported by the finding of a low carotid artery IMT.