The ability of IF to alter fasting levels of insulin and glucose was independent of overall caloric intake. Mice were killed 24 h after KA administration, tissue sections from their brains were stained with cresyl violet, and the numbers of neurons in regions CA3 and CA1 of each hippocampus were counted.
All mice exhibited seizures of similar magnitude and duration data not shown. Mice were killed 24 h after KA administration, tissue sections from their brains were stained with cresyl violet, and the numbers of neurons in regions CA3 and CA1 of each hippocampus were counted. This may imply that there is an optimal level of restriction for neuroprotective effects, a hypothesis that would require further study to verify.
IF is superior to caloric restriction in protecting hippocampal neurons against excitotoxic injury. Mice that had been maintained for 20 weeks on the indicated diets were subjected to an intrahippocampal injection of the excitotoxin KA; PBS was injected into the contralateral hippocampus of each mouse. Mice were killed 24 h later, coronal brain sections were stained with cresyl violet, and the numbers of undamaged neurons in regions CA3 and CA1 of the hippocampus were quantified.
Values are the mean and SD of determinations made in eight mice per group. However, food intake was not determined, and it was assumed that the difference in body weight was due to some factor other than caloric intake.
The present study establishes that it is the ability of this strain of mice to gorge on days when food is provided that allows them to maintain nearly AL body weight when fed every other day, and they thereby avoid a long-term calorie deficit. That IF feeding was more effective than either LDF or PF in protecting neurons from KA-induced damage demonstrates that the IF-feeding schedule itself is neuroprotective independent of overall caloric intake.
In a study of F rats Masoro et al. Although providing evidence that meal frequency does not alter the ability of caloric restriction to extend life span, that study did not allow a conclusion as to whether IF can increase life span independent of overall calorie intake.
The present study suggests that in the absence of explicit restriction, fasting may play a role in at least some of the effects of DR. Because we did not determine life span in this study, we cannot conclude with certainty that the IF regimen used would extend life span. However, a previous study did establish a life-span-extending effect of the identical IF regimen in the identical strain of mice Moreover, a recent study of mice with adipose tissue-selective disruption of the insulin receptor gene showed that the life span of mice can be increased without a reduction in calorie intake Emerging data from this and other laboratories therefore support future studies to determine whether a reduction in caloric intake is the only dietary method to increase longevity or whether IF without caloric restriction might have beneficial effects as well.
Thus, although caloric restriction is one important mechanism underlying the effects of different DR regimens on life span and disease susceptibility, at least some beneficial effects of DR regimens may result from a mechanism other than an overall reduction in calorie intake. One such possible mechanism is stimulation of cellular stress-resistance pathways, which are induced strongly by the IF regimen used in this study 7 , 8 , A consistent hormonal response to a decrease in food intake in rodents, nonhuman primates, and humans 30 , 31 is a reduction in insulin levels and an increase in insulin sensitivity.
The ability of IF to alter fasting levels of insulin and glucose was independent of overall caloric intake. It has been proposed that some beneficial effects of DR result from decreased blood glucose levels integrated over time 2. Glucose levels in the blood, integrated over time, have been postulated to lead to high levels of nonenzymatic glycation, a form of protein damage.
Higher fuel availability may also lead to an increased frequency of mitochondrial state-four respiration, with consequent increases in reactive oxygen species production from the mitochondrial respiratory chain.
DR has been shown to influence oxyradical production and damage 2 and nonenzymatic glycation The present findings are consistent with a role for glucose in the beneficial effects of IF, because the animals spend a large proportion of their life span in a fasted state.
However, it might be predicted that on feeding days, when IF mice gorge on food, their levels of oxyradical production and glycation are much higher than in mice on the LDF regimen. Apparently, confining bouts of high caloric intake to a limited time window with long intervening periods of fasting results in adaptive responses that do not occur when meals are more frequent.
Previous studies have shown that there are large changes in respiratory quotient as restricted animals move from ingested to stored fuel It may be that alternating periods of anabolism and catabolism play a mechanistic role in triggering increases in cellular stress resistance and the repair of damaged biomolecules or cells. Recent findings suggest that many of the beneficial effects of IF may result from a cellular stress response induced by the fasted state.
For example, it was shown that levels of stress protein chaperones 8 , 34 and neurotrophic factors 35 are increased in rats and mice maintained on an IF-feeding regimen. The superior neuroprotective efficacy of IF compared with LDF feeding documented in this study is consistent with enhancement of cellular stress resistance that results from the stress associated with fasting rather than an overall reduction in caloric intake.
Decreased IGF-1 levels have been proposed to contribute to the protective effect of DR against carcinogenesis However, IF also protects against tumor growth 37 , 38 , suggesting that additional mechanisms must be operative in this beneficial effect of IF.
It is well known that utilization of these fuels increases in the fasting state in various tissues including the brain Because mice on the IF regimen weigh a great deal more than mice on the LDF regimen they may have larger adipose reserves and a greater ketogenic response than that of LDF mice.
Ketogenic diets are prescribed for some patients with epilepsy 26 and are also implemented in several popular weight-loss programs 40 , The findings of this study suggest that IF can enhance health and cellular resistance to disease even if the fasting period is followed by a period of overeating such that overall caloric intake is not decreased. The ability of both the IF and LDF paradigms to enhance stress resistance and extend life span provides a useful tool for discerning the mechanism by which DR exerts its effect.
University of Toronto Press, , pp. Lenin, Stalin, and Hitler: The Age of Social Catastrophe , p. Bolshevism and the Myth of the International Jewish Conspiracy , p. A Short History , p. Vokabular des Nationalsozialismus , p. Protectorate of Bohemia and Moravia. Nazi Persecution Policies in the Annexed Territories — , pp. Hitler's Elite Guard at War — , p. The Origins of Nazi Genocide: University of North Carolina Press.
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