The Protective Effects of Dietary Restriction Can be Dissociated From Calorie Intake
R. Michael Anson*, Zhihong Guo, Rafael de Cabo, Titilola Iyun, Michelle Rios, Adrienne Hagepanos, Donald K. Ingram, Mark P. Mattson, Mark A. Lane
Laboratory of Neurosciences, NIA, NIH, 5600 Nathan Shock Drive, Baltimore, MD 21224
*current affiliation: Windward Islands Research Institute & St. George's University, St. George's, Grenada
Restriction of caloric intake slows the rate of aging in many species, including C57Bl/6 mice. Other protective effects, such as resistance to kainic acid (KA) neurotoxicity, have also been established. Two feeding paradigms are commonly used to restrict caloric intake: limited daily feeding (LDF), in which animals are given access to a pre-measured and limited amount of food; and every other day feeding (EOD), in which animals are fed ad libitum and fasted on alternate days. Both paradigms are known to produce dramatic increases in lifespan in comparison to animals fed ad libitum (AL). Animals fed using the LDF paradigm weigh less than animals fed AL. The body weight of LD-fed relative to AL-fed animals is consistently reported to be roughly proportional to the relative food intakes. However, we noticed an anomaly in C57Bl/6J mice fed using the EOD paradigm: bodyweight in these mice was only reduced by 19%. This indicated that despite the similar effects on aging rate, the two paradigms differed in at least some physiological outcomes. This provides an opportunity to separate variables that are critical to the modulation of aging rate from those that are incidental to the feeding paradigm. In the present study, mice were assigned to one of three groups at eight weeks of age: AL, LDF, or EOD. To control for caloric intake versus periodic food deprivation a fourth group was added: these mice were provided daily with an amount of food equal to the average daily intake of mice in the EOD group (pair fed, "PF").
After 14 weeks of restriction, total serum IGF-1 was lowest in the LDF group, and highest in the EOD and PF groups. Fasting insulin and glucose were lower in the restricted groups than in either the AL or PF groups. In contrast, fasting serum beta-hydroxybutyrate was highest in the EOD group, intermediate in the AL and PF groups, and lowest in the LDF group. Behavioral tests intended to measure hunger suggested that the LDF mice were most motivated to seek food, but great inter-individual variability was noted. Preliminary counts indicate that KA-induced damage to the hippocampus was reduced by both restriction paradigms but did not differ between the AL and PF groups. The most startling finding was that the EOD mice were able to gorge on the "fed" days, so that their weekly intake was only 9% below that of the AL mice. The striking differences between the EOD group and the PF group whose caloric intake was identical lead us to conclude that the protection provided by caloric restriction is mediated not by the caloric intake per se, but rather by periodic food deprivation. This could be due to a neuroendocrine response (a hypothesis supported by the lowered fasting insulin), to removal of oxidative or other damage during periods of catabolism, or conceivably to a stress response induced by periodic hunger.
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