Caloric restriction-induced life extension of rats and mice: A critique of proposed mechanisms

In 1935, Clive McCay and colleagues reported that decreasing the food intake of rats extends their life. This finding has been confirmed many times using rat and mouse models. The responsible dietary factor in rats is the reduced intake of energy; thus, this phenomenon is frequently referred to as caloric restriction. Although many hypotheses have been proposed during the past 74 years regarding the underlying mechanism, it is still not known. It is proposed that this lack of progress relates to the fact that most of these hypotheses have been based on a single underlying mechanism and that this is too narrow a focus. Rather, a broad framework is needed. Hormesis has been suggested as providing such a framework. Although it is likely that hormesis is involved in the actions of caloric restriction, it also is probably too narrowly focused. Based on currently available data, a provisional broad framework is presented depicting the complex of mechanisms that likely underlie the life-extending and other anti-aging actions of caloric restriction.