| Laboratory studies consistently demonstrate extended lifespan in animals on calorie restriction (CR), where total caloric intake is reduced by 10-40% but adequate nutrition is otherwise maintained. CR has been further shown to delay the onset and severity of chronic diseases associated with aging such as cancer, and to extend the functional health span of important faculties like cognition. Less understood are the underlying mechanisms through which CR might act to induce such alterations. One theory postulates that CR's beneficial effects are intimately tied to the neuroendocrine response to low energy availability, of which the arcuate nucleus in the hypothalamus plays a pivotal role. Neuropeptide Y (NPY), a neurotransmitter in the front line of the arcuate response to low energy availability, is the primary hunger signal affected by CR.;It was hypothesized that the arcuate nucleus and NPY are critical not only for certain key physiological alterations, but also for increased stress resistance, decreased cancer risk and enhanced cognition noted with CR. These hypotheses were tested using two mouse models---one chemically treated to impair arcuate function and another genetically modified to lack NPY---maintained on CR or unlimited feeding.;Physical performance on locomotor tasks was improved by CR in all mice but benefits to cognition were not observed in either of the neuroendocrine-impaired models. Similarly, while improvements to body composition and reduced serum leptin were induced by CR in all mice, these alterations did not manifest in certain trademark alterations in glucose homeostasis in the models. Resistance to oxidative stress as assessed by survivorship following treatment with the liver toxin diquat and tumorigenicity following a skin tumor induction regimen also suggested the models of impaired hunger sensing fared less well than control mice; liver stress was lethal in NPY knockout mice on CR, and both NPY and arcuate-damaged CR mice were most susceptible to induced skin tumor formation. Taken together these results support the hypothesis that the neuroendocrine response to CR is critical for eliciting some of the beneficial effects of CR. |
