Neuroendocrine and pharmacological manipulations to assess how caloric restriction increases life span

As part of an effort to review current understanding of the mechanisms by w hich caloric restriction (CR) extends maximum life span, the authors of the present review were requested to develop a list of key issues concerning t he potential role of neuroendocrine systems in mediating these effects. It has long been hypothesized that failure of specific neuroendocrine function s during aging leads to key age-related systemic and physiological failures , and more recently it has been postulated that physiological neuroendocrin e responses to CR may increase life span. However, although the acute neuro endocrine responses to fasting have been well studied, it is not clear that these responses are necessarily identical to those observed ill response t o the chronic moderate (30% to 50% reduction) CR that increases maximum lif t: span. Therefore the recommendations of this panel fall into two categori es. First, further characterization of neuroendocrine responses to CR over the entire life span is needed. Second, rigorous interventional studies are needed to test the extent to which neuroendocrine responses to CR mediate the effects of CR on life span, or alternatively if CR protects the functio n of essential neuroendocrine cells whose impairment reduces life span. Com plimentary studies using rodent models, nonhuman primates, and humans will be essential to assess the generality of elucidated mechanisms, and to dete rmine if such mechanisms might apply to humans.