Researchers uncover proteins necessary to the benefits of calorie restriction by the use of genetic engineering to create lineages of laboratory animals that each lack a specific protein of interest, and then observing the results of calorie restriction for each lineage. Unlike most such efforts, in this case some of the mechanisms thought important to calorie restriction still function even without neuropeptide Y, the protein in question, but nonetheless life is not extended.
Since calorie restriction changes near everything in metabolism along the way to extending life, it has been difficult to identify which of these myriad changes are required or which contribute the greatest benefit. This work may prove useful to winnow the list of responses to calorie restriction in order to find those most important to health and longevity.
Knowledge of genes essential for the life-extending effect of dietary restriction (DR) in mammals is incomplete. In this study, we found that neuropeptide Y (Npy), which mediates physiological adaptations to energy deficits, is an essential link between DR and longevity in mice. The lifespan-prolonging effect of lifelong 30% DR was attenuated in Npy-null mice, as was the effect on the occurrence of spontaneous tumors and oxidative stress responses in comparison to wild-type mice.
In contrast, the physiological processes activated during adaptation to DR, including inhibition of anabolic signaling molecules (insulin and insulin-like growth factor-1), modulation of adipokine and corticosterone levels, and preferential fatty acid oxidation, were unaffected by the absence of Npy. This study clearly showed that Npy is a neuropeptide that links DR to longevity in mammals. However, Npy is not required for many of the physiological adaptations to DR.
Among the neuroendocrine changes induced by DR, inhibition of anabolic signaling molecules, including insulin, GH/IGF-1, and mTOR, and upregulation of adiponectin were found to extend lifespan in rodents without restricted food intake. Thus, the effects of DR were attributed to these molecules or related signaling pathways based on the observed physiological adaptations. However, in the present study, the salutary effects of DR were significantly reduced in Npy−/− mice, even though they showed normal physiological adaptions to DR. Therefore, these neuroendocrine adaptations to DR may not be essential for longevity or cancer and stress resistance.