Systematic gene expression profile of hypothalamus in calorie-restricted mice implicates the involvement of mTOR signaling in neuroprotective activity

Abstract

Calorie restriction (CR) delays aging and onset of age-related diseases in a variety of organisms from yeast to mammals. However, the molecular mechanism underlying the CR effect remains to be elucidated. It is well known that the hypothalamus is an important component of the brain neuroendocrine system for the regulation of the aging process. In this report, we have systematically examined the gene expression profiles of hypothalami from 5-, 12-, 19- and 24-month-old mice fed ad libitum or subjected to CR since weaning. Our results demonstrated that CR significantly altered the expression level of 490 genes in an age-dependent manner, with the greatest impact at middle age. Classification based on functional analysis indicated that a large number of these genes were involved in brain development and neurogenesis, including genes involved in Wingless (Wnt) and Notch signaling pathways. In addition, the expression levels of numerous genes involved in the stress and inflammatory responses, as well as apoptosis, were affected by CR. Interestingly, we found that a number of genes involved in the stress response and apoptosis were down-regulated in early but up-regulated in late stage CR. The most notable finding was that CR altered the expression of genes associated with the mammalian target of the rapamycin (mTOR) nutrient sensing pathway, which has recently been shown to be involved in the regulation of energy intake and aging. By applying rapamycin, a specific pharmacological inhibitor of mTOR signaling, we found that the inhibition of mTOR could significantly prevent neuronal apoptosis induced by Paraquat. Taken together, our results provided not only a systematic expression profile of the hypothalamic response to CR, but also revealed the linkage between CR and mTOR signaling in the neuroprotection in mice.