| Caloric restriction is the only intervention that consistently retards the aging process in every model system tested. Despite numerous published studies, little is known regarding its fundamental mode of action. The intent of this thesis is to elucidate the molecular mechanism of caloric restriction, especially regarding the importance of caloric restriction and intake on chaperone expression and protein secretion, and to study global gene expression profiles in different animal models using the recently developed microarray technology. First, we investigated the effects of caloric restriction on endoplasmic reticulum chaperone abundance. The reduction in chaperone levels in CR mice is accompanied by an increase in the secretion rate of three serum proteins. This suggests that caloric restriction may prevent the accumulation of advanced glycation products by promoting serum protein turnover. Second, we studied the rapid response of hepatic chaperones to caloric intake. The expression of many endoplasmic reticulum chaperones and one cytoplasmic chaperone is rapidly induced within hours by each meal, and extends to at least three tissues and two species. This response may be transcriptionally regulated via the action of insulin and glucagon. Third, we performed a microarray analysis to investigate the effects of aging and caloric restriction on hepatic gene expression. Long-term caloric restriction not only prevented many of the age-related changes in expression, but also reprogrammed the genomic profile. Only four weeks of short-term caloric restriction reproduced many changes in gene expression associated with life-long caloric restriction treatment. Therefore, many of the genomic effects of caloric restriction are established rapidly. These results raise the possibility that relatively brief treatments with drugs, nutraceuticals and other procedures can be used to search for caloric restriction mimetics. Forth, we performed a microarray expression profile study to explore the changes during development of diabetes. We found alterations in gene expression of carbohydrate, lipid and protein homeostasis. The abnormality in gene expression patterns was also observed in categories such as cell growth, mitogenesis, detoxification pathways, and inflammatory/immune function. These profiles provide additional molecular insight into diabetes, and may provide targets for gene therapy and rational drug development. |
