Dietary restriction (DR) has been demonstrated to prolong the lifespan of a number of organisms. Fischer 344 rats demonstrate a two-fold increase in plasma corticosterone (B) in response to DR which is maintained during the life span of the animal. This increase in B is related to physiological changes associated with life extension: decreased cell division, alterations in other hormones associated with nutrient allocation and endocrine regulation, and a attenuation of the inflammatory response. Together these physiological changes may be indicators of the role of B as a mediator of the ability of DR to prolong life span. The objective of this pilot proposal is to test the hypothesis that the mechanism by which DR attenuates inflammation through elevated B is to alter the secretion of B and the expression of specific genes involved in the inflammatory process. This hypothesis will be tested using the male Fischer 344 rats, an animal model commonly used in aging studies.
The specific aim of this pilot project is to examine the time course of the inflammatory response in young ad libitum fed (AL) and DR rats in response to lipopolysaccharide (LPS; an inflammatory agent). The response to LPS will be measured by examining the LPS-induced rise in adrenocorticotropin (ACTH) and in the plasma. Additionally, the ability of LPS to induce the expression of genes known to be involved in the inflammatory response (inducible nitric oxide synthase and cytokines) and liver damage (as indicated by the presence of specific hepatic enzymes) will be measured. It is hypothesized that if DR does indeed prolong life span by suppressing the immune response and/or by altering the sensitivity of animals to an inflammatory agent, then the LPS-induced rises in ACTH and B, expression of genes involved in the inflammatory response and the concentration of liver specific enzymes will be decreased in DR compared to AL rats. This pilot project will provide the foundation research necessary to further explore one particular aspect through which DR prolongs provide the foundational research necessary to further explore one particular aspect through which DR prolongs life span, the role of the hypothalamic-hypophyseal-adrenal axis (HPA) in mediating the response to inflammatory challenge. If such a role is indeed elucidate, then it would add further support to the theory that dietary induced hypercorticosteronism is a key mediator of life extension.
