DIETARY RESTRICTION AND ATTENUATION OF INFLAMMATORY RESPONSE

饮食限制（DR）已被证明可以延长许多生物体的寿命。 Fischer 344大鼠显示血浆皮质酮（B）响应于DR增加两倍，其在动物的寿命期间维持。 B的增加与寿命延长相关的生理变化有关：细胞分裂减少，与营养分配和内分泌调节相关的其他激素的改变，以及炎症反应的减弱。 这些生理变化可能共同指示了B作为DR延长寿命能力的介体的作用。 该试验性提案的目的是检验以下假设：DR通过升高B减轻炎症的机制是改变B的分泌和参与炎症过程的特定基因的表达。 将使用雄性Fischer 344大鼠（一种常用于衰老研究的动物模型）检验该假设。 该试点项目的具体目的是检查年轻的自由采食（AL）和DR大鼠对脂多糖（LPS;一种炎症因子）的炎症反应的时间过程。 将通过检查LPS诱导的促肾上腺皮质激素（ACTH）和血浆中的升高来测量对LPS的反应。 此外，还将测量LPS诱导已知参与炎症反应（诱导型一氧化氮合酶和细胞因子）和肝损伤（如存在特异性肝酶所示）的基因表达的能力。据推测，如果DR确实通过抑制免疫应答和/或通过改变动物对炎症因子的敏感性来延长寿命，那么与AL大鼠相比，DR中LPS诱导的ACTH和B升高、参与炎症应答的基因表达和肝脏特异性酶的浓度将降低。 该试点项目将提供必要的基础研究，以进一步探索一个特定的方面，通过该方面，DR可以提供必要的基础研究，以进一步探索DR延长寿命的一个特定方面，即下丘脑-垂体-肾上腺轴（HPA）在介导炎症反应中的作用。 如果这种作用确实被阐明，那么它将进一步支持饮食诱导的皮质酮过多是延长寿命的关键介质的理论。

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.