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大鼠对DR的反应显示血浆皮质酮(B)增加了两倍，并在动物的整个生命周期中保持不变。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。总之，这些生理变化可能是B作为DR延长寿命能力的中介作用的指标。本试点提案的目的是验证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的假设。这一假设将用雄性费舍尔344大鼠进行验证，这是一种常用的动物模型，用于衰老研究。这个试点项目的具体目的是研究年轻的自由喂养（AL）和DR大鼠对脂多糖（LPS，一种炎症剂）的炎症反应的时间过程。对脂多糖的反应将通过检测脂多糖诱导的促肾上腺皮质激素（ACTH）和血浆的升高来测量。此外，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（由特定肝酶的存在所指示）的基因表达的能力。假设DR确实通过抑制免疫反应和/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，lps诱导的DR中ACTH和B的升高、炎症反应相关基因的表达和肝脏特异性酶的浓度将降低。该试点项目将为进一步探索DR延长寿命的一个特定方面提供必要的基础研究，为进一步探索DR延长寿命的一个特定方面提供必要的基础研究，即下丘脑-垂体-肾上腺轴（HPA）在介导炎症挑战反应中的作用。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高皮质酮血症是延长寿命的关键媒介的理论。

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.