Longevity extension and immune function in aging (R21)

描述(申请人提供)：在模式生物(酵母、苍蝇、蠕虫和小鼠)中，通过调节营养摄入和/或感觉、通过限制卡路里(CR)或通过抑制哺乳动物雷帕霉素靶(MTOR)通路信号，已经实现了显著的寿命延长。这些操作正在被考虑用于潜在地延长人类的寿命。由于任何寿命的延长都必须伴随着生活质量的改善，因此了解这些干预措施对老年生物生理功能的影响是至关重要的。虽然CR似乎改善了老年动物的免疫功能和动态平衡，但极少的感染性挑战实验表明，老年CR啮齿动物对感染的易感性增加。雷帕霉素(RapA)抑制mTOR复合体1(MTORC1)，本身就是一种有效的免疫抑制剂，而慢性小剂量RAPA介导的免疫抑制在抵抗感染中的作用尚不清楚。这一探索性建议旨在验证CR和mTOR抑制对保护性免疫产生负面影响的假设，特别是通过抑制效应器T和B细胞反应的充分发展。我们将在两个目标上检验这一假设。目的1：建立CR和RAPA处理的A、O小鼠不同类型感染的存活和免疫应答结果。CR和低剂量RAPA喂养的小鼠将感染西尼罗河病毒或单核细胞增生性李斯特菌，这是一种虫媒病毒和一种食源性细菌的原型，会给老年人带来高死亡率，并将接受生存检查以及保护性T细胞和抗体反应的产生。目的：确定CR和RAPA处理的老年小鼠免疫反应改变的分子相关性。剖析mTORC1AMPK通路调控在不同组织中对健康衰老的有益作用的信号机制(S)，为临床前直接利用已批准和/或新药进行翻译提供数据。

DESCRIPTION (provided by applicant): Remarkable extension of lifespan has been achieved in the model organisms (yeast, fly, worm and mouse) by modulation of nutrient intake and/or sensing, via calorie restriction (CR) or via inhibition of mammalian target of rapamycin (mTOR) pathway signaling. These manipulations are being considered for potential increase of lifespan in humans. Inasmuch as any increase in longevity must be accompanied by improved quality of life, it is critical to understand the effects of these interventions upon physiological function o older organisms. While CR appears to improve immune function and homeostasis in old animals, the preciously few infectious challenge experiments suggest increased susceptibility to infection in old CR rodents. Rapamycin (Rapa), which inhibits the mTOR complex 1 (mTORC1), is a potent immunosuppressant in its own right, and the effects of chronic low-dose Rapa-mediated immune suppression on resistance to infection remain unknown. This exploratory proposal aims to test the hypothesis that CR and mTOR inhibition exert negative effects upon protective immunity, specifically by curtailing full development of effector T and B cell responses. We will test this hypothesis in two Aims. Aim 1: To establish survival and immune response outcome of various types of infection in CR and Rapa-treated A and O mice. CR and low-dose Rapa-fed mice will be infected with the West Nile virus or Listeria monocytogenes, as prototypes of an arbovirus and a food-borne bacterium that impart high mortality upon older adults, and will be examined for survival and for generation of a protective T cell and antibody response. Aim 2: To define molecular correlates of the altered immune response in CR and Rapa-treated old mice. To dissect signaling mechanism(s) by which mTORC1/AMPK pathway manipulation leads to beneficial effects in healthy aging across different tissues and provide preclinical data for direct translation using approved and/or new drugs.