Longevity extension and immune function in aging (R21)

描述（由申请人提供）：通过调节营养摄入和/或感知，通过热量限制（CR）或通过抑制哺乳动物雷帕霉素靶蛋白（mTOR）途径信号传导，在模型生物体（酵母、苍蝇、蠕虫和小鼠）中实现了寿命的显著延长。这些操作正在考虑潜在的增加人类的寿命。由于任何寿命的增加都必须伴随着生活质量的提高，因此了解这些干预措施对老年生物体生理功能的影响至关重要。虽然CR似乎可以改善老年动物的免疫功能和体内平衡，但珍贵的少数感染性攻击实验表明老年CR啮齿动物对感染的易感性增加。抑制mTOR复合物1（mTORC 1）的雷帕霉素（Rapa）本身就是一种有效的免疫抑制剂，慢性低剂量Rapa介导的免疫抑制对感染抵抗力的影响仍然未知。该探索性建议旨在检验CR和mTOR抑制对保护性免疫产生负面影响的假设，特别是通过减少效应T和B细胞应答的完全发展。我们将在两个目标中检验这个假设。 目的1：建立CR和Rapa治疗的A和O小鼠中各种类型感染的存活率和免疫应答结果。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李斯特菌，作为虫媒病毒和食源性细菌的原型，对老年人造成高死亡率，并将检查存活率和保护性T细胞和抗体反应的产生。 目的2：确定CR和Rapa治疗老年小鼠免疫应答改变的分子相关性。剖析mTORC 1/AMPK通路操纵在不同组织中对健康衰老产生有益影响的信号传导机制，并为使用获批和/或新药进行直接翻译提供临床前数据。

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.