Targeting Cellular Senescence to Extend Healthspan

总体--科斯拉/柯克兰项目摘要 此计划项目拨款(PPG)申请反映了梅奥诊所的2个PPG合并Robert和 阿琳·科戈德老龄化中心：P01 AG041122(《细胞衰老和老龄化》，詹姆斯·柯克兰，PI)和 P01 AG004875(《老龄化人群中的骨代谢生理学》，SunDeep Khosla，PI)。在过去的时间里 五年来，这两个研究项目变得越来越一致。因此，与其提交 独立的PPG续签申请，Kirkland博士和Khosla博士联手担任联合首席调查员 在这种多地点应用，以最大限度地发挥协同作用，并优化成本，以NIA。 现在有压倒性的证据表明DNA损伤和/或其他细胞应激源的积累 导致细胞衰老，其特点是染色质发生深刻变化。衰老的细胞也可以 形成一种衰老相关的分泌表型(SASP)，包括促炎细胞因子， 趋化因子和细胞外基质降解蛋白具有有害的旁分泌和全身影响。 重要的是，调查人员在本申请中所做的关键观察已经确定，减少 衰老小鼠衰老细胞负荷延长健康寿命及改进措施 代谢功能障碍、骨骼脆性、血管功能障碍和肌肉功能障碍/脆弱--这些情况 是大多数老年并存疾病的结合点。因此，这一多学科、多领域的总体目标是 现场PPG应用是为细胞衰老的发现科学奠定坚实的基础 将减缓或预防年龄相关疾病的治疗战略的流水线。我们已经组装了一个 具有评估清除衰老细胞对多个器官的影响的专业知识的调查小组 系统；进行详细的组织病理学、分子和细胞分析，以了解遗传或 对衰老细胞的药物清除；以及开发改变衰老的新治疗策略 细胞的功能或负担。我们将利用共享的创新遗传模型和尖端研究 剖析衰老细胞在健康和疾病中特定于组织和疾病的作用的技术。四个 这个PPG项目的重点是细胞衰老在调节年龄相关代谢功能障碍中的作用 (项目1)，骨骼脆性(项目2)，血管功能障碍(项目3)，骨骼肌丢失和 功能障碍(项目4)。这些项目将以4个核心为基础：行政和生物统计核心 (核心A)；药物发现和开发核心(核心B)；综合Healthspan表型核心(核心 C)和老年科学病理学和细胞组织学核心(核心D)。这款高度集成的PPG将使用 一些常用工具和方法，进一步强调了PPG而不是单个R01的必要性 资助金。总而言之，拟议的研究将检验老年科学假说，该假说针对的是基本的 衰老机制，即细胞衰老，将延缓、预防或缓解多种与年龄相关的疾病。

OVERALL – PROJECT SUMMARY Khosla/Kirkland This Program Project Grant (PPG) application reflects the merging of 2 PPGs at the Mayo Clinic Robert and Arlene Kogod Center on Aging: P01 AG041122 (“Cellular Senescence and Aging,” James Kirkland, PI) and P01 AG004875 (“Physiology of Bone Metabolism in an Aging Population,” Sundeep Khosla, PI). Over the past five years, these two research programs have become increasingly aligned. Thus, rather than submitting separate PPG renewal applications, Drs. Kirkland and Khosla are joining forces as Co-Principal Investigators in this multi-site application in order to maximize synergies and optimize costs to NIA. There is now overwhelming evidence that the accumulation of DNA damage and/or other cellular stressors cause cells to undergo senescence, characterized by profound chromatin changes. Senescent cells can also develop a senescence-associated secretory phenotype (SASP), comprising pro-inflammatory cytokines, chemokines, and extracellular matrix-degrading proteins that have deleterious paracrine and systemic effects. Importantly, key observations made by the investigators in this application have established that reducing the burden of senescent cells in chronologically-aged mice extended healthspan and improved measures of metabolic dysfunction, skeletal fragility, vascular dysfunction, and muscle dysfunction/frailty – conditions that lie at the nexus of the majority of aging co-morbidities. Thus, the overall goal of this multi-disciplinary, multi- site PPG application is to build a firm foundation of discovery science in cellular senescence that leads to a pipeline of therapeutic strategies that will slow or prevent age-associated diseases. We have assembled an investigative team with expertise in evaluating the effects of clearing senescent cells on multiple organ systems; performing detailed histopathological, molecular, and cellular analyses on the effects of genetic or pharmacological clearance of senescent cells; and developing novel therapeutic strategies to alter senescent cell function or burden. We will leverage shared innovative genetic models and cutting-edge investigational technologies to dissect the tissue- and disease-specific roles of senescent cells in health and disease. The four projects in this PPG focus on the role of cellular senescence in mediating age-related Metabolic Dysfunction (Project 1), Skeletal Fragility (Project 2), Vascular Dysfunction (Project 3), and Skeletal Muscle Loss and Dysfunction (Project 4). These projects will be anchored by 4 cores: Administrative and Biostatistics Core (Core A); Drug Discovery and Development Core (Core B); Integrated Healthspan Phenotyping Core (Core C); and Geroscience Pathology and Cellular Histology Core (Core D). This highly integrated PPG will use a number of common tools and approaches, further underscoring the need for a PPG rather than individual R01 grants. Collectively, the proposed studies will test the Geroscience Hypothesis that targeting a fundamental aging mechanism, cellular senescence, will delay, prevent, or alleviate multiple age-related disorders.