Targeting Cellular Senescence to Extend Healthspan

Khosla/柯克兰项目概要 该计划项目补助金（PPG）申请反映了马约诊所罗伯特和 Arlene Kogod老化中心：P01 AG 041122（“细胞衰老和老化”，James柯克兰，PI）和 P01 AG 004875（“老年人群骨代谢生理学”，Sundeep Khosla，PI）。过去 五年来，这两个研究项目越来越一致。因此，与其提交 在单独的PPG更新申请中，柯克兰博士和Khosla博士作为共同主要研究者加入 为了最大限度地发挥协同作用并优化NIA的成本， 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 导致细胞经历衰老，特征是染色质的深刻变化。衰老细胞也可以 产生衰老相关分泌表型（SASP），包括促炎细胞因子， 趋化因子和具有有害的旁分泌和全身效应的细胞外基质降解蛋白。 重要的是，研究人员在本申请中进行的关键观察已经确定， 衰老细胞的负荷在按时间老化的小鼠中延长了健康寿命，并改善了 代谢功能障碍、骨骼脆弱性、血管功能障碍和肌肉功能障碍/脆弱性- 与大多数老年合并症有关。因此，这一多学科、多领域的总体目标， 现场PPG应用是建立一个坚实的基础，发现科学的细胞衰老，导致一个 治疗策略的管道，将减缓或预防与年龄相关的疾病。我们制定了一份 在评估清除衰老细胞对多个器官的影响方面具有专业知识的调查小组 系统;进行详细的组织病理学，分子和细胞分析的影响，遗传或 药理学清除衰老细胞;和开发新的治疗策略，以改变衰老的细胞， 细胞功能或负担。我们将利用共享的创新基因模型和尖端的研究 技术来剖析衰老细胞在健康和疾病中的组织和疾病特异性作用。四 本PPG项目的重点是细胞衰老在介导年龄相关代谢功能障碍中的作用 （项目1）、骨骼脆弱性（项目2）、血管功能障碍（项目3）和骨骼肌损失， 功能障碍（项目4）。这些项目将由4个核心锚定：行政和生物统计核心 (Core A）;药物发现和开发核心（核心B）;整合Healthspan表型分析核心（核心 C）;和老年科学病理学和细胞组织学核心（核心D）。这种高度集成的PPG将使用 一些常用工具和方法，进一步强调需要PPG而不是单个R 01 赠款。总的来说，拟议的研究将测试老年科学假设，针对一个基本的 衰老机制，细胞衰老，将延迟，预防或减轻多种与年龄有关的疾病。

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.