Targeting Cellular Senescence to Extend Healthspan

靶向细胞衰老以延长健康寿命

• 批准号: 10561620
• 负责人: JAMES L. KIRKLAND
• 金额: $ 281.97万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10561620
• 关键词: Acceleration; Age; Aging; Apoptosis; Applications Grants; Biostatistics Core; Blood Vessels; CDKN2A gene; Cell Aging; Cell Cycle; Cell Differentiation process; Cell physiology; Cells; Chromatin; Chronology; Clinic; Clinical Trials; DNA Damage; Disease; Drug Evaluation; Drug usage; Extracellular Matrix; Foundations; Functional disorder; Future; Genetic; Genetic Models; Geroscience; Goals; Grant; Health; Histology; Human; Individual; Inflammatory; Investments; Measures; Mediating; Mediator; Metabolic; Metabolic dysfunction; Modeling; Molecular; Mus; Muscle; Outcome; Pathology; Phenotype; Physiology; Pilot Projects; Principal Investigator; Program Research Project Grants; Proliferating; Property; Proteins; Protocols documentation; Rat Transgene; Research; Research Personnel; Resistance; Rodent Model; Role; Science; Site; Specificity; Structure; Technology; Testing; Therapeutic; Tissues; Transgenic Mice; Translations; Vascular Diseases; age related; aged; aging population; body system; bone metabolism; cellular targeting; chemokine; comorbidity; cost; cytokine; drug development; drug discovery; drug efficacy; efficacy testing; first-in-human; frailty; healthspan; improved; inhibitor; innovation; medication safety; multidisciplinary; novel; novel therapeutic intervention; paracrine; pharmacologic; pre-clinical; prevent; programs; senescence; skeletal; skeletal muscle wasting; stressor; synergism; tool; translational pipeline

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.

总体而言——项目摘要 Khosla/Kirkland 该计划项目拨款 (PPG) 申请反映了 Mayo Clinic Robert 和 Robert 的 2 个 PPG 的合并 Arlene Kogod 衰老中心：P01 AG041122（“细胞衰老和衰老”，James Kirkland，PI）和 P01 AG004875（“老龄化人群骨代谢的生理学”，Sundeep Khosla，PI）。 五年来，这两个研究项目变得越来越一致，而不是提交。 Kirkland 博士和 Khosla 博士联手担任联合首席研究员 在此多站点应用程序中，为了最大化协同效应并优化 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 导致细胞衰老，其特征是染色质发生深刻的变化。 形成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作用。 重要的是，研究人员在本申请中所做的关键观察表明，减少 按年龄顺序排列的小鼠中衰老细胞的负担延长了健康寿命并改善了 代谢功能障碍、骨骼脆弱、血管功能障碍和肌肉功能障碍/虚弱——这些情况 因此，这一多学科、多学科的总体目标是大多数老年合并症的关键。 网站 PPG 应用旨在为细胞衰老的发现科学奠定坚实的基础，从而导致 我们已经制定了一系列减缓或预防与年龄相关的疾病的治疗策略。 具有评估清除衰老细胞对多个器官影响的专业知识的研究团队 系统；对遗传或细胞的影响进行详细的组织病理学、分子和细胞分析。 衰老细胞的药理学清除；并开发改变衰老的新治疗策略 我们将利用共享的创新遗传模型和前沿的研究。 剖析衰老细胞在健康和疾病中的组织和疾病特异性作用的技术。 该 PPG 中的项目重点关注细胞衰老在介导与年龄相关的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）以及骨骼肌丧失和 功能障碍（项目 4）。这些项目将由 4 个核心组成：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 表型分析核心（核心） C)；以及老年科学病理学和细胞组织学核心（核心 D）。 通用工具和方法的数量，进一步强调了对 PPG 而不是单独的 R01 的需求 总的来说，拟议的研究将测试针对基础的老年科学假设。 衰老机制，即细胞衰老，将延缓、预防或减轻多种与年龄相关的疾病。

项目成果

Targeting ATM to mitigate intervertebral disc degeneration.

• DOI: 10.18632/aging.203015
• 发表时间: 2021-04-22
• 期刊: Aging
• 作者: Pitcher LE;Wong AK;Robbins PD
• 通讯作者: Robbins PD

Clearance of Senescent Cells From Injured Muscle Abrogates Heterotopic Ossification in Mouse Models of Fibrodysplasia Ossificans Progressiva.

• DOI: 10.1002/jbmr.4458
• 发表时间: 2022-01
• 期刊: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
• 作者: Wang H;Zhang Q;Kaplan FS;Pignolo RJ
• 通讯作者: Pignolo RJ

Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis.

• DOI: 10.4049/jimmunol.2001022
• 发表时间: 2021-02-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Bianchi A;Marchetti L;Hall Z;Lemos H;Vacca M;Paish H;Green K;Elliott B;Tiniakos D;Passos JF;Jurk D;Mann DA;Wilson CL
• 通讯作者: Wilson CL

Recent advances in the discovery of senolytics.

• DOI: 10.1016/j.mad.2021.111587
• 发表时间: 2021-12
• 期刊: Mechanisms of ageing and development
• 影响因子: 5.3
• 作者: Zhang L;Pitcher LE;Prahalad V;Niedernhofer LJ;Robbins PD
• 通讯作者: Robbins PD

Multiparametric senescent cell phenotyping reveals targets of senolytic therapy in the aged murine skeleton.

• DOI: 10.1038/s41467-023-40393-9
• 发表时间: 2023-07-31
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Doolittle, Madison L.;Saul, Dominik;Kaur, Japneet;Rowsey, Jennifer L.;Vos, Stephanie J.;Pavelko, Kevin D.;Farr, Joshua N.;Monroe, David G.;Khosla, Sundeep
• 通讯作者: Khosla, Sundeep