The Role of Cellular Senescence in Mediating Age-Related Bone Loss

细胞衰老在介导与年龄相关的骨质流失中的作用

• 批准号: 9761282
• 负责人: Joshua Nicholas Farr
• 金额: $ 12.8万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9761282
• 关键词: Ablation; Adipose tissue; Adverse effects; Age; Age of Onset; Age-Related Bone Loss; Aging; Animals; Apoptosis; Bone remodeling; CDKN2A gene; Cell Aging; Cell Cycle; Cell Differentiation process; Cells; Chromatin; Chronic; Chronic Disease; Chronology; DNA Damage; Data; Degenerative Disorder; Disease; Drug Interactions; Elderly; Environment; Event; Excision; Extracellular Matrix Proteins; Eye; Fracture; Functional disorder; Genetic; Goals; Growth; Healthcare Systems; Homeostasis; Human; In Vitro; Individual; Inflammatory; Intervention; Knowledge; Lead; Link; Longevity; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Nuclear; Oncogenic; Osteocytes; Osteoporosis; Pathology; Periodicity; Pharmaceutical Preparations; Pharmacology; Phenotype; Play; Polypharmacy; Population; Prevention; Primates; Public Health; Resistance; Risk Factors; Rodent; Role; Skeletal Muscle; Stimulus; Symptoms; Testing; Time; Tissues; Transgenic Mice; Wild Type Mouse; age related; aged; biological adaptation to stress; bone; bone mass; cell type; chemokine; cost; cytokine; frailty; functional decline; healthspan; human old age (65+); human tissue; inhibitor/antagonist; innovation; insight; mitochondrial dysfunction; mouse model; new therapeutic target; novel; phenotypic biomarker; preservation; prevent; public health relevance; response; senescence; skeletal; small molecule; synthetic drug; telomere; therapeutic target; transgenic suicide gene

PROJECT SUMMARY/ABSTRACT Advanced age is the key risk factor for most chronic diseases, including osteoporosis, contributing to enormous costs that will only worsen with our growing elderly population. Thus, there is a critical need to develop interventions that can prevent or reverse age-related diseases as a group and thereby maximize healthspan in humans. This may be feasible by targeting a fundamental aging mechanism – cellular senescence. Emerging evidence suggests that senescent cells and their senescence-associated secretory phenotype (SASP) are promising therapeutic targets to prevent age-related diseases as a group. Indeed, because with advancing age senescent cells accumulate in multiple tissues in temporal and spatial synchrony with age-associated functional decline in both animals and humans, they have been hypothesized to disrupt tissue function and to promote degenerative pathologies. The causal link between senescence and age-related tissue dysfunction has been demonstrated in genetically modified progeroid mice (an accelerated aging model) expressing a “suicide” transgene, which permits inducible elimination of senescent cells upon administration of a synthetic drug. This approach had a profound effect on enhancing healthspan by delaying the onset of aging pathologies in multiple tissues, including adipose, eye, and skeletal muscle. However, how senescent cells impact age-related bone loss and whether their removal can delay or prevent this loss remains unclear. The goal of the proposed studies is to test the hypothesis, for the first time, that the adverse effects of increased cellular senescence play a central role in age-related bone loss. This hypothesis is supported by preliminary data indicating that senescent cells, particularly senescent osteocytes, accumulate in bone with aging. As previous studies have used progeroid mice, there is a critical need to demonstrate a similar benefit of eliminating senescent cells in normal aged mice. Thus, in normal chronologically aged mice, the proposed studies will determine the extent to which systemic elimination of senescent cells through genetic and pharmacological approaches prevents age-related bone loss, and whether local elimination of senescent osteocytes is sufficient to prevent skeletal aging. Further, embedded in these studies will be analyses of highly enriched populations of osteocytes as well as other cell types in the bone microenvironment hypothesized to be of importance in mediating tissue damage in response to the SASP, thereby providing important mechanistic insights. These innovative approaches should lead to new hypotheses regarding the mechanisms by which senescent cells contribute to tissue dysfunction and the onset of age-related degenerative diseases. The significance of these studies is the provocative possibility that targeted elimination of senescent cells may prevent age-related diseases as group, potentially reducing polypharmacy and adverse drug interactions.

项目总结/摘要 高龄是大多数慢性疾病的关键危险因素，包括骨质疏松症， 这只会随着本港老年人口的不断增加而恶化。因此，迫切需要 制定干预措施，可以预防或扭转与年龄有关的疾病，从而最大限度地 人类的健康状况。这可能是可行的，通过针对一个基本的老化机制-细胞 衰老新出现的证据表明，衰老细胞及其衰老相关的分泌 表型（SASP）是预防年龄相关疾病的有希望的治疗靶点。的确， 因为随着年龄的增长，衰老细胞在时间和空间上同步地在多个组织中积累， 随着年龄的增长，动物和人类的功能下降， 组织功能和促进退行性病变。衰老与年龄相关的 组织功能障碍已在遗传修饰的早衰小鼠（加速老化模型）中得到证实 表达“自杀”转基因，其允许在施用 一种合成毒品这种方法通过延缓衰老的开始，对提高健康寿命产生了深远的影响。 包括脂肪、眼睛和骨骼肌在内的多种组织中的病理学。然而，衰老细胞 影响与年龄相关的骨质流失，以及它们的去除是否可以延迟或防止这种流失仍然不清楚。 拟议研究的目标是首次检验以下假设： 增加的细胞衰老在与年龄相关的骨丢失中起中心作用。这一假设得到了 初步数据表明，衰老细胞，特别是衰老的骨细胞，在骨中积累， 衰老由于先前的研究使用了早老小鼠，因此迫切需要证明 清除正常衰老小鼠的衰老细胞。因此，在正常年龄的小鼠中， 研究将确定衰老细胞通过遗传和免疫系统清除的程度。 药理学方法可以防止与年龄相关的骨质流失， 骨细胞足以防止骨骼老化。此外，在这些研究中，将分析高度 骨微环境中的骨细胞以及其他细胞类型的富集群体， 在介导响应SASP的组织损伤中是重要的，从而提供重要的 机械的洞察力。这些创新方法应导致有关机制的新假设 由此衰老细胞导致组织功能障碍和与年龄相关的退行性疾病的发生。 这些研究的重要性在于，有针对性地清除衰老细胞可能 预防与年龄有关的疾病，可能减少多种药物和不良药物相互作用。