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.

项目摘要/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，有助于 巨大的成本只会担心我们不断增长的人口。那是迫切需要的 可以预防或逆转与年龄有关的疾病的发展干预措施，从而最大程度地提高 人类的健康范围。通过靶向基本的老化机制 - 细胞可能是可行的 感应。新兴的证据表明，感觉细胞及其感应相关分泌 表型（SASP）是有希望的治疗靶标，可防止与年龄相关的疾病。的确， 因为随着年龄的增长，感觉细胞以临时和空间同步的多个时间积累 随着年龄相关的动物和人类的功能下降，它们被认为破坏了 组织功能并促进退化性病理。感应与年龄有关的因果关系 组织功能障碍已在转基因的后代小鼠（加速衰老模型）中已证明 表达“自杀”转化，该转化允许在给药时消除感觉细胞 合成药物。这种方法通过延迟衰老的开始对增强健康范围产生了深远的影响 多次病理，包括脂肪，眼睛和骨骼肌。但是，感觉细胞如何 影响年龄相关的骨质流失以及其去除是否会延迟或防止这种损失尚不清楚。 拟议的研究的目的是首次检验假设 增加的细胞感应在与年龄相关的骨质流失中起着核心作用。该假设得到 初步数据表明，感官细胞，尤其是感觉骨细胞，在骨头中积聚 老化。由于以前的研究使用了后代小鼠，因此迫切需要证明类似的好处 消除正常老年小鼠的感觉细胞。在正常年代老化的小鼠中，提出的 研究将确定通过遗传和 药理学方法可以防止与年龄相关的骨质流失，以及局部消除感觉 骨细胞足以防止骨骼老化。此外，将嵌入这些研究中 骨细胞的富集种群以及骨微环境中的其他细胞类型，假设 在响应SASP的介导组织损伤方面非常重要，从而提供了重要 机械见解。这些创新的方法应导致有关机制的新假设 感觉细胞会导致组织功能障碍和与年龄相关的退行性疾病的发作。 这些研究的意义在于，靶向消除感觉细胞的挑衅可能性可能 防止与年龄相关的疾病作为组，可能会降低多药和不良药物相互作用。