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: 9977929
• 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/9977929
• 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; 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; osteoporosis with pathological fracture; 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 高龄是包括骨质疏松症在内的大多数慢性病的关键风险因素，导致 巨大的成本只会随着我们不断增长的老年人口而恶化。因此，迫切需要 制定干预措施，作为一个群体预防或扭转与年龄有关的疾病，从而最大限度地 人类的健康寿命。通过瞄准一种基本的衰老机制--细胞--这可能是可行的 衰老。新的证据表明，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，衰老细胞在多个组织中以时间和空间同步的方式积累 随着动物和人类的年龄相关功能下降，它们被假设为扰乱 组织功能和促进退行性病变。衰老与年龄相关的因果关系 转基因孕激素小鼠(一种加速衰老模型)显示出组织功能障碍 表达一种“自杀”转基因，它允许在给药后诱导地消除衰老细胞 一种合成药物。这种方法通过延缓衰老的开始，对延长健康寿命产生了深远的影响。 多种组织的病理学，包括脂肪、眼睛和骨骼肌。然而，衰老的细胞如何 影响与年龄相关的骨丢失，以及移除它们是否可以延缓或防止这种丢失仍不清楚。 拟议研究的目标是第一次检验这一假设，即 细胞衰老增加在与年龄相关的骨丢失中起着核心作用。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，随着 衰老。由于之前的研究已经使用孕激素小鼠，迫切需要证明类似的好处 消除正常衰老小鼠的衰老细胞。因此，在按时间顺序老化的正常小鼠中，建议的 研究将确定系统性消除衰老细胞的程度通过遗传和 药物治疗可以预防与年龄相关的骨丢失，以及局部消除衰老 骨细胞足以防止骨骼老化。此外，在这些研究中将嵌入对高度 骨微环境中丰富的骨细胞群以及其他类型的细胞被假设为 在调节对SASP的反应中的组织损伤方面具有重要作用，从而提供重要的 机械的洞察力。这些创新的方法应该导致关于机制的新假设 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。 这些研究的意义在于，靶向消除衰老细胞的可能性具有挑衅性 集体预防与年龄相关的疾病，潜在地减少多药联用和不良药物相互作用。