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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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，导致随着老年人口的不断增加，巨大的成本只会变得更加严重，因此，迫切需要这样做。制定可以预防或逆转与年龄相关的疾病的干预措施，从而最大限度地提高通过针对基本的衰老机制——细胞，这可能是可能的。衰老表明衰老细胞及其衰老相关的分泌。事实上，表型（SASP）是预防年龄相关疾病的有希望的治疗靶点。因为随着年龄的增长，衰老细胞在时间和空间上同步积累在多个组织中随着动物和人类与年龄相关的功能衰退，它们已被破坏组织功能并促进退行性病变之间的因果关系。组织功能障碍已在转基因早衰小鼠（加速衰老模型）中得到证实表达“自杀”转基因，允许在施用后诱导消除衰老细胞这种方法通过延缓衰老对延长健康寿命产生了深远的影响。然而，衰老细胞如何影响多种组织的病理，包括脂肪、眼睛和骨骼肌。影响年龄相关的骨质流失，以及去除它们是否可以延迟或防止这种流失仍不清楚。拟议研究的目的是首次检验以下假设：细胞衰老的增加在与年龄相关的骨质流失中发挥着核心作用，这一假设得到了支持。初步数据表明，衰老细胞，特别是衰老骨细胞，在骨中积累由于之前的研究使用了早衰小鼠，因此迫切需要证明衰老的类似益处。消除正常衰老小鼠的衰老细胞因此，在正常年龄的小鼠中，建议研究将确定通过遗传和系统性消除衰老细胞的程度药理学方法可预防与年龄相关的骨质流失，以及是否局部消除衰老此外，这些研究中还包含了对骨细胞的高度分析。骨微环境中丰富的骨细胞群以及其他细胞类型竞相在介导响应 SASP 的组织损伤中具有重要意义，从而提供重要的这些创新方法应该会产生有关机制的新假设。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，有针对性地消除衰老细胞可能会产生令人兴奋的可能性。整体预防与年龄相关的疾病，有可能减少多重用药和不良药物相互作用。