Targeting p21-Highly Expressing Cells to Increase Lifespan and Healthspan in Old Age

靶向 p21 高表达细胞以延长老年寿命和健康寿命

• 批准号: 10419157
• 负责人: Ming Xu
• 金额: $ 49.78万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419157
• 关键词: Age; Aging; Animal Model; Automobile Driving; Autopsy; Biological Aging; Cause of Death; Cell Aging; Cell Nucleus; Cells; Chronic Disease; Chronology; Communicable Diseases; Communities; Coupled; Cytometry; Data; Disease; Dissociation; Elderly; Elements; Estrogen Receptors; Foundations; Future; Goals; Health; Health Status; Heart Diseases; Human; Image; Insulin Resistance; Intervention; Life; Longevity; Malignant Neoplasms; Modeling; Monitor; Morbidity - disease rate; Mus; Obesity; Pathologic; Pathology; Pathway interactions; Patients; Pharmacology; Physical Function; Pilot Projects; Population; Process; Proteins; Quality of life; Research; Risk Factors; Role; Sex Differences; Sorting - Cell Movement; Stress; Syndrome; Tamoxifen; Technology; Testing; Time; Tissues; Transgenic Mice; age related; aged; base; burden of illness; cell type; cellular targeting; disability; drug development; end of life; experience; frailty; healthspan; human old age (65+); improved; in vivo; in vivo Model; indexing; middle age; mortality; mouse model; multiple chronic conditions; novel; promoter; senescence; single cell sequencing; single-cell RNA sequencing; transcriptomics

Project Summary Chronological age is the leading risk factor for most chronic diseases, frailty, and mortality worldwide. Thus, the elderly population usually has multiple chronic conditions at the same time, resulting in poor health and reduced quality of life (prolonged morbidity period) at the later stage of life. There is a big challenge to compress morbidity period and increase healthspan (lifespan with good health). In this project, we propose to examine the role of p21high senescent cells in lifespan and healthspan. We have generated and validated a new p21-Cre transgenic mouse model containing a p21 promoter driving a bicistronic message consisting of Cre fused to a tamoxifen- inducible estrogen receptor (ER) element. This model enables us to monitor, sort, kill or modulate p21high cells with aging in vivo. Our preliminary data shows that p21high and p16high cells are two distinct cell populations, and the p21-Cre mouse model targets 1.5-10% of cells in various tissues in 23-month-old mice. Monthly clearance of p21high cells in mice starting at 20 months reduces frailty index, extends lifespan, and more importantly, improves physical function at the end of life. In this proposal, we will further characterize the role and mechanisms of p21high cells in lifespan and healthspan. Our overarching hypothesis is that targeting p21high cells can extend lifespan and compress morbidity in old age. In aim 1.1, we will investigate whether clearance of p21high cells could extend lifespan and healthspan using a larger group size. We will examine potential sex difference and perform postmortem pathological analysis to examine the cause of death and disease burden. Moreover, we will follow physical function and frailty index of these mice every month from 20-month-old to the end of life to assess late life health status. In aim 1.2, we will leverage p21-Cre mouse models to sort and enrich p21high cells from 6 tissues of 23-month-old mice where we observed p21high cells (2-10%), and perform single cell RNA sequencing on these cells along with non-p21high cells. In addition, we will perform single nucleus sequencing and imaging mass cytometry. In aim 2, we will investigate the role of NF-κB pathway in p21high cells in lifespan and healthspan shortening. This project is likely to have a broad impact on aging research by gaining a comprehensive understanding of p21high cells at both functional and transcriptomic levels in vivo. Results from this project will also enable future testing of pharmacological interventions that eliminate these cells to improve lifespan and compress morbidity.

项目摘要 年代年龄是大多数慢性疾病，脆弱和死亡率的主要危险因素。那， 老年人口通常同时患有多种慢性病，导致健康状况不佳并减少 生活质量（长时间发病时期）在生命的后期。压缩发病率是一个巨大的挑战 时期并增加健康状态（健康状况良好）。在这个项目中，我们建议研究 寿命和健康范围内的P21高感觉细胞。我们已经生成并验证了新的P21-CRE转基因 小鼠模型包含p21启动子驱动双副膜的启动子，该消息由融合到他莫昔芬的CRE组成 可诱导的雌激素受体（ER）元素。该模型使我们能够监视，排序，杀死或调节P21高细胞 体内衰老。我们的初步数据表明，P21高和P16高细胞是两个不同的细胞群，并且 在23个月大的小鼠中，p21-cre小鼠模型靶向各种时序中的1.5-10％的细胞。每月清理 从20个月开始的小鼠的P21高细胞降低了脆弱的指数，延长了寿命，更重要的是 改善生命尽头的身体机能。在此提案中，我们将进一步描述角色和机制 P21高细胞在寿命和健康范围内。我们的总体假设是靶向P21高细胞可以延长 寿命和压缩老年发病率。在AIM 1.1中，我们将研究P21高细胞的清除率是否清除 可以使用较大的组尺寸延长寿命和健康范围。我们将检查潜在的性别差异 进行死后病理分析以检查死亡和疾病伯宁的原因。而且，我们会的 每月遵循这些小鼠的身体功能和虚弱的指数，从20个月大到生命的尽头 晚期健康状况。在AIM 1.2中，我们将利用P21-CRE小鼠模型分类并富含6个P21高细胞 23个月大的小鼠的组织，我们观察到P21高细胞（2-10％），并进行单细胞RNA测序 在这些细胞上以及非P21高细胞。另外，我们将执行单核测序和成像 质量细胞仪。在AIM 2中，我们将研究NF-κB途径在P21高细胞中的作用 缩短。通过获得全面 在体内对P21高细胞的理解。这个项目的结果将 还可以对消除这些细胞的药物干预措施进行未来的测试，以改善寿命和 压缩发病率。