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

项目摘要 实足年龄是世界范围内大多数慢性病、虚弱和死亡的主要风险因素。因此 老年人通常同时患有多种慢性病，导致健康状况不佳， 生命后期的生活质量（发病期延长）。压缩发病率是一个很大的挑战 延长健康寿命（健康的寿命）。在本项目中，我们建议研究 p21高衰老细胞的寿命和健康寿命。我们已经构建并验证了一个新的p21-Cre转基因 含有p21启动子的小鼠模型，该启动子驱动由Cre与他莫昔芬融合组成的双顺反子信息， 可诱导雌激素受体（ER）元件。该模型使我们能够监测、分选、杀死或调节p21 high细胞 与体内衰老有关。我们的初步数据表明，p21 high和p16 high细胞是两个不同的细胞群， p21-Cre小鼠模型靶向23月龄小鼠中各种组织中1.5-10%的细胞。每月清关 从20个月开始，p21 high细胞在小鼠中的作用降低了脆弱指数，延长了寿命，更重要的是， 在生命结束时改善身体功能。在本提案中，我们将进一步描述 p21 high细胞在寿命和健康寿命中的作用。我们的首要假设是，靶向p21 high细胞可以延长 并压缩老年发病率。在目的1.1中，我们将研究是否清除p21 high细胞， 可以通过更大的群体规模来延长寿命和健康寿命。我们将研究潜在的性别差异， 进行尸检病理分析，检查死因和疾病负担。而且还要 从20月龄起至生命末期，每月对这些小鼠的身体机能和虚弱指数进行跟踪评估 晚年健康状况在aim 1.2中，我们将利用p21-Cre小鼠模型，从6只小鼠中分选和富集p21 high细胞， 23月龄小鼠的组织，其中我们观察到p21 high细胞（2-10%），并进行单细胞RNA测序 这些细胞沿着与非p21高细胞。此外，我们将进行单核测序和成像 质谱细胞仪目的二：探讨NF-κB B通路在p21 high细胞中的作用 缩短。该项目可能会对老龄化研究产生广泛的影响， 了解p21 high细胞在体内的功能和转录水平。该项目的成果将 也使未来的药物干预试验，消除这些细胞，以提高寿命， 压缩发病率。

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.