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

项目摘要 时序年龄是全球大多数慢性病、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，导致健康状况不佳而减少 生活后期的生活质量(发病时间延长)。压缩发病率是一个巨大的挑战。 经期和增加健康寿命(健康寿命)。在这个项目中，我们建议研究一下 P21寿命和健康寿命中的高衰老细胞。我们已经产生并验证了一种新的p21-Cre转基因 含有p21启动子的小鼠模型，该启动子驱动由Cre与他莫昔芬融合的双顺反子信息 诱导型雌激素受体(ER)元件。这个模型使我们能够监测、分类、杀死或调节p21High细胞 随着体内年龄的增长。我们的初步数据显示，p21High和p16High细胞是两个不同的细胞群体，并且 P21-CRE小鼠模型以23月龄小鼠不同组织中1.5-10%的细胞为靶点。每月清关 20个月大的小鼠体内的p21High细胞降低了脆弱指数，延长了寿命，更重要的是， 改善生命末期的身体机能。在这项建议中，我们将进一步描述其作用和机制 P21高细胞的寿命和健康寿命。我们的主要假设是靶向p21High细胞可以延伸 延年益寿，降低老年发病率。在Aim 1.1中，我们将研究p21High细胞的清除 可以通过更大的群体规模来延长寿命和健康寿命。我们将检查潜在的性别差异和 进行死后病理分析，检查死因和疾病负担。此外，我们还将 从20月龄到生命结束，每月跟踪观察这些小鼠的身体机能和虚弱指数，进行评估 晚年健康状况。在Aim 1.2中，我们将利用p21-Cre小鼠模型来分类和丰富6个p21High细胞 23月龄小鼠的组织中，我们观察到p21High细胞(2-10%)，并进行单细胞RNA测序 在这些细胞和非p21High细胞上。此外，我们还将进行单核测序和成像 质量细胞术。在目标2中，我们将研究p21High细胞中的NF-κB通路在寿命和健康寿命中的作用 正在缩水。这个项目可能会通过获得一个全面的 了解p21High细胞在体内的功能和转录水平。这个项目的结果将是 还使未来能够测试消除这些细胞的药物干预措施，以延长寿命和 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.