Role of Senolytics in Lower Urinary Tract Aging and Voiding Disorders

项目摘要/摘要 下尿路症状(LUT)，包括尿失禁、膀胱过度活动和活动不足， 影响到一半以上的老年人口，不利于生活质量和独立性。当期药物 治疗方法大多是姑息性的，效果不佳，很容易被患者和处方者放弃，因为 不良副作用。尿液控制是一项复杂的多组分手术，衰老代表着 老年人排尿和尿失禁改变的主要危险因素和潜在的生物驱动因素。衰老 细胞是一种细胞类型，积累在老化的组织中，释放出一系列可能损害组织的化学物质 功能。我们在膀胱组织中发现了这些细胞的证据。与已发表的针对 其他组织，这表明旨在消除衰老细胞的现有药物可能是 治疗与衰老相关的泌尿系疾病的新疗法。在这个探索性的项目中，我们将利用我们的衰老 建立小鼠模型，以证实这些细胞的存在，并研究成熟和老化对其影响 存在于膀胱组织中。我们还将测试感觉剂的能力，这种药物可以去除这些细胞， 减少老年动物膀胱中衰老细胞的存在。最后，我们将测试维护或 使用我们建立的衰老小鼠膀胱测定仪，使用感觉剂恢复老年年轻时的膀胱功能 模特。我们的发现将为未来的研究提供重要的指导和支持数据 衰老细胞参与衰老和相关功能障碍的机制，并可能有助于新的 更有效地预防和治疗晚年的泌尿系统疾病。

Project Summary/Abstract Lower urinary tract symptoms (LUTS), including urinary incontinence, overactive and underactive bladder, affect over half of the elderly population and are detrimental to quality of life and independence. Current drug therapies are mostly palliative, suboptimally effective and readily abandoned by patients and prescribers due to undesirable side effects. Urinary control is a complex multi-component operation, with aging representing a major risk factor and potential biological driver of altered voiding and incontinence in older adults. Senescent cells are a cell type which accumulates in aging tissues, releasing a host of chemicals that can impair tissue function. We have found evidence of these cells in bladder tissue. Together with published studies targeting other tissues, this suggests that available drugs aimed at eliminating senescent cells could be the basis for new therapies for urinary disorders associated with aging. In this exploratory project, we will use our aging mouse model to confirm the presence of these cells and study the impact of maturation and aging on their presence in bladder tissues. We will also test the ability of senolytics, drugs that can remove these cells, to reduce senescent cell presence in bladders from old animals. Finally, we will test the ability to maintain or recover youthful bladder function in old age using senolytics using our established aging mouse cystometry model. Our findings will provide important directive and supportive data for future research into the mechanisms of senescent cell involvement with aging and associated dysfunction, and may contribute to new and more effective prevention and treatment for urinary disorders of later life.