Age-related changes in skeletal muscle and lower urinary tract symptoms in older adults

项目总结/摘要 由于目前缺乏对以下方面的了解，存在着根本性的知识差距和错失的机会： 年龄相关的风险因素之间的关系，如全球和骨盆骨骼肌的损失 功能和下尿路症状（LUTS）在老年妇女和男子。LUTS与 功能损伤和生活质量差，并且福尔斯、骨折和死亡的风险增加。的 目前对泌尿道病理学的狭隘关注导致了对导致这些疾病的原因的最低限度的理解。 症状和相应的有效干预措施很少。一种新的以老龄化为重点的LUTS范式 病理生理学可以通过定义可改变的LUTS风险因素， 与年龄相关的肌肉健康变化，以及衰老综合征的共同机制。 我的目标是建立一个流行病学骨干了解年龄相关的LUTS的危险因素， 利用高质量的现有数据，定义新的和可改变的风险因素和机制， 相关的LUTS，并导致随后的翻译工作，以针对这些风险因素和机制，在老年人 成年人了本申请的目的是评估多个测量值之间的纵向关联， 骨骼肌和LUTS。我的假设是骨骼肌中与年龄相关的变化-在系统中 （力量和体能）、器官（肌肉质量/体积）和细胞（线粒体生物能量学） 水平-与LUTS严重程度相关，独立于实际年龄和混杂因素。 这一假设将通过有效地使用来自前瞻性队列“肌肉流动性研究”的数据进行检验。 （SOMMA）追求以下具体目标：目标1）确定基线和纵向 肌肉功能（力量，功率）和身体性能（步行速度）的变化与 LUTS严重程度的变化;目的2）确定肌肉质量和 全身和骨盆底肌肉体积和形状的基线测量与 3）确定骨骼肌线粒体功能的基线测量值如何影响 与LUTS严重程度的变化相关。这个项目是创新的，因为它利用了快速发展的 老年科学领域，以改善现有的不足泌尿生殖系统为重点的范式下尿路症状的病理生理学。 这项研究具有重要意义，因为它将产生一个与年龄相关的LUTS病理生理学范式 这将通过以下方式改善对患有LUTS的老年人的护理：1）识别与年龄相关的LUTS的生物标志物; 2） 通过基于新的LUTS表型进行分层，改善现有疗法的获益：风险比; 3） 区分在LUTS的发展中全球与骨盆底肌肉的变化的作用; 4） 促进针对年龄相关LUTS机制的新治疗的开发;以及最终5） 预防LUTS并发症（例如，虚弱、活动能力受损、福尔斯和生活质量差）， 由LUTS引起或由共享的可改变因素间接引起，LUTS是其早期标志物。

PROJECT SUMMARY/ABSTRACT There is a fundamental knowledge gap and missed opportunities due to the current lack of understanding of the relationship between age-related risk factors, such as loss of both global and pelvic skeletal muscle function, and lower urinary tract symptoms (LUTS) among older women and men. LUTS are associated with functional impairment and poor quality of life and are at increased risk of falls, fractures, and mortality. The current narrow focus on urinary tract pathology has led to minimal understanding of what causes these symptoms and correspondingly few effective interventions. A new aging-focused paradigm of LUTS pathophysiology could lead to novel interventions to treat LUTs by defining modifiable LUTS risk factors, such as age-related changes in muscle health, and mechanisms shared across syndromes of aging. My goals are to build an epidemiologic backbone for understanding age-related LUTS risk factors by leveraging high-quality existing data, defining novel and modifiable risk factors and mechanisms for age- related LUTS, and to lead subsequent translational efforts to target these risk factors and mechanisms in older adults. The objective of this application is to evaluate longitudinal associations between multiple measures of skeletal muscle and LUTS. My hypothesis is that age-related changes in skeletal muscle – at the system (strength and physical performance), organ (muscle mass/volume), and cellular (mitochondrial bioenergetics) level – are associated with LUTS severity, independent of chronological age and confounding factors. This hypothesis will be tested by efficiently using data from the prospective cohort “Study of Muscle Mobility and Aging” (SOMMA) to pursue the following specific aims: Aim 1) Determine how baseline and longitudinal changes in muscle function (strength, power) and physical performance (walking speed) are associated with change in LUTS severity; Aim 2) Determine how baseline and longitudinal changes in muscle mass and baseline measures of both total body and pelvic floor muscle volume and shape are associated with change in LUTS severity; and Aim 3) Determine how baseline measures of skeletal muscle mitochondrial function are associated with change in LUTS severity. This project is innovative because it leverages the rapidly evolving field of geroscience to improve the inadequate existing urogenital-focused paradigm of LUTS pathophysiology. The proposed research is significant because it will produce a paradigm of age-related LUTS pathophysiology that will result in improved care for older adults with LUTS by 1) identifying biomarkers of age-related LUTS; 2) improving the benefit:risk ratio for existing therapies by stratifying based on novel LUTS phenotypes; 3) distinguishing the role of changes in global versus pelvic floor muscles in the development of LUTS; 4) facilitating the development of new treatments that target age-related LUTS mechanisms; and ultimately 5) preventing LUTS complications (e.g., frailty, impaired mobility, falls, and poor quality of life) that may be directly caused by LUTS or indirectly caused by shared modifiable factors for which LUTS is an early marker.