TFEB-mediated lysosome-to-nucleus signaling in aging and lifespan regulation

摘要 衰老的特征是细胞、组织和器官逐渐丧失维持其功能的能力。 完整性，并伴随着增加的易感性，以病态的几率发展 神经变性、癌症或心血管疾病随着年龄的增长而不断增加。目前没有 减缓衰老生物体中细胞和组织稳态失调的一般可行策略。 因此，现代医疗保健的进步反而增加了虚弱和发病率 在老年人中，通过延长寿命而不显著影响与年龄相关的体内平衡， 失调由于世界人口持续老龄化，因此迫切需要 确定可操作的细胞和分子靶点，以开发旨在提高 健康沿着寿命。衰老的标志是溶酶体介导的降解途径的下降 和染色质失调。这项建议的重点是一个转录因子EB介导的溶酶体到核 信号通路，其调节使雄性小鼠的寿命延长30%。我们将系统地 并从机制上研究了这一信号通路的三个组成部分，即溶酶体， 信号传导器和染色质调节剂--在衰老过程中利用我们拥有的独特工具 用于研究溶酶体含量和信号成分。这项研究的结果将首次提供 年龄相关的哺乳动物大脑中溶酶体含量的图谱，并将开创研究 溶酶体到细胞核的信号传递从这项研究中获得的知识可以为未来的研究奠定基础。 衰老和年龄相关性神经退行性疾病的临床治疗的转化研究。

Abstract Aging is characterized by the progressive inability of cells, tissues, and organs to maintain their functional integrity and is accompanied by an increased susceptibility to morbidity—the odds to develop neurodegeneration, cancer, or cardiovascular disease increase continuously with age. There is currently no general, actionable strategy to slow down dysregulation of cell and tissue homeostasis in the aging organism. As a result, advances in healthcare in the modern era have paradoxically increased frailty and morbidity among the elderly by increasing lifespan without significantly impacting on age-related homeostasis dysregulation. Owing to a continuously aging world population, there is therefore an urgent and unmet need to identify actionable cellular and molecular targets for the development of treatments aimed at increasing healthspan along with lifespan. Hallmarks of aging are a decline in lysosome-mediated degradation pathways and chromatin dysregulation. This proposal focuses on a transcription factor EB-mediated lysosome-to-nucleus signaling pathway, the modulation of which extends mouse lifespan by 30% in males. We will systematically and mechanistically investigate the three components of this signaling pathway—namely the lysosome, the signaling transducers, and chromatin regulators—during aging by leveraging unique tools that we have developed to study lysosomal content and signaling components. Results from this study will provide the first age-associated atlas of the lysosomal content in the mammalian brain and will pioneer the investigation of lysosome-to-nucleus signaling in aging. Knowledge resulting from this study could lay the foundation for future translational investigations of clinical treatment of aging and age-related neurodegenerative disease.