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 正直，并伴随着疾病易感性的增加--发生的几率 神经退行性疾病、癌症或心血管疾病随着年龄的增长不断增加。目前没有 一般的，可行的策略，以减缓衰老有机体中细胞和组织内稳态的失调。 其结果是，现代医疗保健的进步矛盾地增加了脆弱性和发病率 在不显著影响与年龄相关的稳态的情况下延长老年人的寿命 监管失调。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，以开发旨在增加 健康寿命和寿命。衰老的特征是溶酶体介导的降解途径减少 染色质失调。这一建议的重点是转录因子EB介导的溶酶体到核 信号通路，该通路的调节使雄性小鼠的寿命延长30%。我们将系统地 并从机制上研究这一信号通路的三个组成部分--即溶酶体、 信号转换器和染色质调节器-通过利用我们拥有的独特工具在老化过程中 研究溶酶体的含量和信号成分。这项研究的结果将提供第一个 哺乳动物脑中溶酶体含量的年龄相关图谱，将开创研究 衰老过程中的溶酶体核信号传递。从这项研究中获得的知识可以为未来奠定基础 衰老及老年神经退行性疾病临床治疗的转化性研究。

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.