Institute of Molecular and Cell Biology, A*STAR Research Entities, Singapore, 138673, Singapore.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117593, Singapore.
Biogerontology. 2024 Apr;25(2):341-360. doi: 10.1007/s10522-023-10076-5. Epub 2023 Nov 21.
Telomere shortening is a well-established hallmark of cellular aging. Telomerase reverse transcriptase (TERT) plays a crucial role in maintaining the length of telomeres, which are specialised protective caps at the end of chromosomes. The lack of in vitro aging models, particularly for the central nervous system (CNS), has impeded progress in understanding aging and age-associated neurodegenerative diseases. In this study, we aimed to explore the possibility of inducing aging-associated features in cell types of the CNS using hiPSC (human induced pluripotent stem cell) technology. To achieve this, we utilised CRISPR/Cas9 to generate hiPSCs with a loss of telomerase function and shortened telomeres. Through directed differentiation, we generated motor neurons and astrocytes to investigate whether telomere shortening could lead to age-associated phenotypes. Our findings revealed that shortened telomeres induced age-associated characteristics in both motor neurons and astrocytes including increased cellular senescence, heightened inflammation, and elevated DNA damage. We also observed cell-type specific age-related morphology changes. Additionally, our study highlighted the fundamental role of TERT and telomere shortening in neural progenitor cell (NPC) proliferation and neuronal differentiation. This study serves as a proof of concept that telomere shortening can effectively induce aging-associated phenotypes, thereby providing a valuable tool to investigate age-related decline and neurodegenerative diseases.
端粒缩短是细胞衰老的一个既定标志。端粒酶逆转录酶（TERT）在维持端粒的长度方面起着至关重要的作用，端粒是染色体末端的特殊保护帽。缺乏体外衰老模型，特别是中枢神经系统（CNS）的衰老模型，阻碍了人们对衰老和与年龄相关的神经退行性疾病的理解。在这项研究中，我们旨在探讨使用 hiPSC（人诱导多能干细胞）技术在中枢神经系统的细胞类型中诱导与衰老相关特征的可能性。为了实现这一目标，我们利用 CRISPR/Cas9 技术生成了端粒酶功能丧失和端粒缩短的 hiPSC。通过定向分化，我们生成了运动神经元和星形胶质细胞，以研究端粒缩短是否会导致与年龄相关的表型。我们的研究结果表明，缩短的端粒在运动神经元和星形胶质细胞中诱导了与年龄相关的特征，包括细胞衰老增加、炎症加剧和 DNA 损伤增加。我们还观察到了细胞类型特异性的与年龄相关的形态变化。此外，我们的研究强调了 TERT 和端粒缩短在神经祖细胞（NPC）增殖和神经元分化中的基本作用。这项研究证明了端粒缩短可以有效地诱导与衰老相关的表型，从而为研究与年龄相关的衰退和神经退行性疾病提供了有价值的工具。
