From Young to Old: Mimicking Neuronal Aging in Directly Converted Neurons from Young Donors - DATA

A substantial challenge in human brain aging is to find a suitable model to mimic neuronal aging in vitro as accurately as possible. Using directly converted neurons (iNs) from human fibroblasts is considered a promising tool in human aging since it retains the aging-associated mitochondrial donor signature. Still, using iNs from aged donors can pose certain restrictions due to their lower reprogramming and conversion efficacy than those from younger individuals. To overcome these limitations, our study aimed to establish an in vitro neuronal aging model mirroring features of in vivo aging by acute exposure on young iNs to either human stress hormone cortisol or the mitochondrial stressor rotenone, considering stress as a trigger of in vivo aging. The impact of rotenone was evident in mitochondrial bioenergetic properties by showing aging-associated deficits in mitochondrial respiration, cellular ATP, and MMP and a rise in glycolysis, mitochondrial superoxide, and mitochondrial ROS; meanwhile, cortisol only partially induced an aging-associated mitochondrial dysfunction. To replicate the in vivo aging-associated mitochondrial dysfunctions, using rotenone, a mitochondrial complex I inhibitor, proved to be superior to the cortisol model. This work is the first to use stress on young iNs to recreate aging-related mitochondrial impairments.

Varghese, Nimmy, Amandine Grimm, M. Zameel Cader, and Anne Eckert. 2024. "From Young to Old: Mimicking Neuronal Aging in Directly Converted Neurons from Young Donors" Cells 13, no. 15: 1260. https://doi.org/10.3390/cells13151260

人类大脑衰老研究中的一个重大挑战是找到合适的体外模型，以尽可能准确地模拟神经元老化。利用人类成纤维细胞直接转化的神经元（directly converted neurons, iNs）被认为是研究人类衰老的一种有前景的工具，因为它保留了与衰老相关的线粒体供体特征。然而，由于老年供体来源的iNs其重编程和转化效率低于年轻个体来源的iNs，使用这类iNs存在一定限制。为克服这些限制，本研究旨在通过将年轻iNs急性暴露于人类应激激素皮质醇或线粒体应激源鱼藤酮，建立一个能反映体内老化特征的体外神经元老化模型——应激被视为体内老化的触发因素。鱼藤酮对线粒体生物能学特性的影响显著：表现为线粒体呼吸、细胞ATP及线粒体膜电位（MMP）出现与衰老相关的缺陷，同时糖酵解、线粒体超氧化物及线粒体活性氧（ROS）水平升高；而皮质醇仅部分诱导了与衰老相关的线粒体功能障碍。在重现与体内老化相关的线粒体功能障碍方面，使用线粒体复合物I抑制剂鱼藤酮被证明优于皮质醇模型。本研究首次通过对年轻iNs施加应激来重现与老化相关的线粒体损伤。