Danics Lea, Abbas Anna Anoir, Kis Balázs, Pircs Karolina
Institute of Translational Medicine, Semmelweis University, Budapest, Hungary.
Hungarian Centre of Excellence for Molecular Medicine - Semmelweis University (HCEMM-SU), Neurobiology and Neurodegenerative Diseases Research Group, Budapest, Hungary.
Front Aging Neurosci. 2023 Mar 29;15:1125739. doi: 10.3389/fnagi.2023.1125739. eCollection 2023.
As our society ages inexorably, geroscience and research focusing on healthy aging is becoming increasingly urgent. Macroautophagy (referred to as autophagy), a highly conserved process of cellular clearance and rejuvenation has attracted much attention due to its universal role in organismal life and death. Growing evidence points to autophagy process as being one of the key players in the determination of lifespan and health. Autophagy inducing interventions show significant improvement in organismal lifespan demonstrated in several experimental models. In line with this, preclinical models of age-related neurodegenerative diseases demonstrate pathology modulating effect of autophagy induction, implicating its potential to treat such disorders. In humans this specific process seems to be more complex. Recent clinical trials of drugs targeting autophagy point out some beneficial effects for clinical use, although with limited effectiveness, while others fail to show any significant improvement. We propose that using more human-relevant preclinical models for testing drug efficacy would significantly improve clinical trial outcomes. Lastly, the review discusses the available cellular reprogramming techniques used to model neuronal autophagy and neurodegeneration while exploring the existing evidence of autophagy's role in aging and pathogenesis in human-derived models such as embryonic stem cells (ESCs), induced pluripotent stem cell derived neurons (iPSC-neurons) or induced neurons (iNs).
随着我们的社会不可阻挡地老龄化，老年科学以及专注于健康衰老的研究变得越来越紧迫。巨自噬（简称为自噬），作为一种细胞清除和更新的高度保守过程，因其在生物体生死中的普遍作用而备受关注。越来越多的证据表明自噬过程是决定寿命和健康的关键因素之一。在多个实验模型中，诱导自噬的干预措施显著延长了生物体的寿命。与此一致的是，与年龄相关的神经退行性疾病的临床前模型显示自噬诱导具有病理调节作用，这暗示了其治疗此类疾病的潜力。在人类中，这个特定过程似乎更为复杂。最近针对自噬的药物临床试验指出了一些临床应用的有益效果，尽管效果有限，而其他一些试验则未能显示出任何显著改善。我们建议使用更多与人类相关的临床前模型来测试药物疗效，这将显著改善临床试验结果。最后，该综述讨论了用于模拟神经元自噬和神经退行性变的现有细胞重编程技术，同时探讨了自噬在人类来源模型（如胚胎干细胞（ESC）、诱导多能干细胞衍生神经元（iPSC-神经元）或诱导神经元（iN））的衰老和发病机制中作用的现有证据。
