Institute of Healthy Ageing, University College London, London WC1E 6BT, United Kingdom.
Department of Genetics, Evolution and Environment, University College London, London WC1E 6BT, United Kingdom.
Proc Natl Acad Sci U S A. 2021 Feb 23;118(8). doi: 10.1073/pnas.2011491118.
Reduced activity of insulin/insulin-like growth factor signaling (IIS) increases healthy lifespan among diverse animal species. Downstream of IIS, multiple evolutionarily conserved transcription factors (TFs) are required; however, distinct TFs are likely responsible for these effects in different tissues. Here we have asked which TFs can extend healthy lifespan within distinct cell types of the adult nervous system in Starting from published single-cell transcriptomic data, we report that (FKH) is endogenously expressed in neurons, whereas (FOXO) is expressed in glial cells. Accordingly, we find that neuronal FKH and glial FOXO exert independent prolongevity effects. We have further explored the role of neuronal FKH in a model of Alzheimer's disease-associated neuronal dysfunction, where we find that increased neuronal FKH preserves behavioral function and reduces ubiquitinated protein aggregation. Finally, using transcriptomic profiling, we identify , a member of the Atg1 autophagy initiation family, as one FKH-dependent target whose neuronal overexpression is sufficient to extend healthy lifespan. Taken together, our results underscore the importance of cell type-specific mapping of TF activity to preserve healthy function with age.
胰岛素/胰岛素样生长因子信号转导 (IIS) 活性降低会增加多种动物物种的健康寿命。在 IIS 的下游，需要多种进化保守的转录因子 (TF)；然而，不同的 TF 可能负责不同组织中的这些效应。在这里，我们询问了哪些 TF 可以延长成年神经系统不同细胞类型的健康寿命。从已发表的单细胞转录组数据出发，我们报告说，FKH（FoxO 家族的一个成员）在神经元中内源性表达，而 FOXO（叉头框 O 家族的一个成员）在神经胶质细胞中表达。因此，我们发现神经元 FKH 和神经胶质 FOXO 发挥独立的延长寿命作用。我们进一步探索了神经元 FKH 在与阿尔茨海默病相关的神经元功能障碍模型中的作用，我们发现增加神经元 FKH 可以保持行为功能并减少泛素化蛋白聚集。最后，通过转录组分析，我们确定了 Atg1 自噬起始家族的成员，作为一个依赖于 FKH 的靶标，其神经元过表达足以延长健康寿命。总之，我们的结果强调了对 TF 活性进行细胞类型特异性映射以随年龄保持健康功能的重要性。
