Remesal Laura, Sucharov-Costa Juliana, Wu Yuting, Pratt Karishma J B, Bieri Gregor, Philp Amber, Phan Mason, Aghayev Turan, White Charles W, Wheatley Elizabeth G, Zou Bende, Desousa Brandon R, Couthouis Julien, Jian Isha H, Xie Xinmin S, Lu Yi, Maynard Jason C, Burlingame Alma L, Villeda Saul A
Department of Anatomy, University of California, San Francisco, San Francisco, CA, USA.
Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA.
Nat Aging. 2025 Aug 19. doi: 10.1038/s43587-025-00940-z.
Understanding cellular and molecular drivers of age-related cognitive decline is necessary to identify targets to restore cognition at old age. Here we identify ferritin light chain 1 (FTL1), an iron-associated protein, as a pro-aging neuronal factor that impairs cognition. Using transcriptomic and mass spectrometry approaches, we detect an increase in neuronal FTL1 in the hippocampus of aged mice, the levels of which correlate with cognitive decline. Mimicking an age-related increase in neuronal FTL1 in young mice alters labile iron oxidation states and promotes synaptic and cognitive features of hippocampal aging. Targeting neuronal FTL1 in the hippocampi of aged mice improves synaptic-related molecular changes and cognitive impairments. Using neuronal nuclei RNA sequencing, we detect changes in metabolic processes, such as ATP synthesis, and boosting these metabolic functions through NADH supplementation mitigated pro-aging effects of neuronal FTL1 on cognition. Our data identify neuronal FTL1 as a key molecular mediator of cognitive rejuvenation.
了解与年龄相关的认知衰退的细胞和分子驱动因素对于确定恢复老年认知的靶点至关重要。在此，我们确定铁蛋白轻链1（FTL1），一种与铁相关的蛋白质，是一种损害认知的促衰老神经元因子。使用转录组学和质谱方法，我们检测到老年小鼠海马体中神经元FTL1增加，其水平与认知衰退相关。在年轻小鼠中模拟与年龄相关的神经元FTL1增加会改变不稳定铁的氧化状态，并促进海马体衰老的突触和认知特征。在老年小鼠海马体中靶向神经元FTL1可改善与突触相关的分子变化和认知障碍。使用神经元细胞核RNA测序，我们检测到代谢过程的变化，如ATP合成，通过补充NADH增强这些代谢功能可减轻神经元FTL1对认知的促衰老作用。我们的数据确定神经元FTL1是认知恢复活力的关键分子介质。
