Oddo Salvatore, Lanza Marika, Casili Giovanna, Caccamo Antonella
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale F. Stagno d'Alcontres 31, 98166 Messina, Italy.
Int J Mol Sci. 2025 Jun 20;26(13):5923. doi: 10.3390/ijms26135923.
Aging is the greatest risk factor for Alzheimer's disease (AD), but the mechanisms connecting the two remain unclear. The mammalian target of rapamycin (mTOR) pathway, particularly its downstream effector S6 kinase 1 (S6K1), has emerged as a key regulator of aging and neurodegeneration. S6K1 controls translation, autophagy, and mitochondrial function-processes disrupted in both aging and AD. This review examines how S6K1 influences mitochondrial metabolism, autophagy, and metabolic dysfunction in aging. We also discuss its role in the nervous system, including effects on synaptic plasticity, memory, glial activation, and neuroinflammation. In AD, S6K1 contributes to amyloid and tau pathology by regulating translation of BACE1 and tau, and its hyperactivation is linked to synaptic deficits and cognitive decline. We further explore therapeutic strategies targeting S6K1, which have shown benefits for lifespan extension and neuroprotection in preclinical models. Finally, we consider the emerging link between S6K1 and necroptosis, a form of programmed cell death implicated in AD-related neuronal loss. Together, these findings highlight S6K1 as a promising target for interventions aimed at slowing aging and mitigating AD pathogenesis.
衰老为阿尔茨海默病（AD）的最大风险因素，然而二者之间的关联机制仍不明确。雷帕霉素哺乳动物靶蛋白（mTOR）信号通路，尤其是其下游效应分子S6激酶1（S6K1），已成为衰老和神经退行性变的关键调节因子。S6K1控制翻译、自噬及线粒体功能，而这些过程在衰老和AD中均受到破坏。本综述探讨S6K1如何影响衰老过程中的线粒体代谢、自噬及代谢功能障碍。我们还讨论了其在神经系统中的作用，包括对突触可塑性、记忆、胶质细胞激活及神经炎症的影响。在AD中，S6K1通过调节β-分泌酶1（BACE1）和tau蛋白的翻译而促进淀粉样蛋白和tau病理改变，其过度激活与突触缺陷及认知功能下降相关。我们进一步探索靶向S6K1的治疗策略，这些策略在临床前模型中已显示出延长寿命和神经保护的益处。最后，我们考虑S6K1与坏死性凋亡之间新出现的联系，坏死性凋亡是一种程序性细胞死亡形式，与AD相关的神经元丢失有关。总之，这些发现突出了S6K1作为旨在延缓衰老和减轻AD发病机制的干预措施的一个有前景的靶点。
