Zhao Ranran, Ge Weiqi, Xue Weikang, Deng Zaidong, Liu Jiaze, Wang Kaiqi, Jin Youngnam N, Yu Yanxun V
Department of Neurology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
Department of Nuclear Medicine, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China.
Proc Natl Acad Sci U S A. 2025 May 20;122(20):e2423428122. doi: 10.1073/pnas.2423428122. Epub 2025 May 13.
The impact of neural activity on aging and longevity remains poorly understood, with limited understanding of the specific neuron groups and molecular mechanisms that regulate lifespan. In this study, we uncover a correlation between human longevity and reduced CaMK4 expression in the frontal cortex. We further show that this link is conserved in , where the loss of the homolog CMK-1 leads to increased longevity and enhanced proteostasis. These beneficial effects are primarily driven by suppressed excitation in the primary thermosensory AFD neurons, particularly at elevated temperatures that trigger hyperactivation. In the thermosensory neural circuit, suppression of AFD neuron activity promotes the release of INS-1/insulin from AIZ, which in turn activates DAF-16/FOXO in the intestine. Our findings reveal a causal mechanism through which sensory neural activity governs lifespan and organismal proteostasis, highlighting the significance of CaMK in shaping these processes through the regulation of neural activity.
神经活动对衰老和寿命的影响仍知之甚少，对调节寿命的特定神经元群和分子机制的了解有限。在这项研究中，我们发现人类长寿与额叶皮质中CaMK4表达降低之间存在关联。我们进一步表明，这种联系在 中是保守的，其中同源物CMK-1的缺失导致寿命延长和蛋白质稳态增强。这些有益作用主要由初级热感觉AFD神经元中抑制的兴奋驱动，特别是在触发过度激活的高温下。在热感觉神经回路中，抑制AFD神经元活动会促进AIZ释放INS-1/胰岛素，进而激活肠道中的DAF-16/FOXO。我们的研究结果揭示了一种因果机制，通过该机制感觉神经活动控制寿命和机体蛋白质稳态，突出了CaMK通过调节神经活动在塑造这些过程中的重要性。
