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PubMed · 42468523

Skin-innervating glutamatergic neurons modulate aging.

Zhikai Wang·Xinping Jin·Yue Wu·Wenxiang Ding·Fengjiao Zhang·Yang Sun·Fangzhou Lou·Jing Bai·Xiuli Yang·Hong Zhou·Jihuan Liang·Xiaojie Cai·Yan Li·Xichen Zheng·Jiajia Han·Fang Tong·Qing Yang·Zhixiao Fang·Liuqi Zhao·Qingqing Shen·Zhenyao Xu·Siyu Deng·Li Fan·Jiajia Tong·Linhui Tong·Junjie Wang·Min Gao·Zilong Fang·Qun Li·Rui Chen·Lina Huang·Zhen Li·Yuqin Yang·Jing Zou·Ying Wu·Xiwen Zhang·Honglin Wang
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Abstract

Peripheral nerves regulate skin homeostasis by secreting neurotransmitters, but their role during skin aging remains incompletely understood. Here, we report that cutaneous denervation accelerates skin aging, as evidenced by collagen reduction. Neurofilament heavy chain (Nefh) is decreased in aged skin and is predominantly expressed in vesicular glutamate transporter 2-positive (Vglut2+) skin-innervating glutamatergic neurons. Notably, dermal fibroblasts, the primary producers of collagen, frequently contact Nefh+ nerve fibers. Moreover, Nefh deletion in Vglut2+ glutamatergic neurons drives skin fibroblast senescence and collagen loss, whereas additional glutamate improves skin aging phenotypes. Mechanistically, cyclin-dependent kinase 5 (Cdk5) interacts with both Nefh and Vglut2 and maintains glutamate release and collagen homeostasis. Additionally, in skin fibroblasts, solute carrier family 1 member 3 (Slc1a3) governs the collagen-promoting and anti-senescence functions of glutamate. Together, these findings reveal Nefh-mediated glutamatergic neuromodulation of skin aging and provide therapeutic targets for aging-related skin disorders.

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AnimalsNeuronsFibroblastsGlutamic AcidSkinVesicular Glutamate Transport Protein 2Skin AgingCollagenMiceCyclin-Dependent Kinase 5Cellular SenescenceExcitatory Amino Acid Transporter 1AgingMice, Inbred C57BLHumansCdk5NefhSlc1a3Vglut2collagenfibroblast senescenceglutamateskin agingJournal Article

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Zhikai Wang, Xinping Jin, Yue Wu, Wenxiang Ding, Fengjiao Zhang, Yang Sun, Fangzhou Lou, Jing Bai, Xiuli Yang, Hong Zhou, Jihuan Liang, Xiaojie Cai, Yan Li, Xichen Zheng, Jiajia Han, Fang Tong, Qing Yang, Zhixiao Fang, Liuqi Zhao, Qingqing Shen, Zhenyao Xu, Siyu Deng, Li Fan, Jiajia Tong, Linhui Tong, Junjie Wang, Min Gao, Zilong Fang, Qun Li, Rui Chen, Lina Huang, Zhen Li, Yuqin Yang, Jing Zou, Ying Wu, Xiwen Zhang, Honglin Wang. 2026-07-17. Skin-innervating glutamatergic neurons modulate aging.. https://doi.org/10.1016/j.cell.2026.06.032

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