Sun Guoqiang, Fu Xiaolong, Zheng Yandong, Hong Guodong, Liu Ziyi, Luo Bilan, Lei Jinghui, Lv Dongliang, Chang Miao, Xiao Yu, Guo Siwei, Ma Shuai, Lu Ling, Zhang Weiqi, Belmonte Juan Carlos Izpisua, Qu Jing, Wang Si, Chai Renjie, Liu Guang-Hui
State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
Nat Aging. 2025 Jun 20. doi: 10.1038/s43587-025-00896-0.
Cochlear aging causes substantial hearing impairment in older adults, yet primate-specific mechanisms remain poorly characterized. Our comprehensive analysis combining single-cell and histopathological profiling in aging Macaca fascicularis demonstrates progressive cochlear degeneration featuring accelerated sensory hair cell loss, senescent spiral ganglion neurons with elevated neuroinflammation, and marked stria vascularis atrophy. We discovered that downregulation of transmembrane transport proteins, particularly SLC35F1, serves as a critical biomarker of hair cell aging. Functional validation through Slc35f1 knockdown in adult mice successfully recapitulated key aspects of age-related hearing loss, including hair cell degeneration and auditory function decline. Notably, we showed that long-term metformin administration at clinically relevant doses effectively delays cochlear aging in primates. These findings provide fundamental insights into the cellular and molecular basis of primate cochlear aging while establishing a foundation for developing targeted interventions against age-related hearing loss.
耳蜗衰老会导致老年人出现严重的听力障碍,但灵长类动物特有的机制仍未得到充分描述。我们结合对老年食蟹猴进行单细胞和组织病理学分析的综合研究表明,耳蜗会进行性退化,其特征包括感觉毛细胞加速丢失、伴有神经炎症加剧的衰老螺旋神经节神经元以及明显的血管纹萎缩。我们发现跨膜转运蛋白的下调,尤其是SLC35F1,是毛细胞衰老的关键生物标志物。通过在成年小鼠中敲低Slc35f1进行功能验证,成功重现了与年龄相关的听力损失的关键方面,包括毛细胞退化和听觉功能下降。值得注意的是,我们表明以临床相关剂量长期服用二甲双胍可有效延缓灵长类动物的耳蜗衰老。这些发现为灵长类动物耳蜗衰老的细胞和分子基础提供了基本见解,同时为开发针对年龄相关听力损失的靶向干预措施奠定了基础。
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