Single-cell profiling identifies hair cell SLC35F1 deficiency as a signature of primate cochlear aging

Guoqiang Sun; Xiaolong Fu; Yandong Zheng; Guodong Hong; Ziyi Liu; Bilan Luo; Jinghui Lei; Dongliang Lv; Miao Chang; Yu Xiao; Siwei Guo; Shuai Ma; Ling Lu; Weiqi Zhang; Juan Carlos Izpisua Belmonte; Jing Qu; Si Wang; Renjie Chai; Guang-Hui Liu

doi:10.1038/s43587-025-00896-0

Single-cell profiling identifies hair cell SLC35F1 deficiency as a signature of primate cochlear aging

Nat Aging. 2025 Jun 20. doi: 10.1038/s43587-025-00896-0. Online ahead of print.

Authors

Guoqiang Sun^#¹, Xiaolong Fu^#^{2

3}, Yandong Zheng^#^{1

4

5}, Guodong Hong^#², Ziyi Liu^#^{2

6}, Bilan Luo⁴, Jinghui Lei⁴, Dongliang Lv^{1

5}, Miao Chang², Yu Xiao², Siwei Guo², Shuai Ma^{1

3

7}, Ling Lu⁸, Weiqi Zhang^{3

5

9}, Juan Carlos Izpisua Belmonte¹⁰, Jing Qu^{11

12

13

14

15}, Si Wang^{16

17}, Renjie Chai^{18

19

20

21}, Guang-Hui Liu^{22

23

24

25

26}

Affiliations

¹ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
² 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.
³ Aging Biomarker Consortium (ABC), Beijing, China.
⁴ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing, China.
⁵ University of Chinese Academy of Sciences, Beijing, China.
⁶ Institute of Brain Science and Brain-inspired Research, Medical Science and Technology Innovation Center, Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China.
⁷ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
⁸ Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, Southeast University, Nanjing, China.
⁹ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics and China National Center for Bioinformation, Chinese Academy of Sciences, Beijing, China.
¹⁰ Altos Labs, San Diego, CA, USA.
¹¹ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. qujing@ioz.ac.cn.
¹² Aging Biomarker Consortium (ABC), Beijing, China. qujing@ioz.ac.cn.
¹³ University of Chinese Academy of Sciences, Beijing, China. qujing@ioz.ac.cn.
¹⁴ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. qujing@ioz.ac.cn.
¹⁵ Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China. qujing@ioz.ac.cn.
¹⁶ Aging Biomarker Consortium (ABC), Beijing, China. wangsi@xwh.ccmu.edu.cn.
¹⁷ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing, China. wangsi@xwh.ccmu.edu.cn.
¹⁸ Aging Biomarker Consortium (ABC), Beijing, China. renjiec@seu.edu.cn.
¹⁹ Department of Otolaryngology-Head and Neck Surgery, Zhongda Hospital, Southeast University, Nanjing, China. renjiec@seu.edu.cn.
²⁰ State Key Laboratory of Bioelectronics, Jiangsu Province High-Tech Key Laboratory for Bio-Medical Research, School of Life Sciences and Technology, Southeast University, Nanjing, China. renjiec@seu.edu.cn.
²¹ Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China. renjiec@seu.edu.cn.
²² State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. ghliu@ioz.ac.cn.
²³ Aging Biomarker Consortium (ABC), Beijing, China. ghliu@ioz.ac.cn.
²⁴ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, Beijing Municipal Geriatric Medical Research Center, Beijing Key Laboratory of Environment and Aging, Xuanwu Hospital Capital Medical University, Beijing, China. ghliu@ioz.ac.cn.
²⁵ University of Chinese Academy of Sciences, Beijing, China. ghliu@ioz.ac.cn.
²⁶ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. ghliu@ioz.ac.cn.

^# Contributed equally.

PMID: 40542214
DOI: 10.1038/s43587-025-00896-0

Abstract

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.