Senescence-resistant human mesenchymal progenitor cells counter aging in primates

Jinghui Lei; Zijuan Xin; Ning Liu; Taixin Ning; Ying Jing; Yicheng Qiao; Zan He; Mengmeng Jiang; Yuanhan Yang; Zhiyi Zhang; Liyun Zhao; Jingyi Li; Dongliang Lv; Yupeng Yan; Hui Zhang; Lingling Xiao; Baohu Zhang; Haoyan Huang; Shuhui Sun; Fangshuo Zheng; Xiaoyu Jiang; Huifen Lu; Xueda Dong; Shasha Yue; Chencan Ma; Jichen Shuai; Zhejun Ji; Feifei Liu; Yanxia Ye; Kaowen Yan; Qinchao Hu; Gang Xu; Qian Zhao; Ruochen Wu; Yusheng Cai; Yanling Fan; Yaobin Jing; Qiaoran Wang; Pradeep Reddy; Xiaoyong Lu; Zikai Zheng; Beibei Liu; Amin Haghani; Shuai Ma; Keiichiro Suzuki; Concepcion Rodriguez Esteban; Jiayin Yang; Moshi Song; Steve Horvath; Weiqi Zhang; Wei Li; Andy Peng Xiang; Lan Zhu; Xiaobing Fu; Guoguang Zhao; Juan Carlos Izpisua Belmonte; Jing Qu; Si Wang; Guang-Hui Liu

doi:10.1016/j.cell.2025.05.021

Senescence-resistant human mesenchymal progenitor cells counter aging in primates

Cell. 2025 Jun 13:S0092-8674(25)00571-9. doi: 10.1016/j.cell.2025.05.021. Online ahead of print.

Authors

Jinghui Lei¹, Zijuan Xin², Ning Liu³, Taixin Ning¹, Ying Jing¹, Yicheng Qiao³, Zan He¹, Mengmeng Jiang⁴, Yuanhan Yang⁵, Zhiyi Zhang⁶, Liyun Zhao¹, Jingyi Li⁷, Dongliang Lv⁵, Yupeng Yan⁴, Hui Zhang⁸, Lingling Xiao¹, Baohu Zhang⁵, Haoyan Huang¹, Shuhui Sun⁸, Fangshuo Zheng⁹, Xiaoyu Jiang⁵, Huifen Lu¹, Xueda Dong¹⁰, Shasha Yue⁶, Chencan Ma³, Jichen Shuai¹, Zhejun Ji⁴, Feifei Liu⁸, Yanxia Ye⁴, Kaowen Yan⁴, Qinchao Hu¹¹, Gang Xu¹², Qian Zhao¹, Ruochen Wu⁵, Yusheng Cai⁴, Yanling Fan¹³, Yaobin Jing¹⁴, Qiaoran Wang¹⁵, Pradeep Reddy¹⁶, Xiaoyong Lu¹⁵, Zikai Zheng¹⁵, Beibei Liu¹³, Amin Haghani¹⁶, Shuai Ma⁷, Keiichiro Suzuki¹⁷, Concepcion Rodriguez Esteban¹⁶, Jiayin Yang¹², Moshi Song⁷, Steve Horvath¹⁶, Weiqi Zhang¹⁸, Wei Li¹⁹, Andy Peng Xiang²⁰, Lan Zhu²¹, Xiaobing Fu²², Guoguang Zhao²³, Juan Carlos Izpisua Belmonte²⁴, Jing Qu²⁵, Si Wang²⁶, Guang-Hui Liu²⁷

Affiliations

¹ 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 100053, China.
² 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 100053, China; State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
³ State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
⁵ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁶ State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁷ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
⁸ Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
⁹ Chongqing Fifth People's Hospital, Chongqing 400060, China.
¹⁰ State Key Laboratory of Cognitive Science and Mental Health, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Sino-Danish College, Sino-Danish Centre for Education and Research, University of Chinese Academy of Sciences, Beijing 100049, China.
¹¹ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Hospital of Stomatology, Guanghua School of Stomatology, Guangdong Provincial Key Laboratory of Stomatology, Sun Yat-Sen University, Guangzhou 510060, China.
¹² Liver Transplant Center, Organ Transplant Center, West China Hospital of Sichuan University, Chengdu 610000, China; Laboratory of Liver Transplantation, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital of Sichuan University, Chengdu 610000, China.
¹³ Beijing Institute of Genomics, China National Center for Bioinformation, Chinese Academy of Sciences, Beijing 100101, China.
¹⁴ International Center for Aging and Cancer, Hainan Medical University, Haikou 571199, China.
¹⁵ Beijing Institute of Genomics, China National Center for Bioinformation, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
¹⁶ Altos Labs San Diego Institute of Science, San Diego, CA, USA.
¹⁷ Institute for Advanced Co-Creation Studies, The University of Osaka, Osaka 560-8531, Japan.
¹⁸ Beijing Institute of Genomics, China National Center for Bioinformation, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Sino-Danish College, Sino-Danish Centre for Education and Research, University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
¹⁹ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
²⁰ Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University, Guangzhou 510080, Guangdong, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
²¹ National Clinical Research Center for Obstetric and Gynecologic Diseases, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
²² Tissue Repair and Regeneration Research Center, Medical Innovation Department, PLA General Hospital and Medical College, Beijing 100842, China.
²³ Department of Neurosurgery, Beijing Municipal Geriatric Medical Research Center, National Medical Center for Neurological Diseases, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
²⁴ Altos Labs San Diego Institute of Science, San Diego, CA, USA; Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
²⁵ State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: qujing@ioz.ac.cn.
²⁶ 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 100053, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: wangsi@xwh.ccmu.edu.cn.
²⁷ 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 100053, China; State Key Laboratory of Organ Regeneration and Reconstruction, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: ghliu@ioz.ac.cn.

PMID: 40516525
DOI: 10.1016/j.cell.2025.05.021

Abstract

Aging is characterized by a deterioration of stem cell function, but the feasibility of replenishing these cells to counteract aging remains poorly defined. Our study addresses this gap by developing senescence (seno)-resistant human mesenchymal progenitor cells (SRCs), genetically fortified to enhance cellular resilience. In a 44-week trial, we intravenously delivered SRCs to aged macaques, noting a systemic reduction in aging indicators, such as cellular senescence, chronic inflammation, and tissue degeneration, without any detected adverse effects. Notably, SRC treatment enhanced brain architecture and cognitive function and alleviated the reproductive system decline. The restorative effects of SRCs are partly attributed to their exosomes, which combat cellular senescence. This study provides initial evidence that genetically modified human mesenchymal progenitors can slow primate aging, highlighting the therapeutic potential of regenerative approaches in combating age-related health decline.

Keywords: FOXO3; aging; biomarker; brain; gene editing; intervention; rejuvenation; reproductive system; senescence; stem cell.