Metformin decelerates aging clock in male monkeys

doi:10.1016/j.cell.2024.08.021

. 2024 Oct 31;187(22):6358-6378.e29.

doi: 10.1016/j.cell.2024.08.021. Epub 2024 Sep 12.

Metformin decelerates aging clock in male monkeys

Yuanhan Yang¹, Xiaoyong Lu², Ning Liu³, Shuai Ma⁴, Hui Zhang⁵, Zhiyi Zhang⁶, Kuan Yang², Mengmeng Jiang⁷, Zikai Zheng², Yicheng Qiao³, Qinchao Hu⁸, Ying Huang⁹, Yiyuan Zhang⁷, Muzhao Xiong², Lixiao Liu², Xiaoyu Jiang¹, Pradeep Reddy¹⁰, Xueda Dong¹¹, Fanshu Xu³, Qiaoran Wang², Qian Zhao¹², Jinghui Lei¹², Shuhui Sun¹³, Ying Jing¹², Jingyi Li¹⁴, Yusheng Cai⁷, Yanling Fan¹⁵, Kaowen Yan⁷, Yaobin Jing¹⁶, Amin Haghani¹⁰, Mengen Xing¹⁷, Xuan Zhang¹⁸, Guodong Zhu¹⁹, Weihong Song¹⁷, Steve Horvath¹⁰, Concepcion Rodriguez Esteban¹⁰, Moshi Song²⁰, Si Wang²¹, Guoguang Zhao²², Wei Li⁴, Juan Carlos Izpisua Belmonte¹⁰, Jing Qu²³, Weiqi Zhang²⁴, Guang-Hui Liu²⁵

Affiliations

¹ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² China National Center for Bioinformation, Beijing, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁵ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
⁶ State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁷ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
⁸ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, 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.
⁹ Chongqing Fifth People's Hospital, Chongqing 400060, China.
¹⁰ Altos Labs San Diego Institute of Science, San Diego, CA, USA.
¹¹ State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China.
¹² National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
¹³ Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
¹⁴ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
¹⁵ China National Center for Bioinformation, Beijing, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
¹⁶ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; International Center for Aging and Cancer, Hainan Medical University, Haikou 571199, China.
¹⁷ Oujiang Laboratory, Center for Geriatric Medicine and Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research for Mental Disorders, The First-Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
¹⁸ Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing 100730, China.
¹⁹ Institute of Gerontology, Guangzhou Geriatric Hospital, Guangzhou Medical University, Guangzhou, China.
²⁰ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, 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.
²¹ National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
²² Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing 100053, China; National Medical Center for Neurological Diseases, Beijing 100053, China; Beijing Municipal Geriatric Medical Research Center, Beijing 100053, China.
²³ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: qujing@ioz.ac.cn.
²⁴ China National Center for Bioinformation, Beijing, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; Institute for Stem Cell and Regeneration, CAS, 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: zhangwq@big.ac.cn.
²⁵ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing 100053, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: ghliu@ioz.ac.cn.

PMID: 39270656
DOI: 10.1016/j.cell.2024.08.021

Metformin decelerates aging clock in male monkeys

Yuanhan Yang et al. Cell. 2024.

. 2024 Oct 31;187(22):6358-6378.e29.

doi: 10.1016/j.cell.2024.08.021. Epub 2024 Sep 12.

Authors

Affiliations

¹ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
² China National Center for Bioinformation, Beijing, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing 100049, China.
³ State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
⁴ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China.
⁵ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
⁶ State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
⁷ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China.
⁸ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, 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.
⁹ Chongqing Fifth People's Hospital, Chongqing 400060, China.
¹⁰ Altos Labs San Diego Institute of Science, San Diego, CA, USA.
¹¹ State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, China.
¹² National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
¹³ Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China.
¹⁴ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
¹⁵ China National Center for Bioinformation, Beijing, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
¹⁶ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; International Center for Aging and Cancer, Hainan Medical University, Haikou 571199, China.
¹⁷ Oujiang Laboratory, Center for Geriatric Medicine and Institute of Aging, Key Laboratory of Alzheimer's Disease of Zhejiang Province, Zhejiang Provincial Clinical Research for Mental Disorders, The First-Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
¹⁸ Department of Rheumatology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Clinical Immunology Center, Chinese Academy of Medical Sciences, Beijing 100730, China.
¹⁹ Institute of Gerontology, Guangzhou Geriatric Hospital, Guangzhou Medical University, Guangzhou, China.
²⁰ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, 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.
²¹ National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Aging Biomarker Consortium (ABC), Beijing 100101, China.
²² Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing 100053, China; National Medical Center for Neurological Diseases, Beijing 100053, China; Beijing Municipal Geriatric Medical Research Center, Beijing 100053, China.
²³ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Beijing Institute of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: qujing@ioz.ac.cn.
²⁴ China National Center for Bioinformation, Beijing, China; Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; Institute for Stem Cell and Regeneration, CAS, 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: zhangwq@big.ac.cn.
²⁵ Key Laboratory of Organ Regeneration and Reconstruction, State Key Laboratory of Membrane Biology, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, CAS, Beijing 100101, China; Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China; National Clinical Research Center for Geriatric Disorders, Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital Capital Medical University, Beijing 100053, China; University of Chinese Academy of Sciences, Beijing 100049, China; Aging Biomarker Consortium (ABC), Beijing 100101, China. Electronic address: ghliu@ioz.ac.cn.

PMID: 39270656
DOI: 10.1016/j.cell.2024.08.021

Abstract

In a rigorous 40-month study, we evaluated the geroprotective effects of metformin on adult male cynomolgus monkeys, addressing a gap in primate aging research. The study encompassed a comprehensive suite of physiological, imaging, histological, and molecular evaluations, substantiating metformin's influence on delaying age-related phenotypes at the organismal level. Specifically, we leveraged pan-tissue transcriptomics, DNA methylomics, plasma proteomics, and metabolomics to develop innovative monkey aging clocks and applied these to gauge metformin's effects on aging. The results highlighted a significant slowing of aging indicators, notably a roughly 6-year regression in brain aging. Metformin exerts a substantial neuroprotective effect, preserving brain structure and enhancing cognitive ability. The geroprotective effects on primate neurons were partially mediated by the activation of Nrf2, a transcription factor with anti-oxidative capabilities. Our research pioneers the systemic reduction of multi-dimensional biological age in primates through metformin, paving the way for advancing pharmaceutical strategies against human aging.

Keywords: aging; aging clock; metformin; primate; senescence.

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Conflict of interest statement

Declaration of interests J.C.I.B., S.H., C.R.E., P.R., and A.H. are employees of Altos Labs. S.H. is a founder of the non-profit Epigenetic Clock Development Foundation, which has licensed several of his patents from UC Regents and distributes the mammalian methylation array.

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Metformin decelerates aging clock in male monkeys

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Metformin decelerates aging clock in male monkeys

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