SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B

Yanxia Ye^#^{1

2

3}, Kuan Yang^#^{4

5

6}, Haisong Liu^#⁷, Yang Yu^#^{8

9}, Moshi Song^#^{2

3

4

10}, Daoyuan Huang^{11

12}, Jinghui Lei^{11

12}, Yiyuan Zhang^{2

3

10}, Zunpeng Liu^{1

3

5}, Qun Chu^{1

2

3

13}, Yanling Fan⁴, Sheng Zhang^{5

10

14}, Yaobin Jing^{2

3

5

10}, Concepcion Rodriguez Esteban¹⁵, Si Wang^{11

12

13}, Juan Carlos Izpisua Belmonte¹⁵, Jing Qu^{16

17

18

19}, Weiqi Zhang^{20

21

22

23}, Guang-Hui Liu^{24

25

26

27

28

29}

Affiliations

¹ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
² Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
³ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
⁴ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China.
⁵ University of Chinese Academy of Sciences, Beijing, China.
⁶ Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.
⁷ School of Biomedical Sciences, Hunan University, Changsha, China.
⁸ Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
⁹ Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China.
¹⁰ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
¹¹ Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China.
¹² Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, China.
¹³ The Fifth People's Hospital of Chongqing, Chongqing, China.
¹⁴ State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Brain-Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
¹⁵ Altos Labs, Inc., San Diego, CA, USA.
¹⁶ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. qujing@ioz.ac.cn.
¹⁷ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. qujing@ioz.ac.cn.
¹⁸ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. qujing@ioz.ac.cn.
¹⁹ University of Chinese Academy of Sciences, Beijing, China. qujing@ioz.ac.cn.
²⁰ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. zhangwq@big.ac.cn.
²¹ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China. zhangwq@big.ac.cn.
²² University of Chinese Academy of Sciences, Beijing, China. zhangwq@big.ac.cn.
²³ Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China. zhangwq@big.ac.cn.
²⁴ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. ghliu@ioz.ac.cn.
²⁵ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. ghliu@ioz.ac.cn.
²⁶ University of Chinese Academy of Sciences, Beijing, China. ghliu@ioz.ac.cn.
²⁷ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. ghliu@ioz.ac.cn.
²⁸ Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China. ghliu@ioz.ac.cn.
²⁹ Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, China. ghliu@ioz.ac.cn.

^# Contributed equally.

PMID: 37783815
DOI: 10.1038/s43587-023-00486-y

SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B

Yanxia Ye et al. Nat Aging. 2023 Oct.

. 2023 Oct;3(10):1269-1287.

doi: 10.1038/s43587-023-00486-y. Epub 2023 Oct 2.

Authors

Affiliations

¹ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
² Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China.
³ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China.
⁴ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China.
⁵ University of Chinese Academy of Sciences, Beijing, China.
⁶ Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China.
⁷ School of Biomedical Sciences, Hunan University, Changsha, China.
⁸ Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology and Key Laboratory of Assisted Reproduction, Ministry of Education, Center of Reproductive Medicine, Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
⁹ Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, China.
¹⁰ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
¹¹ Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China.
¹² Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, China.
¹³ The Fifth People's Hospital of Chongqing, Chongqing, China.
¹⁴ State Key Laboratory of Brain and Cognitive Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Brain-Intelligence Technology (Shanghai), Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
¹⁵ Altos Labs, Inc., San Diego, CA, USA.
¹⁶ State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. qujing@ioz.ac.cn.
¹⁷ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. qujing@ioz.ac.cn.
¹⁸ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. qujing@ioz.ac.cn.
¹⁹ University of Chinese Academy of Sciences, Beijing, China. qujing@ioz.ac.cn.
²⁰ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. zhangwq@big.ac.cn.
²¹ CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China. zhangwq@big.ac.cn.
²² University of Chinese Academy of Sciences, Beijing, China. zhangwq@big.ac.cn.
²³ Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China. zhangwq@big.ac.cn.
²⁴ Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. ghliu@ioz.ac.cn.
²⁵ Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. ghliu@ioz.ac.cn.
²⁶ University of Chinese Academy of Sciences, Beijing, China. ghliu@ioz.ac.cn.
²⁷ State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. ghliu@ioz.ac.cn.
²⁸ Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China. ghliu@ioz.ac.cn.
²⁹ Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, China. ghliu@ioz.ac.cn.

^# Contributed equally.

PMID: 37783815
DOI: 10.1038/s43587-023-00486-y

Abstract

Aging is a major risk factor contributing to pathophysiological changes in the heart, yet its intrinsic mechanisms have been largely unexplored in primates. In this study, we investigated the hypertrophic and senescence phenotypes in the hearts of aged cynomolgus monkeys as well as the transcriptomic and proteomic landscapes of young and aged primate hearts. SIRT2 was identified as a key protein decreased in aged monkey hearts, and engineered SIRT2 deficiency in human pluripotent stem cell-derived cardiomyocytes recapitulated key senescence features of primate heart aging. Further investigations revealed that loss of SIRT2 in human cardiomyocytes led to the hyperacetylation of STAT3, which transcriptionally activated CDKN2B and, in turn, triggered cardiomyocyte degeneration. Intra-myocardial injection of lentiviruses expressing SIRT2 ameliorated age-related cardiac dysfunction in mice. Taken together, our study provides valuable resources for decoding primate cardiac aging and identifies the SIRT2-STAT3-CDKN2B regulatory axis as a potential therapeutic target against human cardiac aging and aging-related cardiovascular diseases.

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Comment in

SIRT2 counteracts primate cardiac aging.
Cox L, Olivier M. Cox L, et al. Nat Aging. 2023 Oct;3(10):1178-1179. doi: 10.1038/s43587-023-00496-w. Nat Aging. 2023. PMID: 37783814 No abstract available.
Sirtuin 2 protects against cardiac ageing.
Fernández-Ruiz I. Fernández-Ruiz I. Nat Rev Cardiol. 2023 Dec;20(12):796. doi: 10.1038/s41569-023-00950-7. Nat Rev Cardiol. 2023. PMID: 37853159 No abstract available.

References

1. Lakatta, E. G. & Levy, D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part II: the aging heart in health: links to heart disease. Circulation 107, 346–354 (2003). - PubMed - DOI
1. Stern, S., Behar, S. & Gottlieb, S. Aging and diseases of the heart. Circulation 108, E99–E101 (2003). - PubMed - DOI
1. Lakatta, E. G. & Levy, D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part I: aging arteries: a ‘set up’ for vascular disease. Circulation 107, 139–146 (2003). - PubMed - DOI
1. Paneni, F., Canestro, C. D., Libby, P., Luscher, T. F. & Camici, G. G. The aging cardiovascular system understanding it at the cellular and clinical levels. J. Am. Coll. Cardiol. 69, 1952–1967 (2017). - PubMed - DOI
1. Li, H. B. et al. Targeting age-related pathways in heart failure. Circ. Res. 126, 533–551 (2020). - PubMed - PMC - DOI

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SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B

Affiliations

SIRT2 counteracts primate cardiac aging via deacetylation of STAT3 that silences CDKN2B

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