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

  • Nat Aging. 2023 Oct;3(10):1269-1287. doi: 10.1038/s43587-023-00486-y.
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 Fan  4 ,  Sheng Zhang  5  10  14 ,  Yaobin Jing  2  3  5  10 ,  Concepcion Rodriguez Esteban  15 ,  Si Wang  11  12  13 ,  Juan Carlos Izpisua Belmonte  15 ,  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. [email protected].
  • 17. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. [email protected].
  • 18. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. [email protected].
  • 19. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 20. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. [email protected].
  • 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. [email protected].
  • 22. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 23. Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 24. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China. [email protected].
  • 25. Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China. [email protected].
  • 26. University of Chinese Academy of Sciences, Beijing, China. [email protected].
  • 27. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China. [email protected].
  • 28. Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China. [email protected].
  • 29. Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, China. [email protected].
  • # 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.