International Business Department           Liu Bojia           October 06, 2023

  Aging is a primary risk factor for cardiovascular disease and can lead to structural abnormalities and functional decline of the heart, such as ventricular wall hypertrophy, diastolic dysfunction, and fibrillation. These age-related cardiac changes tend to increase the prevalence of multiple heart diseases, which in turn affect human health and longevity. As the global population is aging, it has become particularly important to explore the core mechanisms of human cardiac aging and develop appropriate early warning, prevention and treatment strategies.

 Cardiac aging is a complex and dynamic process that is influenced by multiple factors. To date, there are few reports on the cross-dimensional study of primate cardiac aging, and its key molecular mechanisms need to be revealed urgently.

  Recently, Guanghui Liu's group and Jing Qu's group at the Institute of Zoology, Chinese Academy of Sciences (IZCAS) and Wei-Qi Zhang's group at the Beijing Institute of Genomics, Chinese Academy of Sciences (BIGCAS) collaborated to publish a paper online in Nature Aging, which for the first time, based on the proteomic study of the aging heart in the Crab-Eating Monkey (Cebus monkeys), revealed a new mechanism of delaying myocardial aging of the primate cardiac muscle by the de-acetylase SIRT2 protein and reversed the aging process through the SIRT2 gene therapy. SIRT2 gene therapy reversed the function of aging hearts in mice. The paper was also selected as the cover article for the October issue of Nature Aging.

  To explore the aging mechanisms of the heart, the team first comparatively analyzed young versus naturally aging models of aged non-human primates (Crab-eating monkeys), and found that aging phenotypes such as cardiac hypertrophy, myonodal disorders and inflammation were present in the aged individuals.

  To determine the molecular mechanisms behind these phenotypic differences, the researchers analyzed the senescence differential proteins identified in the hearts of Crab Monkeys in conjunction with a diverse set of protein-coding genes, including genes associated with aging-related cardiovascular disease, Aging Atlas aging-related genes, and genes associated with epigenetic regulation, and found that the deacetylase SIRT2 was the only senescence differential protein that was associated with both cardiovascular disease and epigenetic regulation of aging. genetic regulation of aging.

  The Sirtuins family of proteins (from SIRT1 to SIRT7) is a well-known family of longevity proteins that are deacetylases in mammals and can regulate various biological events (e.g., metabolism and longevity) by modulating post-translational modifications of histones and transcription factors. Among them, the role of SIRT2 in regulating aging, metabolism and cellular activities has also received increasing attention, but no previous study has linked it to primate cardiac aging.

  To investigate the potential impact of SIRT2 on cardiac aging, researchers obtained SIRT2 knockout human cardiomyocytes for the first time using CRISPR-Cas9-mediated gene editing and human pluripotent stem cell directed induced differentiation, and found that SIRT2-deficient human cardiomyocytes exhibited a series of cardiac aging-related phenotypes such as accelerated senescence, abnormal hypertrophy, and exhibited gene expression profiling changes similar to those of the aged cervid monkey heart and showed similar altered gene expression profiles as aged crab-eating monkeys.

  These findings confirm that downregulation of SIRT2 protein expression is a key factor driving senescence in primate cardiomyocytes. Then, through what pathway does SIRT2 affect the cardiomyocyte senescence process?

  Based on the in-depth study of multi-dimensional technology, the research team found that SIRT2 protein interacts with the transcription factor STAT3 to promote the deacetylation of the latter K685, which in turn inhibits the transcription of the cell cycle blocker gene CDKN2B. SIRT2 deficiency induces an increase in the level of acetylation of STAT3, which promotes the expression of the CDKN2B gene, leading to cardiomyocyte senescence and hypertrophy. In contrast, overexpression of SIRT2 or knockdown of CDKN2B delayed human cardiomyocyte senescence. Thus, the team demonstrated that SIRT2 can serve as a key target for regulating human cardiac muscle senescence.

  The researchers speculate that gene therapy based on SIRT2 might slow cardiac aging. To test this, the researchers injected lentivirus encoding SIRT2 protein into the myocardium of 24-month-old mice at multiple points and found that after 2 weeks, the hearts of the aged mice showed significant "rejuvenation" in ejection fraction (EF), short-axis shortening (FS), and cardiac hypertrophy, suggesting that SIRT2 could be a key target for in vivo intervention in myocardial aging. SIRT2 could be used as a molecular switch to intervene in myocardial aging in vivo. Therefore, the prevention and treatment of cardiac aging and related cardiovascular diseases may be realized through the development of SIRT2-enhanced gene therapy or SIRT2-specific agonists in the future.