Because cardiomyocytes are difficult to regenerate and culture, it is difficult for researchers to conduct in-depth studies of the heart. Because of this, what causes the heart to age? What changes occur at the molecular level in the aging heart? These issues have not been thoroughly studied. Recently, “Nature·Aging” published the latest research results of Chinese scientists in the form of a cover article, which directly addresses the mystery of cardiac aging.
In this study, researchers Liu Guanghui’s research group and Qu Jing’s research group from the Institute of Zoology, Chinese Academy of Sciences, and Zhang Weiqi’s research group, a researcher from the Beijing Institute of Genomics, Chinese Academy of Sciences, used a non-human primate (monkey) model of natural aging to discover that Based on the phenotype of the aging heart, using multiple technical means such as multi-level high-throughput sequencing, it was discovered that the sirtuin SIRT2 with epigenetic regulatory function is a key protein in regulating cardiac aging.
“High-throughput sequencing technology allows us to more systematically and efficiently analyze and compare the differences in the content of genes, proteins and other molecules in aging hearts and young hearts, thereby more comprehensively understanding the changes in cardiac aging and capturing the changes in aging hearts. key biological events and the identification of key genes, proteins, etc.,” Zhang Weiqi introduced.
Using proteome sequencing technology, the team jointly analyzed the identified differential proteins in the aging heart and various cardiovascular disease-related genes, and identified the sirtuin SIRT2, the only aging down-regulated protein related to different cardiovascular diseases. “After finding it, we need to verify its function. The clearest way is to verify if the SIRT2 gene encoding the sirtuin SIRT2 protein disappears, will it cause myocardial cells to age.” Co-first author of the paper, Animal Science, Chinese Academy of Sciences Ye Yanxia, an assistant researcher at the institute, explained that to this end, the researchers used gene editing methods to knock out the SIRT2 gene in human pluripotent stem cells, and then successfully obtained SIRT2 gene-knocked out human cardiomyocytes through targeted induction differentiation technology.
“We have broken through the problem of using stem cells to obtain aging human cardiomyocytes.” Ye Yanxia said that through a series of aging-related phenotype studies, the researchers have effectively verified that once the SIRT2 protein is missing in human cardiomyocytes, accelerated aging will occur. , abnormal hypertrophy and a series of conditions.
After discovering that sirtuin SIRT2 is indeed a key protein affecting cardiac aging, its mechanism of action must still be clarified. The researchers combined transcription factor network analysis and conducted in-depth research using a variety of advanced technical methods. They found that SIRT2 can combine with the transcription factor STAT3 to promote STAT3 deacetylation, thereby inhibiting the “work” of the downstream cell cycle arrest gene CDKN2B and delaying Cardiomyocyte senescence.
“We hope that this discovery can help humans find the ‘key’ to delay cardiac aging.” Zhang Weiqi said that the team also conducted intervention studies on elderly mice, injecting lentivirus encoding SIRT2 protein into the myocardium of mice at multiple points to provide Elderly mice were supplemented with SIRT2 protein. The researchers found that the hearts of the older mice became younger and more energetic after two weeks.
“The key proteins found in the study may be used for clinical diagnosis, early warning and medical intervention of cardiac aging and related diseases.” Zhang Weiqi said that in the future, enhanced gene therapy or the development of specific agonists may be considered to achieve the goal of treating cardiac aging and related diseases. Prevention and treatment of related cardiovascular diseases. As mRNA technology wins the Nobel Prize, more convenient RNA intervention strategies can also be explored.