Release date: 2015-05-06
Aging has always been a core link in the life process and an important issue affecting the healthy development of the entire human society. At present, all countries in the world are facing a serious population aging. The data show that by 2050, about one-third of the Chinese population will be over 60 years old. Therefore, an in-depth understanding of the mechanism of aging is an important part of human anti-aging and treatment-related diseases. However, the process of human aging is long and complicated. The aging process of mouse and other model animals is far from human, and the translational medical research of human aging has always faced enormous challenges. Werner Syndrome is a rare autosomal recessive disorder caused by a mutation in the WRN gene (encoding a DNA repair/helicase). Adult premature aging patients start the aging process in advance from puberty, accelerating the appearance of natural aging and accompanying a variety of senile diseases. Therefore, studying adult premature aging has important scientific significance for revealing the mystery of human natural aging and for achieving prevention and treatment of aging-related diseases.
Liu Guanghui from the Institute of Biophysics of the Chinese Academy of Sciences, Tang Fuzhong from Peking University, and Juan Carlos Izpisua Belmonte from the Salk Institute recently published the latest issue in the journal Science entitled "A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging". The results of the study reported a breakthrough in their research on the mechanism of stem cell aging. This study, combined with pluripotent stem cell directed differentiation technology, genome-targeted editing technology, and epigenetic analysis technology, reveals for the first time that high-level structural disorganization is one of the driving forces of human stem cell senescence, in order to delay aging and Research and prevention of aging-related diseases provide new potential targets and ideas.
The researchers put forward the hypothesis that "accelerated senescence (depletion) of tissue stem cells may be the cause of premature aging in humans." Based on this hypothesis, the researchers made homozygous deletion mutations in the WRN gene in human mesenchymal stem cells (MSC) through genome-targeted editing technology, and "manufactured" MSCs specific for human premature aging in the laboratory. These premature senescence MSCs not only showed signs of aging such as slower growth rate, increased DNA damage response and secretion of a large number of inflammatory factors, but also showed accelerated loss of inner nuclear membrane proteins and perinuclear chromatin. Through genome-wide scanning of histone covalent modifications, DNA methylation, and RNA transcripts, the researchers found that the heterochromatin of premature senescent stem cells undergoes significant structural degenerative changes, mainly as centromeres and ends. Deletion of the H3K9me3 "mountain" near the grain. Further studies have found that WRN proteins coexist with heterologous chromatin proteins SUV39H1 and HP1? in a protein complex that maintains the stability of heterochromatin and lamellar layers and prevents MSC aging. Deletion of WRN results in a decrease in heterochromatin-binding proteins and transcription of centromeric satellite DNA, which in turn induces cellular senescence. By comparing MSCs isolated from healthy older adults and young adults, the downregulation of WRN levels and abnormalities in nuclear membrane proteins and heterochromatin structures were also observed, suggesting that remodeling of heterochromatin may be one of the drivers of normal cellular senescence. Finally, the study found that overexpression of HP1 can inhibit the accelerated senescence of premature senescent cells, thus providing a possible molecular target for future intervention in the aging of human stem cells.
This study not only reveals for the first time the novel function of WRN protein in epigenetic regulation, but also establishes for the first time the central role of chromatin high-order structural changes in driving human cell aging. These novel findings lay the theoretical foundation for delaying or reversing cellular aging at the epigenetic level.
Source: Bio Valley
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