Gene therapy of stem cell aging
Cellular aging, or the state of cessation of growth, is the fundamental driving force of aging of the body. It is regulated by both genetic and epigenetic factors. Many genes whose activity is associated with the aging of the body have already been described; however, there are no systematic studies of the effects on them to slow down aging and treat aging-related diseases.
Researchers from the Institute of Zoology of the Chinese Academy of Sciences (CAS), Peking University and the Beijing Institute of Genomics CAS using the CRISPR/Cas9 screening system identified new genes that contribute to human aging, outlined ways to create new strategies to slow aging and treat age-related diseases.
In their study, the scientists conducted a full-genome screening of human premature aging stem cells based on CRISPR/Cas9 using two types of mesenchymal progenitor cells demonstrating accelerated aging. These cells were obtained from human embryonic stem cells carrying pathogenic mutations that cause accelerated aging in Werner syndrome and Hutchinson-Guilford progeria syndrome. During the screening, more than 100 genes were identified, probably contributing to aging. The researchers confirmed the effectiveness of inactivation of each of the 50 main candidate genes in promoting cellular rejuvenation using targeted guide RNAs.
The KAT7 gene encoding the histone acetyltransferase enzyme has been identified as one of the main targets in slowing cellular aging. He actively participated in both cellular models of progeria, as well as in the process of physiological aging: turning off KAT7 weakened cellular aging, while overexpression of KAT7 accelerated it.
The researchers showed that inactivation of KAT7 led to a decrease in lysine acetylation in histone H3 (H3K14), suppression of transcription of the p15INK4b gene encoding a cyclin-dependent kinase inhibitor, and rejuvenation of aging cells.
According to previous studies, the age-related accumulation of aging and pro-inflammatory cells in tissues and organs contributes to the development and progression of aging, as well as the development of aging-related diseases. Preventive removal of aging cells reduces tissue degeneration and increases the lifespan of mice.
In this study, the team found that intravenous injection of a lentiviral vector carrying Cas9/sg-KAT7 endonuclease, which removes the KAT7 gene from the genome, led to a decrease in the proportion of aging and pro-inflammatory cells in the liver, a decrease in serum levels of secretory phenotype factors associated with aging of blood circulation, and an increase in the lifespan of old mice.
Thus, this study, using full-genome CRISPR/Cas9 screening, expanded the list of genes that contribute to aging and demonstrated that gene therapy based on single-factor inactivation can slow down aging. It not only deepens the understanding of the mechanism of aging, but also provides new potential targets for aging interventions.
Article W.Wang et al. A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence published in the journal Science Translational Medicine.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the Chinese Academy of Sciences: Scientists Develop a New Gene Therapy Strategy to Delay Aging.