Cellular aging, a state of permanent cessation of growth, is emerging as a hallmark and a major driver of aging. It is regulated by both genetic and epigenetic factors. Despite several previously reported genes related to aging, the identity and role of additional genes involved in the regulation of human cellular aging remains to be elucidated. However, there is no systematic investigation into the interference of these genes in the treatment of aging and aging-related diseases.
How many genes to promote aging are there in the human genome? What are the molecular mechanisms by which these genes regulate aging? Can gene therapy alleviate individual aging? Recently, researchers from the Chinese Academy of Sciences have shed new light on the regulation of aging.
Recently, researchers from the Institute of Zoology of the Chinese Academy of Sciences (CAS), Peking University and the Beijing Institute of Genomics have collaborated to identify new genes that promote human aging using the CRISPR / Cas9 screening system for the entire genome and provide a new therapeutic approach to the treatment of aging and age-related pathologies.
In this study, researchers conducted genomic CRISPR / Cas9-based stem cell screens for human premature aging and identified more than 1
Among them, KAT7, encoding histone acetyltransferase, has been identified as one of the best targets for alleviating cellular aging. It is increased in human mesenchymal progenitor cells during physiological and pathological aging. Depletion of KAT7 weakens cellular aging, while overexpression of KAT7 accelerates cellular aging.
Mechanical inactivation of KAT7 reduces the acetylation of histone H3 lysine 14, suppressed p15INK4b transcription and rejuvenated aging human stem cells.
Cumulative studies have shown that age-related accumulation of aging cells and proinflammatory cells in tissues and organs contributes to the development and progression of aging, as well as aging-related disorders. Prophylactic ablation of aging cells alleviates tissue degeneration and prolongs the health of mice.
In this study, researchers found that intravenous injection of a lentiviral vector encoding Cas9 / sg-KAT7 reduced the proportions of aging cells and proinflammatory cells in the liver, reduced circulatory aging-related secretory phenotype (SASP) factors in serum, and prolonged health. life expectancy of obsolete mice.
These results suggest that gene therapy based on single-factor inactivation may be sufficient to prolong the life of the mouse. The researchers also found that treatment with a lentiviral vector encoding Cas9 / sg-KAT7 or KAT7 inhibitor WM-3835 facilitated the aging of human hepatocytes and reduced SASP gene expression, suggesting the possibility of these interventions in clinical settings.
Overall, this study successfully expanded the list of genes that promote human aging using the entire CRISPR / Cas9 genome screen and conceptually demonstrated that gene therapy based on inactivation of a single factor is able to slow individual aging. This study not only deepens our understanding of the mechanism of aging, but also provides new potential targets for aging interventions.
The study, entitled “Genome-based CRISPR screen identifies KAT7 as a driver of cellular aging,” was published online in Science Translational Medicine on January 6, 2021.
The enzyme NSD2 appears to prevent cellular aging
Wei Wang et al. A screen based on CRISPR, a genome, identifies KAT7 as a driver of cellular aging, Science Translational Medicine (2021). DOI: 10.1126 / scitranslmed.abd2655
Provided by the Chinese Academy of Sciences
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