Scientist Designs A New Gene Therapy For Slowing Ageing And Extending Life
The cellular senescence has become a hallmark and fundamental catalyst of organismic aging. Both genetic and epigenetic factors control it. While a few aging-associated genes have previously been identified, the identity and function of additional genes involved in controlling human cellular aging remain unknown. However, the role of these genes in the treatment of aging and aging-related diseases lacks systematic study.
How many aging genes in the human genome are there? What molecular pathways control the aging of these genes? Can gene therapy mitigate the aging of individuals? Researchers from the Chinese Academy of Sciences recently shed new light on the topic of aging control.
The CAS Institute of Zoology (CAS), Peking University, and Beijing Institute of Genomics recently worked on discovering new genes for human senescence by applying genome-wide screening CRISPR/Cas9 and offering a new therapeutic approach to the management of aging and aging-related diseases.
The researchers carried out CRISPR/Cas9-based genome screens in human premature aging stem cells, finding more than 100 candidate genes that induce senescence in this sample. They further confirmed that each of the top 50 candidate genes was inactivated to facilitate cellular rejuvenation by targeted sgRNA.
KAT7 encoding a histone acetyltransferase was among the highest targets for cellular senescence alleviation. It increased during physiological and pathological aging in human mesenchymal precursor cells. Depletion of KAT7 reduced cellular senescence, while overexpression of KAT7 accelerated cellular senescence.
Inactivation of KAT7 mechanistically reduced acetylation of histone H3 lysine 14, repressed P15INK4b transcription, and rejuvenated human stem cells.
Cumulative studies have shown that age-based aggregation in tissue and organ of senescent cells and the proinflammatory cells leads to the growth and development of aging and aging disorders. Senescent cell prophylactic elimination mitigates tissue degeneration and increases the duration of the health of the mice.
In this analysis, the researchers found that intravenous injection of the Cas9/sG-KAT7 Cas9/sg lentiviral vector reduced the proportion of senescent cells and the proinflammatory cells in the liver, decreased the secretory phenotype (SASP) of circulatory senescence and increased the health and lifespan of an old mouse.
These findings indicate that inactivation-based gene therapy could be necessary to prolong the lifespan of the mouse. They also observed that treatment with Cas9/sg-KAT7 or the KAT7 inhibitor WM-3835 lentiviral vector encoding alleviated man hepatocyte senescence and decreased SASP gene expression, indicating the potential for clinical application of these therapies.
In all this research, the list of human senescence promoting genes with CRISPR/Cas9 genome-wide screen has been successfully extended and conceptually shown that gene therapy based on single-factor inactivation is capable of slowing person aging. This research not only strengthens our understanding of the aging process but also offers new possible objectives foraging initiatives.
Reference: “A genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular senescence” by Wei Wang, Yuxuan Zheng, Shuhui Sun, Wei Li, Moshi Song, Qianzhao Ji, Zeming Wu, Zunpeng Liu, Yanling Fan, Feifei Liu, Jingyi Li, Concepcion Rodriguez Esteban, Si Wang, Qi Zhou, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Fuchou Tang and Guang-Hui Liu, 6 January 2021, Science Translational Medicine.