Cellular aging, a condition of permanent growth arrest, has emerged as a characteristic and fundamental driving force for aging of organisms. It is regulated by both genetic and epigenetic factors. Despite some previously reported genes associated with aging, the identity and roles of additional genes involved in the regulation of human cellular aging need to be elucidated. Yet there is a lack of systematic investigation into the intervention of these genes to treat aging and aging diseases.
How many aging-promoting genes 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), the University of Beijing and the Beijing Institute of Genomics of CAS collaborated to identify new human aging-promoting genes using a genome-wide CRISPR / Cas9 screening system and offers a new therapeutic approach for the treatment of aging and aging-related pathologies.
In this study, the researchers performed genomic CRISPR / Cas9-based screens in human premature aging stem cells and identified more than 100 candidates for senescence-promoting genes. They further verified the effectiveness of inactivating each of the top 50 candidate genes for the promotion of cellular rejuvenation using targeted sgRNAs.
Between them, KAT7 the coding of a histone acetyltransferase has been identified as one of the most important targets to alleviate cellular aging. It increased in human mesenchymal progenitor cells during physiological and pathological aging. KAT7 exhaustion attenuated cellular aging while KAT7 overexpression accelerated cellular aging.
Mechanically reduced inactivation of CAT7 histone H3 lysine 14 acetylation suppressed p15INK4b transcription, and rejuvenated senescent human stem cells.
Cumulative studies have described that the accumulation of tendon cells and proinflammatory cells in tissues and organs through age contributes to the development and progression of aging, as well as aging-related disorders. Preventative ablation of senescent cells reduces tissue degeneration and prolongs the health team in mice.
In this study, the researchers found that intravenous injection of a lentiviral vector containing Cas9 / sg-KAT7 reduces the ratios of senescent cells and pro-inflammatory cells in the liver, reduces the circulatory senescence-associated secretory phenotype (SASP) factors in the serum, and prolongs the health span and lifespan of elderly mice.
Figure. Gene therapy aimed at Kat7 prolongs the lifespan of mice with natural age and progeria. Credit: IOZ
These results suggest that gene therapy based on a single factor inactivation may be sufficient to prolong the lifespan of the mouse. The researchers also found that treatment with the lentiviral vector containing Cas9 / sg-KAT7 or a CAT7 inhibitor WM-3835 has alleviated human hepatocyte aging and reduced the expression of SASP genes, suggesting the possibility of applying these interventions in clinical conditions.
Overall, the study successfully expanded the list of human aging-promoting genes using the CRISPR / Cas9 genome-wide screen and conceptually showed that gene therapy based on one-factor inactivation can delay individual aging. This study not only deepens our understanding of aging mechanisms, but also offers new potential targets for aging interventions.
Reference: “A Genome-wide CRISPR-based screen identifies KAT7 as a driver of cellular aging” 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, January 6, 2021, Science Translational Medicine.
DOI: 10.1126 / scitranslmed.abd2655