Identification of replicative aging and inflammatory aging signatures via whole-genome CRISPRi screens

Aging is one of the greatest risk factors for chronic diseases. Research on aging at the cellular level, especially in adult stem cells, is conducive to a comprehensive understanding of the molecular processes of aging. We performed multiple systematic genome-wide CRISPR interference (CRISPRi) screenings in human primary mesenchymal stem cells (MSC) derived from adipose tissues. Notably, we identified potential novel regulators in the progress of MSC senescence in terms of both replicative senescence and inflammatory induced senescence. Combining the functional genomic data with 405 GWAS datasets, including 50 aging-related studies, we observed that the inflammatory aging signatures identified from the CRISPRi screenings were significantly associated with diverse aging processes, suggesting novel signatures to analyze and predict aging status and aging-related disease. These novel signatures verified from the comprehensive functional genomics and genetic datasets may provide targets to interfere with the aging process as well as to improve cell therapy products. Overall design: The goals of this study were (i) to identify novel senescence-promoting genes in adult stem cells, (ii) to characterize novel senescence-promoting genes in a specific inflammatory milieu(iii) and to decipher the inflammatory aging process by comparing two solid screening platforms (IL-6 minus and IL6 plus), thus highlight the biomarker for pathological aging and therapeutic potential of MSC by manipulating the senescence-promoting genes.