Research reveals the rhythm switch controlling primate aging

Liu Guanghui research group of Institute of zoology, Chinese Academy of Sciences and Xiang Peng research group of Sun Yat sen University, together with Qu Jing research group of Institute of zoology, published a research paper entitled BMAL1 moonlighting as a gatekeeper for Line1 expression and cellular sensitivity in prices online on nuclear acids research. This study used CRISPR / cas9 mediated gene editing technology to produce BMAL1 deficient human stem cells and non-human primate research models, and revealed that the core rhythm protein BMAL1 has a new function of maintaining genomic stability, inhibiting the activation of transposon Line1, and antagonizing primate tissue and cell aging.

BMAL1 is one of the core components of biological clock. As a transcription factor, BMAL1 plays an important role in maintaining cell molecular biological clock and individual rhythm. So far, the regulatory role of BMAL1 protein in primate cell homeostasis and aging is not clear. This study found that BMAL1 was gradually emptied from the nucleus during the aging process of human and monkey cells, suggesting that BMAL1 may be related to the gene expression regulation of cell aging. In order to explore the regulatory function of BMAL1 on primate cell aging, researchers combined CRISPR / cas9 mediated gene editing technology and stem cell directional differentiation technology to obtain BMAL1 knockout human mesenchymal stem cells, and then found that the deletion of BMAL1 protein caused the accelerated aging of human mesenchymal stem cells. Although BMAL1 relies on its transcriptional activity to participate in rhythm regulation, wild-type BMAL1 and its mutants with loss of transcriptional activity can inhibit the accelerated aging of human mesenchymal stem cells caused by BMAL1 deletion, indicating that the regulation of aging by BMAL1 does not depend on classical transcriptional function. Mechanism study found that BMAL1 combined with nuclear fiber layer and heterochromatin protein, which helps to maintain the structural stability of heterochromatin, and then inhibit the activation of "jumping gene" Line1. The lack of BMAL1 leads to the expression and aggregation of "nucleic acid waste" such as Line1 in the cytoplasm, which induces the activation of the downstream CGAs sting natural immune pathway and accelerates the aging of stem cells. Treatment with lamivudine, a reverse transcriptase inhibitor, can effectively inhibit the accelerated aging of cells caused by BMAL1 deletion. At the same time, studies have shown that BMAL1 deficient monkey mesenchymal stem cells and tissues also have the activation of Line1 and CGAs sting pathway, indicating that the new function of BMAL1 to inhibit the accumulation of "junk nucleic acid" and stabilize the natural immune pathway is conserved in human and non-human primates.

This study reveals for the first time the new function and mechanism of core rhythm protein inhibiting Line1 CGAs sting pathway and regulating primate aging. This achievement expands the understanding of the biological function of core rhythm proteins, establishes the scientific connection between circadian rhythm and aging regulation, provides a new molecular target for delaying primate aging, and opens up new ideas for the prevention and treatment of aging related diseases.