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Sirt1 , a member of the sirtuin gene family, encodes the most conserved mammalian NAD + -dependent deacetylase enzyme responsible for removing acetyl groups from many proteins. The  Sirt1  gene is known as a longevity gene whose knockout in mice leads to decreased lifespan relative to the wild type. This study aimed to explore phenotypic changes in zebrafish  Sirt1 -knockouts and to investigate the function of the Sirt1 gene. Targeted knockout of  Sirt1  in zebrafish ( Danio rerio ) was achieved using the CRISPR-Cas9 genome editing system. We created a 4-bp insertion-homozygote  Sirt1 -knockout zebrafish. Although there was no evident difference in appearance in the early stages of development, a significant increase in reactive oxygen species and in the extent of apoptosis in  Sirt1 -knockout zebrafish was observed. Sirt1 knockout caused inflammatory genes, including IL-1b, IL-6 and TNF-α to be highly expressed. Additionally, the lack of Sirt1 caused chronic inflammation and intestinal atrophy, thereby increasing pro-apoptotic events, which ultimately reduced the lifespan of transgenic zebrafish. Overall, our data demonstrate that lack of  Sirt1  caused a significantly increased generation of reactive oxygen species that resulted in chronic inflammation and regeneration. Continuous repetition of these events played an important role in accelerating aging, thereby decreasing lifespan. Our findings using the knockout zebrafish model confirmed the association of the  Sirt1  gene to aging processes and lifespan. Furthermore, the  Sirt1 -knockout mutant zebrafish developed in our study will surely be a valuable model to explore the mechanism of chronic inflammation.

Knockout of longevity gene Sirt1 in zebrafish leads to oxidative injury, chronic inflammation, and reduced life span