Fibrosis is a common trait of the aging phenotype and is caused by the increase in the myofibroblast population. Sirt6 negatively regulates myofibroblasts generation by deacetylating H3K9ac and H3K56ac in the promoter of SMAD3. Repressing SMAD3 transcription attenuates the response of fibroblasts to TGF-β and reduces the fibrotic processes. Here, SIRT6 is linked to fibrosis.