The epithelial-to-mesenchymal transition (EMT) is important for the development of cancer metastases and organ fibrosis, conditions prevalent in aging. Because sirtuins affect the pathology of aging, we tested the effect of SirT1 on EMT. Reduced SIRT1 levels in HMLER breast cancer cells led to increased metastases in nude mice, and the loss of SIRT1 in kidney tubular epithelial cells exacerbated injury-induced kidney fibrosis. SIRT1 reduces EMT in cancer and fibrosis by deacetylating Smad4 and repressing the effect of TGF-β signaling on MMP7, a Smad4 target gene. Consequently, less E-cadherin is cleaved from the cell surface and β-catenin remains bound to E-cadherin at the cell-cell junctions. Our findings suggest that the SIRT1/Smad4/β-catenin axis may be a target for diseases driven by EMT. Display omitted •SIRT1 suppresses breast cancer metastases and kidney fibrosis•SIRT1 deacetylates Smad4 and represses its activity on MMP7•Reduced MMP7 leads to less E-cadherin cleavage and β-catenin remains at adherens junctions•SIRT1 suppresses TGF-β-driven EMT in breast cancer and kidney epithelial cells Sirtuins are longevity-related molecules that affect aging-related diseases. Guarente and colleagues now show that SIRT1, a member of the sirtuin family, reduces organ fibrosis and cancer metastases, conditions prevalent in aging. Reduced SIRT1 levels in breast cancer cells led to increased metastases and mortality in mice, and loss of SIRT1 in kidney tubular cells exacerbated injury-induced kidney fibrosis and progression to chronic kidney disease. SIRT1 mitigates fibrosis and metastases by suppressing the epithelial-to-mesenchymal transition, a shared event in these diseases.