Loss-of-SIRT1 function during vascular ageing: hyperphosphorylation mediated by cyclin-dependent kinase 5.

The longevity regulator SIRT1 is an enzyme catalyzing the deacetylation of protein substrates, in turn modulating their biological functions. In endothelial cells, downregulation of SIRT1 evokes cellular senescence. In aged arteries, SIRT1 expression and activity is blunted, which contributes to the development of atherosclerosis and abnormal vascular responses. A recent study suggests that cyclin-dependent kinase 5 (CDK5) is responsible for the phosphorylation of SIRT1 at the serine 47 residue. This modification blocks the anti-senescence activity of SIRT1 and plays a critical role in the loss-of-SIRT1 function during vascular ageing. Thus, by inhibiting CDK5, SIRT1 function can be improved, in turn preventing the development of atherosclerosis and slowing down the process of vascular ageing.