Vascular calcification is prevalent in the ageing population yet little is known of the mechanisms driving age-associated vascular smooth muscle cell (VSMC) phenotypic change. Recent evidence has implicated nuclear lamina dysfunction, especially the accumulation of premature forms of lamin A, in promoting premature cellular ageing, as typified in the premature ageing disorder Hutchison-Gilford Progeria Syndrome.[1, 2] Our previous data showed that Prelamin A, the unprocessed form of the nuclear lamina protein lamin A, accumulates in aged and atherosclerotic arteries and, acts as a specific hallmark of VSMC ageing, within the general population.[3] In the current study we investigated whether prelamin A accumulation plays a role in driving VSMC osteogenic differentiation. We found that prelamin A accumulated in cacifying VSMCs both in vitro and in vivo and that overexpression of prelamin A in vitro promoted VSMC osteogenic differentiation and mineralization. During VSMC ageing in vitro prelamin A accumulation occurred concomitantly with increased p16 expression and osteogenic differentiation and was associated with increased levels of DNA damage. Microarray analysis showed that DNA damage repair pathways were significantly impaired in VSMCs expressing prelamin A and chemical inhibition or siRNA depletion of the DNA damage response (DDR) kinases ATM/ATR effectively blocked VSMC osteogenic differentiation and mineralization. In co-culture experiments, prelamin A expressing VSMCs induced alkaline phosphatase (ALP) activity in mesenchymal progenitor cells and this was abrogated by inhibition of ATM signalling suggesting DNA damage induces the secretion of pro-osteogenic factors by VSMCs. Cytokine array analysis identified a number of ATM-dependent senescence associated secretory phenotype (SASP) factors/cytokines released by prelamin A positive VSMCs including the calcification regulators BMP2, OPG and IL6, and these data were validated by quantitative PCR and ELISA. This study demonstrates that prelamin A promotes premature VSMC calcification and ageing, in part, by inducing persistent DNA damage signalling which acts upstream of VSMC osteogenic differentiation and the SASP. Agents that target the DDR and/or prelamin A toxicity may be potential therapies for the treatment of vascular calcification.