Hyperlipidaemia, diabetes, and hypertension are risk factors for atherosclerosis, and pharmacological targets in its prevention, but cardiovascular diseases (CVD) remain the main cause of death globally (Lozano et al., 2012). CVD accumulate in old age, therefore a better understanding of aging related changes such as cellular senescence is necessary as it could offer new treatment options. To compare the effects of hyperlipidaemia and aging, we assigned young (8 weeks) and old (20 months) C57BL/6 wildtype mice to an atherosclerotic and a control group, respectively. To induce atherosclerosis, AAV-mediated PCSK9-overexpression was combined with feeding the mice a high-cholesterol western diet for 21 weeks. Echocardiographic analysis at the end of the trial showed decreased ejection fraction in old atherosclerotic mice (OA) compared to young healthy mice (YH). In strain analysis even old healthy mice (OH) showed a decrease in cardiac function whereas young atherosclerotic mice (YA) showed only a slight, but not significant decrease in function. OH and OA had decreased distensibility in their carotids compared to YH, while YA showed no changes. In the aortas OA, OH and YA had reduced distensibility. These findings indicate that aging might be the more relevant risk factor for decreased heart and vessel function compared to hyperlipidaemia. OsteoSense imaging allowed for post mortem ex vivo quantification of calcification levels in the aortas. We found the highest signal in OA followed by OH. YA only had a very slight and not significant increase in signal compared to YH. These findings were congruent with von Kossa stainings we performed. Only mice in the atherosclerotic groups developed plaque and OA had higher ratio of calcified areas in the plaque compared to YA. We found media calcification in OH, explaining their increased OsteoSense signal. The difference in plaque calcification indicates that the pathways causing atherosclerosis differ in old and young mice. One important factor for these differences could be senescent cells which accumulate with age and have been found in atherosclerotic plaques (Minamino et al., 2002). As recent studies have shown, cells outside of the arterial lumen such as vascular smooth muscle cells (VSMCs) (Shankmann et al., 2015) and adventitial cells (Kramann et al., 2016) are important drivers of plaque formation and calcification, leading to our hypothesis that endothelial-mesenchymal crosstalk is an important factor in atherosclerosis. This crosstalk is not fully understood, and we do not know the effect of senescent cells and their senescence-associated secretory phenotype (SASP) on it. Ablation of senescent cells or targeting SASP-associated pathways and mechanisms might offer new therapeutic strategies. We determined the contribution of senescent immortalized murine adventitia cells to calcification in vitro and the effects of the senolytic drugs Fisetin and Dasatinib on this process. We found significantly less osteogenic differentiation and downstream calcification in senescent cells compared to control cells. This effect was reversed after treatment with Fisetin. Dasatinib in contrast did not change the outcome. Thus, senescent adventitia cells seem to lose their ability to differentiate into osteoblast-like cells. We conclude that these cells contribute to atherosclerosis induction by changing the cellular environment and activating other drivers of plaque formation.