Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature aging disease resulting from the c.1824C>T de novo mutation and progressive accumulation of a truncated lamin A protein called progerin. Progerin acts by disrupting the properties and functions of the nuclear lamina, leading to numerous cellular and molecular defects. HGPS children display many features characteristic of physiological aging, and in particular show a severely accelerated vascular aging phenotype resulting in premature atherosclerosis and cardiovascular disease leading to death their teens. Although the disease has been well studied since the discovery of the mutation 17 years ago, its underlying molecular mechanisms still remain unclear, and to date, drug-based clinical trials have shown only limited success. In this project, we aim to elucidate whether and how progerin accumulation may impair specific cell types and vascular beds by defining relevant transcriptional profiles, which will permit the development of a new therapy. To this end, we will take advantage of a systemic mouse model of HGPS, the LmnaG609G, which replicates the disease phenotypes in vivo such as the loss of vascular smooth muscle cells. With the use of single-cell RNA sequencing technologies, we will investigate the transcriptional changes occurring upon progerin accumulation between the aortic arch and thoracic aorta, but also between and within endothelial cells and vascular smooth muscle cells of the LmnaG609G mice. The role of long non-coding RNAs being still poorly determined in the context of HGPS, we will therefore put emphasis on discovering their potential contribution to the disease, and assess the effectiveness of antisense oligonucleotide-based therapy against telomeric long non-coding RNAs on the cardiovascular system. Altogether, the newly generated data will help unravel the mechanisms behind the severe vascular phenotype observed in HGPS patients, and could be relevant to design specifically targeted therapies. This study may also greatly contribute to increasing our current understanding of physiological aging and associated cardiovascular diseases.