Hutchinson-Gilford progeria syndrome (HGPS) is a rare and fatal human premature aging disease1–5, characterized by premature arteriosclerosis and degeneration of vascular smooth muscle cells (SMCs)6–8. HGPS is caused by a single-point mutation in the LMNA gene, resulting in the generation of progerin, a truncated splicing mutant of lamin A. Accumulation of progerin leads to various aging-associated nuclear defects including disorganization of nuclear lamina and loss of heterochromatin9–12. Here, we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts obtained from patients with HGPS. HGPS-iPSCs show absence of progerin, and more importantly, lack the nuclear envelope and epigenetic alterations normally associated with premature aging. Upon differentiation of HGPS-iPSCs, progerin and its aging-associated phenotypic consequences are restored. Specifically, directed differentiation of HGPS-iPSCs to SMCs leads to the appearance of premature senescence phenotypes associated with vascular aging. Additionally, our studies identify DNA-dependent protein kinase catalytic subunit (DNAPKcs) as a downstream target of progerin. The absence of nuclear DNAPK holoenzyme correlates with premature as well as physiological aging. Since progerin als
