Objective-Children with Hutchinson-Gilford progeria syndrome (HGPS) exhibit dramatically accelerated cardiovascular disease (CVD), causing death from myocardial infarction or stroke between the ages of 7 and 20 years. We undertook the first histological comparative evaluation between genetically confirmed HGPS and the CVD of aging. Methods and Results-We present structural and immunohistological analysis of cardiovascular tissues from 2 children with HGPS who died of myocardial infarction. Both had features classically associated with the atherosclerosis of aging, as well as arteriolosclerosis of small vessels. In addition, vessels exhibited prominent adventitial fibrosis, a previously undescribed feature of HGPS. Importantly, although progerin was detected at higher rates in the HGPS coronary arteries, it was also present in non-HGPS individuals. Between the ages of 1 month and 97 years, progerin staining increased an average of 3.34% per year (PϽ0.0001) in coronary arteries. Conclusion-We find concordance among many aspects of cardiovascular pathology in both HGPS and geriatric patients.HGPS generates a more prominent adventitial fibrosis than typical CVD. Vascular progerin generation in young non-HGPS individuals, which significantly increases throughout life, strongly suggests that progerin has a role in cardiovascular aging of the general population. Key Words: aging Ⅲ atherosclerosis Ⅲ pathology Ⅲ peripheral arterial disease Ⅲ progeria H utchinson-Gilford progeria syndrome (HGPS) is a rare, autosomal-dominant, fatal, progressive premature aging syndrome. Symptoms usually begin with failure to thrive or sclerodermatous skin changes, heralding generalized loss of subcutaneous fat, alopecia, osteopenia and acroosteolysis, and joint contracture. Death occurs at a mean age of 13 years because of myocardial infarction or stroke. 1 The majority of HGPS cases are caused by a single de novo nucleotide substitution at position 1824 (C3 T) in the LMNA gene. 2,3 The normal LMNA protein product, lamin A, is a key component of the inner nuclear lamina, which functions in nuclear structure, chromatin organization, and gene transcription. 4 The silent mutation in HGPS leads to alternative splicing at the 3Ј end of the LMNA mRNA and a 150-nucleotide deletion from the prelamin A transcript resulting in a mutant lamin A protein called progerin, which lacks 50 amino acids near its C-terminal end. 5 In non-HGPS individuals, there is convincing evidence that the HGPS splice site is functional and can lead to progerin accumulation over time, although to a lesser degree than in children with HGPS. 6 In HGPS, the cryptic donor splice site shares 6 of 7 bases with the consensus splice sequence, while non-HGPS individuals share 5 of 7 bases with the consensus splice sequence. Thus, non-HGPS individuals utilize the splice site less often. Progerin is not apparent in early passage non-HGPS cultured fibroblasts and skin biopsies, but it accumulates with increasing cell passage and donor age. 7,8 Thus, progerin is likely a previous...

Hutchinson-Gilford progeria syndrome (HGPS) is a lethal genetic disorder characterized by premature aging. HGPS is most commonly caused by a de novo single-nucleotide substitution in the lamin A/C gene (LMNA) that partially activates a cryptic splice donor site in exon 11, producing an abnormal lamin A protein termed progerin. Accumulation of progerin in dividing cells adversely affects the integrity of the nuclear scaffold and leads to nuclear blebbing in cultured cells. Progerin is also produced in normal cells, increasing in abundance as senescence approaches. Here, we report the effect of rapamycin, a macrolide antibiotic that has been implicated in slowing cellular and organismal aging, on the cellular phenotypes of HGPS fibroblasts. Treatment with rapamycin abolished nuclear blebbing, delayed the onset of cellular senescence, and enhanced the degradation of progerin in HGPS cells. Rapamycin also decreased the formation of insoluble progerin aggregates and induced clearance through autophagic mechanisms in normal fibroblasts. Our findings suggest an additional mechanism for the beneficial effects of rapamycin on longevity and encourage the hypothesis that rapamycin treatment could provide clinical benefit for children with HGPS.

Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disease, is caused by a point mutation in the lamin A gene (LMNA). This mutation constitutively activates a cryptic splice donor site, resulting in a mutant lamin A protein known as progerin. Recent studies have demonstrated that progerin is also produced at low levels in normal human cells and tissues. However, the cause-and-effect relationship between normal aging and progerin production in normal individuals has not yet been determined. In this study, we have shown in normal human fibroblasts that progressive telomere damage during cellular senescence plays a causative role in activating progerin production. Progressive telomere damage was also found to lead to extensive changes in alternative splicing in multiple other genes. Interestingly, elevated progerin production was not seen during cellular senescence that does not entail telomere shortening. Taken together, our results suggest a synergistic relationship between telomere dysfunction and progerin production during the induction of cell senescence, providing mechanistic insight into how progerin may participate in the normal aging process.