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Progeria of Stem Cells: Stem Cell Exhaustion in Hutchinson-Gilford Progeria Syndrome

Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, BC Cancer Research Centre, Vancouver.

Address correspondence to Julius Halaschek-Wiener, PhD, Genome Sciences Centre, BC Cancer Agency, 675 West 10th Avenue, Vancouver, BC V5Z 1L3, Canada. E-mail: juliushw{at}bcgsc.ca

Abstract

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, fatal genetic disorder that is characterized by segmental accelerated aging. The major causal mutation associated with HGPS triggers abnormal messenger RNA splicing of the lamin A gene leading to changes in the nuclear architecture. To date, two models have been proposed to explain how mutations in the lamin A gene could lead to HGPS, structural fragility and altered gene expression. We favor a compatible model that links HGPS to stem cell-driven tissue regeneration. In this model, nuclear fragility of lamin A-deficient cells increases apoptotic cell death to levels that exhaust tissues' ability for stem cell-driven regeneration. Tissue-specific differences in cell death or regenerative potential, or both, result in the tissue-specific segmental aging pattern seen in HGPS. We propose that the pattern of aging-related conditions present or absent in HGPS can provide insight into the genetic and environmental factors that contribute to normal aging.

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