Unraveling the mysteries of aging through a Hutchinson-Gilford progeria syndrome model.

Overview

Hutchinson-Gilford progeria syndrome (HGPS) is a rare, deadly laminopathy. Research into its nature has provided valuable insights into understanding molecular mechanisms underlying cell senescence. Phenotypic changes in nuclear structure and heterochromatin, resulting from increased progerin production following overuse of a cryptic splice site in the LMNA gene have profound effects on cell cycle progression and DNA repair mechanisms. A high degree of genomic instability occurs as DNA double-strand breaks are introduced but not repaired, despite appropriate machinery. Damage-response mechanisms become deregulated as a result of failed recruitment of elongation factors and possibly ancillary to disruption of chromatin organization. Key regulatory regions on mRNA transcripts governing splicing activity have been exposed using antisense technology, and identification of novel molecular targets, such as xeroderma pigmentosum group A, have generated optimism for the possibility of finally yielding an effective therapy for slowing the aging process in HGPS patients while concomitantly providing valuable insights into physiological aging in general.