Molecular Basis of Progeroid Diseases

Aging is a universal and inevitable process that affects virtually all living organisms; in humans, aging is characterized by a gradual decline of physical and psychological functions that ultimately leads to death. Over the past decades, the study of progeroid syndromes, a group of premature aging disorders that recapitulates multiple features of physiological aging, has provided insightful information toward the identification of mechanisms underlying aging. In this chapter, we provide an updated description of the main progeroid syndromes affecting humans, including their clinical manifestations and the genetic and molecular basis underlying their pathogenesis. Most progeroid syndromes originate from defective DNA repair and nuclear structure systems, highlighting a key role of genome stability in aging. A special emphasis is given to Hutchinson Gilford Progeria Syndrome (HGPS), the most well-studied premature aging disorder, which is characterized by accelerated aging and early death due to cardiovascular complications. HGPS is typically caused by a silent mutation in the LMNA gene that provokes the expression of progerin, a dominant-negative mutant protein that anchors aberrantly to the nuclear envelope, thereby inducing cellular toxicity and organismal detriment. Thus, we provide a description of established cellular and animal models for HGPS and discuss the perspectives for therapeutic developments, including an updated presentation of treatment strategies that have been tested so far in vitro (human HGPS fibroblast cultures) and in vivo (HGPS mice models) and in clinical trials, with argumentation of their main limitations.