Aging is a complex biological process characterized by the progressive decline of physiological functions resulting from cellular and molecular alterations that accumulate over time. Progeroid syndromes (PS) are rare genetic disorders that mimic the physiological aging process at an early age. Individuals affected by these syndromes exhibit age-related clinical manifestations much earlier than expected and display an appearance that is older than their chronological age. The best-known example of a progeroid syndrome is Hutchinson–Gilford Progeria Syndrome (HGPS), an extremely rare and progressive genetic disorder characterized by accelerated aging beginning in early childhood.
HGPS is caused by a de novo mutation in the Lamin A (LMNA) gene, an essential component of the nuclear lamina. This mutation results in the production and accumulation of progerin, an abnormal and permanently farnesylated form of the lamin A. Progerin accumulation leads to nuclear dysfunction, genomic instability, epigenetic alterations, telomere shortening, and premature cellular senescence. Clinically, patients exhibit growth retardation, alopecia, scleroderma-like skin lesions, osteolysis, and accelerated atherosclerosis. Most affected individuals die during the second decade of life due to cardiovascular complications such as myocardial infarction or stroke.
Although no curative treatment is currently available for HGPS, advances in understanding the molecular basis of the disease have facilitated the development of novel therapeutic strategies. The FDA approval of lonafarnib, a farnesyltransferase inhibitor, marked a significant milestone in the treatment of HGPS and has been shown to significantly increase patient survival. Furthermore, the identification of the LMNA mutation and the elucidation of progerin’s role in disease pathogenesis have enabled the development of targeted therapeutic approaches. This chapter reviews the genetic and molecular basis of HGPS, its pathogenesis, clinical manifestations, diagnostic methods, current treatment options, and emerging therapeutic strategies with potential future clinical applications.