Progeria syndromes and ageing: what is the connection?

Key Points Despite decades of research, the extent to which human progerias resemble accelerated ageing is still unclear and highly debated. To understand this connection, an ongoing characterization of genetic pathways that influence the ageing process in model systems and investigations into molecular pathways that define the pathogenesis of human progerias are required. Ageing research has focused on lifespan-extending pathways in model organisms. This has led to the identification of several pathways that impinge on the ageing process, fortifying a multifactorial hypothesis to explain the underlying causes of organismal ageing. Hutchinson–Gilford progeria syndrome (HGPS) and other human progerias allow researchers a unique glimpse at the molecular pathways that accelerate age-associated phenotypes. These insights can be translated back to model systems to identify the molecular events underlying pathology. HGPS cells show defects in cellular proliferation and premature senescence, suggesting that advanced ageing of tissues may be the result of impaired growth or decreased replicative potential at the cellular level. Multiple progeria models are associated with enhanced DNA damage, implicating this form of cellular damage as a cause of these diseases. Disease-causing mutations in lamin A/C ( LMNA ) impair the ability of mesenchymal stem cells to differentiate down specific lineages. These results suggest that the loss of tissue homeostasis plays an important part in multicellular ageing. A comprehensive understanding of the molecular basis of ageing will benefit from a fusion of studies in long-lived models and models resembling accelerated ageing. Despite decades of research, the extent to which human progerias resemble accelerated ageing is still unclear and highly debated. Understanding this connection will require the ongoing characterization of genetic pathways that influence the ageing process in model systems and investigations into molecular pathways that define the pathogenesis of human progerias. One of the many debated topics in ageing research is whether progeroid syndromes are really accelerated forms of human ageing. The answer requires a better understanding of the normal ageing process and the molecular pathology underlying these rare diseases. Exciting recent findings regarding a severe human progeria, Hutchinson–Gilford progeria syndrome, have implicated molecular changes that are also linked to normal ageing, such as genome instabilit