Key Points
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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.
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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.
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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.
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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.
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Multiple progeria models are associated with enhanced DNA damage, implicating this form of cellular damage as a cause of these diseases.
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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.
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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.
Abstract
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 instability, telomere attrition, premature senescence and defective stem cell homeostasis in disease development. These observations, coupled with genetic studies of longevity, lead to a hypothesis whereby progeria syndromes accelerate a subset of the pathological changes that together drive the normal ageing process.
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Acknowledgements
The authors apologize to researchers whose data we did not have space to incorporate into this Review. Given reference limits and the scope of the material to be covered, reviews were referenced whenever possible to direct readers to sources of more detailed information. Ageing research in the University of Washington laboratory of B.K.K. is supported by funding from the National Institute of Aging and by a Julie Martin Mid-Career Award in Aging Research. C.R.B. was supported in part by a grant to the University of Washington from the Howard Hughes Medical Institute through the Med into Grad Initiative, and by the National Institutes of Health Training Grant T32 AG00057.
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Glossary
- Proteotoxicity model
-
A model in which the accumulation of aggregated or misfolded proteins causes cellular dysfunction that contributes partially to tissue damage and an ageing phenotype.
- Forward genetic screen
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A screening approach in which the phenotype is identified initially in a natural or mutagenized population, and the responsible gene is subsequently characterized.
- Reverse genetics
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A screening approach in which genotypic variation is identified initially in a natural or mutagenized population, and the phenotype or mutational effect is subsequently characterized.
- Replicative lifespan
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The lifespan of dividing cells, measured as the number of generations (or the number of daughter cells) produced by a single mother cell.
- Hypomorphic mutation
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A mutation that results in reduced, but not eliminated, function.
- A-type lamin
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A type V intermediate filament protein in the nucleus that is mutated in several human dystrophies and at least one severe progeria.
- Cell senescence
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The phenomenon in which replicatively dividing cells enter a non-dividing or quiescent phase that is accompanied by changes in gene transcription and metabolism.
- Clavicular agenesis
-
The incomplete development of the clavicle.
- Mesenchymal stem cell
-
A pluripotent progenitor cell of mesenchymal origin that gives rise to adult tissues such as bone, cartilage and adipose.
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Burtner, C., Kennedy, B. Progeria syndromes and ageing: what is the connection?. Nat Rev Mol Cell Biol 11, 567–578 (2010). https://doi.org/10.1038/nrm2944
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DOI: https://doi.org/10.1038/nrm2944
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