Ageing is a general, intrinsic, and progressively deleterious process that affects all cells, tissues, and organs albeit at different extent and rate in each individual. The complexity and universality of its phenotypic manifestations suggest a multifactorial origin. The autosomal recessive disorder Werner syndrome likely represents a segmental progeroid disorder since patients show several, but not all phenotypes of premature ageing. Proliferative senescence of diploid cells in culture provided a model system in which ageing can be studied experimentally. Cultures of cells from patients with Werner syndrome experienced an extreme form of proliferative senescence and a clonal succession of translocations, known as variegated translocation mosaicism. In addition, Werner syndrome cells showed spontaneous deletion formation and a prolongation of and arrest in the S phase of the cell cycle. The WRN protein harbours a helicase, an exonuclease and a RecQ interaction domain. With the latter, the WRN protein may interact with NBS1, Replication Protein A (RPA), MRE11, TREX1, MUTYH, POT1, TRF1, FEN-1, PAPRP-1, p97/VCP, TRF2, DNA polymerase(beta), Ku76/80, EXO-1, NEIL1, and p53, which are key to DNA damage response pathways including canonical NHEJ, homologous recombination, base excision repair, and telomere maintenance. The WRN exonuclease domain is a target of WRNIP1 binding, which links WRN to resolution of stalled replication due to collision with transcription and the ATM-mediated cell cycle checkpoint. Patients with an incomplete complement of Werner syndrome phenotypes, called atypical Werner syndrome patients, were found to carry variants in LMNA, POLD1, SPRTN, MDM2, CTC1, SAMHD1. These findings broaden the genotypic landscape and the phenotypic spectrum of Werner syndrome. In this review potential molecular mechanisms underlying genomic instability in Werner syndrome, including chromothripsis due to asynchronous S phase traverse and telomere crises followed by bridge fusion breakage cycles are discussed. The participation of WRN in multiple gene networks is consistent with the multifactorial nature of ageing in general.

Progeroid syndromes are rare genetic disorders that impact patients' health and lifespans and are characterized by symptoms that mimic the normal aging process. Telomere length is one of the aging hallmarks, a phenomenon linked to cellular aging. Telomere attrition was observed in different progeroid syndromes, such as Nijmegen breakage syndrome patients and Werner syndrome, indicating its contribution to the progeroid phenotype. However, whether it is a common feature in all progeroid syndromes is still unclear. Therefore, in this study, we aimed to estimate telomere length using the DNA methylation-based estimator of human telomere length in publicly available DNA methylation data from patients with Werner Syndrome, Hutchinson-Gilford Progeria Syndrome, Berardinelli-Seip Congenital Lipodystrophy type 2, and Dyskeratosis congenita, along with additional data provided by our laboratory from patients with Cerebroretinal Microangiopathy with Calcifications and Cysts and Wiedemann-Rautenstrauch Syndrome. Our findings revealed that certain progeroid syndromes, including classical Werner Syndrome, Berardinelli-Seip Congenital Lipodystrophy type 2, and Dyskeratosis congenita, have significant telomere attrition conversely to Hutchinson-Gilford Progeria Syndrome, Cerebroretinal Microangiopathy with Calcifications and Cysts, Wiedemann-Rautenstrauch Syndrome, and atypical Werner Syndrome. In conclusion, this study addresses a critical gap by providing new insights into the role of telomere attrition across different progeroid conditions. Further research is needed to elucidate the effect of telomere attrition on progeroid syndromes and its implications.

Segmental progeroid syndromes are groups of genetic disorders with multiple features resembling accelerated aging. The International Registry of Werner Syndrome (Seattle, WA) recruits pedigrees of progeroid syndromes from all over the world. We identified two novel LMNA mutations, p.Asp300Gly in a patient from Myanmar, and p.Asn466Lys, in a patient from Greece. Both were referred to our Registry for the genetic diagnosis because of the accelerated aged-appearance and cardiac complications. LMNA mutations are the second most common genetic cause of progeroid syndromes after WRN mutations in our Registry. As the next generation sequencing becomes readily available, we expect to identify more cases of rare genetic diseases in the developing countries.

Lamin A, a main constituent of the nuclear lamina, is the major splicing product of the LMNA gene, which also encodes lamin C, lamin A delta 10 and lamin C2. Involvement of lamin A in the ageing process became clear after the discovery that a group of progeroid syndromes, currently referred to as progeroid laminopathies, are caused by mutations in LMNA gene. Progeroid laminopathies include Hutchinson-Gilford Progeria, Mandibuloacral Dysplasia, Atypical Progeria and atypical-Werner syndrome, disabling and life-threatening diseases with accelerated ageing, bone resorption, lipodystrophy, skin abnormalities and cardiovascular disorders. Defects in lamin A post-translational maturation occur in progeroid syndromes and accumulated prelamin A affects ageing-related processes, such as mTOR signaling, epigenetic modifications, stress response, inflammation, microRNA activation and mechanosignaling. In this review, we briefly describe the role of these pathways in physiological ageing and go in deep into lamin A-dependent mechanisms that accelerate the ageing process. Finally, we propose that lamin A acts as a sensor of cell intrinsic and environmental stress through transient prelamin A accumulation, which triggers stress response mechanisms. Exacerbation of lamin A sensor activity due to stably elevated prelamin A levels contributes to the onset of a permanent stress response condition, which triggers accelerated ageing.