Hallmarks of progeroid syndromes: lessons from mice and reprogrammed cells

Ageing is a process that inevitably affects most living organisms and involves the accumulation of macromolecular damage, genomic instability and loss of heterochromatin. Together, these alterations lead to a decline in stem cell function and to a reduced capability to regenerate tissue. In recent years, several genetic pathways and biochemical mechanisms that contribute to physiological ageing have been described, but further research is needed to better characterize this complex biological process. Because premature ageing (progeroid) syndromes, including progeria, mimic many of the characteristics of human ageing, research into these conditions has proven to be very useful not only to identify the underlying causal mechanisms and identify treatments for these pathologies, but also for the study of physiological ageing. In this Review, we summarize the main cellular and animal models used in progeria research, with an emphasis on patient-derived induced pluripotent stem cell models, and define a series of molecular and cellular hallmarks that characterize progeroid syndromes and parallel physiological ageing. Finally, we describe the therapeutic strategies being investigated for the treatment of progeroid syndromes, and their main limitations

Loss of the proteostasis modulator AIRAPL causes myeloid transformation by deregulating IGF-1 signaling

AIRAPL (arsenite-inducible regulatory particle-associated protein-like) is an evolutionarily conserved regulator of cellular proteostasis linked to longevity in nematodes, but whose biological function in mammals is unknown1-3. We show herein that AIRAPL-deficient mice develop a fully-penetrant myeloproliferative neoplastic process4-6. Proteomic analysis of AIRAPL-deficient mice revealed that this protein exerts its antineoplastic function through the regulation of the insulin/IGF-1 signaling pathway. We demonstrate that AIRAPL interacts with newly synthesized insulin-related growth factor-1 receptor (IGF1R) polypeptides, promoting their ubiquitination and proteasome-mediated degradation. Accordingly, genetic and pharmacological IGF1R inhibitory strategies prevent the hematological disease associated with AIRAPL deficiency, demonstrating its causal involvement in the pathogenesis of myeloproliferative neoplasms. Consistent with its proposed role as a tumor suppressor of myeloid transformation, we have found a widespread down-regulation of AIRAPL in human myeloproliferative disorders, through a silencing mechanism mediated by miR-125a-3p. Collectively, these findings support the oncogenic relevance of proteostasis deregulation in hematopoietic cells, and unveil novel therapeutic targets for these frequent hematological neoplasias