IBCS Seminar - Professor Lorna Harries, Professor of Molecular Genetics

Common, chronic diseases associated with age have common roots. Rather than each disease arising from a unique set of causes, it is now apparent that many such disorders have their origins in the age-related decline of a number of basic health maintenance mechanisms, termed the ‘hallmarks of ageing’. Interventions targeting ageing hallmarks (‘senotherapeutics’) are now the subject of intense study to treat the causes, rather than the consequences of ageing. I present here evidence that the age-related dysregulation of alternative splicing (AS) comprises a new, druggable, hallmark of ageing. Splicing factors; transcripts involved in temporal or tissue specific regulation of AS are amongst the most deregulated mRNAs in human populations and aged cells, demonstrate associations with median strain lifespan and dietary restriction in animal models, and are similarly dysregulated in young fibroblasts from individuals suffering from progeroid symptoms. Finally, drugging this new hallmark in senescent (aged) human skin, lung or endothelial cells using small molecules or targeted genetic interventions is capable of restoring splicing factor levels to those comparable with young cells, and rescuing multiple features of cellular senescence. Drugs that target the regulation of splicing factors may therefore represent promising novel anti-degenerative therapies in the future.