The Tock Tick of Senescence

Professor Cleo Bishop; Barts and The London Faculty of Medicine and Dentistry, Queen Mary University of London

Cleo received her PhD in Biological Sciences from University College London in 2001. She then spent four years as a MRC Career Development Fellow in the laboratory of Prof. Chris Higgins at the MRC Clinical Sciences Centre (now the London Institute of Medical Sciences), Imperial College London, where she developed a keen interest in cancer biology. In 2006, she moved to the Blizard Institute to pursue her interest in senescence and cancer, spending four years in the laboratory of Prof. David Beach (FRS). During this time, she established our Phenotypic Screening facility, and has used this technology to discover novel regulators of the ageing and senescence biomarker, p16. In 2010, Cleo started her own group, and in 2022 was promoted to Professor. Current projects in Cleo’s lab aim to illuminate senescence mechanisms, understand how cells age, explore the interplay between healthy ageing and cellular rejuvenation, and target senescence for ageing and cancer therapy. Cleo is also currently Academic Lead for The QMUL Phenotypic Screening Facility and MB PhD Programme, and Research Lead for her Centre.

Restraining or slowing ageing hallmarks at the cellular level have been proposed as a route to increased organismal lifespan. Consequently, there is great interest in anti-ageing drug discovery. However, this currently requires laborious and lengthy longevity analysis. Here, we report a novel screening platform for the expedited discovery of compounds that restrain cellular ageing in vitro and enable extension of in vivo lifespan. For this, we developed a novel epigenetic clock, the CellAgeClock, to accurately monitor cellular ageing in adult human primary cells. We find that the CellAgeClock can detect decelerated passage-based cellular ageing of human primary cells treated with Rapamycin or Trametinib, well established longevity drugs. We then utilise the CellAgeClock as a screening tool for the identification of compounds which decelerate cellular ageing, uncovering novel anti-ageing drugs. We demonstrate that delayed cellular ageing in human primary cells treated with anti-ageing compounds is accompanied by a reduction in senescence and ageing biomarkers. Finally, we extend our screening platform in vivo by taking advantage of a specially formulated holidic medium for increased drug bioavailability in Drosophilia. We show that the novel anti-ageing drugs increase longevity in vivo. In summary, our method expands the scope of CpG methylation profiling to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro and in vivo, providing a novel accelerated discovery platform to test sought after anti-ageing compounds and geroprotectors.