Periodic Reporting for period 1 - AgePhagy (An integrated high-throughput human cell and Drosophila screening platform for the expedited discovery of anti-ageing compounds)
Berichtszeitraum: 2019-04-01 bis 2020-09-30
We aim to improve anti-ageing drug discovery, currently achieved through laborious and lengthy longevity analysis. Our DNA can be methylated, which can affect gene expression and which proteins the cell is making. Recent studies demonstrated that the most accurate molecular method to measure human age is based on DNA methylation, more specifically, CpG methylation profiles, and this method is called epigenetic clock. Currently, there are several epigenetics clocks that can accurately predict an individual’s age. However, none of the epigenetic clocks is suitable for cells in culture. Therefore, here, we developed CellAgeClock, a new epigenetic clock that measures subtle ageing changes in primary human cells in vitro. As such, it provides a unique tool to measure how relatively short pharmacological treatments affect ageing. We validated the CellAgeClock against known longevity drugs such as rapamycin and trametinib. Moreover, we uncovered novel anti-ageing drugs, torin2 and Dactolisib (BEZ-235), demonstrating the value of our approach as a screening and discovery platform for anti-ageing strategies. The CellAgeClock outperforms other epigenetic clocks in measuring subtle ageing changes in primary human cells in culture. The tested drug treatments reduced senescence and other ageing markers, further consolidating our approach as a screening platform. Finally, we show that the novel anti-ageing drugs we uncovered in vitro, indeed increased longevity in vivo. Our method expands the scope of CpG methylation profiling from measuring human chronological and biological age from human samples in years, to accurately and rapidly detecting anti-ageing potential of drugs using human cells in vitro, providing a novel accelerated discovery platform to test sought after geroprotectors. These anti-ageing drugs or geroprotectors are expected to improve health in the elderly, thereby delaying or preventing age-related diseases. This could have a great socioeconomic impact in future, given that the number of elderly individuals is steeply increasing in modern societies.