10027203Developing a molecular clock for evaluation of senotherapeuticsClosedCollaborative R&DInnovate UKAt SENISCA we have discovered a new way by which cells age; loss of alternative splicing, a form of fine-tuning of gene expression. We can restore this process to 'turn back the ageing clock' in old (senescent) human cells. This presents a possible solution to many of the healthcare challenges faced by our ageing society, offering restorative, as well as potentially preventative treatments for common diseases of ageing.? Realisation of the full potential of our technology requires a set of robust and accurate outcome measures with which to measure the?rejuvenative?effect of our interventions in vitro and in vivo. One such measure will be a multi-tissue 'alternative splicing clock' specific to senescence which can be linked to cellular age.? With this project, we will create a multi-tissue senescence signature for 2 different disease relevant cell types (relevant to cardiovascular and lung function) by growing cells to senescence in culture. Results will also be integrated with data from blood to provide a tissue-relevant clock from an accessible tissue. Samples will be collected at multiple time-points for a full battery of cell ageing measurements alongside the collection of an 'RNA barcode' comprising every splicing event in the cells under test. This dataset will allow us to develop an accurate picture of the gene expression changes that occur during cellular ageing. We will perform a variety of exploratory analyses including differential expression and gene set enrichment to build a network model of cellular ageing, leading to the identification of a minimal-viable set of genes with sufficient power to predict biological age. We will then correlate expression of this subset of genes to the cellular phenotype data, followed by evaluation of their predictive power in a human cohort.? To our knowledge, this will be the first time globally that a multi-tissue transcriptomic biological clock has been mapped specifically to both cellular senescence and chronological age in human samples. This work will produce a number of cell type specific molecular clocks that are specific to senescence. These will be an integral part of SENISCA's toolkit of evaluation measures for our emerging therapeutics, but will have inherent and commercial value of their own. Specific biomarkers for senescence are currently lacking, and the production of a series of tissue specific senescence-specific clocks would be of great interest to other companies striving to attenuate age-related disease by?senotherapies?and to consumers looking to monitor their biological age.