Determining the mechanisms regulating immune-directed clearance of senescent cells to promote healthy ageing (360G-Wellcome-206224_Z_17_Z)

The number of people over the age of 65 is predicted to double by 2060, accompanied by an increase in chronic diseases, which already consume up to 80% of healthcare costs. Developing therapies for chronic ageing diseases is, therefore, an urgent priority. A key driver of ageing diseases is telomere dysfunction and consequent cell senescence. Genetic ablation of senescent cells ameliorates diseases of ageing in mice, highlighting senescence as a promising therapeutic target. The immune system clears senescent cells, but with ageing, senescent cells accumulate causing disease. The mechanisms regulating senescent cell clearance in telomere-dependent ageing in vivo are unknown. I will test the hypothesis that senescent cells are not cleared with ageing due to telomerase-dependent dysfunction of the immune system. I will use the premature ageing telomerase mutant zebrafish I developed, which age in a telomere- dependent manner, and are exceptionally amenable for imaging and genetic manipulation. I will determine which leukocytes clear senescent cells in aged tissues in vivo, identify the key mechanisms involved and determine how these change with ageing. I will then test whether manipulation of these targets is sufficient to prevent or delay tissue degeneration and frailty in old zebrafish.