CenAGE · CenAGE, a 'Centromeric' view on AGEing: unveiling centromere instability in ageing

Ageing is the primary risk factor for chronic diseases. Amongst the ageing hallmarks, genomic instability has emerged as a unifying cause of ageing, since it drives most of the other hallmarks, namely senescence and chronic inflammation. These hallmarks are all typically portrayed by the aged immune system, with compelling evidence pointing to genomic instability in immune cells as a driver of organismal ageing. Intriguingly, while the role of telomeres, mutations, transposons, etc, in age-related genomic instability has been widely investigated, the centromeres have remained largely overlooked. Centromeres are unique specialised regions of repetitive sequences regulated epigenetically that ensure chromosome segregation fidelity. Emergent evidence shows that centromeres are inherently unstable, and recent findings from our labs indicate that centromere instability can lead to genome instability, inflammation, and senescence, including in non-cycling immune cells. In CenAGE, we propose a multi-layer synergistic approach to deliver a ‘centromeric’ view on ageing by: i) characterizing age-associated changes in centromere features in cellular models; ii) identifying the intrinsic (genetic and epigenetic) and extrinsic (viral infection) mechanisms behind centromere-driven senescence hallmarks; iii) establishing the role of centromere dysfunction in physiological decline, focusing on the immune system; and iv) testing how geroprotective interventions that implicate centromeres impact immunosenescence and systemic ageing. There is a timely opportunity to study centromeres in ageing now due to technological advances that enable the sequencing of these ‘blind spots’ of the genome. We expect the CenAGE project, grounded in solid preliminary results and complementary expertise, will deliver a transformative breakthrough in the field: centromeres as key players of genomic instability in ageing.