Ulysse Cherqui

Fibrosis and accumulation of senescent cells are common tissue changes associated with aging. Here, we show that the CDK inhibitor p21 (CDKN1A), known to regulate the cell cycle and the viability of senescent cells, also controls the expression of extracellular matrix (ECM) components in senescent and proliferating cells of the fibrotic lung, in a manner dependent on CDK4 and Rb phosphorylation. p21 knockout protects mice from the induction of lung fibrosis. Moreover, inducible p21 silencing during fibrosis development alleviates disease pathology, decreasing the inflammatory response and ECM accumulation in the lung, and reducing the amount of senescent cells. Furthermore, p21 silencing limits fibrosis progression even when introduced during disease development. These findings show that one common mechanism regulates both cell cycle progression and expression of ECM components, and suggest that targeting p21 might be a new approach for treating age-related fibrotic pathologies.

Abstract Dementia in general, and Alzheimer’s disease (AD) in particular, are age-related diseases 1,2 . AD is associated with multiple causative factors 3,4 , among which local brain inflammation plays a significant role 5 . Microglia, the brain-resident immune cells 6,7 , are activated along the disease course 7 . Yet, their contribution to the disease progression is still controversial. Here, using high-throughput mass cytometry for microglial immuno-phenotyping, we identified accumulation of senescent microglia in several pathologies associated with cognitive decline. These senescent microglia have a unique profile conserved across the multiple conditions investigated, including aging, mouse models of amyloidosis, and tauopathy. Moreover, we found that the expression of markers of senescence correlates with levels of TREM2, whose polymorphism was identified by GWAS as an AD risk factor 8,9 . A TREM2-null AD mouse model showed lower levels of senescent microglia, relative to TREM2-intact AD mice. Senolysis using the drug ABT-737 10,11 in an AD mouse model reduced the abundance of TREM2-senescent microglia without affecting levels of TREM2-dependent activated microglia, ameliorated cognitive deficits, and reduced brain inflammation. These results reveal the unexpected contribution of TREM2 to accumulation of senescent microglia in AD pathology, an effect that must be considered when targeting TREM2 as a therapeutic approach.

Abstract Cellular senescence, a hallmark of ageing, drives tissue dysfunction by promoting inflammation and fuelling disease. Yet, the dynamics of senescent cell accumulation across tissues and their cell type identity remain poorly understood. Here, we introduce the first, single-cell, protein-level approach, combining multiple senescence markers for the identification and quantification of senescent cells across multiple tissues in mice and in human PBMCs. Applying this method, we reveal widespread but heterogeneous changes in senescence marker expression across cell types and tissues. The cells we identify as senescent displayed transcriptomic senescence signatures, providing a direct molecular link between protein- and mRNA-level detection of senescence. Importantly, senescence accumulation was strongly coordinated within organs but showed little correlation across them, supporting the idea of a tissue specific progression of ageing. These findings refine our understanding of the tissue-specific dynamics of senescence accumulation with age, and provide a framework for evaluating diverse therapeutic interventions.