Inflammageing and clonal haematopoiesis interplay and their impact on human disease

Clonal haematopoiesis of indeterminate potential (CHIP) is an ageing-related condition associated with a substantial fraction of circulating leukocytes having descended from a single somatically mutated haematopoietic stem cell (HSC). CHIP increases the risk of haematological malignancies and several chronic diseases (for example, cardiovascular pathologies) and contributes to persistent, low-grade inflammation or inflammageing. Inflammageing, in turn, promotes functional impairment of normal HSCs, including reduced self-renewal potential. By contrast, CHIP-mutant HSCs not only are resistant to inflammageing-induced functional decline but also gain a selective expansion advantage in an inflammatory environment. A recent surge of discoveries has increased our understanding of the CHIP-inflammageing interplay, from a mechanistic and clinical perspective, highlighting its broader relevance to age-related diseases. In this Review, we discuss the molecular and cellular mechanisms that cause CHIP, its interplay with inflammageing, as well as the pathophysiological consequences and the translational implications for diseases that affect older individuals.