New insights into the dynamics of age-related clonal hematopoiesis

Altered hematopoiesis is increasingly recognized as a hallmark of aging and an important contributor to age-related inflammation and cardiovascular disease (CVD). In an adult individual, hematopoiesis is supposed to be polyclonal, relying on thousands of hematopoietic stem cells (HSC)([1]), which in most cases can be regarded as equipotent when contributing to hematopoiesis. In contrast, accumulating evidence suggests that hematopoiesis turns oligoclonal in many elderly individuals, in whom it is dominated by a smaller number of HSC clones that contribute disproportionately to blood cell production [Figure 1'. While other mechanisms, such as stochastic loss of HSC clones, cannot be ruled out completely, this age-related clonal hematopoiesis (CH) seems to be driven primarily by the acquisition of somatic mutations in HSCs[2]. Over a lifetime, an individual acquires hundreds of thousands of mutations in the HSC pool. Whereas all HSCs accumulate mutations with no functional consequences (known as passenger mutations), some HSCs acquire mutations that confer a competitive advantage and drive their clonal expansion (driver mutations), leading to CH. CH associated with the acquisition of known driver mutations has emerged as a potent risk factor for CVD, and experimental studies in mice suggest a direct causal contribution of some of these mutations to CVD by exacerbating inflammatory responses([3]) . A consistent finding in most CH studies is that those with larger clones tend to have a higher CVD risk. Therefore, there is an increasing interest in understanding the factors and mechanisms that modulate the dynamics of expansion of mutant hematopoietic clones. Two recent articles in Nature provide key new insights into this topic([4,5]) .