Clonal Hematopoiesis, Somatic Mosaicism, and Age-Associated Disease

Somatic mosaicism - the occurrence of multiple genetically distinct cell clones within the same tissue - is an evitable consequence of human aging. The hematopoietic system is no exception to this, where studies have revealed the presence of expanded blood cell clones carrying mutations in preleukemic driver genes and/or genetic alterations in chromosomes. This phenomenon is referred to as clonal hematopoiesis and is remarkably prevalent in elderly individuals. Whilst clonal hematopoiesis represents an early step towards a hematological malignancy, most individuals will never develop a blood cancer. Somewhat unexpectedly, epidemiological studies have found that clonal hematopoiesis is associated with an increase in risk of all-cause mortality and age-related disease, particularly of the cardiovascular system. Studies using murine models of clonal hematopoiesis have begun to shed light on this relationship, suggesting that driver mutations in mature blood cells can causally contribute to aging and disease by augmenting inflammatory processes. Here we provide an up-to-date review of clonal hematopoiesis within the context somatic mosaicism and aging and describe recent epidemiological studies which have reported associations with age-related disease. We will also discuss the experimental studies which have provided important mechanistic insight into how driver mutations promote age-related disease and how this knowledge could be leveraged to treat individuals with clonal hematopoiesis.

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