Clonal hematopoiesis, somatic mosaicism, and age-associated disease

Abstract

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.

DNMT3A clonal hematopoiesis-driver mutations induce cardiac fibrosis by paracrine activation of fibroblasts

“…Clonal hematopoiesis of indeterminate potential, or CHIP, is a common age-related condition, in which acquired mutations in hematopoietic stem cells lead to the expansion of a genetically distinct subpopulation of blood cells 1 . The incidence of clonal hematopoiesis increases with age and was previously shown to associate with a variety of cardiovascular diseases, including heart failure [2][3][4][5][6][7] . Mutations in the epigenetic modifiers DNA methyltransferase 3A (DNMT3A) and ten eleven translocation 2 (TET2) are the most common CHIP-driver mutations 2 .…”

“…The incidence of clonal hematopoiesis increases with age and was previously shown to associate with a variety of cardiovascular diseases, including heart failure [2][3][4][5][6][7] . Mutations in the epigenetic modifiers DNA methyltransferase 3A (DNMT3A) and ten eleven translocation 2 (TET2) are the most common CHIP-driver mutations 2 . Importantly, previous studies demonstrated that harboring either DNMT3A or TET2 CHIP-driver mutations in circulating blood cells confers increased mortality in patients with established heart failure as well as aortic valve stenosis [8][9][10][11][12] .…”

Hematopoietic Stem Cells and the Immune System in Development and Aging

“…While the other part, under the influence of inflammatory stress and external and internal stimuli, begins to actively proliferate, which increases the risk of driver mutations accumulation that contribute to the selective advantage of some HSCs. The symmetrical propagation of HSC clones or the advantage in the asymmetric differentiation of one or more HSCs generates haematopoiesis clonality [ 17 , 130 , 156 ].…”

Cell Tree Rings: the structure of somatic evolution as a human aging timer

“…Somatic mutations in a small set of (growth and cancer associated) genes have been shown to propagate clones that become dominant in the hematopoietic system of older individuals [Mitchell et al, 2022] and have been directly linked to increased risk of cancer and other chronic diseases [Marongiu and DeGregori, 2022]. Additionally, somatic mosaicism has been shown, in multiple tissues, to rise with age and to predict disease in animal models [Evans and Walsh, 2022] From the perspective of designing interventions, it is important to understand which of the somatic mutations are simply passive indicators and which are active drivers of the aging process. In addition, it will be important to establish which can be targeted with clinical interventions.…”

“…In blood, mutations can lead to somatic mosaicism and eventually clonal hematopoiesis, where cell populations harbouring particular allele variants outgrow others. Animal models of clonal hematopoiesis have been shown to contribute to disease progression [Evans and Walsh, 2022]. More generally, diseases characterized by accelerated aging typically involve the increased accumulation of DNA damage [Lodato et al, 2018] Given its importance as a driver of aging, it would seem that somatic evolution could form the basis for a new type of aging timer.…”