Clonal hematopoiesis in human aging and disease

Cryptic signs of aging in our blood Time is not a friend to our DNA. Aging is associated with an accumulation of somatic mutations in normal dividing cells, including the hematopoietic stem cells (HSCs) that give rise to all blood cells. Certain mutations in HSCs confer a fitness advantage that results in clonal expansions of mutant blood cells that sometimes—but not always—forecast the development of cancer and other age-related diseases. Jaiswal and Ebert review this process of “clonal hematopoiesis,” including the mechanisms by which it arises and the current state of knowledge regarding its effects on human health. Science, this issue p. eaan4673 BACKGROUND Somatic mutations accumulate in normal tissues as a function of time. The great majority of these mutations have no effect on fitness, so selection does not act upon them. Rarely, a mutation will arise that confers a selective growth advantage to the cell in which it occurs. Such a mutation would allow that cell and its progeny, referred to as a “clone,” to progressively expand over time. This is now appreciated to occur in a number of tissues, particularly in aged individuals. When this happens in a hematopoietic stem cell (HSC), “clonal hematopoiesis” may result if the mutated clone contributes to the production of a substantial proportion of mature blood cells. Mutations in genes involved in epigenetic regulation (DNMT3A, TET2, ASXL1) account for the majority of mutation-driven clonal hematopoiesis in humans. These mutations are rare in the young but highly prevalent in the elderly, with between 10 and 20% of those older than age 70 harboring a clone of appreciable size. These individuals usually have only a single driver gene mutated, in contrast to individuals with frank malignancy, where there might be several such mutations. Clonal hematopoiesis of indeterminate potential (CHIP) is a clinical entity defined by the presence of a cancer-associated clonal mutation in at least 4% of nucleated blood cells of individuals without frank neoplasia. ADVANCES Large-scale genetic studies have revealed the prevalence and clinical associations of somatic, clonal mutations in blood cells of individuals without hematologic malignancies. One expected consequence of harboring a cancer-associated mutation in blood is an increased risk of developing an overt hematologic malignancy, as the initiating mutation may progress to cancer if additional cooperating mutations are acquired. Indeed, recent studies have demonstrated that CHIP is associated with an increased risk of developing blood cancers, confirming that it is a bona fide premalignant state. Individuals with CHIP progress to malignancy at a rate of about 0.5 to 1% per year. Factors that influence the likelihood of progression to malignancy include the size of the clone, the number of mutations, and the specific gene or genes that are mutated. The process of precancerous clonal expansion likely occurs in all mitotically active tissues, as has recently been shown in studies of human skin and esophagus. Clonal hematopoiesis may also be relevant to phenotypes apart from malignancy. The blood stem cells that harbor the mutations give rise to immune cells such as granulocytes, monocytes, macrophages, and lymphocytes. As these cells reside in nearly all tissues, mutations that alter their function could have a variety of phenotypic consequences. For example, recent studies have suggested that CHIP is associated with an increased risk of all-cause mortality and an increased risk of cardiovascular diseases such as myocardial infarction, stroke, and venous thrombosis. The risk appears to be substantial, as the hazard ratio associated with CHIP is as great as or greater than many commonly assessed risk factors for cardiovascular disease, such as smoking, cholesterol levels, and high blood pressure. Mouse models that carry some of the common CHIP mutations display enhanced atherosclerosis, consistent with a causal relationship between the mutations and the disease. At a mechanistic level, the mutations may amplify the inflammatory response by the innate immune system, a known contributing factor in the development of atherosclerosis. CHIP may be a general factor underlying age-related inflammation and could potentially influence several diseases of aging. OUTLOOK Although the past few years have seen an explosion of research on clonal hematopoiesis, many mysteries remain. The exact mechanisms by which CHIP-associated mutations cause clonal expansion remain unknown, as does a role for environmental or heritable factors in this process. Nor is it understood why some people develop rapid clonal expansion and progression to malignancy, whereas others have clones that lay dormant for many years. It is likely that the presence of CHIP influences several other diseases of aging, in addition to cancer and cardiovascular disease, but this has not yet been studied systematically. In addition to addressing questions directed at the basic science underlying clonal hematopoiesis, we need to develop strategies aimed at mitigating the adverse consequences of CHIP, such as lifestyle modifications or drugs that lower the risk of hematologic cancer and heart disease. The process of mutation and clonal selection is likely to be universal across all organs and tissues. Understanding the causes and consequences of clonal hematopoiesis may provide a framework to understand this process, and aging, more broadly. Somatic mutations, clonal hematopoiesis, and aging. Somatic mutations are acquired by all cells throughout life. Most are inconsequential, but rare mutations will lead to clonal expansion of hematopoietic stem cells (HSCs). If additional mutations are acquired, blood cancers may result. Emerging data also associate the presence of such clones with increased risk of cardiovascular disease (CVD) and death. Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues. As people age, their tissues accumulate an increasing number of somatic mutations. Although most of these mutations are of little or no functional consequence, a mutation may arise that confers a fitness advantage on a cell. When this process happens in the hematopoietic system, a substantial proportion of circulating blood cells may derive from a single mutated stem cell. This outgrowth, called “clonal hematopoiesis,” is highly prevalent in the elderly population. Here we discuss recent advances in our knowledge of clonal hematopoiesis, its relationship to malignancies, its link to nonmalignant diseases of aging, and its potential impact on immune function. Clonal hematopoiesis provides a glimpse into the process of mutation and selection that likely occurs in all somatic tissues.