Arguing the Direction of Causation in Atherosclerosis and Clonal Hematopoiesis

A major challenge in the study of aging and age-related disease is establishing the direction of causation. A great many mechanisms of aging are known, but it is difficult to firmly establish the relationships between them. The body is made up of many interacting systems, and changes in any one system tend affect the others, directly or indirectly. Equally, any two specific aspects of aging can be quite disconnected from one another but nonetheless proceed in parallel because they are both influenced by a third underlying mechanism. For example, the chronic inflammation of aging is a systemic problem, driving dysfunction in tissues throughout the body and accelerating the onset and progression of a wide range of age-related conditions.

Today's research materials are an example of this point. Here, researchers debate the direction of causation between atherosclerosis and clonal hematopoiesis. In atherosclerosis, macrophage cells in blood vessel walls become overwhelmed by oxidized and excessive amounts of cholesterol, resulting in fatty lesions that weaken and narrow the blood vessels. Because immune cells are involved, inflammation tends to make things worse by further impacting the ability of macrophages to repair tissues. In clonal hematopoiesis, mutational damage to the hematopoietic cells in the bone marrow leads to growing populations of (possibly mildly dysfunctional) immune cells. It is a specific instance of the more general age-related issue of somatic mosiacism, in which mutations in stem cells spread throughout tissues via their daughter somatic cells. It remains unclear as to just how big of a problem this is, in terms of the degree to which it contributes to aging.

Is the relationship between these two aspects of aging bidirectional, or are the observed correlations driven by an underlying process such as chronic inflammation? Questions of this nature are hard to answer definitively. The best approach is to find a way to reverse and repair one of the processes, and observe the result on the other. In general this is what the research and medical communities should be working towards in any case. It is far better to forge ahead to produce therapies of rejuvenation rather than first establishing how all of the mechanisms of aging interact, as success in rejuvenation will answer most of those questions about the inner workings of aging along the way.

Atherosclerosis can accelerate the development of clonal hematopoiesis, study finds

Billions of peripheral white blood cells are produced every day by the regular divisions of hematopoietic stem cells and their descendants in the bone marrow. Clonal hematopoiesis is a common age-related condition in which the descendants of one of these hematopoietic stem cells begin to dominate substantial portions of the blood. Genome-wide analyses have determined that clonal hematopoiesis is frequently driven by recurrent genetic alterations that confer a competitive advantage to specific hematopoietic stem cells, thus giving them the ability to expand disproportionately. Multiple independent studies have shown that clonal hematopoiesis often goes hand in hand with atherosclerosis and cardiovascular disease. Since its discovery, this surprising association has been the subject of intense interest from clinicians and researchers alike.

In a new study, researchers now suggest a different, additional possibility: Atherosclerosis causes clonal hematopoiesis. Patients with atherosclerosis suffer from hyperlipidemia and inflammation, two conditions that are known to chronically boost hematopoietic stem cell division rates. In the new study, the researchers now demonstrate that this increased division accelerates the development of clonal hematopoiesis. "Patients with atherosclerosis essentially experience 'accelerated time.' This is because the speed with which genetic alterations arise and spread through the hematopoietic system is determined by the underlying rate of stem cell division. From a genetic point of view, you could say that atherosclerosis accelerates aging of the blood. Since clonal hematopoiesis is an age-related condition, atherosclerosis patients are prone to developing it earlier than healthy individuals."

Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis

Clonal hematopoiesis, a condition in which individual hematopoietic stem cell clones generate a disproportionate fraction of blood leukocytes, correlates with higher risk for cardiovascular disease. The mechanisms behind this association are incompletely understood. Here, we show that hematopoietic stem cell division rates are increased in mice and humans with atherosclerosis. Mathematical analysis demonstrates that increased stem cell proliferation expedites somatic evolution and expansion of clones with driver mutations. The experimentally determined division rate elevation in atherosclerosis patients is sufficient to produce a 3.5-fold increased risk of clonal hematopoiesis by age 70. We confirm the accuracy of our theoretical framework in mouse models of atherosclerosis and sleep fragmentation by showing that expansion of competitively transplanted Tet2-/- cells is accelerated under conditions of chronically elevated hematopoietic activity. Hence, increased hematopoietic stem cell proliferation is an important factor contributing to the association between cardiovascular disease and clonal hematopoiesis.