To what degree does random mutation in nuclear DNA contribute to aging over the present human life span? The present consensus is that this is a cause of disarray in metabolic processes, and that it does reach a significant level of consequence for tissue function. Unfortunately there is little direct evidence for this view - it is hard to split out just nuclear DNA damage from the rest of aging in order to isolate its effects, though there a few lines of research showing promise in this direction. Researchers here take a different approach to the question; they suggest that some forms of random mutational damage that occurs in stem cells will expand throughout that population over time, because the damage in some way confers a replication advantage. In this way it can come to have a significant effect, and it should be feasible to correlate different degrees of the expansion of this sort of mutational damage with specific measures of aging. In this case, the correlation is with cardiovascular disease.
Several explanations have been offered for how age contributes to cardiovascular disease. Aging is associated with the acquisition and exposure duration of other established risk factors for cardiovascular disease, including high systolic blood pressure and increased levels of low-density lipoprotein cholesterol. However, analyses that adjust for the concomitant burden of other risk factors consistently identify age as an independent predictor of cardiovascular disease. Modifiable risk factors account for only about 12% of the age effect in men and 40% in women. Thus, the aging process itself must promote cardiovascular risk, although the mechanisms that are involved are poorly understood.
Researchers now provide new insight into how aging can promote atherosclerosis and cardiovascular events in their investigation of a phenomenon termed clonal hematopoiesis of indeterminate potential, or CHIP. This condition is an age-related disorder characterized by the acquisition of somatic mutations in hematopoietic stem cells that confer on these cells a selective advantage. As a consequence, instead of the normal polyclonal generation of blood cells, mutation-containing clones expand over time and make up an increasing percentage of the stem cells and their progeny and may include granulocytes, lymphocytes, and monocytes. CHIP is rarely found in patients who are younger than 40 years of age, whereas this condition may exist in up to 10% of persons over the age of 70 years. Patients with CHIP have a higher rate of death from noncancer causes (particularly cardiovascular disease) than do age-matched controls without CHIP.
To address the cause of excess cardiovascular mortality, researchers identified CHIP (which they define as clonal dominance of hematopoietic cells bearing pathogenic mutations in any of 74 known driver genes of hematologic cancers) among participants in several studies that ascertained cardiovascular disease. In studies involving participants with a mean age of 60 years or older, carriers of CHIP had nearly twice the risk of coronary heart disease as noncarriers. Among younger participants (below 50 years of age), CHIP carriers had four times the risk of myocardial infarction as noncarriers. Preclinical coronary disease, as assessed on imaging as coronary-artery calcification, was also associated with CHIP. Finally, four of the most commonly mutated genes in CHIP (DNMT3A, TET2, ASXL1, and JAK2) were each individually associated with coronary heart disease.
Collectively, the work supports the hypothesis that CHIP is linked to the clinical events of atherosclerosis and that certain CHIP driver genes are involved in regulating inflammation. Both TET2 and DNMT3A appear to inhibit inflammation, so loss-of-function mutations in these genes could plausibly promote inflammatory responses. Similarly, there is a large body of literature suggesting that JAK2 regulates both inflammation and thrombosis, two important factors in the clinical manifestations of atherosclerosis. Thus, the data is consistent with established paradigms that inflammation is an accelerator of atherosclerosis and coronary heart disease. Moreover, their findings should prompt a discourse about studying the use of anti-inflammatory agents in patients with CHIP to limit the most common cause of death in these patients - cardiovascular disease.