TET2 Mutations and Atherosclerosis

There is some debate over whether accumulated stochastic nuclear DNA damage is significant in aging over the present human life span in ways other than increased cancer risk, and a lack of good studies that provide evidence to support theoretical arguments in either direction. Stochastic DNA damage is observed, different in every cell, but like many of the changes of aging this cannot yet be effectively repaired, and thus it is very challenging to distinguish its effects in isolation. On the side of arguing for significance, the mechanism by which it contributes to aging is assumed to be a growing level of general dysfunction in cellular populations. This conjecture is supported by work such as that shown here, in which specific mutations are pointed out as problematic for the normal function of tissues, but the challenge here is still that there is no good demonstration of its significance in normal aging over and above other mechanisms, such as those outlined in the SENS vision of aging. It might only be a problem if ten times as many cells are mutated than normally happens. Or a hundred times. One possible next step would be gene therapy to repair mutated instances of the gene where they occur in order to assess the size of the effect, but that sort of study hasn't taken place yet.

Though cardiovascular disease, which is characterized in part by atherosclerosis, or plaque build-up, is a leading cause of death in the elderly, almost 60 percent of elderly patients with atherosclerotic cardiovascular disease (CVD) exhibit no conventional risk factors, or just one. This and other data suggest that age-dependent risk factors that haven't yet been identified may contribute to CVD. Scientists know that accumulation of somatic DNA mutations is a feature of aging, though little data exists on the role of such mutations in age-associated disorders beyond cancer. Meanwhile, recent human studies indicate that aging is associated with an increase in somatic mutations in the hematopoietic system, which gives rise to blood cells; these mutations provide a competitive growth advantage to the mutant hematopoietic cells, allowing for their clonal expansion - a process that has been shown to be associated with a greater incidence of atherosclerosis, though specifically how remains unclear.

In this study, researchers investigated whether there is a direct relationship between such mutations and atherosclerosis. They generated an experimental model to investigate how one of the genes commonly mutated in blood cells of elderly humans, TET2, affects plaque development. Plaque formation accelerated in the models transplanted with Tet2-deficient bone marrow cells, likely through increasing macrophage-driven inflammation in the artery wall. The results strengthen support for the hypothesis that hematopoietic mutations play a causal role in atherosclerosis. "Our studies show that mutations in our white blood cells, that we acquire as we age, may cause cardiovascular disease. Understanding this new mechanism of cardiovascular disease could lead to the development of new therapies to treat individuals who suffer from heart and blood vessel ailments due to these mutations. Furthermore, because these mutations become prevalent starting at middle age, these studies suggest that genetic analyses of blood samples could add to the predictive value of traditional risk factors - high cholesterol, hypertension, diabetes, and smoking - that are currently monitored."

Link: https://www.eurekalert.org/pub_releases/2017-01/bumc-arf011917.php


I thought that except for certain tissues such as the brain and muscle fibers, most cells of the body are eventually replaced. Only for some reason with aging this process slows down or stops? Probably due to stem cells ceasing to divide in response to a damaged external environment as a shorter term anti cancer mechanism (causing death in the longer term). Intrinsic DNA damage of these stem cells may also be important.

Maybe the DNA damage theory of aging (excluding cancer) could be divided into a strong and a weak form. In the strong form it is DNA damage in all cells that leads to aging, in the weak form it is just DNA damage in stem cell populations that contributes to aging.

Have there been any in vivo experiments conducted to try and replace a 'damaged' population of stem cells with one with more pristine DNA?

Posted by: Jim at January 21st, 2017 11:10 PM

Re-reading that, I realize my question is a bit silly. If the external environment is the major inhibiting factor on stem cell replenishment of tissues in an aged animal, then putting in stem cells with pristine DNA won't have any effect (unless it is only DNA damage in the stem cells that causes the negative effects).

Could you do the reverse, by replacing a population of stem cells in a young animal with DNA damaged 'old' stem cells? How would you ensure that the DNA damaged stem cells are damaged in a similar way to 'naturally' aged stem cells? Transplant muscle tissue from an old animal to a younger clone?

And have parabiosis experiments already resolved these questions?

Posted by: Jim at January 22nd, 2017 12:11 AM

@Jim: I'm not aware of such an experiment; you are right in that it would be interesting to carry out, but how to separate DNA damage in old stem cells from other aspects of their damage?

Posted by: Reason at January 22nd, 2017 10:13 AM

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