Clonal Mutation in Immune Cells Correlates with Epigenetic Age Acceleration

The nuclear DNA encoding near all of the protein machinery necessary to cell function is constantly damaged and constantly repaired. The repair mechanisms are highly efficient, and are backed up by numerous other systems intended to destroy cells that suffer particularly critical DNA damage, mutations that can lead to cancer or severe dysfunction. Nonetheless, damage accumulates. Near all of this damage is irrelevant, as it occurs randomly in single somatic cells with a limited life span, in genes that the cell isn't using. Unfortunately, there are ways for DNA damage to become significant.

The first is obviously cancer, a condition arising from particular combinations of mutational damage that allow a cell to replicate aggressively without limit. The second is when damage occurs in a stem cell or progenitor cell that will create large numbers of descendant somatic cells. A mutation can be spread widely throughout a tissue, and the resulting patchwork of mutations is known as somatic mosaicism. It is thought that somatic mosaicism contributes to the general level of dysfunction in aging tissue, but this is hard to prove at the present time: the compelling experiment that isolates only this class of nuclear DNA damage as a factor and links it to specific aspects of aging has yet to be designed and carried out. It is easy to generate nuclear DNA damage in animal models, via radiation or genetic engineering to disable repair mechanisms, and indeed this causes harm, but it is not the same thing at all.

Today's research is focused on a form of somatic mosaicism in the immune system, known as age-related clonal haemopoiesis (ARCH), this designation limited to mutations in a small range of genes associated with cancer risk. Mutations arise in hematopoietic stem cells or progenitor cells, just as elsewhere, and as a consequence large numbers of immune cells bear those mutations. When this occurs in the ARCH genes related to cancers of the immune system, such as leukemia, it raises the risk of cancer and earlier mortality, the latter possibly due to increased risk of cardiovascular disease. One can speculate on why the increased risk of cardiovascular disease occurs, such as the importance of macrophages to the development of atherosclerosis, but a solid understanding is lacking.

In the same vein, researchers here show that age-related clonal haemopoiesis is correlated with an increased epigenetic age. At this point an acceleration of epigenetic age, to have a higher epigenetic age than chronological age, should probably be expected for any underlying state that raises all cause mortality, given the large amount of evidence for patients with specific age-related diseases to have higher epigenetic age measures. Unfortunately we don't yet have a reliable technology that allows low-risk replacement of hematopoietic stem cell populations: it is possible via hematopoietic stem cell transplantation, but this is a traumatic procedure involving chemotherapy and significant side-effects. But given a way to safely destroy existing hematopoietic cell populations and introduce new undamaged populations, a great many issues in aging might be addressed meaningfully. It is a goal to work towards.

DNA changes accelerate body's ageing

DNA changes throughout a person's life can significantly increase their susceptibility to heart conditions and other age-related diseases, research suggests. Such alterations - known as somatic mutations - can impact the way blood stem cells work and are associated with blood cancers and other conditions. A study says that these somatic mutations and the associated diseases they cause may accelerate a person's biological age - how old their body appears - faster than their chronological age - the number of years they have been alive.

A study examined these changes and their potential effects in more than 1000 older people from the Lothian Birth Cohorts (LBCs), born in 1921 and 1936. The LBCs are a group of people - now in their 80s and 90s - who sat intelligence tests as 11-year olds. They are some of the most-intensively studied research participants in the world. Scientists studied people where the biological and chronological age was separated by a large gap. They found the participants with somatic mutations - around six per cent - had a biological age almost four years older than those with no alterations. Experts say they will now explore the link between these DNA changes and biological ageing acceleration.

Age-related clonal haemopoiesis is associated with increased epigenetic age

Age-related clonal haemopoiesis (ARCH) in healthy individuals was initially observed through an increased skewing in X-chromosome inactivation. More recently, several groups reported that ARCH is driven by somatic mutations, with the most prevalent ARCH mutations being in the DNMT3A and TET2 genes, previously described as drivers of myeloid malignancies. ARCH is associated with an increased risk for haematological cancers. ARCH also confers an increased risk for non-haematological diseases, such as cardiovascular disease, atherosclerosis, and chronic ischemic heart failure, for which age is a main risk factor.

Whether ARCH is linked to accelerated ageing has remained unexplored. The most accurate and commonly used tools to measure age acceleration are epigenetic clocks: they are based on age-related methylation differences at specific CpG sites. Deviations from chronological age towards an increased epigenetic age have been associated with increased risk of earlier mortality and age-related morbidities. Here we present evidence of accelerated epigenetic age in individuals with ARCH.

Comments

Chemo-free strategies for stem cell transplants are coming, a saw a talk from Mark Chao form Forthy Seven, a company out of Stanford that develops macrophage-checkpoints.

https://www.youtube.com/watch?v=9eYyVpdzH38

he talks about it at minute 35

I agree a synthetic immune system with more bells and whistles than your current one, that is better at destroying senescent cells and cancer even plaques is quite attractive. I suspect aging will be solved with stem cell therapy as a core component, putting the mitochondria genes into the nucleus, engineering better DNA damage repair and so on is far easier if you have cells outside the body

Posted by: Tom at September 10th, 2019 3:26 PM

Magenta Therapeutics are looking to develop safe autologous (self) blood stem cell transplants:

https://lifescivc.com/2017/10/transplant-tailwinds-momentum/

"Imagine in a few years' time as part of your annual physical that alongside your cholesterol and hemoglobin levels you scroll down on your smartphone app to find the set of mutations from your sequencing results. You have a greater than 10% chance at your 60th birthday that you will be carrying a mutation that confers an increased risk of developing a blood cancer or dying of a stroke. You pause to wonder: What should I do? Diet and exercise, a statin or two, and other drugs may help but they are not going to change that mutation. Your doctor suggests rebooting your blood and immune system to get rid of that mutation through a stem cell transplant."

Posted by: jimofoz at September 11th, 2019 5:13 PM

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