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A new collaborative study from researchers at the MRC Molecular Haematology Unit, the Wellcome-MRC Cambridge Stem Cell Institute, and the MRC Laboratory of Molecular Biology, published in Molecular Cell, sheds light on the causes of blood cell ageing.
As we get older, our blood systems age and start to function differently. In particular, aged blood stem cells become less efficient at making blood cells. These older stem cells also become biased towards producing more myeloid cells (red blood cells, platelets, neutrophils), and fewer lymphoid cells (B and T lymphocytes). This can impact our blood’s normal functions, such as the ability to defend against infections and increase the risk of blood cancers.
So, what causes our blood to age? Understanding the answers to this question could lead to the development of treatments that slow down or even reverse ageing in our blood.
In this new study, the researchers (led by members of the Patel group) showed that one cause of ageing in the blood is DNA damage caused by aldehydes produce by our metabolism.
Previous studies published by Professor KJ Patel’s group have shown aldehydes to be natural chemical by-products of mammalian metabolism. They have also shown that these aldehydes can react with DNA to cause damage and mutations. This latest study showed that blood stem cells from 8-week-old mice with elevated levels of aldehyde-induced DNA damage in their blood stem cells now looked like blood stem cells from 2-year-old mice when examined using single cell RNA sequencing and DNA methylation profiling. Furthermore, the DNA-damaged blood stem cells were found to have shorter telomeres (the regions of DNA and proteins at the ends of chromosomes) and behaved like old stem cells - producing more myeloid cells and fewer lymphoid cells.
The study also found that accelerated ageing in the blood stem cells appeared to arise as a result of a programmed response to DNA damage driven by a key transcription factor called P53. When the P53 transcription factor was deleted the DNA-damaged blood stem cells no longer exhibited features of ageing.
Co-first author, Meng Wang (now an Assistant Professor at Cornell University) said:
“It is indeed intriguing why blood stem cells may ‘actively’ undergo ageing in response to DNA damage. One possibility may be to protect against the development of blood cancers by diverting the output of DNA-damaged stem cells away from long-lived lymphocytes, to instead produce short-lived ‘dead-end’ cells like red cells and platelets.
Additional studies are underway to dissect how the P53 pathway triggers this ageing response in blood stem cells and to identify the exact metabolic pathways that give rise to aldehydes in order to design therapies aimed to reduce the level of aldehydes in the body.”
Read the paper here.