The blood system changes over time: a subset of stem cells outcompete their neighbors and gradually take over blood production. In addition, the blood stem cell reservoir shrinks and becomes dominated by clones that show a preference for producing myeloid cells, immune cells linked to chronic inflammation.
“Our blood stem cells compete for survival,” noted Lars Velten, PhD, group leader at the Centre for Genomic Regulation (CRG) in Barcelona. “In youth, this competition produces a rich, diverse ecosystem, while in old age, some drop out entirely. A few stem cells take over, and these work extra hard to compensate. This reduces diversity, which is bad for the blood system’s resilience. Diverse stem cells can respond to different stresses, so the dominance of a handful of clones makes the whole system more fragile.”
This work is published in Nature in the article, “Clonal tracing with somatic epimutations reveals dynamics of blood ageing.”
In youth, humans have between 50,000 to 200,000 active blood stem cells, which create between 100 to 200 billion new blood cells every day. Tracking every blood cell back to its original stem cell requires genetically modifying DNA.
The researchers found that “DNA methylation of a subset of CpG sites reflects cellular differentiation, whereas another subset undergoes stochastic epimutations and can serve as digital barcodes of clonal identity.” They write that targeted single-cell profiling of DNA methylation at single-CpG resolution can accurately extract both layers of information.
In turn, the team developed a new technique, EPI-Clone, which reads methylation barcodes from individual cells. It was built by modifying Mission Bio’s single-cell sequencing platform Tapestri. They used it to reconstruct the history of blood production in both mice and humans, helping trace which stem cells contributed to making blood. More specifically, they captured “hundreds of clonal differentiation trajectories across tens of individuals and 230,358 single cells.”
In young blood, thousands of different stem cells contribute to a rich and diverse pool of red blood cells, white blood cells, and platelets. But EPI-Clone revealed that in older mice, up to 70% of blood stem cells belonged to just a few dozen large clones, compared with around 50% in younger mice.
In humans, the exact percentage varied between the dozen healthy donors between 35 and 70 years old. The study found that by age 50, many blood stem cells begin to drop out and larger clones begin to take over, while by age 60 and beyond, the shift becomes even more pronounced. The authors suspect the loss of clone diversity could help explain “inflammaging,” the persistent chronic inflammation that emerges during aging and which can make people more vulnerable to disease.
“The change from diversity to dominance isn’t random but clock-like,” said Indranil Singh, a PhD student at IRB Barcelona. “By age 50, you can already see it starting, and after 60, it becomes almost inevitable.”
The study also found that some large clones harbored mutations linked to clonal hematopoiesis. In this process, some blood stem cells acquire mutations that allow them to grow and multiply faster than others. The phenomenon becomes more common with age and has been shown to increase the risk of heart disease, stroke, and leukemia. However, many of the dominant clones identified by EPI-Clone had no known mutations at all, suggesting that clonal expansion is a general feature of aging blood, not just a sign of cancer risk.
The findings could enable the assessment of clonal behavior for early detection, offering a way to monitor how a person’s blood stem cell pool is aging years before disease develops. People with faster loss of diversity, or rapid expansion of risky clones, could be flagged for preventive care.
The study also observed that in both older humans and mice, many of the dominant clones show a preference for producing myeloid cells. Previous studies in mice have shown that selectively removing myeloid-biased stem cells can restore a younger profile of blood stem cells, boosting the production of lymphocytes and improving immune responses.
But to study rejuvenation therapies in humans, researchers would first need to identify which clones are problematic, something which has not been possible until now. “If we want to move beyond generic anti-aging treatments and into real precision medicine for aging, this is exactly the kind of tool we need,” said Velten. “We can’t fix what we can’t see and for the first time, EPI-Clone can facilitate this for humans.”
