A new study in the journal Nature explains how age reshapes the blood system. In both humans and mice, a few stem cells, or "clones", outcompete their neighbours and gradually take over blood production. The blood stem cell reservoir shrinks and becomes dominated by clones which show a preference for producing myeloid cells, immune cells linked to chronic inflammation.
The changes were detectable by age 50 and almost universal by age 60. The authors of the study suspect the loss of clone diversity could help explain 'inflammaging', the persistent chronic inflammation that emerges during ageing and which can make us more vulnerable to disease. The team observed the pattern in both mice and humans, suggesting the findings are a fundamental feature of blood ageing across species.
The work can lead to new strategies which spot early warning signs of unhealthy ageing long before symptoms appear, helping prevent diseases like cancer or immune disorders. It also opens the door to studying the viability of rejuvenation therapies in humans, efforts which have traditionally been the focus of animal research.
"Our blood stem cells compete for survival. 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," says Dr. Lars Velten, Group Leader at the Centre for Genomic Regulation (CRG) in Barcelona and co-corresponding author of the study.
The scientists had to solve a long-standing technical challenge to make their discovery. 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. In humans, this type of genetic engineering is neither practical nor ethical.
Instead, the team turned to epimutations. These are epigenetic changes in the chemical tags, also known as methylation marks, attached to DNA. The tags help cells know which genes to switch on or off. When a stem cell divides, methylation marks are copied to its daughter cells, leaving behind a permanent, natural 'barcode' that researchers can 'scan' or read to chart each cell's position in the family tree.
"Our cells carry genetic alterations which collectively make us unique individuals. But we're also a mosaic of epigenetic alterations. Groups of cells, even if they end up doing different jobs, carry shared methylation marks which tie them back to a common ancestor stem cell. We've been finally able to construct the epigenetic family tree by reading information written directly into the DNA of each cell," says Dr. Alejo Rodriguez-Fraticelli, co-corresponding author of the study and Group Leader at IRB Barcelona.
The researchers developed a new technique called EPI-Clone which reads methylation barcodes from individual cells. It was built 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, and which had dropped out of the race over time.
"DNA methylation works like a kind of binary code. At each position in the genome, a site is either methylated or not, like a 1 or a 0," explains Dr. Michael Scherer, bioinformatician and co-first author of the study who led the work at the CRG and is now group leader at the German Cancer Research Center (DKFZ).
"This simple on-off information can be transformed into a natural barcode, one that each stem cell passes on to its descendants. Five years ago, I wouldn't have thought this possible at single-cell resolution, across tens of thousands of cells. It's been a huge leap forward in technology," he adds.
In young blood, thousands of different stem cells contributed 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 percent of blood stem cells belonged to just a few dozen large clones, compared with around 50 percent in younger mice.
The picture is similar in humans, though the exact percentage varied between the dozen healthy donors between 35 and 70 years old which formed part of the study. The study found that by age 50, many blood stems 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 change from diversity to dominance isn't random but clock-like," says Indranil Singh, co-first author of the study and final year 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 harboured mutations linked to clonal haematopoiesis (CH), a process where 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 leukaemia. 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 ageing blood, not just a sign of cancer risk.
The findings mean clinicians could one day assess clonal behaviour itself for early detection, offering doctors a way to monitor how a person's blood stem cell pool is ageing 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. These are immune cells linked to chronic inflammation. 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 infection-fighting 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. EPI-Clone is suited for clinical research because it works with naturally-occurring barcodes rather than artificial labels which require genetic modification.
"If we want to move beyond generic anti-ageing treatments and into real precision medicine for ageing, this is exactly the kind of tool we need," says Dr. Velten. "We can't fix what we can't see and for the first time, EPI-Clone can facilitate this for humans."
However, these limitations remain easier to overcome than genetic modification. "We have only shown what's possible," concludes Dr. Rodriguez-Fraticelli. "Now the goal is to refine EPI-Clone so it can boost clinical research efforts."
The study was jointly led by a team at the Centre for Genomic Regulation (CRG) and the Institute for Research in Biomedicine (IRB Barcelona). It was funded by the European Haematology Association and the Spanish Association Against Cancer (AECC).
