Published on: May 21, 2025
A new study published in Nature sheds light on how aging transforms the blood system in both humans and mice. Researchers found that with age, a small number of blood stem cells—referred to as “clones”—gradually outcompete others, becoming dominant in blood production. This shift reduces the overall diversity of the blood stem cell pool and favors clones that primarily produce myeloid cells, which are linked to chronic inflammation.
These changes become noticeable around age 50 and are nearly universal by age 60. The loss of stem cell diversity may help explain “inflammaging”—a chronic, low-grade inflammation associated with aging and increased disease risk. The fact that this pattern occurs in both mice and humans suggests it is a fundamental aspect of blood aging across species.
The study could pave the way for early detection of unhealthy aging well before clinical symptoms or blood cancers emerge. It also opens up possibilities for investigating rejuvenation therapies in humans, a field that has traditionally been limited to animal models.
“Our blood stem cells compete for survival. In youth, this results in a diverse and resilient system. But with age, some clones drop out, and a few dominant ones take over, reducing the system’s adaptability,” said Lars Velten of the Centre for Genomic Regulation (CRG), co-author of the study.
One of the major challenges the team overcame was tracking which of the tens of thousands of blood stem cells remained active with age. Humans typically have 50,000 to 200,000 blood stem cells producing hundreds of billions of blood cells daily. To trace this, researchers used a new technique called EPI-Clone, which reads “epigenetic barcodes”—methylation marks on DNA that are passed from parent stem cells to their descendants.
These methylation patterns act like a biological barcode, allowing us to reconstruct a family tree of blood cells, explained Alejo Rodriguez-Fraticelli of IRB Barcelona, co-corresponding author. “It’s like reading a history of stem cell activity written into the DNA.”
Michael Scherer, co-first author and now at the German Cancer Research Center (DKFZ), added, “Five years ago, decoding these barcodes at single-cell resolution across thousands of cells seemed impossible. EPI-Clone represents a major technological breakthrough.”
The researchers found that in young blood, thousands of stem cells contributed to a rich mix of red and white blood cells and platelets. In contrast, older mice showed up to 70% of blood being produced by just a few dozen large clones—compared to about 50% in younger mice. A similar trend was seen in human donors aged 35 to 70, with the shift starting around age 50 and becoming much more apparent by 60.
“The loss of diversity follows a steady, clock-like pattern,” said Indranil Singh, co-first author at IRB Barcelona. “By age 60, dominant clones take over in most individuals.”
Some of these dominant clones carried mutations associated with clonal hematopoiesis (CH), a condition where certain stem cells gain a growth advantage, raising the risk of diseases like heart attack, stroke, and leukemia. Interestingly, many dominant clones showed no known mutations, implying that this dominance is a natural part of aging, not solely a marker of disease risk.
This suggests that monitoring clonal behavior could serve as a powerful early warning system for unhealthy aging. People with rapid clonal expansion or loss of diversity could be identified early and offered preventative care.
The study also confirmed that many dominant clones in older individuals favor producing myeloid cells—key drivers of inflammation. Previous animal research showed that removing these myeloid-biased clones can restore a more youthful blood profile and enhance immune function. Though rejuvenation therapies in humans are still in the early stages, EPI-Clone now makes it possible to identify and track problematic clones, a critical step toward targeted interventions.
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