Epigenetic lineage tracing offers insight into hematopoietic complexity and its gradual decline with age – without genetic engineering.
As interest in the cellular roots of aging intensifies, a new study published in Nature places clonal hematopoiesis – often viewed through the lens of oncogenic risk – into a broader biological narrative. Researchers from the Centre for Genomic Regulation and IRB Barcelona have developed EPI-clone, a transgene-free method for clonal lineage tracing that uses somatic epimutations as natural barcodes. By pairing this with Mission Bio’s Tapestri platform, the team analyzed over 230,000 single cells across murine and human hematopoietic systems, revealing how functional stem cell clones emerge, persist or fade during aging [1]. Crucially, this technique captures both clonal identity and cellular differentiation state from the same single-cell readout – sidestepping the limitations of genetic labeling or reliance on known mutational drivers.
Aging hematopoiesis without transplants
While traditional approaches often involve transplantation or genetically modified models, EPI-clone works directly on unperturbed samples, offering an unusually faithful view of clonal behavior in vivo. In mice, the researchers found that the decline in clonal diversity with age is not simply a matter of attrition; rather, a small number of expanded, often functionally inert stem cell clones become dominant, while many youthful clones quietly persist.
In parallel, human data showed that both known clonal hematopoiesis (CH) mutations and previously invisible clones exhibit similar lineage biases – suggesting that current definitions may be overly narrow. The ability to detect lineage output and epigenetic drift in parallel could have implications beyond hematopoiesis, particularly if similar patterns exist in other somatic stem cell compartments.
Reading the epigenetic tea leaves
For geroscience, this work speaks to one of the field’s central concerns: how functional reserve erodes over time and how early we might be able to detect it. That epigenetic marks can provide both lineage history and cell state without invasive manipulation opens up possibilities for longitudinal tracking of tissue aging, perhaps even identifying preclinical shifts before functional decline becomes apparent. With its compatibility across species and scalability via commercial platforms, EPI-clone may find its way into broader studies of clonal drift, regenerative potential and tissue resilience in later life.
Longevity.Technology: This study elegantly demonstrates that the epigenome – long appreciated for its role in gene regulation – can also serve as a durable, natural barcode of cellular lineage. By enabling high-throughput, transgene-free clonal tracking at single-cell resolution, EPI-clone provides a powerful new lens on how hematopoiesis – and perhaps other stem cell-driven systems – age. The finding that expanded clones can lack known driver mutations, yet still exhibit functionally distinct behaviors, is a timely reminder that age-related clonal dynamics are more complex than the mutational narrative alone suggests. From a translational standpoint, the scalability of this approach on a commercial platform is promising, and its applicability to human samples without genetic manipulation brings it tantalizingly close to clinical research.
Whether this method can one day help stratify aging trajectories or inform early intervention remains to be seen, but the groundwork laid here is robust, compelling and very much aligned with the field’s shift toward proactive, precision approaches to healthy longevity. To find out more, we sat down with Dr Lars Velten, the Nature paper’s lead author.
From barcodes to biomarkers: rethinking blood aging with epigenetic lineage tracing
The authors’ work with EPI-clone reframes how we understand hematopoietic aging – not as a uniform decline, but as a selective, dynamic process shaped by clonal behavior. Using naturally occurring somatic epimutations as stable barcodes, EPI-clone enables high-throughput, transgene-free lineage tracing in vivo [1].
“We found that a small number of hematopoietic stem cell clones expand with age and take over large parts of blood production, whereas the majority of stem cells remain small, but are functionally more similar to young stem cells,” Velten explains. The persistence of these youthful clones, previously obscured in bulk analyses, highlights untapped regenerative potential even in aged marrow.
Removing the old to make space for the young
Velten sees this pattern not only as descriptive, but therapeutically actionable. “Our findings support the idea that by ablating the large, expanded clones, one might create space in the bone marrow microenvironment for the small clones to take over blood production,” he explains.
A recent study in mice using a therapeutic antibody provides early evidence for this strategy; now, with EPI-clone, expanded clones in humans can be identified and profiled at molecular resolution. This opens the door to targeted interventions that could restore a more youthful hematopoietic landscape without the need for transplantation or gene therapy.
Clonal expansion as a driver, not just a marker, of aging
Beyond its diagnostic potential, Velten believes loss of clonal diversity contributes directly to functional aging. “Loss of clonal complexity is a great biomarker of biological age of the blood forming system, but it’s more: clonal expansions functionally contribute to aging,” he says. These dominant clones often produce more myeloid and fewer lymphoid cells, skewing the immune system toward inflammation and reducing adaptive capacity. This imbalance, observed in both mice and humans, suggests that age-related clonal selection may actively shape systemic immune decline.
Beyond mutation: the importance of ‘driverless’ clones
Notably, most expanded clones identified with EPI-clone lack canonical driver mutations. “We discovered that most clonal expansions do not have known driver mutations,” Velten explains. “Clonal expansions rather appear inevitable, probably as a result of decades of competition between blood stem cells during the human lifespan.” This insight shifts the framing of age-related clonal hematopoiesis away from purely oncogenic risk, positioning it instead as an emergent property of long-term stem cell dynamics. EPI-clone captures this evolution at the epigenetic level – before overt genetic change or clinical symptoms emerge.
Toward population screening and broader tissue applications
Velten is optimistic about translating EPI-clone beyond research settings. With per-sample costs already reduced from €100,000 to €5,000, and a projected drop to €50 within three years, he sees real potential for integration into longitudinal health monitoring. “Once we get to €50 per sample, I think this will become one of the tools that allow us to study how lifestyle and environmental factors shape human blood, and to monitor aging in high-risk individuals.”
Although the method was developed for hematopoiesis, the team has successfully applied it to endothelial cells – and Velten anticipates that similar clonal patterns will be found in other somatic tissues maintained by stem cells. That could make EPI-clone not just a window into blood biology, but a general-purpose tool for tracking aging itself.
[1] https://www.nature.com/articles/s41586-025-09041-8
Photographs courtesy of Mission Bio
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