A groundbreaking study published in Nature has shed new light on how the aging process reshapes the blood system by tracing the dynamics of blood stem cells through innovative epigenetic barcoding techniques. Scientists discovered that as humans and mice age, a shrinking pool of blood-forming stem cells, known as hematopoietic stem cells (HSCs), undergoes clonal expansion, where a few dominant clones outcompete others to monopolize blood production. This phenomenon disrupts the diversity and resilience of the blood system, potentially underpinning age-related chronic inflammation, or “inflammaging,” and opening critical avenues for disease prevention and rejuvenation therapies.
Blood stem cells are crucial for producing the billions of blood cells circulating daily, maintaining a finely balanced ecosystem that ensures the immune system’s vitality and the ability to respond to environmental stressors. However, researchers have long faced a significant obstacle in directly monitoring the behavior of thousands of individual stem cells over a lifespan, as genetic modification techniques suitable for model organisms cannot ethically or practically be applied to humans. The novel approach, detailed in this study, circumvents these challenges by exploiting naturally occurring epigenetic modifications called DNA methylation marks.
DNA methylation involves the addition of chemical tags to DNA at specific genomic sites, regulating gene expression without altering the underlying genetic code. These methylation patterns are faithfully copied during cell division and serve as a natural “barcode” reflecting each cell’s lineage history. By reading these binary on-off methylation states in individual cells, researchers crafted an epigenetic family tree of hematopoietic cells, providing unprecedented insights into clonal dynamics throughout aging.
The researchers developed a pioneering technique termed EPI-Clone, which modifies an existing single-cell sequencing platform to decode these methylation barcodes at remarkable resolution. Using EPI-Clone, they traced the lineage trajectories of tens of thousands of blood stem cells from both mice and human donors aged between 35 and 70 years. Their analyses revealed a striking age-associated shift from a richly diverse stem cell pool in youth to dominance by fewer, larger clones by age 50, a trend that becomes nearly universal after age 60.
This clonal dominance is accompanied by a preference of these prolific clones to produce myeloid cells—immune cells implicated in chronic inflammation—while other stem cells fade from the active compartment. The loss of stem cell diversity destabilizes the blood system’s adaptability, making it more vulnerable to physiological stress and reducing its ability to mount robust immune responses. Such changes provide a plausible biological underpinning for inflammaging, the persistent low-grade inflammation that characterizes aging and predisposes individuals to cancer, cardiovascular diseases, and autoimmunity.
Interestingly, while some of the dominant clones harbored mutations typically linked to clonal hematopoiesis (CH)—a condition associated with increased risks of leukemia and cardiovascular events—a substantial fraction lacked known mutations entirely. This finding challenges the current paradigm that clonal expansion is largely driven by oncogenic mutations, indicating that the aging blood system may naturally favor clonal selection mechanisms independent of mutation status. Thus, clonal expansion appears to be an intrinsic feature of hematopoietic aging rather than solely a herald of malignancy.
By precisely mapping the decline in stem cell diversity and identifying problematic clones before clinical symptoms emerge, this research paves the way for revolutionary diagnostic tools. Clinicians could employ epigenetic barcoding to monitor blood stem cell dynamics as early biomarkers of unhealthy aging and disease risk. Such early warnings would enable timely preventative interventions, revolutionizing precision medicine approaches to age-related blood disorders and immune dysfunction.
Moreover, the study’s detailed insights are crucial for evaluating the potential of rejuvenation therapies, which aim to restore youthful cellular profiles and immune function. While experimental approaches in mice have demonstrated that selectively removing myeloid-biased stem cells can revitalize the blood system, similar strategies in humans have been hindered by the inability to accurately identify and track clonal behaviors. EPI-Clone’s reliance on natural epigenetic barcodes, rather than artificial genetic labels, makes it uniquely suitable for clinical research, bypassing ethical and technical roadblocks.
This innovative technology and the resulting biological insights represent a significant leap forward for the field of hematology and aging research. As Dr. Lars Velten from the Centre for Genomic Regulation (CRG) explains, blood stem cells compete dynamically for survival, producing a rich ecosystem in youth that deteriorates with age as some clones dominate while others are lost. This loss of diversity undermines the hematopoietic system’s robustness, highlighting how stem cell ecology shifts detrimentally over time.
Further development and refinement of EPI-Clone hold immense promise for expanding clinical research capabilities. By enabling longitudinal studies of blood stem cell populations in living humans, it offers a window into the fundamental mechanisms driving blood aging and the potential to develop targeted therapies to combat age-associated diseases. The approach heralds a new era wherein we can “see” and measure healthy versus unhealthy aging at the cellular lineage level, bridging the gap between molecular biology and translational medicine.
In conclusion, this study elegantly demonstrates that the aging of the blood system is marked not simply by random decline but by orderly, clock-like clonal evolution governed by epigenetic changes. The discovery that clonal expansion is a natural aging feature, rather than only a cancer precursor, reframes understanding of hematopoiesis and opens realistic pathways for intervention. With tools like EPI-Clone, the prospect of precision healthcare strategies tailored to an individual’s unique stem cell dynamics is rapidly approaching reality, offering hope for healthier aging and enhanced resilience against disease.
Subject of Research: Animals
Article Title: Clonal tracing with somatic epimutations reveals dynamics of blood ageing
News Publication Date: 21-May-2025
Web References: http://dx.doi.org/10.1038/s41586-025-09041-8
Image Credits: Joe Bowness/Centro de Regulación Genómica
Keywords: Cancer, Blood, Molecular biology
