Chronic alcohol consumption drives inflammaging and transposon derepression in hematopoietic stem and progenitor cells

Keywords

●  Alcohol consumption

●  Aging

●  Transposable elements

Main Findings

Chronic alcohol consumption synergizes with aging to accelerate the decline of the hematopoietic system through a process of inflammaging and epigenetic dysregulation. Yuda et al. showed that alcohol drives a significant myeloid bias in both human and murine models, shifting hematopoietic stem cell (HSC) differentiation toward inflammatory monocytes and neutrophils at the expense of B-lymphocytes. This skewing is particularly pronounced in aged long-term HSCs (LT-HSCs), which exhibit elevated DNA damage (measured by γH2AX), increased cell cycling, and heightened replicative stress.

Single cell RNA-Seq captured from HSCs demonstrated that alcohol exposure in the aged bone marrow niche leads to the loss of epigenetic silencers, resulting in the derepression of transposable elements (TEs) such as LINE, SINE, and LTR retrotransposons. Furthermore, the reactivation of TEs leads to an accumulation of double-stranded RNA (dsRNA), triggering a "viral mimicry" response and chronic type I interferon signaling that perpetuates HSC inflammation.

Single-cell ATAC-seq identified a specific "inflammatory memory" HSC subset, termed LT-HSC2, which expands significantly under alcohol stress and is characterized by reshaped 3D chromatin architecture and enriched CTCF motifs. TEs also act as de novo enhancers, activating pro-myeloid gene programs like Cebpa in LT-HSCs. Notably, while alcohol alters the differentiation trajectory and induces genomic instability, serial transplantation experiments demonstrate that HSCs retain their long-term self-renewal capacity after alcohol cessation, suggesting that the functional core of the hematopoietic system may recover if the toxic stimulus is removed.

Limitations & Suggestions

Limitations of the following study include the following:

• Lack of studies in the paper which might address the mechanistical insights of findings observed

• It remains unclear whether the inflammatory response is driven primarily by the physical movement of transposable elements (transposition) or by the cellular sensing of TE-derived RNA transcripts

• Lack of human and clinical data

Suggestions on how these limitations can be addressed:

• Analyze bone marrow aspirates or peripheral blood from patients with documented Alcohol Use Disorder (AUD), specifically comparing young vs. elderly patients to validate the "age-dependent" synergy observed in mice

• Perform loss-of-function studies on key identified regulators (e.g. Cebpa) to confirm if their absence prevents alcohol-induced myeloid bias.

• Conduct longitudinal studies on humans after they stop drinking to see if the "inflammatory memory" (the LT-HSC2 subset) truly resets or if it leads to permanent clonal hematopoiesis in older adults.

The manuscript currently tells a compelling descriptive story: alcohol + aging = chromatin changes and inflammation. However, to move from a "correlation" story to a "causation" story, mechanistic validation is highly recommended to strengthen the authors claims.

Significance/Novelty

Discovery of Transposon-Driven Myeloid Bias: While it was known that aging causes a shift toward myeloid cells, the study demonstrates that alcohol accelerates this by "unlocking" transposable elements (TEs). These TEs act as de novo enhancers that directly activate the Cebpa gene, a master regulator of myeloid differentiation, providing a specific epigenetic mechanism for alcohol-induced blood disorders. For immunologists, the study provides a concrete model of how environmental toxins like alcohol contribute to "inflammaging" (age-related chronic inflammation). The persistence of myeloid bias in primary transplant recipients, even without further alcohol exposure, suggests that alcohol induces a form of "trained immunity" or epigenetic memory in stem cells.

Credit

Reviewed by Mariia Saliutina as part of a cross-institutional journal club between the Max-Delbrück Center Berlin, the Ragon Institute Boston (Mass General, MIT, Harvard), the University of Virginia, the Medical University of Vienna and other life science institutes in Vienna.

The author declares no conflict of interests in relation to their involvement in the review.