For decades, chronic low-grade inflammation in aging adults was treated as a background condition — an unfortunate byproduct of getting older. Emerging evidence now reframes inflammaging as an active driver of clonal blood cell expansion, creating a feedback loop that accelerates cardiovascular disease, blood cancers, and broader organ dysfunction. Understanding this bidirectional relationship may fundamentally alter how clinicians approach aging-related disease prevention.
Clonal haematopoiesis of indeterminate potential (CHIP) occurs when a single somatically mutated haematopoietic stem cell (HSC) proliferates to dominate a substantial portion of the circulating leukocyte pool. This review in Nature Reviews Molecular Cell Biology synthesizes recent discoveries illuminating how CHIP and inflammaging sustain each other: chronic inflammatory signaling impairs normal HSC self-renewal and function, while CHIP-mutant HSCs — carrying mutations most commonly in genes such as DNMT3A, TET2, and ASXL1 — are paradoxically resistant to these inflammatory insults and gain a selective expansion advantage precisely within inflamed microenvironments. The mutant clones then amplify inflammatory cytokine output, further disadvantaging normal HSCs and compounding cardiovascular and haematological risk.
This review arrives at a moment when CHIP has moved from a curiosity of aging biology to a recognized independent cardiovascular risk factor, with population studies estimating prevalence above 10% in adults over 70. The mechanistic clarity offered here — particularly the resistance of mutant HSCs to inflammaging-driven decline — is potentially paradigm-shifting because it suggests that anti-inflammatory interventions might selectively benefit normal HSC populations without equivalently suppressing their mutant competitors, an important caveat for therapeutic design. Most existing data remain observational or mechanistic rather than derived from interventional trials, meaning causal directionality in humans is not yet fully established. The translational gap between mouse models and human clinical outcomes also warrants careful scrutiny. Nevertheless, CHIP surveillance combined with inflammaging biomarkers could eventually stratify cardiovascular and oncological risk more precisely than conventional approaches alone.
