Clonal hematopoiesis of undetermined potential as an emerging determinant of inflammageing, and age-related diseases: Potential role as biomarker and target

Clonal hematopoiesis of undetermined potential (CHIP), initially discovered as a mere hematological curiosity, now represents a clinically significant factor that is changing our view of ageing, inflammaging and the risk of age-related diseases (ARDs). In line with this, new meta-analyses link the presence of CHIP to higher all-cause mortality from ARDs and to an increase in adverse events in the presence of larger clones. Mechanistically, CHIP induces inflammaging, but a bidirectional relationship has also been highlighted. In both cases, the pro-inflammatory pathways primarily involved are IL-1β/IL-6 signaling, activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, and Toll-Like Receptors (TLRs). However, these pathways only partially explain the role of CHIP in the complex pathophysiology of ARDs. Despite this, it is proposing it as an ARDs biomarker and pharmacological target for their prevention. However, the clinical risk of CHIP triggering the onset and severe progression of ARDs depends on the mutation type, clone size, co-mutations, and host and environmental factors, and current high-risk models require adjustments to overcome some limitations. Omics technique can likely be integrated into CHIP mutation sequencing to predict and monitor ARDs risk. Consequently, pragmatic screening strategies currently remain limited. Furthermore, although potential therapeutic targets exist, translating the findings into effective interventions is currently challenging. Ethical, patient-centered clinical trial designs with validated endpoints are essential to avoid over medicalization and ensure safety, feasibility, and generalizability, as is the use of artificial intelligence. An overview of these aspects is reported in such review.