Figure 2 |. Multi-level drivers of aging-related chronic inflammation (inflammaging) and clonal hematopoiesis.

a | Major aging-related pathophysiological alterations (acting systemically or in the bone marrow or other tissues) that contribute to inflammaging, i.e., low-grade inflammation without evidence of obvious infection. The list focuses on aspects of relevance to this review and is not exhaustive; the reader is referred to specialized reviews on the topic^23,30,31. CHIP, clonal hematopoiesis of indeterminate potential; DAMPs; damage-associated molecular patterns; HSC, hematopoietic stem cell. b | Although aging is a primary driver of CHIP emergence, this condition is additionally promoted by various genetic, biological, and lifestyle risk factors, as indicated^{4,81,88,89,92–95}. Aging in itself is a complex factor that can exert multiple effects on the hematopoietic stem cells (HSCs) and their bone marrow (BM) niche at different levels, that collectively increase the risk of CHIP. c | Although FOXO activity supports adaptive responses to cellular stress and helps preserve viability, its prolonged activation can trigger cell-cycle arrest or apoptosis. TCL1A appears to enhance the activity of all AKT isoforms, which in turn suppress FOXO-mediated transcription. As a result, TCL1A-expressing HSCs exhibit reduced expression of FOXO target genes and increased expression of genes that promote cell division⁹⁰. By maintaining HSCs in a proliferative state while dampening stress-induced responses, TCL1A may play a critical role in clonal hematopoiesis, as illustrated in the next panel. d | Under normal conditions, the TCL1A promoter is inaccessible in HSCs, resulting in transcriptional repression (top). However, in the presence of driver mutations — such as those in TET2, ASXL1, or spliceosome components like SF3B1 and SRSF2— TCL1A becomes aberrantly expressed (potentially due to the CHIP-associated epigenetic remodeling) and promotes clonal expansion of the mutated HSCs (middle). Notably, the alternative (protective) allele of rs2887399 limits chromatin accessibility at the TCL1A promoter, thereby reducing TCL1A expression and neutralizing the clonal advantage conferred by CHIP-associated mutations (bottom).