bims-minfam 2025-08-10 papers

Issue of 2025–08–10
five papers selected by
Ayesh Seneviratne, McMaster University

Int J Hematol. 2025 Aug 07.

ASXL1 mutation-related clonal hematopoiesis and age-related diseases: clinical evidence and molecular insights.

Naru Sato, Susumu Goyama, Toshio Kitamura.

Clonal hematopoiesis (CH) is defined as the age-associated expansion of hematopoietic stem and progenitor cells harboring somatic mutations, most frequently in epigenetic regulators such as DNMT3A, TET2, and ASXL1. Although CH was initially recognized as a precursor to hematological malignancies, accumulating evidence has led to its broad recognition as a relevant factor in various age-related nonmalignant diseases, particularly those with inflammatory components, such as cardiovascular disease, autoimmune disorders, and solid tumors. Notably, the increased overall mortality associated with CH is primarily driven by cardiovascular complications rather than hematological malignancies. Among CH-associated genes, ASXL1 mutations are distinguished by their strong associations with adverse clinical outcomes and pro-inflammatory signatures. However, compared to TET2 and DNMT3A, the molecular and pathological implications of ASXL1-mutated CH remain underexplored. Recent studies have expanded the disease spectrum of ASXL1 mutations beyond hematological malignancies, implicating them in clonal expansion and systemic inflammation. This review aims to summarize the current epidemiological and experimental insights into ASXL1-mutated CH, focusing on its potential contributions to inflammation-associated diseases. By integrating clinical observations and emerging mechanistic data, we highlight the urgent need for deeper investigation into ASXL1-driven CH and its systemic consequences beyond hematological transformation.

Keywords: ASXL1; autoimmune disease; chronic inflammation,; clonal hematopoiesis

DOI: https://doi.org/10.1007/s12185-025-04038-5

bioRxiv. 2025 Jul 30. pii: 2025.07.23.666334. [Epub ahead of print]

Aggressive Cholesterol Lowering Normalizes Atherosclerosis Regression in Jak2 V617F Clonal Hematopoiesis.

Brian D Hardaway, Trevor P Fidler, Mojdeh Tavallaie, Kleopatra Avrampou, Cheng-Chieh Hsu, Sandra Schiavone, Tong Xiao, Nan Wang, Alan R Tall.

Background: Clonal hematopoiesis (CH) has emerged as an important risk factor for atherosclerotic cardiovascular disease (ACVD). Mouse studies have established a causal role of CH in atherosclerosis progression and have defined macrophage inflammatory responses as a key underlying mechanism. We undertook the present study to assess the hypothesis that ongoing inflammation would impede atherosclerosis regression in Jak2 V617F ( Jak2 VF ) CH mice.
Methods and Results: Chimeric Jak2 VF/WT or control WT/WT bone marrow was transplanted into Ldlr -/- mice and, following 13-16 weeks of Western diet-induced atherosclerosis progression, cholesterol was lowered either moderately (to 200-300 mg/dl) or markedly (to 100 mg/dl). With moderate cholesterol lowering there was impaired regression in Jak2 VF CH mice compared to controls. However, with marked cholesterol lowering, regression was similar in Jak2 VF CH and control mice. Two mechanisms of low-density lipoprotein (LDL) lowering-induced suppression of inflammation in plaques were implicated: 1) reversal of increased proliferation, DNA damage and Absent in Melanoma 2 (AIM2) inflammasome activation specifically in Jak2 VF macrophages and 2) markedly increased macrophage triggering receptor expressed on myeloid cells 2 (TREM2), c-myc expressing macrophages in both Jak2 VF and control mice.
Conclusions: Aggressive LDL lowering reverses inflammasome activation and induces pro-resolving changes in macrophages in Jak2 VF CH, halting atherosclerosis progression and promoting features of plaque stabilization. These findings suggest that aggressive LDL cholesterol lowering could effectively reverse ACVD risk in individuals with JAK2 VF clonal hematopoiesis.
Translational Perspective: Clonal hematopoiesis increases the risk of atherosclerotic cardiovascular disease. Amongst mutations associated with clonal hematopoiesis, Jak2 V617F confers the greatest increased risk of atherosclerotic cardiovascular disease. Our findings demonstrate that aggressive LDL lowering normalizes atherosclerosis regression in Jak2 V617F clonal hematopoiesis by reversing inflammasome activation and inducing pro-resolving changes in macrophages. These changes lead to increased features of plaque stability, including decreased macrophage burden, increased collagen, and improved efferocytosis. These results suggest that aggressive LDL-C lowering in Jak2 V617F clonal hematopoiesis patients would mitigate the increased atherosclerotic cardiovascular disease risk.

DOI: https://doi.org/10.1101/2025.07.23.666334

Ageing Res Rev. 2025 Aug 05. pii: S1568-1637(25)00203-X. [Epub ahead of print]112 102857

Beyond the 900-day rule: Reclaiming healthspan as geroscience's primary goal.

Stef F Verlinden.

The recently proposed "900-day rule" in mouse aging studies-requiring lifespan extension over ultra-long-lived controls-aims to identify interventions that modulate intrinsic aging. While this standard raises scientific rigor, it may reduce relevance to how most organisms, including humans, actually age. In reality, aging unfolds under metabolically and immunologically stressful conditions-not in sterile, genetically uniform environments. Most people experience chronic inflammation, metabolic drift, and functional decline long before death. Prioritizing only pristine models risks overlooking the hallmarks of manifest aging: frailty, cognitive loss, immune erosion. This Viewpoint argues for a dual-track strategy: rigorous lifespan testing in ideal models should be complemented by phenotype-driven studies in real-world aging models-such as conventionally housed mice in academic settings-that reflect typical aging trajectories. Interventions like GlyNAC, NLRP3 inhibition, and CaAKG demonstrate broad functional benefits in real-world aging models-effects that may be dismissed as "noise" but are likely the most translationally meaningful. In the case of CaAKG, substantial reductions in frailty occurred even when lifespan gains were modest-highlighting the decoupling of healthspan from longevity. By embracing both intrinsic and manifest aging, geroscience can better target what matters most: improving healthspan for the many-not just lifespan for the few.

Keywords: 900-day rule; Geroscience; Healthspan; Intrinsic aging; Manifest aging; Real-world aging models

DOI: https://doi.org/10.1016/j.arr.2025.102857