bims-minfam 2025-08-03 papers

Issue of 2025–08–03
seven papers selected by
Ayesh Seneviratne, McMaster University

Int J Hematol. 2025 Jul 31.

Recent progress in clonal hematopoiesis: expanding the concept.

Clonal hematopoiesis (CH) has emerged as a common age-related phenomenon and a central concept linking somatic mutations in hematopoietic stem cells to both malignant and non-malignant diseases. While initially recognized in the context of hematologic neoplasms, CH is now known to contribute to increased all-cause mortality, particularly through heightened risk of cardiovascular and inflammatory diseases. Frequent mutations in genes such as DNMT3A, TET2, and ASXL1 alter epigenetic regulation and immune signaling, thereby promoting clonal expansion and systemic consequences. Longitudinal studies have illuminated the dynamics of clonal growth and revealed how germline variants influence somatic selection. VEXAS syndrome, driven by UBA1-mutated CH, exemplifies the broader clinical reach of clonal expansion beyond malignancy. CH occupies an intermediate biological state with far-reaching implications. In this Progress in Hematology series, contributors explore the natural history, genetic underpinnings, and inflammatory manifestations of CH, offering insights into its role as both a biomarker and a potential therapeutic target in aging populations.

Keywords: Clonal hematopoiesis; Hematopoietic stem cell; Mutation

DOI: https://doi.org/10.1007/s12185-025-04034-9

Aging (Albany NY). 2025 Jul 30. 17

Exosomes released from senescent cells and circulatory exosomes isolated from human plasma reveal aging-associated proteomic and lipid signatures.

Sandip Kumar Patel, Joanna Bons, Jacob P Rose, Jessie R Chappel, Rebecca L Beres, Mark A Watson, Corey Webster, Jordan B Burton, Roland Bruderer, Pierre-Yves Desprez, Lukas Reiter, Judith Campisi, Erin S Baker, Birgit Schilling.

Senescence emerged as significant mechanism of aging and age-related diseases, offering an attractive target for clinical interventions. Senescent cells release a senescence-associated secretory phenotype (SASP), including exosomes that may act as signal transducers between distal tissues, and propagate secondary senescence. However, the composition of exosomal SASP components remains underexplored. We identified ~1,300 exosome proteins released by senescent primary human lung fibroblasts induced by three different senescence inducers. In parallel, a small human plasma cohort from young (20-26 years) and old (65-74 years) individuals revealed 1,350 exosome proteins and 171 plasma exosome proteins were altered in old individuals. Of the age-regulated plasma exosome proteins, we observed 52 exosomal SASP factors that were also regulated in exosomes from the senescent fibroblasts, SERPINs, Prothrombin, Coagulation factor V, Plasminogen, and Reelin. We identified 247 exosome lipids. Following senescence induction phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins increased significantly indicating cellular membrane changes. Significantly changed proteins were related to extracellular matrix remodeling and inflammation, both potentially detrimental pathways that can damage surrounding tissues and even induce secondary senescence. Our proof-of-principle study - even though initially from a rather small human cohort - suggested potential senescence biomarker candidates, enabling future surveillance of senescence burden in the aging population.

Keywords: aging; data-independent acquisitions; exosomes; proteomics; senescence

DOI: https://doi.org/10.18632/aging.206292

Blood Rev. 2025 Jul 25. pii: S0268-960X(25)00068-2. [Epub ahead of print] 101323

Target practice: Opportunities for therapeutic intervention in CHIP and CCUS.

Ayman Mohammad, John Mascarenhas, Bridget K Marcellino, Daniel I Nathan.

Clonal hematopoiesis (CH) is defined by the expansion of hematopoietic stem and progenitor cells (HSPCs) harboring somatic mutations that confer a competitive advantage. Clonal cytopenia of undetermined significance (CCUS), a subtype of CH characterized by cytopenias, represents a high-risk precursor to myeloid malignancies and is increasingly associated with cardiovascular disease, thrombosis, and chronic inflammatory conditions. Despite its clinical significance, therapeutic strategies for CCUS remain limited, and prospective trial frameworks are still evolving. In this review, we outline emerging therapeutic opportunities in CCUS, including inflammatory targets (e.g., NLRP3, IL-1β, IL-6), epigenetic modulators (e.g., hypomethylating agents, Vitamin C), mutation-specific inhibitors (e.g., JAK2, IDH1/2), and repurposed agents (e.g., statins, metformin, colchicine). We also discuss key elements of early-phase clinical trial design, such as risk stratification, endpoint selection, and ethical enrollment of at-risk individuals. CCUS offers a unique window for preventive intervention before the onset of overt malignancy or irreversible end-organ damage. Realizing this potential will require translating biologic insights into well-designed randomized clinical trials that incorporate careful patient selection, ethical enrollment practices, and clinically relevant endpoints. Establishing such frameworks will be essential to developing effective, targeted strategies in this high-risk population.

Keywords: Clinical trials; Clonal cytopenia of undetermined significance; Clonal hematopoiesis; Inflammation

DOI: https://doi.org/10.1016/j.blre.2025.101323

Nature. 2025 Jul 25.

Ageing accelerates at around age 50 - some organs faster than others.

Heidi Ledford.

Keywords: Ageing; Medical research; Proteomics

DOI: https://doi.org/10.1038/d41586-025-02333-z

Adv Pharmacol. 2025 ;pii: S1054-3589(25)00048-1. [Epub ahead of print]104 37-85

Game changer: Navigating between challenges and hopes in geropharmacology.

Qian Chen, Reid Hartman, Lidia Dankiv, Emily Yan, Lindon Young, Robert Barsotti.

The aging population is expanding rapidly to reshape the social and economic structures. Aging signifies the close to the end of life and threatens health because it features unavoidable compression of body reserve and gradual suppression of organ function. Tremendous research has established twelve essential aging hallmarks that shed light on mitigation frameworks. Interestingly, aging harbors inherent heterogeneity and plasticity, reflecting its multifaceted nature. Additionally, age-related diseases, such as cardiovascular and neurodegenerative diseases, often undergo the exact mechanisms with more devastating damage and speed. Therefore, interventions to promote healthy aging improve life quality and delay the disease's prevalence to later age. Clinical studies in humans have demonstrated the potential of several interventions, including lifestyle modifications, NAD+ supplementation, gut microbiota modulation, antidiabetic drugs (e.g., metformin), rapamycin, and senolytics, to mitigate the aging process and delay the onset of age-related diseases. Remarkably, clinical trials exhibit heterogeneity by showing substantial inter-individual differences in response to the interventions. It is often attributed to basal health status, tissue senescent burden, and immunity level. Continuous research would validate these correlations and solidify the personalized approaches. Lastly, generative artificial intelligence can pave a promising avenue to revolutionize anti-aging research and tailor aging management to promote healthy aging and extend health span.

Keywords: Aging; Aging-associated diseases; Artificial intelligence; Cell senescence; Geropharmacology; Heterogeneity; Incretin mimetics; Inflammation; Metformin; Mitochondrial dysfunction; Nicotinamide adenine dinucleotide; Plasticity; Rapamycin; Senolytics; Stem cell

DOI: https://doi.org/10.1016/bs.apha.2025.02.007