bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2025–09–21
eleven papers selected by
Ayesh Seneviratne, McMaster University
  1. A blood DNA methylation test reveals how quickly each organ system is aging.
  2. Optimized Synthetic Flavonols Support Senescence Clearance and Lung Fibrosis Resolution.
  3. Aging by the clock and yet without a program.
  4. An Inflammatory and Quiescent HSC Subpopulation Expands with Age in Humans.
  5. Advancing biological understanding of cellular senescence with computational multiomics.
  6. DP1 Receptor Blockade Attenuates Microglial Senescence and Cognitive Decline Caused by PTGDS in Exosomes From Aged Brains.
  7. A phase-of-care approach to improve geriatric fracture care.
  8. Appetite loss as a clinical marker of loss of function during aging.
  9. Systems Age: a single blood methylation test to quantify aging heterogeneity across 11 physiological systems.
  10. Mesenchymal Stem Cell Senescence and Biomaterial-Based Next-Generation Rejuvenation Strategy.
  11. Subtle changes in clonal dynamics: Challenges in quantifying the slow expansion of small hematopoietic stem cell clones.
  1. Nat Aging. 2025 Sep;5(9): 1665-1666
    A blood DNA methylation test reveals how quickly each organ system is aging.
      
    DOI:  https://doi.org/10.1038/s43587-025-00959-2
  2. ACS Pharmacol Transl Sci. 2025 Sep 12. 8(9): 3033-3046
    Optimized Synthetic Flavonols Support Senescence Clearance and Lung Fibrosis Resolution.
    Jeffrey A Meridew, John A Vu, Daniela Chow, Ana Maria Diaz Espinosa, Namita Saraf, Ashley Y Gao, Jair Machado Espindola-Netto, Sara Dresler, Madison G Whaley, Kyoung M Choi, Yong Li, Helene Martini, Eva Carmona Porquera, Patrick A Link, Thomas M Kollmeyer, Joao F Passos, Marissa J Schafer, Nathan K LeBrasseur, Daniel J Tschumperlin, Andrew J Haak.
      Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with undefined etiology and minimally effective therapies. The greatest risk factor for developing IPF is aging. The central paradigm to developing antifibrotic drugs for the last half century has focused on directly targeting proliferative lung fibroblasts. However, recent high-resolution analyses of IPF patient lungs suggests disease unique populations of resident lung cells are enriched for markers of senescence. Published work by our group and others further supports that senescent cells are key drivers of fibrosis and may provide an opportunity to develop an effective antifibrotic drug. Multiple naturally derived flavonoids can selectively induce apoptosis in senescent cells (senolytic) and improve end points in models of lung fibrosis; however, these natural phytochemicals are not structurally optimized to maximize their translational potential. Inspired by this opportunity we have performed hit-to-lead studies and medicinal chemistry optimization to generate a novel synthetic flavanoid (F-4N) with ∼ 50× greater senolytic potency in vitro- compared to fisetin or quercetin, two naturally derived senolytic flavonols. Furthermore, in bleomycin injury models of lung fibrosis we have shown treatment with F-4N (10 mg/kg-30 mg/kg, daily) promotes reduced senescence burden, resolution of chronic lung fibrosis, and markers of enhanced alveolar epithelial repair.
    Keywords:  Aging; Fibrosis; Flavonol; Lung; Senescence; Senolytics
    DOI:  https://doi.org/10.1021/acsptsci.5c00231
  3. Nat Aging. 2025 Sep 18.
    Aging by the clock and yet without a program.
    David H Meyer, Alexei A Maklakov, Björn Schumacher.
      The mechanisms of aging are becoming increasingly well mapped; however, there remains ongoing debate about the ultimate and proximate causes of aging. The recent development of highly precise aging clocks led to a resurgence of arguments in support of a biological program of aging. However, the declining force of natural selection after the onset of reproduction means that cellular function could deteriorate without requiring a specific program. Here, we argue that aging clocks do not imply an intrinsic program but rather reflect the stochastic accumulation of molecular errors and damage. Damage accumulates due to insufficient maintenance and repair and contributes to system-wide entropy. In support of this, cross-species comparisons indicate that enhanced DNA repair capacity is a key determinant of exceptional longevity in mammals. By better understanding the nature of the stochasticity that governs the aging process, we will have a stronger mechanistic basis for developing geroprotective interventions to promote healthy aging in humans.
    DOI:  https://doi.org/10.1038/s43587-025-00975-2
  4. bioRxiv. 2025 Sep 04. pii: 2025.09.01.673389. [Epub ahead of print]
    An Inflammatory and Quiescent HSC Subpopulation Expands with Age in Humans.
    Ksenia R Safina, Dylan A Kotliar, Michelle Curtis, Jonathan D Good, Chen Weng, Shawn David, Soumya Raychaudhuri, Antonia Kreso, Jennifer Trowbridge, Vijay G Sankaran, Peter van Galen.
      Aging of the blood system impacts systemic health and can be traced to hematopoietic stem cells (HSCs). Despite multiple reports on human HSC aging, a unified map detailing their molecular age-related changes is lacking. We developed a consensus map of gene expression in HSCs by integrating seven single-cell datasets. This map revealed previously unappreciated heterogeneity within the HSC population. It also links inflammatory pathway activation (TNF/NFκB, AP-1) and quiescence within a single gene expression program. This program dominates an inflammatory HSC subpopulation that increases with age, highlighting a potential target for further experimental studies and anti-aging interventions.
    DOI:  https://doi.org/10.1101/2025.09.01.673389
  5. Nat Genet. 2025 Sep 15.
    Advancing biological understanding of cellular senescence with computational multiomics.
    SenNet Consortium
      Cellular senescence is a complex biological process that plays a pathophysiological role in aging and age-related diseases. The biological understanding of senescence at the cellular and tissue levels remains incomplete due to the lack of specific biomarkers as well as the relative rarity of senescent cells, their phenotypic heterogeneity and dynamic features. This Review provides a comprehensive overview of multiomic approaches for the characterization and biological understanding of cellular senescence. The technical capability and challenges of each approach are discussed, and practical guidelines are provided for selecting tools for identifying, characterizing and spatially mapping senescent cells. The importance of computational analyses in multiomics research, including senescent cell identification, signature detection and interactions of senescent cells with microenvironments, is highlighted. Moreover, tissue-specific case studies and experimental design considerations for individual organs are presented. Finally, future directions and the potential impact of multiomic approaches on the biological understanding of cellular senescence are discussed.
    DOI:  https://doi.org/10.1038/s41588-025-02314-y
  6. Aging Cell. 2025 Sep 19. e70228
    DP1 Receptor Blockade Attenuates Microglial Senescence and Cognitive Decline Caused by PTGDS in Exosomes From Aged Brains.
    Yaru Liu, Pan Liao, Bo Yan, Dai Li, Shishuang Zhang, Wei Zhang, Zexi Jia, Zihan Zhang, Han Gao, Qiang Liu, Fanglian Chen, Ping Lei, Zhenyu Yin.
      Aging leads to neurodegenerative diseases, such as cognitive decline, which are induced by persistent chronic low-grade inflammation in the brain driven by microglial activation. However, whether and how brain-derived exosomes from aged mice (A-exo) induce a pro-inflammatory state and cellular senescence in microglia within the aging brain is poorly understood. Here, we report that brain-derived exosomes from aged mice (A-exo) cause cognitive decline in normal young mice, inducing microglial overactivation, lipid droplet accumulation, and senescence-associated secretory phenotype (SASP) secretion. This abnormal microglial activity arises from the elevated expression of PTGDS in A-exo due to mouse aging, resulting in increased central and peripheral D-prostanoid receptor 1 (DP1) ligand PGD2 levels, which subsequently leads to sustained DP1 signaling activation. Consequently, this process promotes myeloid cell infiltration, cellular senescence, and cognitive decline by generating a senescent, pro-inflammatory microglial phenotype. Blocking the DP1 receptor ameliorates A-exo-mediated microglial overactivation, myeloid cell infiltration, and cellular senescence. Strikingly, DP1 receptor blockade improves cellular senescence, neuroinflammation, and cognitive decline in aged mice. Our findings reveal a systemic mechanism underlying the sustained activation of microglia following brain aging, paving the way for improving chronic neuroinflammation, cellular senescence, and cognitive decline associated with aging.
    Keywords:  DP1 receptors; aging; exosomes; microglia; neuroinflammation
    DOI:  https://doi.org/10.1111/acel.70228
  7. Nat Aging. 2025 Sep 17.
    A phase-of-care approach to improve geriatric fracture care.
    Andrew Nguyen, Philip M Lee, Edward K Rodriguez, Lewis Lipsitz, Karen Chahal, Ara Nazarian.
      
    DOI:  https://doi.org/10.1038/s43587-025-00974-3
  8. Proc Nutr Soc. 2025 Sep 15. 1-30
    Appetite loss as a clinical marker of loss of function during aging.
    Wan-Hsuan Lu, Juan Luis Sánchez-Sánchez, Philipe de Souto Barreto.
      Recent literature has shown that appetite loss during aging can lead to negative health outcomes in older adults, particularly malnutrition and mortality. However, its association with functional decline and the mechanisms driving this relationship are not well explored. This review summarizes the current evidence regarding the potential effects of appetite loss on frailty and functional outcomes. Despite the limitations due to heterogeneous methodologies, including study designs, population characteristics, and appetite assessments, most studies indicate that older adults with poor appetite tended to exhibit poor physical performance and increased functional limitations. Furthermore, the simultaneous weight loss in individuals experiencing appetite loss was associated with a higher risk of functional impairments. Finally, emerging evidence connects reduced appetite to biomarkers of aging, including epigenetic alterations, chronic inflammation, and the upregulation of GDF-15. Therefore, loss of appetite is a potential earlier marker of loss of function that deserves further investigation. Adopting a geroscience perspective may enhance our understanding of appetite loss during aging and foster the development of effective interventions.
    Keywords:  Appetite loss; ICOPE; geroscience; intrinsic capacity; older adults
    DOI:  https://doi.org/10.1017/S0029665125101778
  9. Nat Aging. 2025 Sep;5(9): 1880-1896
    Systems Age: a single blood methylation test to quantify aging heterogeneity across 11 physiological systems.
    Raghav Sehgal, Yaroslav Markov, Chenxi Qin, Margarita Meer, Courtney Hadley, Aladdin H Shadyab, Ramon Casanova, JoAnn E Manson, Parveen Bhatti, Ann Z Moore, Eileen M Crimmins, Sara Hagg, Themistocles L Assimes, Eric A Whitsel, Albert T Higgins-Chen, Morgan Levine.
      Aging occurs at different rates across individuals and physiological systems, but most epigenetic clocks provide a single age estimate, overlooking within-person variation. Here we developed systems-based DNA methylation clocks that measure aging in 11 distinct physiological systems-Heart, Lung, Kidney, Liver, Brain, Immune, Inflammatory, Blood, Musculoskeletal, Hormone and Metabolic-using data from a single blood draw. By integrating supervised and unsupervised machine learning with clinical biomarkers, functional assessments and mortality risk, we derived system-specific scores that outperformed existing global clocks in predicting relevant diseases and aging phenotypes. We also created a composite Systems Age score to capture overall multisystem aging. Clustering individuals based on these scores revealed distinct biological aging subtypes, each associated with unique patterns of health decline and disease risk. This framework enables a more granular and clinically relevant assessment of biological aging and may support personalized approaches to monitor and target system-specific aging processes.
    DOI:  https://doi.org/10.1038/s43587-025-00958-3
  10. Tissue Eng Part B Rev. 2025 Sep 15.
    Mesenchymal Stem Cell Senescence and Biomaterial-Based Next-Generation Rejuvenation Strategy.
    Yiran Zhang, Rana Judeh, Sidharth Aravind, Hala Zreiqat, Zufu Lu.
      The capacity for tissue regeneration declines with age, and cellular senescence is recognized as a critical driver of aging and impaired tissue regeneration potential. Advances in stem cell research have provided new insights into tissue regeneration and stem cell therapy in aging-related diseases. However, stem cell senescence significantly limits their therapeutic efficacy, highlighting the need for effective rejuvenation strategies. Current antisenescence approaches have shown promise, but they still face limitations. This review summarizes and discusses the characteristics and consequences of mesenchymal stem cells (MSCs) senescence and evaluates existing antisenescence strategies. Additionally, recent advancements in biomaterials have demonstrated considerable potential in modulating stem cell fate and enhancing tissue regeneration outcomes. In this context, we explore biomaterial-based approaches for rejuvenating senescent MSCs, offering novel perspectives for advancing tissue regeneration therapies targeting aging-related diseases.
    Keywords:  aging; biomaterials; senescence; stem cells; tissue regeneration
    DOI:  https://doi.org/10.1177/19373341251372962
  11. Comput Biol Med. 2025 Sep 16. pii: S0010-4825(25)01431-3. [Epub ahead of print]197(Pt B): 111079
    Subtle changes in clonal dynamics: Challenges in quantifying the slow expansion of small hematopoietic stem cell clones.
    Sebastian Wagner, Lars Thielecke, Ingmar Glauche.
      Clonal dynamics within hematopoietic stem cells (HSCs) provide critical insights into both hematopoietic regeneration and the development of hematological diseases. Advances in sequencing technologies and temporal clonal analysis have revealed that mutations driving clonal dominance often emerge early in life and gradually expand over decades. This slow progression, often coupled with sub-percentage clonal abundances, presents significant challenges in detecting and monitoring clones that may contribute to disease development. Using a stochastic mathematical model of clonal competition at HSC level, we take a novel approach to investigate the limitations of accurately quantifying the dynamics of small but slowly expanding clones over short observation periods. Our results provide new insights showing that intrinsic stochastic fluctuations dominate early-stage clonal competition, particularly for low-abundance clones (around 1% clonal contribution), leading to an overrepresentation of apparently stable or shrinking clones in short-term analyses. Measurement uncertainty and limited sampling intervals further complicate accurate inference of clonal growth. Furthermore, we investigate the impact of increased proliferative activity, potentially driven by chronic inflammation, on clonal progression. Our model shows that higher proliferation rates act as a time-lapse mechanism accelerating the expansion of pre-malignant clones. Our findings underscore the challenges of short-term monitoring in identifying and tracking slowly expanding clones. They also highlight the need for extended follow-up periods and improved measurement precision to accurately assess clonal dynamics in clinical and therapeutic contexts. While simplified, our approach offers valuable insights into clonal competition and serves as a cautionary reminder about the limitations of inferring clonal behavior from short-term data.
    Keywords:  Clonal expansion; Clonal hematopoiesis; Quantification; Stochastic modeling
    DOI:  https://doi.org/10.1016/j.compbiomed.2025.111079
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