bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–09–06
twenty-two papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Daily briefing: GLP-1 obesity drugs slow signs of ageing in mice.
  2. Somatic mutations reveal the ontogeny of microglia in human ageing.
  3. Unbiased screen of human transcriptome reveals an unexpected role of 3'UTRs in translation initiation.
  4. GLP-1 receptor agonism extends median lifespan in mice.
  5. Single-nucleus analysis of human white adipose tissue reveals adipocyte subsets with distinct metabolic profiles.
  6. Blood cells replace the immune cells of the ageing human brain.
  7. India has an ambitious plan to lure scientists back - will it work?
  8. The regulatory logic linking inflammation and fibrosis.
  9. RAS P21 Protein Activator 3 finetunes Type I immunity by limiting HCK-mediated STAT4 phosphorylation.
  10. Premature Menopause Linked to Increased Hypertension Risk.
  11. Tissue mitochondrial activity dictates the macrophage pool size.
  12. Beyond the Randle cycle: A four-nutrient model of competitive catabolism.
  13. OmicsPred as a centralized resource for genetic prediction of multi-omic traits.
  14. Altered oligodendrocyte function promotes cognitive decline in aging.
  15. Gene alteration in human brain suggests genetic and epigenetic roots of major depression.
  16. Mapping structural aging across human tissues reveals tissue-specific trajectories and coordinated deterioration.
  17. Functional annotation of insulin-responsive genes in human adipocytes reveals PLCXD1 as a lipid storage regulator.
  18. Associations between diet quality, epigenetic aging and epigenome in two population-based cohorts.
  19. Integrating transposable elements into blood gene regulatory networks reveals connectivity loss for schizophrenia genes.
  20. Weight-loss drug slows ageing in female mice.
  21. Adaptive motility enables neutrophils to rapidly navigate confined capillaries.
  22. Genetic evidence supports the combined targeting of lipoprotein(a) and LDL cholesterol to reduce coronary artery disease risk.
  1. Nature. 2026 Sep 03.
    Daily briefing: GLP-1 obesity drugs slow signs of ageing in mice.
    Jacob Smith.
      
    DOI:  https://doi.org/10.1038/d41586-026-02781-1
  2. Nature. 2026 Jul 30.
    Somatic mutations reveal the ontogeny of microglia in human ageing.
    Julia A Belk, Yaowen Zhang, Emily E Reilly, Quanming Shi, Daniel Dan Liu, Nicole Womack-Gambrel, Maarten van der Linde, Lisa Ma, Debasmita Paul, Alejandro Medina Enciso, Raja Kalluru, Jacob Weiss, Rui Li, Anna E Eastman, Chunfang Zhu, Arnav Chakravarthy, Syed Bukhari, Dipabarna Bhattacharya, Suyash Raj, Daniel Richard, Simone Brioschi, Matthew R Chrostek, Daniel C Nachun, Christopher M Arends, Jayakrishnan Gopakumar, Isak W Tengesdal, Ademar Bynum, Shaneice Mitchell, Katalin Sandor, Wenxi Zhang, Badri N Vardarajan, Inma Cobos, Donald E Born, Robert B West, Anne Brunet, Marco Colonna, Krishna L Bharani, Hannes Vogel, Thomas J Montine, Caitlin S Latimer, Irving L Weissman, Magdalena Matusiak, Jody E Hooper, C Dirk Keene, Howard Y Chang, Siddhartha Jaiswal.
      Microglia are the resident macrophages of the central nervous system1. In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult haematopoiesis2-4. The origins of human microglia are less clear, but recent evidence suggests that bone-marrow-derived cells contribute to the human microglial pool in certain individuals5-9. Here, to investigate the ontogeny of human microglia, we develop an approach that uses the collection of accumulated somatic mutations that uniquely labels each clone of cells to track the infiltration of bone-marrow-derived cells into the human brain. Applying this approach to 20 older individuals, we find evidence of an influx of bone-marrow-derived cells into the brain in all examined individuals. Single-cell analysis, including single-cell lineage tracing using mitochondrial DNA variants, demonstrates that these infiltrating cells are similar to microglia and can comprise a large fraction of the microglial pool. Analysis of human cohort data demonstrates a protective association between most types of clonal haematopoiesis and Alzheimer's disease. Together, we identify a widespread influx of myeloid cells into the healthy human brain that contributes to the pool of human microglia and becomes common with ageing.
    DOI:  https://doi.org/10.1038/s41586-026-10939-0
  3. Nat Commun. 2026 08 03. pii: 9320. [Epub ahead of print]17(1):
    Unbiased screen of human transcriptome reveals an unexpected role of 3'UTRs in translation initiation.
    Yun Yang, Xiaojuan Fan, Yanwen Ye, Zhenzhen Zhang, Chuyun Chen, Sebastian E J Ludwig, Sirui Zhang, Qianyun Lu, Cindy L Will, Henning Urlaub, Jing Sun, Reinhard Lührmann, Zefeng Wang.
      Although most eukaryotic mRNAs require a 5'-cap for translation initiation, some can also be translated through a poorly studied cap-independent pathway. Here we develop a circRNA-based system and unbiasedly identify more than 10,000 sequences in the human transcriptome that contain Cap-independent Translation Initiators (CiTIs). Surprisingly, most of the identified CiTIs are located in 3'UTRs, which mainly promote translation initiation in mRNAs bearing highly structured 5'UTR. Mechanistically, CiTI recruits several translation initiation factors including eIF3 and DHX29, which in turn unwind 5'UTR structures and facilitate ribosome scanning. Functionally, we show that the translation of HIF1A mRNA, an endogenous DHX29 target, is antagonistically regulated by its 5'UTR structure and a new 3'-CiTI in response to hypoxia. Consistently, deletion of 3'-CiTI suppresses cell growth in hypoxia and tumor progression in vivo. Collectively, our study uncovers a new regulatory mode for translation where the 3'UTR actively participate in the translation initiation.
    DOI:  https://doi.org/10.1038/s41467-026-75574-9
  4. Nat Aging. 2026 Sep 03.
    GLP-1 receptor agonism extends median lifespan in mice.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-026-01224-w
  5. Nat Commun. 2026 Aug 05. pii: 9471. [Epub ahead of print]17(1):
    Single-nucleus analysis of human white adipose tissue reveals adipocyte subsets with distinct metabolic profiles.
    Vissarion Efthymiou, Adhideb Ghosh, Sean D Kodani, Habib Muallem, Xavier Caubit, Waqar Ali, Lindsay S Poulos, Henrique Camara, Anushka Gupta, Yasmine Belaidouni, A Sina Booeshaghi, Shiyi Yang, Ruchir Rastogi, Farnaz Shamsi, Ashley Vernon, Laurent Fasano, Assaf Rudich, Aaron Streets, Yu-Hua Tseng, Mary Elizabeth Patti.
      Anatomic location of white adipose tissue is a determinant of cardiometabolic risk. To understand differences within/between adipose depots, we generated 65,668 single-nucleus transcriptomes from human subcutaneous or intraabdominal adipose tissue (SAT/IAT). Unsupervised analysis reveals 26 adipose-resident cell clusters including two subpopulations of mature adipocytes, characterized by high vs. low expression of adipocyte maturation genes (ADIPOMAThi vs. ADIPOMATlo). ADIPOMATlo adipocytes demonstrate a low-differentiation, pro-inflammatory, and pro-fibrotic transcriptome. IAT-resident ADIPOMATlo were more abundant in higher BMI donors, while SAT-resident ADIPOMATlo associated with impaired glycemia. TSHZ3 is identified as a candidate regulator of ADIPOMATlo transcriptome. TSHZ3 knockdown in adipogenic progenitors inhibits differentiation, with downregulation of early adipogenic regulators (e.g., CEBPA/B, PPARG) and mature adipocyte genes. Heterozygous deletion of Tshz3 in mice reduces SAT and IAT weight. Here, we show that adipocyte subsets with distinct transcriptomic signature reside in human WAT; altered TSHZ3-mediated transcriptional regulation may contribute to low-maturation subpopulation linked to metabolic disease.
    DOI:  https://doi.org/10.1038/s41467-026-75426-6
  6. Nature. 2026 Sep 02.
    Blood cells replace the immune cells of the ageing human brain.
      
    Keywords:  Ageing; Brain; Genetics
    DOI:  https://doi.org/10.1038/d41586-026-02694-z
  7. Nature. 2026 Sep 01.
    India has an ambitious plan to lure scientists back - will it work?
    Mohana Basu.
      
    Keywords:  Funding; Institutions; Research management
    DOI:  https://doi.org/10.1038/d41586-026-02636-9
  8. Cell. 2026 Sep 03. pii: S0092-8674(26)00928-1. [Epub ahead of print]189(18): 5488-5503
    The regulatory logic linking inflammation and fibrosis.
    Michael Alexanian, Deepak Srivastava.
      Whether tissue injury resolves or progresses to chronic scarring is determined by regulatory choices that remain only partially understood. In this review, we propose that immune cells and fibroblasts function as dynamic interpreters of intercellular cues, integrating these signals through chromatin-regulated gene circuits that govern cell state and fate. Drawing on insights from cardiac biology and from settings where tissues regenerate or resolve injury without scarring, we outline a molecular framework in which immune-stromal crosstalk and gene regulatory networks dictate the choice between recovery and chronic fibrosis across organs, including the heart, lung, liver, and kidney. Reframing fibrosis as a reversible state shaped by disrupted regulatory logic opens therapeutic avenues that move beyond suppressing fibrotic outputs toward rewiring the regulatory programs that sustain them.
    DOI:  https://doi.org/10.1016/j.cell.2026.08.001
  9. Nat Commun. 2026 Aug 05. pii: 9418. [Epub ahead of print]17(1):
    RAS P21 Protein Activator 3 finetunes Type I immunity by limiting HCK-mediated STAT4 phosphorylation.
    Jiayu Song, Xiaoyu Liu, Jie Sun, Xi Cheng, Chuan He, Yunhong Zhong, Jinfang Zhang, Junjie Zhang, Hui Xiong, Bing Wu.
      Type I immunity, mediated by IFN-γ, is essential for combating intracellular pathogens but also drives inflammatory diseases. How the immune system balances protective type I responses with pathological inflammation is elusive. While the IL-12-STAT4 pathway that promotes IFN-γ production is well-established, the intrinsic negative regulators remain unclear. We establish that RASA3 serves as a permissive checkpoint for type I immune responses. T cell-specific ablation of RASA3 amplified Th1/Tc1 immunity and IFN-γ expression, enhancing the clearance of Listeria monocytogenes but exacerbating allergic contact dermatitis. We further identify the hematopoietic cell kinase (HCK) as a direct kinase for STAT4, which binds to and phosphorylates it at the Tyr693 residue to elicit IFN-γ production. Mechanistically, RASA3 represses the translation of HCK via constraining ribosomal protein RPL36A expression. Additionally, the RASA3-HCK axis is conserved in human Th1 cells. Thus, we define a critical role of the RASA3-HCK-STAT4 axis in fine-tuning type I immunity and offer promising targets for intervening in Th1/Tc1-driven pathologies.
    DOI:  https://doi.org/10.1038/s41467-026-76201-3
  10. JAMA. 2026 Sep 04.
    Premature Menopause Linked to Increased Hypertension Risk.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.12069
  11. Sci Immunol. 2026 Sep 04. 11(123): eaeb9244
    Tissue mitochondrial activity dictates the macrophage pool size.
    Laura Pena-Couso, Jon Sicilia, Sofía Vieto, Roberto Silva-Rojas, María Sánchez-Díaz, Enrique Calvo, Rafael Romero-Becerra, Cintia Folgueira, Leticia Herrera-Melle, Raquel Justo-Méndez, Xiaotong Hong, Silvia Campanario, Juan A López, Georgiana Crainiciuc, María Gil, Sandra Martín-Salamanca, Vera Lukesova, Jessica Segalés, Antonio L Serrano, Iván Ballesteros, Marta León, Macarena de Andrés-Laguillo, Sebastian A Stifter, Lorena Esteban-Martínez, Joan Isern, Jorge Alegre-Cebollada, Miguel Torres, Melanie Greter, Jesús Vázquez, José A Enríquez, Guadalupe Sabio-Buzo, Pura Muñoz-Cánoves, Andrés Hidalgo, José A Nicolás-Ávila.
      Removal of cellular waste from the extracellular space is fundamental for tissue health. Because the rate of material ejected by parenchymal cells varies across tissues, we searched for mechanisms that couple waste production and removal. Here, we show that the uptake of parenchyma-released mitochondria by macrophages is prominent across organs that rely on oxidative respiration-including heart, skeletal muscle, and brown adipose tissue-and that macrophage numbers closely align with the mitochondrial activity of each of these organs. We found that the mitochondrial activity of myofibers dictates the abundance of macrophages by modulating colony-stimulating factor 1 (CSF1) availability and the number of CSF1-producing fibroblasts in the tissue. Consequently, inhibition of CSF1-CSF1 receptor (CSF1R) signaling depleted macrophages and collapsed the mitochondrial activity of skeletal muscles. We propose that, by coupling macrophage abundance to the mitochondrial activity of their parenchyma, tissues ensure efficient waste disposal and fitness.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb9244
  12. Cell Metab. 2026 Sep 01. pii: S1550-4131(26)00331-1. [Epub ahead of print]38(9): 1742-1743
    Beyond the Randle cycle: A four-nutrient model of competitive catabolism.
    Alexander S Banks.
      Competitive catabolism mechanistically links increased fat mass to hyperglycemia and hyperinsulinemia. Weilandt et al. develop a differential equation model of metabolic homeostasis incorporating four circulating nutrients and insulin, which extends the framework of the Randle cycle and reveals a physiological circuit by which obesity drives type 2 diabetes.
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.006
  13. Nat Genet. 2026 Sep 01.
    OmicsPred as a centralized resource for genetic prediction of multi-omic traits.
    Carles Foguet, Laurent Gil, Yu Xu, Sofía Salazar-Magaña, Scott C Ritchie, Elodie Persyn, Hae Kyung Im, Michael Inouye, Samuel A Lambert.
      
    DOI:  https://doi.org/10.1038/s41588-026-02726-4
  14. Nat Med. 2026 Sep 01.
    Altered oligodendrocyte function promotes cognitive decline in aging.
      
    DOI:  https://doi.org/10.1038/s41591-026-04630-0
  15. Nat Med. 2026 Sep 03.
    Gene alteration in human brain suggests genetic and epigenetic roots of major depression.
      
    DOI:  https://doi.org/10.1038/s41591-026-04682-2
  16. Nat Aging. 2026 Aug 31.
    Mapping structural aging across human tissues reveals tissue-specific trajectories and coordinated deterioration.
    Anamika Yadav, Kyle Alvarez, Anna Chechenina, Kevin Y Yip, Eytan Ruppin, Alexandre Colas, Jacqueline C Yano Maher, Veronica Gomez-Lobo, Caroline Kumsta, Sanju Sinha.
      Organ structure, including the organization of cells, vasculature and extracellular matrix, underpins its function, yet how structure changes with age remains mostly unknown. Here we developed PathStAR, a framework that quantifies tissue structural aging from routine histopathology images, without being trained to predict chronological age. Applying PathStAR to 25,306 post-mortem biopsies from 40 tissues in 970 donors aged 21-70 years revealed that organ structural aging progresses via distinct, nonlinear temporal trajectories: vascular tissue structural aging accelerates early, uterus and vagina structural aging accelerates late (around menopause) and certain tissues including digestive and male reproductive organs show biphasic accelerations. We show that accelerations of structural aging are characterized across organs by increased inflammation alongside reduced energy production, repair and quality control. Cross-organ analysis reveals coordinated deterioration within individuals, including digestive and male reproductive tissues, linked by sex hormones. Together, our analysis provides a systematic map of structural aging across the human body.
    DOI:  https://doi.org/10.1038/s43587-026-01200-4
  17. Nat Commun. 2026 Sep 03. pii: 9458. [Epub ahead of print]17(1):
    Functional annotation of insulin-responsive genes in human adipocytes reveals PLCXD1 as a lipid storage regulator.
    Scott Frendo-Cumbo, Danae Zareifi, Joëlle Bigay, Ana Rita Dias Araújo, Alina Lapp, Mattias Hansen, Teresa P Reindl, Beatrice Engelmann, Felix Klingelhuber, Lina Cordeddu, Merve Elmastas, Jutta Jalkanen, Gianluca Renzi, Océane Buvry, Delphine Debayle, Hanin Allos, Marta López Yus, Sophie Weinbrenner, Katharina Schormair, Oveis Jamialahmadi, Alastair G Kerr, Stefano Romeo, Ulrike Rolle-Kampczyk, Martin von Bergen, Lucas Massier, Natalie Krahmer, Romain Gautier, Bruno Antonny, Mikael Rydén, Niklas Mejhert.
      Insulin-driven gene regulation is central to adipocyte function, but the roles of many of these genes in lipid metabolism remain unclear. Here, we integrate three transcriptomic datasets to identify insulin-responsive genes and define their functions in human adipocytes using a multiparametric lipid turnover screen. Our results reveal four major clusters involved in metabolic regulation, transcription, stress responses, and lipid metabolism. Among lipid-related hits, phospholipase C X domain-containing protein-1 (PLCXD1) emerges as a regulator of insulin-stimulated lipogenesis, without affecting lipolysis or adipogenesis. PLCXD1 is induced by insulin via sterol regulatory element-binding proteins, a response attenuated in insulin-resistant states. This atypical phospholipase is genetically associated with fat mass-related traits, localizes to early endosomes and catalyzes phosphatidylinositol conversion into diacylglycerol. Through structure-function analyses, we show that PLCXD1 catalytic activity is required for insulin-stimulated lipogenesis. Altogether, our results uncover PLCXD1 as an insulin-regulated enzyme linking endosomal phosphoinositide metabolism to lipid storage in adipocytes.
    DOI:  https://doi.org/10.1038/s41467-026-77280-y
  18. Nat Commun. 2026 08 29. pii: 9232. [Epub ahead of print]17(1):
    Associations between diet quality, epigenetic aging and epigenome in two population-based cohorts.
    Juliana F Tavares, Dan Liu, Valentina Talevi, Fabian Eichelmann, Franziska Jannasch, Matthias B Schulze, N Ahmad Aziz, Ute Nöthlings, Monique M B Breteler.
      Several dietary patterns have been associated with better health outcomes. However, the extent to which adherence to different so-called healthy diets overlaps, whether these dietary patterns are equally beneficial, and whether they are associated with similar DNA methylation profiles, remains unclear. Therefore, we investigate the overlap in adherence to ten diet quality scores, and examine the associations of these scores with both biological aging markers and DNA methylation profiles. We use data from the Rhineland Study, a large population-based cohort, and validated our findings using corresponding data from the EPIC-Potsdam cohort. Here, we show minimal overlap of participants classified in the highest quartile (top 25%) of adherence across different diet quality scores. Adherence to a healthy dietary pattern is associated with reduced epigenetic aging, although associations differed in magnitude across diet quality scores. Different dietary patterns are associated with distinct methylation profiles, which however largely converged onto the same biological pathways. Our findings suggest that general adherence to a healthy dietary pattern could promote health through similar epigenetic mechanisms, despite variations in dietary composition.
    DOI:  https://doi.org/10.1038/s41467-026-77064-4
  19. J Clin Invest. 2026 Sep 01. pii: e203491. [Epub ahead of print]136(17):
    Integrating transposable elements into blood gene regulatory networks reveals connectivity loss for schizophrenia genes.
    Helena Reyes-Gopar, Matthew L Bendall, Rodrigo Rr Duarte, Timothy R Powell, Douglas F Nixon.
      In patients with schizophrenia we found that genes and dark genome disconnect. This opens new areas for possible diagnostics and treatments.
    Keywords:  Bioinformatics; Biomarkers; Genetics; Neuroscience; Schizophrenia
    DOI:  https://doi.org/10.1172/JCI203491
  20. Nature. 2026 Sep 02.
    Weight-loss drug slows ageing in female mice.
    Maria Emilia Fernandez, Rafael de Cabo.
      
    Keywords:  Ageing; Nutrition; Physiology; Therapeutics
    DOI:  https://doi.org/10.1038/d41586-026-02468-7
  21. Sci Immunol. 2026 Sep 04. 11(123): eaea1426
    Adaptive motility enables neutrophils to rapidly navigate confined capillaries.
    Mathieu Deygas, Mathilde Bernard, Pierre Nivoit, Henry De Belly, Alexandre Deslys, Theresa Jakuszeit, Damien Cuvelier, Moira Garcia-Gomez, Lucie Barbier, Li Wang, Mathieu Maurin, Emmanuel Tejerina, Oumaima Baaziz, Emmanuel Terriac, Rafaele Attia, Anna Kniazeva, Serge Garbay, Marina Ortega-Zapero, Angela Saez, Raquel Gomez-Bris, Pilar Gonzalo, Jose M Gonzalez-Granado, Vicente Andrés, Orion D Weiner, Ana-Maria Lennon-Duménil, Guillaume Duménil, Matthieu Piel, Pablo Vargas.
      To reach inflamed tissues, neutrophils must traverse capillaries as narrow as 2 micrometers. However, how they do so without compromising blood flow or capillary function has remained unclear. By combining intravital live-cell imaging with biomimetic microdevices, we show that neutrophils maintain migration speed in capillaries across increasing levels of confinement. This behavior was not shared by other leukocytes and was independent of nuclear properties. Instead, confinement rapidly engaged Rho-dependent actomyosin contractility at the cell rear, thereby offsetting the increased mechanical resistance imposed by confinement. Disrupting this adaptive response caused neutrophil jamming and eventual occlusion of confined capillary-like networks. These findings identify a neutrophil-intrinsic mechanism that couples capillary confinement to rapid migratory adaptation, helping preserve vascular patency and potentially limiting tissue dysfunction during inflammation.
    DOI:  https://doi.org/10.1126/sciimmunol.aea1426
  22. Nat Cardiovasc Res. 2026 Sep 03.
    Genetic evidence supports the combined targeting of lipoprotein(a) and LDL cholesterol to reduce coronary artery disease risk.
    Shaoqi Wang, Yuzhong Tang, Yang Sui, Hongqiang Zhao, Asifullah Khan, Wanqing Yin, Qiuli Chen, Tingfeng Xu, Zhaoqi Liu, Zhang Zhang, Fei Wang, Shuangli Mi, Kelvin Supriami, Min Seo Kim, Yuan Zhou, Hongjie Shi, Xudong Xing, Ying Yang, Yajing Hao, Jianping Li, Jie Du, Chenglong Yu, Sarah Urbut, Michael C Honigberg, Pradeep Natarajan, JinPing Liu, Akl C Fahed, Minxian Wang.
      Distinct genetic mechanisms govern how lipoprotein(a) (Lp(a)) and low-density lipoprotein cholesterol (LDL-C) promote atherosclerosis. It remains unclear whether targeting both provides additive cardiovascular benefits. Here we use coding loss-of-function variants in LPA and PCSK9 and genetic scores associated with Lp(a) and LDL-C levels to evaluate the effects of lowering Lp(a) and LDL-C on coronary artery disease (CAD) risk. Among 408,039 individuals from the UK Biobank, LPA or PCSK9 loss-of-function carriers have lower CAD risk than noncarriers (odds ratio (OR) 0.91 and 0.81). Carriers of both variants have even lower CAD risk (OR 0.73). Genetic lowering of Lp(a) and LDL-C showed a stronger reduction of CAD risk (OR 0.70) than either trait individually (OR 0.85 and 0.81) in the two-factor genetic score analysis. Among statin users, Lp(a) reduction was linearly associated with CAD risk. A phenome-wide association study revealed that combined therapy was associated with cardiometabolic benefits without adverse effects. The additive benefits were replicated in 65,171 individuals from the Mass General Brigham Biobank.
    DOI:  https://doi.org/10.1038/s44161-026-00865-9
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