bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–04–26
fourteen papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Islet cell DNA methylation in human ageing and diabetes.
  2. Spatiotemporal Transcriptomics Characterizes Immune Microenvironment During Mouse Liver Aging.
  3. Hepatic SEC16B regulates lipid homeostasis by coordinating VLDL secretion and lipid droplet expansion.
  4. Exposure to negative physical and social factors accelerates brain aging.
  5. A generative AI framework unifies human multi-omics to model aging, metabolic health, and intervention response.
  6. The misunderstood sex chromosome: how X affects your health.
  7. Transcription factor 19 modulates fatty acid elongation and unfolded protein response to attenuate palmitic acid-induced hepatic dysfunction.
  8. Whey Protein Ingestion Stimulates Glucagon Secretion and Raises Blood Glucose Levels in Adults With Type 1 Diabetes.
  9. Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.
  10. B cell deficiency limits exercise capacity by remodeling liver glutamate metabolism.
  11. Tissue-selective COPII modulator SEC16B aggravates cardiovascular disease by promoting lipid export.
  12. Adipose single cell epigenome and transcriptome localize genetic risk for cardiometabolic disease and accelerated aging.
  13. Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes.
  14. Therapeutic Spp1 silencing in TREM2+ cardiac macrophages suppresses atrial fibrillation.
  1. Nat Metab. 2026 Apr 24.
    Islet cell DNA methylation in human ageing and diabetes.
    Emily Hodges, Guoqiang Gu.
      
    DOI:  https://doi.org/10.1038/s42255-026-01502-2
  2. Aging Cell. 2026 May;25(5): e70482
    Spatiotemporal Transcriptomics Characterizes Immune Microenvironment During Mouse Liver Aging.
    Jiahua Lu, Yuqian Wang, Wenxue Zhao, Zihao Zhao, Zhaoya Gao, Jin Gu, Cheng Li, Jie Cheng.
      The liver is a major metabolic organ, responsible for synthesizing and breaking down diverse metabolites. Recently, the liver's immunological functions have gradually been unveiled: combating pathogens and maintaining tissue homeostasis. Age-related functional alterations in these immune cells emerge as potential drivers of hepatic dysfunction and age-associated pathologies. However, systematic investigations into spatiotemporal immune cell dynamics during liver aging remain limited. To address this gap, we analyzed young and old mouse livers using single-cell/nuclei and spatial transcriptomics, revealing T cells as the immune cell population with the most pronounced transcriptomic alterations, marked by enrichment of exhausted CD8+ T cells in aged livers. Spatial mapping showed exhausted CD8+ T cells accumulating in portal vein (PV) zone, co-localizing with periportal hepatocytes (PP hepatocytes). Up-regulation of LPIN1 in PP hepatocyte promoted T cell exhaustion. CD8+ T cell exhaustion was tightly associated with disease progression. Therefore, our findings suggest that targeting LPIN1 may alleviate T cell exhaustion, offering potential therapeutic strategies for age-related liver diseases.
    Keywords:  T cell exhaustion; aging; liver; single‐cell/nuclei transcriptome; spatial transcriptome
    DOI:  https://doi.org/10.1111/acel.70482
  3. J Clin Invest. 2026 Apr 24. pii: e204602. [Epub ahead of print]
    Hepatic SEC16B regulates lipid homeostasis by coordinating VLDL secretion and lipid droplet expansion.
    Wei Lu, Zhiming Zhao, Donald Molina, Huaxun Fan, Ruicheng Shi, Ye Tian, Raja Gopoju, Tiantian Yang, Xinyuan Zhang, Yanqiao Zhang, Kai Zhang, Jaume Amengual, Bo Wang.
      The liver plays a critical role in lipid homeostasis, where lipids are either secreted as very-low-density lipoproteins (VLDL) or stored in lipid droplets (LDs). However, the regulatory mechanisms governing these two interconnected processes remain poorly understood. Here, we demonstrate that SEC16B functions as a lipid-responsive regulator in the liver, promoting VLDL secretion and LD expansion to handle lipid flux and maintain lipid homeostasis. Genome-wide association studies have identified single-nucleotide polymorphisms in SEC16B to be highly associated with serum lipid levels in humans. Hepatic Sec16b deficiency decreases serum lipid levels by impairing VLDL secretion through mechanisms that are at least partially independent of microsomal triglyceride transfer protein (MTP)-mediated ApoB lipidation and COPII-mediated intracellular trafficking. SEC16B partially localizes at ER-LD contact sites and promotes LD expansion by facilitating the targeting of ER proteins to LDs. More importantly, suppression of Sec16b dramatically lowers serum lipid levels and reduces atherosclerotic lesion size in Ldlr null mice. These data reveal a mechanism that coordinates VLDL and LD metabolism and suggest SEC16B as a potential therapeutic target for atherosclerosis treatment.
    Keywords:  Atherosclerosis; Cardiovascular disease; Hepatology; Lipoproteins; Metabolism
    DOI:  https://doi.org/10.1172/JCI204602
  4. Nat Med. 2026 Apr 21.
    Exposure to negative physical and social factors accelerates brain aging.
      
    DOI:  https://doi.org/10.1038/s41591-026-04348-z
  5. Cell Metab. 2026 Apr 21. pii: S1550-4131(26)00108-7. [Epub ahead of print]
    A generative AI framework unifies human multi-omics to model aging, metabolic health, and intervention response.
    Jiawei Chen, Ya Ren, Yong Zhou, Ziyang Wang, Kehang Mao, Zhengqing Yu, Jiyang Li, Xiaoxiao Guo, Hao Xu, Yiyang Wang, Yi Wang, Bo Pang, Hongxiao Liu, Huiru Tang, Jing-Dong J Han.
      Understanding aging and complex diseases requires diverse data, ranging from molecular profiles to imaging and routine clinical tests. However, most multi-omic datasets measure only a subset of modalities and are confounded by batch effects. Here, we present AURORA (AI unification and reconstruction of omics reassembly atlas), a generative deep-learning platform that integrates seven modalities (including transcriptomics, metabolomics, microbiome, 3D and thermal facial imaging, and clinical laboratory tests) across 581,763 samples from 425,258 individuals. AURORA harmonizes batch effects and reconstructs missing data across modalities, enabling highly accurate multimodal aging clocks and disease risk predictors. It also supports personalized in silico perturbation analyses to predict intervention and drug responses, validated using longitudinal cohorts. As a proof of concept, we provide a prototype AI agent that converts single-input modalities into a multimodal report for users and researchers. Together, AURORA links non-invasive inputs to comprehensive aging biomarkers and therapeutic discovery.
    Keywords:  aging clocks; biological aging; digital twin; disease risk prediction; drug repurposing; facial imaging; generative AI; in silico perturbation; multi-omics integration; personalized medicine
    DOI:  https://doi.org/10.1016/j.cmet.2026.03.014
  6. Nature. 2026 Apr;652(8111): 851-853
    The misunderstood sex chromosome: how X affects your health.
    Claire Ainsworth.
      
    Keywords:  Developmental biology; Genetics; Medical research
    DOI:  https://doi.org/10.1038/d41586-026-01256-7
  7. Nat Commun. 2026 Apr 22.
    Transcription factor 19 modulates fatty acid elongation and unfolded protein response to attenuate palmitic acid-induced hepatic dysfunction.
    Atanu Mondal, Arnab Chakraborty, Sandhik Nandi, Vipin Singh, Siddhesh S Kamat, Chandrima Das.
      Saturated fatty acids, which increase during high-fat diets and metabolic disease, disrupt lipid homoeostasis, leading to hepatic dysfunction. Understanding how hepatocytes adapt to this stress is essential for delineating the early events of fatty liver disease and its progression to more severe inflammation and fibrosis. Here, we show that the transcription factor TCF19 acts as a central regulator that helps hepatocytes manage lipid overload and cellular stress in both MAFLD mice model and human clinical samples. Combining lipidomic and transcriptomic analysis, we found that TCF19 controls genes involved in fatty-acid elongation and protein-folding responses, thereby linking lipid metabolism with endoplasmic-reticulum stress-response pathways. Elevated TCF19 levels are associated with lipid accumulation, whereas reducing TCF19 worsens inflammation and fibrotic features of the liver. Together, our findings identify TCF19 as a protective regulator during the transition from early hepatic fat accumulation to inflammatory liver disease, highlighting a potential target for early therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41467-026-72138-9
  8. Diabetes. 2026 Apr 24. pii: db260059. [Epub ahead of print]
    Whey Protein Ingestion Stimulates Glucagon Secretion and Raises Blood Glucose Levels in Adults With Type 1 Diabetes.
    Giang M Dao, Sam Zhao, Cara Schofield, Sara Vogrin, Declan T Hennessy, Carmel E Smart, Dessi P Zaharieva, David N O'Neal, Clinton R Bruce, Greg M Kowalski, Dale J Morrison.
       ARTICLE HIGHLIGHTS: The effect of protein ingestion on glucagon and glycemic responses in individuals with type 1 diabetes is not well characterized. This study examined how ingestion of varying amounts of fast-absorbing whey protein (in the absence of other macronutrients) affected glucagon secretion, glucose levels, and associated metabolic hormone levels in adults with type 1 diabetes. Whey protein ingestion stimulated glucagon secretion and endogenous glucose production and increased blood glucose in adults with type 1 diabetes. Our findings highlight the potential of whey protein as a tool to support glycemic management and mitigate hypoglycemia in type 1 diabetes.
    DOI:  https://doi.org/10.2337/db26-0059
  9. Nat Commun. 2026 Apr 18. pii: 3589. [Epub ahead of print]17(1):
    Aging-associated decline of phosphatidylcholine synthesis is a malleable trigger of natural mitochondrial aging.
    Tetiana Poliezhaieva, Yuting Li, Prerana Shrikant Chaudhari, Ulas Isildak, Pol Alonso-Pernas, Isabela Santos Valentim, Fengting Su, Lilia Espada, Melike Bayar, Li Fu, Andreas Koeberle, Handan Melike Dönertaş, Maria A Ermolaeva.
      Mitochondrial dysfunction is a prominent hallmark of aging contributing to the decline of metabolic plasticity in late life. While genetic distortions of mitochondrial integrity elicit premature aging, the mechanisms leading to "natural" aging of mitochondria are less clear. Here we use proteomics, lipidomics, genetics and functional tests in wild type Caenorhabditis elegans and long-lived clk-1(qm30) and isp-1(qm150) mitochondrial mutants to identify molecular pathways that support longevity amid persistent mitochondrial inefficiency. These tests and subsequent transcriptomics and metabolomics analyses in humans reveal aging-associated decline of phosphatidylcholine synthesis as a trigger of mitochondrial network disruption, which contributes to mitochondrial dysfunction during normal aging. Moreover, ectopic boosting of phosphatidylcholine levels via diet restores late life mitochondrial integrity in vivo in nematodes and reinstates metabolic resilience in human cell culture tests. We thus describe a previously unrecognized natural driver of mitochondrial decline in aging that is malleable by dietary interventions.
    DOI:  https://doi.org/10.1038/s41467-026-71508-7
  10. Cell. 2026 Apr 17. pii: S0092-8674(26)00340-5. [Epub ahead of print]
    B cell deficiency limits exercise capacity by remodeling liver glutamate metabolism.
    Youxiang Mao, Ziyan Xia, Xu Pan, Wenjun Xia, Peng Jiang.
      B cells are an essential component of humoral immunity, and B cell depletion therapies have clinically succeeded in eliminating cancerous B cells and treating autoimmune diseases. Here, we report an immune-independent function of B cells that spatially and metabolically drives exercise capacity. During exercise, B cell deficiency reduces transforming growth factor (TGF)-β1 production, which alters hepatic glutamate metabolism and decreases blood and muscle glutamate. Mechanistically, B cell-derived TGF-β1 transcriptionally upregulates hepatic glutaminase 2 (GLS2) and solute carrier family 7 member 5 (SLC7A5) expression, increasing glutamine catabolism and thus glutamate production in the liver. The resulting increase in glutamate fosters skeletal muscle calcium oscillations, calmodulin-dependent protein kinase (CaMK) kinase activity, and mitochondrial biogenesis, thereby improving exercise performance. Thus, we identify a metabolite-driven liver-muscle connection that regulates exercise capacity, linking B cell function to skeletal muscle calcium signaling via alteration of hepatic glutamate metabolism.
    Keywords:  B cells; TGF-β1; exercise capacity; hepatic glutamate metabolism; immune-independent regulation; immunoexercise; skeletal muscle function; transforming growth factor
    DOI:  https://doi.org/10.1016/j.cell.2026.03.039
  11. EMBO J. 2026 Apr 24.
    Tissue-selective COPII modulator SEC16B aggravates cardiovascular disease by promoting lipid export.
    Xiao Wang, Yating Hu, Lu Liu, Runze Huang, Yawei Wang, Bing Liu, Yifei Zhao, Yuangang Zhu, Jia Lv, Liang Liu, Huimin Wang, Lingzhi Wu, Xinxuan Xu, Yaxin Li, Guanlin Wang, Xiao-Wei Chen.
      The biogenesis and transport of lipoproteins are essential for systemic homeostasis and cardiometabolic health, yet how the secretory pathway acquires specialization to support high-capacity lipoprotein export remains unclear. Here, we report SEC16B as a tissue-selective modulator of the COPII machinery, critical for the efficient secretion of APOB-containing lipoproteins. Integrative bioinformatic analyses identify that SEC16B co-emerges with core genes involved in lipoprotein biogenesis. Functional studies, coupled with AI-driven prediction, reveal that SEC16B acts as a molecular brake to fine-tune COPII condensation for lipoprotein export. Mining of UK biobank data links SEC16B to metabolic traits in humans and suggests HNF4A-dependent regulation of SEC16B expression. Hepatic deletion of SEC16B in mice markedly reduces circulating APOB, triglycerides and cholesterol, while conferring robust protection against atherosclerosis and cardiac dysfunction and maintaining liver health. Collectively, these findings position SEC16B as a specialized modulator of lipoprotein export via the general secretory (SEC) pathway in the liver, suggesting potential therapeutic avenues for combating cardiometabolic diseases.
    Keywords:   SEC16B ; COPII; Cardio-metabolic Health; Lipid Metabolism; Lipoprotein Secretion
    DOI:  https://doi.org/10.1038/s44318-026-00754-8
  12. Nat Commun. 2026 Apr 20.
    Adipose single cell epigenome and transcriptome localize genetic risk for cardiometabolic disease and accelerated aging.
    Seung Hyuk T Lee, Asha Kar, Kyla Z Gelev, Zeyuan Johnson Chen, Sankha Subhra Das, Sini Heinonen, Tuure Saarinen, Maija Vaittinen, Dorota Kaminska, Hilkka Peltoniemi, Chongyuan Luo, Anne Juuti, Ville Männistö, Jussi Pihlajamäki, Minna U Kaikkonen, Kirsi H Pietiläinen, Brunilda Balliu, Päivi Pajukanta.
      Obesity impairs subcutaneous adipose tissue function, which predisposes to chronic cardiometabolic comorbidities and accelerated biological aging. However, regulatory variants, their target genes and epigenomic landscape underlying this predisposition in each subcutaneous adipose tissue cell-type remain elusive. Our subcutaneous adipose tissue cell-type level cis-expression quantitative trait and colocalization analyses reveal cis-expression quantitative trait locus variants, regulating 279 genes for 33 cardiometabolic disease and aging traits. Most of these genes are cell-type-specific (90%), led by adipocytes (55%), and missed in previous bulk tissue colocalization studies. Conducting subcutaneous adipose tissue cell-type level epigenome analysis, we discover that the vast majority (81%) of these colocalized cardiometabolic disease and aging risk variants map to the active chromatin compartments that comprise only 45% of the human genome, revealing three-dimensional epigenome in the center of cardiometabolic disease and aging risk. These findings uncover genetic and epigenomic regulation of genes underlying 33 cardiometabolic disease and aging traits in subcutaneous adipose tissue cell-types and offer critical insights into the principal role of three-dimensional chromatin in disease risk.
    DOI:  https://doi.org/10.1038/s41467-026-72248-4
  13. Nat Metab. 2026 Apr 24.
    Cell-specific DNA methylation in human alpha and beta cells regulates gene expression in type 2 diabetes.
    Jones K Ofori, Sabrina Ruhrmann, Axel Lindström, Alexander Perfilyev, Melina Martin, Alexandros Karagiannopoulos, Lucia Scisciola, Katja Kost, Josefine Jönsson, Åsa Nilsson, Boris Kantor, Monika Dudenhöffer-Pfeifer, Marianne G Rots, Anna Wendt, Tina Rönn, Lena Eliasson, Karl Bacos, Charlotte Ling.
      Epigenome-wide studies of pancreatic islets provide valuable insights into type 2 diabetes (T2D) but lack methylomes from individual cell types. Here we show changes to alpha and beta cell-specific methylomes and transcriptomes from people with or without T2D, using whole-genome bisulfite sequencing and RNA sequencing. We discover 22,544 differentially methylated regions annotated to 7,975 genes in alpha versus beta cells, such as INS, GCG, PDX1 and PCSK1, with ~50% showing differential expression. CRISPR-dCas9-DNMT3A-based epigenetic editing increases INS and TH DNA methylation, while CRISPR-dCas9-TET1-based editing decreases GCG methylation, each altering INS, TH or GCG expression and content in beta cells. Pre-T2D/T2D-associated differentially methylated regions in alpha and beta cells overlap 12-18% of T2D-associated genome-wide association study candidates. Additionally, ONECUT2 is epigenetically upregulated in beta cells from people with pre-T2D/T2D and elevated in male Goto-Kakizaki rat islets. ONECUT2 overexpression in beta cells/islets downregulates gene sets impacting insulin secretion and glucose homeostasis, and reduces mitochondrial activity, ATP/ADP ratio and insulin secretion. We also provide 'alpha-beta-methylome' ( https://alpha-beta-methylome.serve.scilifelab.se/app/alpha-beta-methylome/ ), a resource exploring T2D, age and sex associations on methylation, highlighting cell-specific epigenetic regulation and dysfunctions contributing to T2D.
    DOI:  https://doi.org/10.1038/s42255-026-01498-9
  14. Nat Cardiovasc Res. 2026 Apr 23.
    Therapeutic Spp1 silencing in TREM2+ cardiac macrophages suppresses atrial fibrillation.
    Noor Momin, Steffen Pabel, Arnab Rudra, Nina Kumowski, I-Hsiu Lee, Hana Seung, Kyle I Mentkowski, Aneesh Bapat, Masahiro Yamazoe, Laura Stengel, Charlotte G Muse, Alexandre Paccalet, Farid F Kadyrov, Cristina González-Correa, Emily Jacobs, Ellie Feng, Jisoo Park, Jana Grune, Maximilian J Schloss, Samuel Sossalla, Gregory Wojtkiewicz, Yoshiko Iwamoto, Patrick McMullen, Richard N Mitchell, Patrick T Ellinor, Daniel G Anderson, Kamila Naxerova, Matthias Nahrendorf, Maarten Hulsmans.
      Atrial fibrillation and the risk of its lethal complications are propelled by fibrosis, which induces electrical heterogeneity and gives rise to reentry circuits. Atrial TREM2+ macrophages secrete osteopontin (encoded by Spp1), a matricellular signaling protein that engenders fibrosis, inflammation, and atrial fibrillation. Here we developed an antibody-siRNA conjugate (ARC) drug candidate to silence Spp1. The ARC relies on an anti-TREM2 antibody for delivering Spp1-targeted siRNA to a pathogenic macrophage subset that expands in human atrial fibrillation. The ARC preferentially targeted atrial TREM2+ macrophages with limited uptake by other immune or stromal cells of the heart. We observed efficient silencing of the target gene in human myocardium and in mice, where it reduced pro-fibrotic fibroblast activation and atrial fibrosis. Four weeks of systemic ARC treatment suppressed inducible atrial fibrillation in mice exposed to clinically prevalent risk factors. These results suggest that macrophage subset targeting offers a viable immunomodulatory strategy for atrial fibrillation.
    DOI:  https://doi.org/10.1038/s44161-026-00806-6
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