bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–03–15
thirty-one papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Memory loss is fuelled by gut microbes in ageing mice.
  2. TRACKing the tissue-specific origins of diverse effector T cell functions.
  3. Defining the vascular niche of human adipose tissue across metabolic states.
  4. A mechanism to initiate emergency type 2 myelopoiesis.
  5. Shared genetic and neuroimmune architecture links type 1 diabetes with neurocognitive traits.
  6. Transient steatosis reprograms MDMs for liver repair.
  7. Angiocrine breakdown in metabolically stressed fat.
  8. scTWAS: a powerful statistical framework for single-cell transcriptome-wide association studies.
  9. Daily briefing: A daily multivitamin slows the signs of biological ageing.
  10. How the brain can harm the heart.
  11. Impaired glycosylation promotes rapid transition to hepatocellular carcinoma in model of diet induced steatotic liver disease.
  12. Facile induction of immune tolerance by an interleukin-2-TGFβ surrogate agonist.
  13. Liver-derived exercise factor boosts brain vasculature.
  14. 'Baked, not fried': five highlights from nutrition research.
  15. Out of many, IL-1.
  16. Monthly HIV-drug injections offer potent alternative to daily tablets.
  17. Big-eaters choking? Macrophages can't stomach microplastics.
  18. Inflammatory ILC2s migrate to distal tissues during infection using stage-specific S1P receptors.
  19. Immune austerity: How the body balances its books when calories run low.
  20. Youthful antics predict lifespan - at least for these fish.
  21. Scientists revive activity in frozen mouse brains for the first time.
  22. Gut microbes affect cognition during ageing.
  23. Saccades orchestrate intraocular glucose dynamics to shape visual responses in birds.
  24. Daily multivitamin slows signs of biological ageing.
  25. National statistics are in crisis around the world - and the impacts will be severe.
  26. Aged Male Mice Remain Glucose Tolerant Despite Increased Energy Storage Efficiency Favoring Diet-Induced Obesity.
  27. Cell type-specific epigenetic regulatory circuitry of coronary artery disease loci.
  28. Cell-type-specific transposon demethylation and TAD remodeling in aging mouse brain.
  29. Alzheimer Disease Sex Differences May Be Tied to P-Tau217.
  30. Butyrate extends health and lifespan in mice with mitochondrial deficiency.
  31. Lipid-dependent accrual of a subset of monocyte-derived macrophages is essential for tissue regeneration.
  1. Nature. 2026 Mar 11.
    Memory loss is fuelled by gut microbes in ageing mice.
    Edward Chen.
      
    Keywords:  Ageing; Brain; Microbiome; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-026-00768-6
  2. Nat Immunol. 2026 Mar 12.
    TRACKing the tissue-specific origins of diverse effector T cell functions.
    Orian Bricard, Adrian Liston.
      
    DOI:  https://doi.org/10.1038/s41590-026-02475-w
  3. Nat Metab. 2026 Mar 12.
    Defining the vascular niche of human adipose tissue across metabolic states.
    Ibrahim AlZaim, Mohamed N Hassan, Maja Schröter, Luca Mannino, Katarina Dragicevic, Marie Balle Sjogaard, Joseph Festa, Lolita Dokshokova, Sophie Weinbrenner, Blanca Tardajos Ayllon, Bettina Hansen, Rikke Kongsgaard Rasmussen, Julie N Christensen, Olivia Wagman, Ruby Schipper, Min Cai, Wouter Dheedene, Anja Bille Bohn, Jean Farup, Lin Lin, Samuele Soraggi, Anna Dalsgaard Thorsen, Amanda Bæk, Henrik Holm Thomsen, Maximilian von Heesen, Lena-Christin Conradi, Paul Evans, Carolina E Hagberg, Joerg Heeren, Margo Emont, Evan D Rosen, Aernout Luttun, Anders Etzerodt, Lucas Massier, Mikael Rydén, Niklas Mejhert, Matthias Blüher, Konstantin Khodosevich, Robert A Fenton, Bilal N Sheikh, Niels Jessen, Laura P M H de Rooij, Joanna Kalucka.
      Adipose tissue homeostasis depends on an intact vascular network that ensures adequate nutrient delivery and immune regulation. In obesity, vascular dysfunction, particularly within endothelial cells (ECs), contributes to inflammation and metabolic disease progression, yet the cellular organization of the human adipose vasculature remains poorly defined. Here we show, using single-cell RNA sequencing of nearly 70,000 vascular cells from human subcutaneous adipose tissue of 65 individuals, that the adipose vasculature is highly heterogeneous and consists of seven canonical EC subtypes. In addition, we identify a distinct population of ECs that display mixed endothelial, mesenchymal, adipocytic and immune transcriptional features. Computational analyses and whole-mount imaging support their presence and suggest that they emerge through endothelial-to-mesenchymal transition. Comparative analyses further reveal inflammatory and fibrotic vascular signatures in obesity and type 2 diabetes. Together, this atlas delineates the cellular complexity of the human adipose vasculature and highlights its contribution to metabolic disease.
    DOI:  https://doi.org/10.1038/s42255-026-01475-2
  4. Nature. 2026 Mar 11.
    A mechanism to initiate emergency type 2 myelopoiesis.
    Alexandre Fagnan, Cristina Di Genua, Yiran Meng, Roy Drissen, Zishan Zhang, Bowen Zhang, Padraic G Fallon, Vassilis Pachnis, Erika J Mancini, Fränze Progatzky, Claus Nerlov.
      Immune responses to parasite infection involve the increased production of basophils and eosinophils. These two myeloid cell types have key roles in type 2 anti-parasite immunity1 and rely on GATA family transcription factors for their specification2,3. The first committed step in basophil and eosinophil production is generation of basophil-eosinophil-mast cell progenitors (BEMPs) from oligopotent erythroid-primed multipotent progenitors (EMPPs). However, it is not well established how immune responses act on progenitors to initiate type 2 myelopoiesis. Here we show that infection with the helminth Heligmosomoides polygyrus increases EMPP commitment to myeloid fate at the expense of erythropoiesis. Upon infection with H. polygyrus, the IL-33 alarmin accumulated in the bone marrow, causing EMPPs to upregulate the GATA co-factor LMO4 and preferentially differentiate into myeloid cells. LMO4 was sufficient to instruct myeloid fate in EMPPs by interacting with GATA2, displacing the FOG1 co-factor and redistributing GATA binding from megakaryocyte-erythroid-specific to basophil, eosinophil and mast cell (BEM)-specific chromatin. Accordingly, mice carrying a GATA2 mutation that selectively impairs the LMO4-GATA2 interaction were deficient in GATA factor allocation to BEM chromatin, myeloid lineage commitment, basophil and eosinophil production, and parasite control. This identifies LMO4 as an IL-33-regulated master regulator of type 2 myelopoiesis, and transcription factor reallocation as a mechanism of lineage commitment.
    DOI:  https://doi.org/10.1038/s41586-026-10256-6
  5. Nat Commun. 2026 Mar 13.
    Shared genetic and neuroimmune architecture links type 1 diabetes with neurocognitive traits.
    Priscilla Saarah, Zehra A Syeda, Ziang Xu, Yikai Dong, Habei Jiang, Michelle Shanguyhia, Sourav Roy, Biqing Zhu, Le Zhang, Andrew T Dewan, Samira Asgari, David A Alagpulinsa.
      Type 1 diabetes, particularly with childhood onset, is associated with altered neurocognitive traits, yet the underlying biological mechanisms are unclear. Here, we integrate genome-wide association results with single-cell epigenomic profiles and show that type 1 diabetes heritability is enriched in accessible chromatin of human brain-resident cells, most notably microglia, across neurodevelopment into adulthood. Bonferroni-corrected cross-trait genetic correlation analyses reveal negative correlations of type 1 diabetes with intelligence, executive function, and bipolar disorder, and a positive correlation with myasthenia gravis. Conjunctional false discovery rate analysis identifies pleiotropic loci jointly influencing type 1 diabetes and neurocognitive traits, including the 17q21.31 neurogenomic hub. Mendelian randomization further demonstrates protective effects of educational attainment, intelligence, Alzheimer's disease, and bipolar disorder on type 1 diabetes risk, whereas liability to multiple sclerosis and myasthenia gravis increases type 1 diabetes risk. In the reverse direction, liability to type 1 diabetes is associated with increased risk of myasthenia gravis. We identify several gene expression regulatory variants in brain and immune cells that jointly influence type 1 diabetes and neurocognitive traits, some of which show concordant differential expression in disease-affected versus control tissue. Together, these findings highlight pleiotropic genetic and neuroimmune mechanisms that link type 1 diabetes with cognition and neuropsychiatric disease risk.
    DOI:  https://doi.org/10.1038/s41467-026-70694-8
  6. Nat Metab. 2026 Mar 11.
    Transient steatosis reprograms MDMs for liver repair.
    Ashwin Woodhoo, Marta Varela-Rey.
      
    DOI:  https://doi.org/10.1038/s42255-026-01479-y
  7. Nat Metab. 2026 Mar 12.
    Angiocrine breakdown in metabolically stressed fat.
    Shannon M Reilly, Yang Lin, Shahin Rafii.
      
    DOI:  https://doi.org/10.1038/s42255-026-01481-4
  8. Nat Commun. 2026 Mar 12.
    scTWAS: a powerful statistical framework for single-cell transcriptome-wide association studies.
    Zhaotong Lin, Chang Su.
      Transcriptome-wide association studies (TWAS) have successfully identified genes associated with complex traits and diseases, but most have been performed using bulk gene expression data, which aggregate signals across heterogeneous cell types. Population-scale single-cell RNA sequencing data now make it possible to perform TWAS at the cell-type resolution, but present unique challenges due to strong noises, technical variations, and high sparsity. Here, we propose scTWAS, a statistical method to conduct cell-type-specific TWAS using single-cell data. Leveraging a latent-variable model and moment-based estimation to address the challenges of single-cell data, scTWAS consistently improves the prediction of genetically regulated gene expression across cell types in both blood and brain tissues. Compared to existing methods, scTWAS identifies substantially more gene-trait associations across 29 hematological traits and three immune-related diseases in immune cell types. An application to Alzheimer's disease also reveals cell-subtype-specific associations, including MS4A6A in the disease-associated microglial subtype and PPP1R37 in the inflammatory microglial subtype.
    DOI:  https://doi.org/10.1038/s41467-026-70374-7
  9. Nature. 2026 Mar 10.
    Daily briefing: A daily multivitamin slows the signs of biological ageing.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-026-00792-6
  10. Nat Neurosci. 2026 Mar;29(3): 514
    How the brain can harm the heart.
    Leonie Welberg.
      
    DOI:  https://doi.org/10.1038/s41593-026-02243-x
  11. J Clin Invest. 2026 Mar 10. pii: e197719. [Epub ahead of print]
    Impaired glycosylation promotes rapid transition to hepatocellular carcinoma in model of diet induced steatotic liver disease.
    Abhishek K Singh, Balkrishna Chaube, Kathryn M Citrin, Joseph Fowler, Sungwoon Lee, Jonatas Catarino, James Knight, Sarah C Lowery, Sonal Shree, Keira E Mahoney, Nabil E Boutagy, Inmaculada Ruz-Maldonado, Kathy Harry, Marya Shanabrough, Trenton T Ross, Stacy A Malaker, Yajaira Suárez, Carlos Fernández-Hernando, Kariona A Grabińska, William C Sessa.
      Obesity-linked steatosis is a significant risk factor for hepatocellular carcinoma (HCC); however, the molecular mechanisms underlying the transition from Metabolic dysfunction-associated steatotic liver disease (MASLD) to HCC remains unclear. We explored the role of the endoplasmic reticulum (ER)-associated protein NgBR, an essential component of the cis-prenyltransferases (cis-PTase) enzyme, in chronic liver disease. Hepatocyte-specific NgBR deletion in mice (N-LKO) intensifies triacylglycerol (TAG) accumulation, inflammatory responses, ER/oxidative stress, and fibrosis, ultimately resulting in HCC development with 100% penetrance after four months on a high-fat diet. Similarly, liver-specific knockout of DHDDS (D-LKO) NgBR's cis-PTase partner and a knock-in model carrying a human NgBR mutation that impairs cis-PTase activity developed HCC under high-fat diet conditions, although with lower penetrance. Single cell transcriptomic atlas from affected livers provides a detailed molecular analysis of the transition from liver pathophysiology to HCC development. Mechanistically, NgBR deficiency promotes excessive hepatic TAG accumulation by enhancing lipid uptake and impairing very-low-density lipoprotein (VLDL) secretion. Importantly, pharmacological inhibition of diacylglycerol acyltransferase-2 (DGAT2), a key enzyme in TAG synthesis, abrogates diet-induced liver damage and HCC burden in N-LKO mice. Overall, our findings establish cis-PTase as a critical suppressor of MASLD-HCC conversion and suggest DGAT2 inhibition may serve as a promising therapeutic approach to delay HCC formation in advanced metabolic dysfunction-associated steatohepatitis (MASH).
    Keywords:  Hepatology; Lipoproteins; Liver cancer; Metabolism; Mouse models; Oncology
    DOI:  https://doi.org/10.1172/JCI197719
  12. Nature. 2026 Mar 11.
    Facile induction of immune tolerance by an interleukin-2-TGFβ surrogate agonist.
    Qinli Sun, Alison K Barrett, Masato Ogishi, Huiyun Lyu, Hua Jiang, Honghui Liu, Yang Zhao, Grayson E Rodriguez, Pingdong Tao, Matthias Obenaus, Karsten D Householder, Qizhi Tang, Tobias V Lanz, K Christopher Garcia.
      CD4+ regulatory T cells (Treg cells) are essential for immune tolerance1. Peripherally induced Treg cells (pTreg cells) complement thymic Treg cells by broadening Treg cell reactivity in response to a changing antigenic landscape2. Although both TGFβ and IL-2 synergistically promote functional pTreg cell development in vitro3-6, their combined roles in inducing pTreg cell generation in vivo have not been exploited for tolerizing immunotherapy. Here we designed an IL-2-TGFβ 'surrogate' co-agonist by creating a single-chain fusion protein between IL-2 and a low-affinity TGFβ mimic agonist derived from a helminth parasite7. This IL-2-TGFβ surrogate functions as an AND-gated co-agonist and enabled simultaneous cis-activation of IL-2-STAT5 and TGFβ-SMAD2/3 signalling specifically in T cells that express IL-2 receptors. The IL-2-TGFβ surrogate agonist robustly induced antigen-specific, functional and stable pTreg cells in vivo within peripheral lymphoid organs in mice immunized with ovalbumin (OVA) and myelin oligodendrocyte glycoprotein (MOG)35-55. The induced pTreg cells display an effector-like, actively expanding state with high RORγt expression, enabling efficient migration and suppression of intestinal inflammation. Treatment with this agonist effectively quelled immune activation in mouse models of allergen-induced allergic inflammation and self-antigen-driven autoimmune neuroinflammation, suggesting a strategy for the induction of antigen-specific pTreg cells in vivo to establish immune tolerance in inflammatory, allergic and autoimmune diseases.
    DOI:  https://doi.org/10.1038/s41586-026-10208-0
  13. Nat Neurosci. 2026 Mar;29(3): 514
    Liver-derived exercise factor boosts brain vasculature.
    Rebecca Wright.
      
    DOI:  https://doi.org/10.1038/s41593-026-02241-z
  14. Nature. 2026 Mar 12.
    'Baked, not fried': five highlights from nutrition research.
    Bianca Nogrady.
      
    Keywords:  Diseases; Metabolism; Nutrition; Obesity
    DOI:  https://doi.org/10.1038/d41586-026-00598-6
  15. Immunity. 2026 Mar 10. pii: S1074-7613(26)00078-6. [Epub ahead of print]59(3): 521-523
    Out of many, IL-1.
    Jinsu Lee, Michael A Wheeler.
      Sick animals often show reduced social engagement, a form of adaptive behavioral distancing thought to limit pathogen transmission beyond the infected individual. In a recent issue of Cell, Yang et al. identified a defined molecular and anatomical pathway through which inflammatory signals are sensed by the brain and translated into active social withdrawal.
    DOI:  https://doi.org/10.1016/j.immuni.2026.02.008
  16. Nature. 2026 Mar;651(8105): 284
    Monthly HIV-drug injections offer potent alternative to daily tablets.
      
    Keywords:  HIV infections
    DOI:  https://doi.org/10.1038/d41586-026-00669-8
  17. Immunity. 2026 Mar 10. pii: S1074-7613(26)00079-8. [Epub ahead of print]59(3): 509-511
    Big-eaters choking? Macrophages can't stomach microplastics.
    Luke A Neufeld, Zhe Qi Liu, Tracy L McGaha.
      Microplastics are detectable in diverse human tissues, yet their biological impact remains unclear. In this issue of Immunity, Codo et al.1 dissect the mechanisms involved and find that polystyrene microplastics inhibit tissue-resident phagocyte clearance of dead cells, resulting in concerning consequences for organ function.
    DOI:  https://doi.org/10.1016/j.immuni.2026.02.009
  18. Sci Immunol. 2026 Mar 13. 11(117): eadw4613
    Inflammatory ILC2s migrate to distal tissues during infection using stage-specific S1P receptors.
    Takamasa Ito, Christine F Wu, Yingyu Zhang, Yoshihiro Ishida, Kristjan H Gretarsson, Xinjing Xu, Raymond Zou, Vincent Guichard, Lei H Huang, Richard P Han, Kevin Guckian, Jerold Chun, Jianwen Que, Allen Smith, Joseph F Urban, Chao Lu, Yuefeng Huang.
      Tissue-resident lymphocytes can recirculate, but the underlying molecular mechanism is poorly understood. During helminth infection, intestinal group 2 innate lymphoid cells (ILC2s) rapidly proliferate and give rise to inflammatory ILC2s (iILC2s), which migrate from the intestine to distal tissues. Here, we show in mice that the redistribution of iILC2s requires access to lymphatic vessels. Interleukin-25 (IL-25) induces a substantial change in the epigenetic landscape of iILC2s, with transcription factors KLF2 and ZEB2 driving increased expression of sphingosine-1-phosphate receptor 1 (S1PR1) and S1PR5, respectively. S1PR5 regulates iILC2 exit from the intestine to the lymph, whereas S1PR1 is critical for iILC2 egress from the mesenteric lymph nodes to the blood and then to distal tissues including the lung, where iILC2s contribute to tissue repair. The requirement of two S1PRs is largely due to the dynamic expression of CD69, which mediates S1PR1 internalization. Thus, S1PRs modulate iILC2 emigration from nonlymphoid and lymphoid organs in a stage-specific manner, which provides a framework for understanding the multistep migration of tissue-resident immune cells.
    DOI:  https://doi.org/10.1126/sciimmunol.adw4613
  19. Immunity. 2026 Mar 10. pii: S1074-7613(26)00080-4. [Epub ahead of print]59(3): 512-514
    Immune austerity: How the body balances its books when calories run low.
    Francesco Siracusa, Nicola Gagliani.
      Immune responses are energetically costly and must adapt to systemic nutrient availability. How immunity is reorganized to preserve host glucose during caloric restriction remains unclear. In this issue of Immunity, Menezes-Silva et al. show that dietary restriction, via glucocorticoids, rewires innate and adaptive immunity, and this leads to the conservation of glucose while maintaining protective host defense.
    DOI:  https://doi.org/10.1016/j.immuni.2026.02.010
  20. Nature. 2026 Mar 12.
    Youthful antics predict lifespan - at least for these fish.
    Gemma Conroy.
      
    Keywords:  Ageing; Animal behaviour; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-026-00782-8
  21. Nature. 2026 Mar 11.
    Scientists revive activity in frozen mouse brains for the first time.
    Tosin Thompson.
      
    Keywords:  Biophysics; Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-026-00756-w
  22. Nature. 2026 Mar 11.
    Gut microbes affect cognition during ageing.
    Yi-Ting Cheng, Sarkis K Mazmanian.
      
    Keywords:  Microbiology; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-026-00492-1
  23. Nat Commun. 2026 Mar 13.
    Saccades orchestrate intraocular glucose dynamics to shape visual responses in birds.
    Xi Xu, Tong Xiao, Yibing Chen, Lijuan Song, Chen Wu, Qian Wang, Tao Zhang, Yan Yang.
      Birds exhibit remarkable vision despite lacking the classical retinal vasculature, raising an enigmatic question about how avascular retinas fulfill energy demands necessary for sight. Avian saccades couple rapid gaze shifts with cyclotorsional oscillations. In pigeons, we show that these saccades orchestrate intraocular metabolic dynamics and visual processing. Using combined measurements of eye movements, intraocular glucose, and neuronal activity in retinorecipient brain regions, we found that saccades induce intraocular glucose fluctuations that are closely linked to changes in visual responses over seconds to minutes. Pharmacologically manipulating glucose availability or eliminating saccadic oscillations produced corresponding changes in neuronal responses, demonstrating causality. Thus, stimulus-driven saccades not only serve visual exploration but also propel retinal metabolism, facilitating neuronal visual responses in the absence of retinal vasculature. These findings underscore an intrinsic interplay among eye movements, metabolic regulation, and visual function, offering insight into how oculomotor behavior supports retinal health and visual performance across species.
    DOI:  https://doi.org/10.1038/s41467-026-70672-0
  24. Nature. 2026 Mar 09.
    Daily multivitamin slows signs of biological ageing.
    Jacob Smith.
      
    Keywords:  Ageing; Epigenetics; Nutrition
    DOI:  https://doi.org/10.1038/d41586-026-00741-3
  25. Nature. 2026 Mar;651(8105): 298-300
    National statistics are in crisis around the world - and the impacts will be severe.
    Ehsan Masood, Subhra Priyadarshini, Lucila Pinto.
      
    Keywords:  Economics; Education; Government
    DOI:  https://doi.org/10.1038/d41586-026-00699-2
  26. Aging Cell. 2026 Mar;25(3): e70441
    Aged Male Mice Remain Glucose Tolerant Despite Increased Energy Storage Efficiency Favoring Diet-Induced Obesity.
    Liz Gray, Kaylynn Vidmar, Marita Rivir, Vishnupriya J Borra, Diego Perez-Tilve.
      Obesity and aging are converging health challenges, contributing to morbidity in older populations. However, the specific contribution of age to susceptibility to obesity is unclear. This study examined the impact of age on susceptibility to diet-induced obesity (DIO) and calorie restriction (CR) in male mice. Young (2-3 months) and old (17-24 months) lean C57BL/6J male mice were fed a standard chow diet (CD) or a high-fat diet (HFD) for 28 days, then underwent 18 days of CR. We monitored body weight, body composition, energy intake and expenditure, glucose tolerance, and gene expression in metabolically relevant tissues. HFD-fed old mice exhibited more fat mass gain but, surprisingly, protection from glucose intolerance. In comparison, young controls exhibited resistance to DIO due to reduced calorie storage efficiency. Gene expression analysis suggested reduced plasticity and lipid turnover in visceral adipose tissue but increased subcutaneous adipose tissue plasticity in old mice. The increased energy storage did not protect old mice from body weight loss following CR. Old mice exhibit increased susceptibility to DIO due to near optimal efficiency storing calories as fat. This susceptibility correlates with increased energy storage efficiency and the absence of energy demanding anabolic processes, like lean mass accrual, exhibited by young mice. Despite increased predisposition to obesity, lifelong leanness confers resilient glycemic control to old mice, emphasizing the importance of maintaining a healthy body weight and dietary habits throughout life to mitigate age-related metabolic risks.
    DOI:  https://doi.org/10.1111/acel.70441
  27. Nat Commun. 2026 Mar 10. pii: 2367. [Epub ahead of print]17(1):
    Cell type-specific epigenetic regulatory circuitry of coronary artery disease loci.
    Dennis Hecker, Xiaoning Song, Nina Baumgarten, Anastasiia Diagel, Nikoletta Katsaouni, Ling Li, Shuangyue Li, Ranjan Kumar Maji, Fatemeh Behjati Ardakani, Lijiang Ma, Zhaolong Li, Aldo Moggio, Daniel Tews, Hendrik Sager, Lars Maegdefessel, Martin Wabitsch, Johan L M Björkegren, Heribert Schunkert, Zhifen Chen, Marcel H Schulz.
      Coronary artery disease is the leading cause of death worldwide. Recently, hundreds of genomic loci have been shown to increase risk for the disease, however, the molecular mechanisms underlying signals from risk loci remain largely unclear. Here, we integrate the latest statistics of coronary artery disease genetics from over one million individuals with epigenetic data from 45 cell types to identify genes and transcription factors whose regulation is affected by variants. Applying two statistical approaches, we identify 1580 candidate disease genes, including 23.5% non-coding RNA genes. Enrichment analysis and phenome-wide association studies link the candidate genes to disease-specific pathways and risk factors. We conduct a proof-of-concept biological validation for the non-coding RNA gene IQCH-AS1 via knockout in a human preadipocyte strain. Our study not only pinpoints CAD candidate genes in a cell type-specific manner but also highlights the roles of an understudied ncRNA gene in CAD genetics.
    DOI:  https://doi.org/10.1038/s41467-026-70216-6
  28. Cell. 2026 Mar 11. pii: S0092-8674(26)00222-9. [Epub ahead of print]
    Cell-type-specific transposon demethylation and TAD remodeling in aging mouse brain.
    Qiurui Zeng, Wenliang Wang, Wei Tian, Amit Klein, Anna Bartlett, Hanqing Liu, Joseph R Nery, Rosa G Castanon, Julia Osteen, Nicholas D Johnson, Wubin Ding, Huaming Chen, Jordan Altshul, Mia Kenworthy, Cynthia Valadon, William Owens, Zhanghao Wu, Maria Luisa Amaral, Nathan R Zemke, Yuru Song, Cindy Tatiana Báez-Becerra, Silvia Cho, Chumo Chen, Jackson Willier, Stella Cao, Jonathan Rink, Jasper Lee, Ariana Barcoma, Jessica Arzavala, Nora Emerson, Yuancheng Ryan Lu, Bing Ren, M Margarita Behrens, Joseph R Ecker.
      Aging is a major risk factor for neurodegenerative diseases, yet the underlying epigenetic mechanisms remain unclear. Here, we generated a comprehensive single-nucleus cell atlas of brain aging across multiple brain regions, comprising 132,551 single-cell methylomes and 72,666 joint chromatin conformation-methylome nuclei. Integration with companion transcriptomic and chromatin accessibility data yielded a cross-modality taxonomy of 36 major cell types. We observed that transposable element (TE) methylation alone distinguished age groups, showing cell-type-specific genome-wide demethylation. Chromatin conformation analysis demonstrated age-related increases in topologically associated domain (TAD) boundary strength with enhanced accessibility at CCCTC-binding factor (CTCF) binding sites. Spatial transcriptomics across 895,296 cells revealed regional heterogeneity during aging within identical cell types. Finally, we developed deep-learning models that reliably predict age-related gene expression changes using multi-modal epigenetic features, providing mechanistic insights into gene regulation. Age-related comparisons use a 2-month baseline reflecting the late-adolescent/early-young adult stage. This dataset advances our understanding of brain aging and offers potential translational applications.
    Keywords:  3D genome; DNA methylation; brain aging; deep learning; multi-omic; neurons and glias; single-cell; spatial transcriptome; topologically associating domains; transposable elements
    DOI:  https://doi.org/10.1016/j.cell.2026.02.015
  29. JAMA. 2026 Mar 13.
    Alzheimer Disease Sex Differences May Be Tied to P-Tau217.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.1013
  30. Nat Commun. 2026 Mar 13.
    Butyrate extends health and lifespan in mice with mitochondrial deficiency.
    Enrique Gabandé-Rodríguez, Manuel M Gómez de Las Heras, Pablo Ramírez-Ruiz de Erenchun, Carolina Simó, Virginia García-Cañas, Naohiro Inohara, Inés Berenguer-López, Violeta Enríquez-Zarralanga, Álvaro Fernández-Almeida, Jorge Oller, Gonzalo Soto-Heredero, Elisa Carrasco, Cristina Vázquez-Muñoz, Sandra Delgado-Pulido, José Ignacio Escrig-Larena, Isaac Francos-Quijorna, Raquel Justo-Méndez, Juan Francisco Aranda, Joanna Poulton, Ana Victoria Lechuga-Vieco, José Antonio Enríquez, Gabriel Núñez, María Mittelbrunn.
      Mitochondrial diseases progressively lead to multisystemic failure with treatment options remaining extremely limited. Here, to investigate strategies that alleviate mitochondrial dysfunction, we first generate a ubiquitous and tamoxifen-inducible knockout mouse model of mitochondrial transcription factor A (TFAM), a nuclear-encoded protein involved in mitochondrial DNA (mtDNA) maintenance - Tfamfl/flUbcCre-ERT2 (iTfamKO) mice. Systemic TFAM deficiency triggers mitochondrial decline in a myriad of tissues in adult mice. Consequently, iTfamKO mice manifest multiorgan dysfunction including lipodystrophy, sarcopenia, metabolic alterations, kidney failure, neurodegeneration, and locomotor dysregulation, which result in the premature death of these mice. Interestingly, iTfamKO mice display intestinal barrier disruption and gut dysbiosis, with diminished levels of microbiota-derived short-chain fatty acids (SCFAs), such as butyrate. Mice with a deficient proof-reading version of the mtDNA polymerase gamma (mtDNA-mutator mice) phenocopy the dysfunction of the intestinal barrier and bacterial dysbiosis with reduced levels of butyrate, suggesting that different mouse models of mitochondrial dysfunction share insufficient generation of butyrate. Transfer of microbiota from healthy control mice or administration of tributyrin, a butyrate precursor, delay multiple signs of multimorbidity, extending lifespan in iTfamKO mice. Mechanistically, butyrate supplementation recovers epigenetic histone acylation marks that are lost in the intestine of Tfam deficient mice. Overall, our findings highlight the relevance of preserving host-microbiota symbiosis in disorders related to mitochondrial dysfunction.
    DOI:  https://doi.org/10.1038/s41467-026-70547-4
  31. Nat Metab. 2026 Mar 11.
    Lipid-dependent accrual of a subset of monocyte-derived macrophages is essential for tissue regeneration.
    Tao Yao, Xin Tian, Linbin Rao, Jinling Ni, Jiayong Yu, Hongguo Yang, Yuexiao Tang, Xingxiao Huang, Xintong Xia, Lin Zhao, Bowen Diao, Yan Ping, Danni Wei, Siqi Li, Hui Chai, Zhiming Hu, Xiongzhong Ruan, Suihan Feng, Mengle Shao, Bo Shan, Ying Wu.
      Tissue regeneration is essential for maintaining tissue homoeostasis and influences disease progression. In the liver, injury evokes a complex regenerative response with robust immune activation and metabolic rewiring, yet how these processes coordinate hepatocyte proliferation remains unclear. Here we show the presence of an injury-induced, lipid-dependent accrual of a distinct monocyte-derived macrophage (MDM) subset characterized by abundant cytosolic lipid content and heightened inflammatory response. Multi-omic analyses, spanning both single-cell transcriptomics and quantitative lipidomics, unveil substantial cellular diversity and heterogeneity between these 'lipo-inflammatory MDMs' (termed LIMMs) and other hepatic macrophages, including Kupffer cells. Blocking CD36-dependent LIMM induction markedly impairs hepatocyte proliferation and liver regeneration in injured livers. Mechanistically, CD36-mediated increase in ceramide biosynthesis activates IRE1α-XBP1 signalling pathway in LIMMs, driving production of the regenerative cytokine interleukin-6. Disrupting CD36-dependent IRE1α activation in LIMMs compromises liver repair. These findings identify a lipid-laden MDM subcluster as a key regulator of regenerative inflammation in injured livers.
    DOI:  https://doi.org/10.1038/s42255-026-01480-5
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