bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–05–18
23 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. The cost of health.
  2. A protein association atlas for human tissues.
  3. Differential regulation of fetal bone marrow and liver hematopoiesis by yolk-sac-derived myeloid cells.
  4. Mice grow bigger brains when given this stretch of human DNA.
  5. Towards a consensus atlas of human and mouse adipose tissue at single-cell resolution.
  6. Pre-existing epigenetic state and differential NF-κB activation shape type 2 immune cell responses.
  7. C/EBPα activates Irf8 expression in myeloid progenitors at the +56-kb enhancer to initiate cDC1 development.
  8. scPrediXcan integrates deep learning methods and single-cell data into a cell-type-specific transcriptome-wide association study framework.
  9. Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV.
  10. Fibroblasts in immune responses, inflammatory diseases and therapeutic implications.
  11. dVGLUT Is a Mediator of Sex Differences in Dopamine Neuron Mitochondrial Function Across Aging and in a Parkinson's Disease Model.
  12. Prediction of protein subcellular localization in single cells.
  13. Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity.
  14. A systematic assessment of transcription factor function.
  15. Cell biological insights into human STING variants.
  16. You know my NAMs.
  17. Acute regulation of murine adipose tissue lipolysis and insulin resistance by the TGFβ superfamily protein GDF3.
  18. Combining cross-sectional and longitudinal genomic approaches to identify determinants of cognitive and physical decline.
  19. Ancient viruses sustain mammalian reproduction.
  20. Ppp1r3b is a metabolic switch that shifts hepatic energy storage from lipid to glycogen.
  21. Programmable gene insertion in human cells with a laboratory-evolved CRISPR-associated transposase.
  22. GDF8 and activin A blockade protects against GLP-1-induced muscle loss while enhancing fat loss in obese male mice and non-human primates.
  23. Cross-regulation between the nervous system and type 2 immunity.
  1. Science. 2025 May 15. 388(6748): 790
    The cost of health.
    Lara de Macedo Monteiro.
      
    DOI:  https://doi.org/10.1126/science.ady8982
  2. Nat Biotechnol. 2025 May 12.
    A protein association atlas for human tissues.
      
    DOI:  https://doi.org/10.1038/s41587-025-02692-y
  3. Nat Commun. 2025 May 14. 16(1): 4427
    Differential regulation of fetal bone marrow and liver hematopoiesis by yolk-sac-derived myeloid cells.
    Benjamin Weinhaus, Shelli Homan, Morgan Kincaid, Aryan Tadwalkar, Xiaowei Gu, Sumit Kumar, Anastasiya Slaughter, Jizhou Zhang, Qingqing Wu, J Matthew Kofron, Ty D Troutman, Tony DeFalco, Daniel Lucas.
      Fetal hematopoiesis takes place in the liver before colonizing the bone marrow where it will persist for life. This colonization is thought to be mediated by specification of a microenvironment that selectively recruits hematopoietic cells to the nascent bone marrow. The identity and mechanisms regulating the specification of this colonization niche are unclear. Here we identify a VCAM1+ sinusoidal colonization niche in the diaphysis that regulates neutrophil and hematopoietic stem cell colonization of the bone marrow. Using confocal microscopy, we find that colonizing hematopoietic stem and progenitor cells (HSPC) and myeloid cells selectively localize to a subset of VCAM1+ sinusoids in the center of the diaphysis. Vcam1 deletion in endothelial cells impairs hematopoietic colonization while depletion of yolk-sac-derived osteoclasts disrupts VCAM1+ expression, and impairs neutrophil and HSPC colonization to the bone marrow. Depletion of yolk-sac-derived myeloid cells increases fetal liver hematopoietic stem cell numbers, function and erythropoiesis independent of osteoclast activity. Thus, the yolk sac produces myeloid cells that have opposite roles in fetal hematopoiesis: while yolk-sac derived myeloid cells in the bone marrow promote hematopoietic colonization by specifying a VCAM1+ colonization niche, a different subset of yolk-sac-derived myeloid cells inhibits HSC in the fetal liver.
    DOI:  https://doi.org/10.1038/s41467-025-59058-w
  4. Nature. 2025 May 14.
    Mice grow bigger brains when given this stretch of human DNA.
    Gemma Conroy.
      
    Keywords:  Brain; Genetics; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-01515-z
  5. Nat Metab. 2025 May 13.
    Towards a consensus atlas of human and mouse adipose tissue at single-cell resolution.
    Anne Loft, Margo P Emont, Ada Weinstock, Adeline Divoux, Adhideb Ghosh, Allon Wagner, Ann V Hertzel, Babukrishna Maniyadath, Bart Deplancke, Boxiang Liu, Camilla Scheele, Carey Lumeng, Changhai Ding, Chenkai Ma, Christian Wolfrum, Clarissa Strieder-Barboza, Congru Li, Danh D Truong, David A Bernlohr, Elisabet Stener-Victorin, Erin E Kershaw, Esti Yeger-Lotem, Farnaz Shamsi, Hannah X Hui, Henrique Camara, Jiawei Zhong, Joanna Kalucka, Joseph A Ludwig, Julie A Semon, Jutta Jalkanen, Katie L Whytock, Kyle D Dumont, Lauren M Sparks, Lindsey A Muir, Lingzhao Fang, Lucas Massier, Luis R Saraiva, Marc D Beyer, Marc G Jeschke, Marcelo A Mori, Mariana Boroni, Martin J Walsh, Mary-Elizabeth Patti, Matthew D Lynes, Matthias Blüher, Mikael Rydén, Natnael Hamda, Nicole L Solimini, Niklas Mejhert, Peng Gao, Rana K Gupta, Rinki Murphy, Saeed Pirouzpanah, Silvia Corvera, Su'an Tang, Swapan K Das, Søren F Schmidt, Tao Zhang, Theodore M Nelson, Timothy E O'Sullivan, Vissarion Efthymiou, Wenjing Wang, Yihan Tong, Yu-Hua Tseng, Susanne Mandrup, Evan D Rosen.
      Adipose tissue (AT) is a complex connective tissue with a high relative proportion of adipocytes, which are specialized cells with the ability to store lipids in large droplets. AT is found in multiple discrete depots throughout the body, where it serves as the primary repository for excess calories. In addition, AT has an important role in functions as diverse as insulation, immunity and regulation of metabolic homeostasis. The Human Cell Atlas Adipose Bionetwork was established to support the generation of single-cell atlases of human AT as well as the development of unified approaches and consensus for cell annotation. Here, we provide a first roadmap from this bionetwork, including our suggested cell annotations for humans and mice, with the aim of describing the state of the field and providing guidelines for the production, analysis, interpretation and presentation of AT single-cell data.
    DOI:  https://doi.org/10.1038/s42255-025-01296-9
  6. Immunity. 2025 May 09. pii: S1074-7613(25)00179-7. [Epub ahead of print]
    Pre-existing epigenetic state and differential NF-κB activation shape type 2 immune cell responses.
    Vincent Guichard, Felipe Batista Leão, Jingyao Zhao, Yingyu Zhang, Takamasa Ito, Simon Shirley, Thomas S Postler, Ruxiao Tian, Yuefeng Huang, Sankar Ghosh.
      CD4+ T helper 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s) drive type 2 immune responses via similar effector molecules that are primarily induced by different signals-interleukin (IL)-33 in ILC2s and TCR engagement in Th2 cells. Here, we examined the transcriptional regulation of type 2 immunity, focusing on the NF-κB pathway, which is differentially activated by TCR engagement or cytokine signaling. Conditional deletion of the NF-κB subunits c-Rel and p65 limited the expression of key type 2 genes, including Il13 and Il5, in ILC2s but not in Th2 cells. Genome-wide analysis revealed that the regulatory regions of such genes exist in an open chromatin state in ILC2s, allowing NF-κB binding upon IL-33 stimulation. These regions are less accessible in unstimulated Th2 cells, where NFAT plays a dominant role. Accordingly, p65 deletion impaired ILC2 activation and function during airway inflammation and helminth infection. Thus, innate and adaptive lymphocytes leverage distinct epigenetic landscapes and transcriptional regulators to control shared effector genes.
    Keywords:  ILC2; Il-13; Il-33; Il-4; Il-5; NF-κB; Th2; c-rel; p65; type 2 cytokines
    DOI:  https://doi.org/10.1016/j.immuni.2025.04.016
  7. Sci Immunol. 2025 May 16. 10(107): eadt5899
    C/EBPα activates Irf8 expression in myeloid progenitors at the +56-kb enhancer to initiate cDC1 development.
    Jing Chen, Tian-Tian Liu, Feiya Ou, Ray A Ohara, Suin Jo, Joshua Luke Postoak, Takeshi Egawa, Ryan B Day, Theresa L Murphy, Kenneth M Murphy, Sunkyung Kim.
      Development of type 1 conventional dendritic cells (cDC1s) underlies the capacity to generate antiviral and antitumor immune responses. Here, we identify the basis for cDC1 development from its earliest progenitors, determining the hierarchy of several required transcription factors and uncovering a series of mandatory cis interactions between constituent enhancers within the Irf8 superenhancer. We produced in vivo mutations of two C/EBPα binding sites that comprise the Irf8 +56-kilobase (kb) enhancer that markedly reduced IRF8 expression in all myeloid progenitors and impaired cDC1 development. These sites did not bind RUNX1 or RUNX3, and C/EBPα expression was instead regulated by their action at the Cebpa +37-kb enhancer, placing RUNX factors upstream of Cebpa in regulating Irf8. Last, we demonstrate that cis interactions between the +56-kb Irf8 enhancer and the previously reported +41- and +32-kb Irf8 enhancers are mandatory in the sequential progression of these stage-specific constituent elements.
    DOI:  https://doi.org/10.1126/sciimmunol.adt5899
  8. Cell Genom. 2025 May 14. pii: S2666-979X(25)00131-4. [Epub ahead of print]5(5): 100875
    scPrediXcan integrates deep learning methods and single-cell data into a cell-type-specific transcriptome-wide association study framework.
    Yichao Zhou, Temidayo Adeluwa, Lisha Zhu, Sofia Salazar-Magaña, Sarah Sumner, Hyunki Kim, Saideep Gona, Festus Nyasimi, Rohit Kulkarni, Joseph E Powell, Ravi Madduri, Boxiang Liu, Mengjie Chen, Hae Kyung Im.
      Transcriptome-wide association studies (TWASs) help identify disease-causing genes but often fail to pinpoint disease mechanisms at the cellular level because of the limited sample sizes and sparsity of cell-type-specific expression data. Here, we propose scPrediXcan, which integrates state-of-the-art deep learning approaches that predict epigenetic features from DNA sequences with the canonical TWAS framework. Our prediction approach, ctPred, predicts cell-type-specific expression with high accuracy and captures complex gene-regulatory grammar that linear models overlook. Applied to type 2 diabetes (T2D) and systemic lupus erythematosus (SLE), scPrediXcan outperformed the canonical TWAS framework by identifying more candidate causal genes, explaining more genome-wide association study (GWAS) loci and providing insights into the cellular specificity of TWAS hits. Overall, our results demonstrate that scPrediXcan represents a significant advance, promising to deepen our understanding of the cellular mechanisms underlying complex diseases.
    Keywords:  Enformer; GWAS; PrediXcan; TWAS; deep learning; single-cell; single-cell RNA-seq; systemic lupus erythematosus; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.xgen.2025.100875
  9. Cell Metab. 2025 May 08. pii: S1550-4131(25)00253-0. [Epub ahead of print]
    Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV.
    Jessica W Davidson, Raghav Jain, Thomas Kizzar, Gisela Geoghegan, Daniel J Nesbitt, Amy Cavanagh, Akira Abe, Kwamina Nyame, Andrea Hunger, Xiaojuan Chao, Isabella James, Helaina Walesewicz, Dominique A Baldwin, Gina Wade, Sylwia Michorowska, Rakesh Verma, Kathryn Schueler, Vania Hinkovska-Galcheva, Evgenia Shishkova, Wen-Xing Ding, Joshua J Coon, James A Shayman, Monther Abu-Remaileh, Judith A Simcox.
      Cold exposure is a selective environmental stress that elicits a rapid metabolic shift to maintain energy homeostasis. In response to cold exposure, the liver rewires the metabolic state, shifting from glucose to lipid catabolism. By probing the liver lipids in cold exposure, we observed that the lysosomal bis(monoacylglycero)phosphate (BMP) lipids were rapidly increased during cold exposure. BMP lipid changes occurred independently of lysosomal abundance but were dependent on the lysosomal transcriptional regulator transcription factor EB (TFEB). Knockdown of Tfeb in hepatocytes decreased BMP lipid levels and led to cold intolerance in mice. We assessed TFEB-binding sites of lysosomal genes and determined that the phospholipase a2 group XV (PLA2G15) regulates BMP lipid catabolism. Decreasing Pla2g15 levels in mice increased BMP lipids, ablated the cold-induced rise in BMP lipids, and improved cold tolerance. Mutation of the catalytic site of PLA2G15 ablated the BMP lipid breakdown. Together, our studies uncover TFEB regulation of BMP lipids through PLA2G15 catabolism.
    Keywords:  BMP; LC-MS; Pla2g15; TFEB; bis(monoacylglycero)phosphate; cold exposure; lipidomics; liquid chromatography-mass spectrometry; liver; lysosome; phospholipase A2 G15; transcription factor EB
    DOI:  https://doi.org/10.1016/j.cmet.2025.04.015
  10. Nat Rev Rheumatol. 2025 May 14.
    Fibroblasts in immune responses, inflammatory diseases and therapeutic implications.
    Angela E Zou, Suppawat Kongthong, Alisa A Mueller, Michael B Brenner.
      Once regarded as passive bystander cells of the tissue stroma, fibroblasts have emerged as active orchestrators of tissue homeostasis and disease. From regulating immunity and controlling tissue remodelling to governing cell growth and differentiation, fibroblasts assume myriad roles in guiding normal tissue development, maintenance and repair. By comparison, in chronic inflammatory diseases such as rheumatoid arthritis, fibroblasts recruit and sustain inflammatory leukocytes, become dominant producers of pro-inflammatory factors and catalyse tissue destruction. In other disease contexts, fibroblasts promote fibrosis and impair host control of cancer. Single-cell studies have uncovered striking transcriptional and functional heterogeneity exhibited by fibroblasts in both normal tissues and diseased tissues. In particular, advances in the understanding of fibroblast pathology in rheumatoid arthritis have shed light on pathogenic fibroblast states in other chronic diseases. The differentiation and activation of these fibroblast states is driven by diverse physical and chemical cues within the tissue microenvironment and by cell-intrinsic signalling and epigenetic mechanisms. These insights into fibroblast behaviour and regulation have illuminated therapeutic opportunities for the targeted deletion or modulation of pathogenic fibroblasts across many diseases.
    DOI:  https://doi.org/10.1038/s41584-025-01259-0
  11. Aging Cell. 2025 May 12. e70096
    dVGLUT Is a Mediator of Sex Differences in Dopamine Neuron Mitochondrial Function Across Aging and in a Parkinson's Disease Model.
    Silas A Buck, Samuel J Mabry, Tenzin Kunkhyen, Zilu Yang, Sophie A Rubin, Jinting Yang, Claire E J Cheetham, Zachary Freyberg.
      Sex differences in Parkinson's disease (PD) offer insights into mechanisms of dopaminergic cell resilience. Female dopamine (DA) neurons are more resilient via mechanisms that remain unclear. Here, we discovered key sex and regional differences in mitochondrial generation of cytotoxic reactive oxygen species (ROS) and their implications for DA neuron resilience using the Drosophila model. While aging raised mitochondrial ROS in DA neurons of both sexes, we observed a sexually dimorphic response in the paraquat (PQ) PD model. DA neuron knockdown of the Drosophila vesicular glutamate transporter (dVGLUT) increased mitochondrial ROS only in males, leaving females protected. Cell depolarization, a physiological stressor, similarly raised mitochondrial ROS in DA neurons selectively in males following dVGLUT knockdown. We also identified dVGLUT-dependent changes in intracellular ATP in both sexes. Overall, we discovered sexually dimorphic relationships between dVGLUT, ATP synthesis, and ROS generation in DA neurons, providing a mechanistic basis for DA neuron resilience.
    Keywords:   Drosophila ; Parkinson's disease; aging; dVGLUT; dopamine; glutamate; mitochondria; reactive oxygen species
    DOI:  https://doi.org/10.1111/acel.70096
  12. Nat Methods. 2025 May 13.
    Prediction of protein subcellular localization in single cells.
    Xinyi Zhang, Yitong Tseo, Yunhao Bai, Fei Chen, Caroline Uhler.
      The subcellular localization of a protein is important for its function, and its mislocalization is linked to numerous diseases. Existing datasets capture limited pairs of proteins and cell lines, and existing protein localization prediction models either miss cell-type specificity or cannot generalize to unseen proteins. Here we present a method for Prediction of Unseen Proteins' Subcellular localization (PUPS). PUPS combines a protein language model and an image inpainting model to utilize both protein sequence and cellular images. We demonstrate that the protein sequence input enables generalization to unseen proteins, and the cellular image input captures single-cell variability, enabling cell-type-specific predictions. Experimental validation shows that PUPS can predict protein localization in newly performed experiments outside the Human Protein Atlas used for training. Collectively, PUPS provides a framework for predicting differential protein localization across cell lines and single cells within a cell line, including changes in protein localization driven by mutations.
    DOI:  https://doi.org/10.1038/s41592-025-02696-1
  13. Nat Commun. 2025 May 12. 16(1): 4374
    Twin pair analysis uncovers links between DNA methylation, mitochondrial DNA quantity and obesity.
    Aino Heikkinen, Vivienne F C Esser, Seung Hyuk T Lee, Sara Lundgren, Antti Hakkarainen, Jesper Lundbom, Juho Kuula, Per-Henrik Groop, Sini Heinonen, Sergio Villicaña, Jordana T Bell, Alice Maguolo, Emma Nilsson, Charlotte Ling, Allan Vaag, Päivi Pajukanta, Jaakko Kaprio, Kirsi H Pietiläinen, Shuai Li, Miina Ollikainen.
      Alterations in mitochondrial metabolism in obesity may indicate disrupted communication between mitochondria and nucleus, and DNA methylation may influence this interplay. Here, we leverage data from the Finnish Twin Cohort study subcohort (n = 173; 86 full twin pairs, 1 singleton), including comprehensive measurements of obesity-related outcomes, mitochondrial DNA quantity and nuclear DNA methylation levels in adipose and muscle tissue, to identify one CpG at SH3BP4 significantly associated with mitochondrial DNA quantity in adipose tissue (FDR < 0.05). We also show that SH3BP4 methylation correlates with its gene expression. Additionally, we find that 14 out of the 35 obesity-related traits display significant associations with both SH3BP4 methylation and mitochondrial DNA quantity in adipose tissue. We use data from TwinsUK and the Scandinavian T2D-discordant monozygotic twin cohort, to validate the observed associations. Further analysis using ICE FALCON suggests that mitochondrial DNA quantity, insulin sensitivity and certain body fat measures are causal to SH3BP4 methylation. Examining mitochondrial DNA quantity and obesity-related traits suggests causation from mitochondrial DNA quantity to obesity, but unmeasured within-individual confounding cannot be ruled out. Our findings underscore the impact of mitochondrial DNA quantity on DNA methylation and expression of the SH3BP4 gene within adipose tissue, with potential implications for obesity.
    DOI:  https://doi.org/10.1038/s41467-025-59576-7
  14. Nat Genet. 2025 May;57(5): 1061
    A systematic assessment of transcription factor function.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-025-02216-z
  15. Cell Struct Funct. 2025 May 14.
    Cell biological insights into human STING variants.
    Shogo Koide, Eisuke Yumoto, Jun Nakayama, Shigeki Higashiyama, Yoshihiko Kuchitsu, Tomohiko Taguchi.
      Stimulator of interferon genes (STING) is an endoplasmic reticulum (ER)-localized transmembrane protein. STING induces the type I interferon and inflammatory responses against a variety of double-stranded DNA (dsDNA) viruses, which is critical to limiting their infection and replication. In certain settings where self-DNAs (genomic or mitochondrial DNA) emerge in the cytosol or the intracellular membrane traffic is impaired, STING becomes activated and triggers inflammation, which may contribute to the pathogenesis of various autoinflammatory and neurodegenerative diseases including COPA syndrome and Parkinson's disease. The human STING gene holds genetic heterogeneity with R232, HAQ (R71H-G230A-R293Q), and H232 being the most common variants, and population stratification. A very recent study has shown that HAQ, not R232 or H232, mediates completely clinical protection in the pathogenesis of COPA syndrome. These results reveal, for the first time, the distinct activities of the major variants in the context of pathogenesis of autoinflammatory diseases. Besides these major variants, there exist minor pathogenic STING variants that cause an autoinflammatory disease called STING-associated vasculopathy with onset in infancy (SAVI). This review summarizes recent insights into human STING variants and their inflammatory activities.Key words: innate immunity, STING variants, COPA syndrome, membrane traffic, the Golgi.
    Keywords:  COPA syndrome; STING variants; innate immunity; membrane traffic; the Golgi
    DOI:  https://doi.org/10.1247/csf.25020
  16. Immunity. 2025 May 13. pii: S1074-7613(25)00188-8. [Epub ahead of print]58(5): 1179-1181
    You know my NAMs.
    Sourav Ghosh, Carla V Rothlin.
      The critical immunoregulatory function of the lung nerve- and airway-associated macrophages (NAMs) is increasingly becoming evident. In this issue of Immunity, Yeung et al. report that NAMs' response to type I interferon limits SARS-CoV-2 spread, inflammation, lung injury, and mortality.
    DOI:  https://doi.org/10.1016/j.immuni.2025.04.025
  17. Nat Commun. 2025 May 13. 16(1): 4432
    Acute regulation of murine adipose tissue lipolysis and insulin resistance by the TGFβ superfamily protein GDF3.
    Nagasuryaprasad Kotikalapudi, Deepti Ramachandran, Daniel Vieira, William B Rubio, Gregory R Gipson, Luca Troncone, Kylie Vestal, David E Maridas, Vicki Rosen, Paul B Yu, Thomas B Thompson, Alexander S Banks.
      TGFβ superfamily proteins can affect cellular differentiation, thermogenesis, and fibrosis in mammalian adipose tissue. Here we describe a role for Growth Differentiation Factor 3 (GDF3) on mature adipocyte biology. We find inducible GDF3 loss of function in obese adult mice leads to reduced lipolysis, improved glucose tolerance, and reduced glycemic variability. The effects on lipolysis are driven by lower levels of β3-adrenergic receptor, decreased cAMP and PKA signaling. GDF3 is an ALK5, ALK7, ACVR2A and ACVR2B agonist and also a BMPR2 antagonist. Unlike ALK7 or activin E knockouts, acute GDF3 loss of function does not affect body weight or energy balance but significantly improves metabolic health. These results suggest that blocking GDF3 can improve metabolic health independent of body weight and food intake, an intriguing new model for developing anti-diabetic therapies. Together these results provide much-needed clarity to both the molecular pathways involved in GDF3 signaling and its physiological effects.
    DOI:  https://doi.org/10.1038/s41467-025-59673-7
  18. Nat Commun. 2025 May 15. 16(1): 4524
    Combining cross-sectional and longitudinal genomic approaches to identify determinants of cognitive and physical decline.
    Tabea Schoeler, Jean-Baptiste Pingault, Zoltán Kutalik.
      Large-scale genomic studies focusing on the genetic contribution to human aging have mostly relied on cross-sectional data. With the release of longitudinally curated aging phenotypes by the UK Biobank (UKBB), it is now possible to study aging over time at genome-wide scale. In this work, we evaluated the suitability of competing models of change in realistic simulation settings, performed genome-wide association scans on simulation-validated measures of age-related deweekcline, and followed up with LD-score regression and Mendelian Randomization (MR) analyses. Focusing on global cognitive and physical function, we observed marked differences between baseline function (θ) and accelerated decline (Δ). Both outcomes showed distinct heritability levels (e.g., 31.38% hθ2 versus 3.15% hΔ2 for physical function) and different associated loci (e.g., DUSP6 specific to physical Δ). Further, we found little commonalities across the two dimensions of aging-while cognitive decline was largely driven by Alzheimer's disease liability (standardized MR-effect, γ = 0.17), physical decline was mostly impacted by telomere length (γ = -0.05) and bone mineral density (γ = -0.05). Our work highlights the utility of longitudinal genomic efforts to scrutinize age-dependent genetic and environmental effects on physical and cognitive outcomes. Careful modelling and attention to participation characteristics are, however, crucial for valid inference.
    DOI:  https://doi.org/10.1038/s41467-025-59383-0
  19. Nat Aging. 2025 May 14.
    Ancient viruses sustain mammalian reproduction.
    Caroline A Doherty, Diana J Laird.
      
    DOI:  https://doi.org/10.1038/s43587-025-00867-5
  20. Sci Adv. 2025 May 16. 11(20): eado3440
    Ppp1r3b is a metabolic switch that shifts hepatic energy storage from lipid to glycogen.
    Kate Townsend Creasy, Minal B Mehta, Carolin V Schneider, Joseph Park, David Zhang, Swapnil V Shewale, John S Millar, Marijana Vujkovic, Nicholas J Hand, Paul M Titchenell, Joseph A Baur, Daniel J Rader.
      The PPP1R3B gene, encoding PPP1R3B protein, is critical for liver glycogen synthesis and maintaining blood glucose levels. Genetic variants affecting PPP1R3B expression are associated with several metabolic traits and liver disease, but the precise mechanisms are not fully understood. We studied the effects of both Ppp1r3b overexpression and deletion in mice and cell models and found that both changes in Ppp1r3b expression result in dysregulated metabolism and liver damage, with overexpression increasing liver glycogen stores, while deletion resulted in higher liver lipid accumulation. These patterns were confirmed in humans where variants increasing PPP1R3B expression had lower liver fat and decreased plasma lipids, whereas putative loss-of-function variants were associated with increased liver fat and elevated plasma lipids. These findings support that PPP1R3B is a crucial regulator of hepatic metabolism beyond glycogen synthesis and that genetic variants affecting PPP1R3B expression levels influence if hepatic energy is stored as glycogen or triglycerides.
    DOI:  https://doi.org/10.1126/sciadv.ado3440
  21. Science. 2025 May 15. 388(6748): eadt5199
    Programmable gene insertion in human cells with a laboratory-evolved CRISPR-associated transposase.
    Isaac P Witte, George D Lampe, Simon Eitzinger, Shannon M Miller, Kiara N Berríos, Amber N McElroy, Rebeca T King, Olivia G Stringham, Diego R Gelsinger, Phuc Leo H Vo, Albert T Chen, Jakub Tolar, Mark J Osborn, Samuel H Sternberg, David R Liu.
      Programmable gene integration in human cells has the potential to enable mutation-agnostic treatments for loss-of-function genetic diseases and facilitate many applications in the life sciences. CRISPR-associated transposases (CASTs) catalyze RNA-guided DNA integration but thus far demonstrate minimal activity in human cells. Using phage-assisted continuous evolution (PACE), we generated CAST variants with >200-fold average improved integration activity. The evolved CAST system (evoCAST) achieves ~10 to 30% integration efficiencies of kilobase-size DNA cargoes in human cells across 14 tested genomic target sites, including safe harbor loci, sites used for immunotherapy, and genes implicated in loss-of-function diseases, with undetected indels and low levels of off-target integration. Collectively, our findings establish a platform for the laboratory evolution of CASTs and advance a versatile system for programmable gene integration in living systems.
    DOI:  https://doi.org/10.1126/science.adt5199
  22. Nat Commun. 2025 May 13. 16(1): 4377
    GDF8 and activin A blockade protects against GLP-1-induced muscle loss while enhancing fat loss in obese male mice and non-human primates.
    Jason W Mastaitis, Daniel Gomez, José G Raya, Diana Li, Soo Min, Michael Stec, Sandra Kleiner, Toya McWilliams, Judith Y Altarejos, Andrew J Murphy, George D Yancopoulos, Mark W Sleeman.
      Glucagon-like peptide-1 receptor agonists act via appetite suppression and caloric restriction. These treatments can result in significant muscle loss, likely due to evolutionary mechanisms protecting against food scarcity as muscle is a major energy utilizer. One mechanism that reduces muscle mass involves activation of type II activin receptors, ActRIIA/B, which yield profound muscle growth in humans when blocked. We previously demonstrated GDF8, also known as myostatin, and activin A are the two major ActRIIA/B ligands mediating muscle minimization. Here, we report that dual blockade can also prevent muscle loss associated with glucagon-like peptide-1 receptor agonists - and even increase muscle mass - in both obese mice and non-human primates; moreover, this muscle preservation enhances fat loss and is metabolically beneficial. These data raise the possibility that supplementing glucagon-like peptide-1 receptor agonist treatment with GDF8 and activin A blockade could greatly improve the quality of weight loss during the treatment of obesity in humans.
    DOI:  https://doi.org/10.1038/s41467-025-59485-9
  23. Sci Immunol. 2025 May 16. 10(107): eadp6450
    Cross-regulation between the nervous system and type 2 immunity.
    Nicholas M Mroz, Pailin Chiaranunt, Anna V Molofsky, Ari B Molofsky.
      Interactions between the nervous and immune systems are critical to healthy physiology and are altered in many human diseases. Many of the major players in type 2 immune responses, including type 2 lymphocytes and cytokines, mast cells, and immunoglobulin E, have been implicated in neuronal function and behavior. Conversely, neurons in both the central and peripheral nervous systems can affect type 2 immune responses and behaviors relevant to allergy, such as food avoidance. Defining this complex circuitry and its molecular intermediates in physiology may reveal type 2 immunomodulators that can be harnessed for therapeutic benefit in neurologic diseases including Alzheimer's disease, brain injury, and neurodevelopmental disorders. Conversely, modulation of the nervous system may be an important adjunct to treating immunologic disorders including atopic dermatitis, asthma, and food allergy. This Review covers recent work defining how the nervous system can both regulate and be regulated by type 2 immune responses.
    DOI:  https://doi.org/10.1126/sciimmunol.adp6450
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