bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–09–20
twenty-six papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Cagrilintide and retatrutide combination therapy enhances weight loss and metabolic outcomes in obese male rats.
  2. Cognitive resilience helps to predict Alzheimer's dementia.
  3. Acute activation of Gq-signaling in pancreatic islet macrophages inhibits insulin secretion through AMPK-sphingolipid axis.
  4. APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics.
  5. AMPK/Autophagy-Dependent Pro-Adipogenic Effect Coupled With Enhanced Lipid Mobilization and Thermogenesis Underlies the Dual Action of Canagliflozin Against Obesity.
  6. Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency.
  7. mRNA methylation safeguards pancreatic α-cell identity against cellular plasticity.
  8. Multi-organelle signatures map cell-state diversity and metabolic adaptation in tissues.
  9. Evolutionary conservation analysis reveals a primordial function of STING as a regulator of lipid metabolism via FADS2.
  10. Chromatin decompaction within the nucleus increases plasma membrane tension promoting NETosis execution, independently of transcription.
  11. FDA Approves 2 New Alzheimer Disease Blood Tests.
  12. How Do Cardiovascular Risks Vary Across Nicotine Products?
  13. Weight Loss in Older Adults With Persistent Atrial Fibrillation-Reply.
  14. Large nutritional and environmental improvements can be achieved across the product portfolios of major UK food and beverage manufacturers.
  15. VPS13D protects against alcohol- associated steatohepatitis by regulating organelle contacts and VLDL secretion.
  16. Cytotoxic CD4+ T cells support age-associated myelopoiesis.
  17. ENPP1 buffers extracellular cGAMP in brown adipose tissue to limit insulin resistance.
  18. Cysteine excess triggers a mitochondrial iron-dependent cell death.
  19. Weight Loss in Older Adults With Persistent Atrial Fibrillation.
  20. Why the NIH must resist the metrics trap.
  21. Synaptic Mitochondrial Oxidative Stress Contributes to Individual Variability in Age-Related Cognitive Inflexibility in Mice.
  22. Natural Killer Cell Dysfunction Is Emerging During Midlife Obesity.
  23. Weight Loss in Older Adults With Persistent Atrial Fibrillation.
  24. How research funding took me out of the lab and into leadership.
  25. In vitro induction of human germinal center B cells.
  26. Earlier Menopause Linked to Faster Cognitive Decline.
  1. Nat Metab. 2026 Sep 15.
    Cagrilintide and retatrutide combination therapy enhances weight loss and metabolic outcomes in obese male rats.
    Jonas Petersen, Christoffer Merrild, Stephanie Kjærulff Holm, Nigel Kurgan, Shad Hassan, Cecilie Vad Mathiesen, Stina Börchers, Charlotte Svendsen, Sergio D'Anna, Nicoline R Andersen, Anders Bue Klein, Andreas M Fritzen, Atul S Deshmukh, Tune H Pers, Christoffer Clemmensen.
      Peptide multi-receptor agonists have advanced obesity treatment, yet challenges remain in achieving maximal weight loss and metabolic control, especially in patients with obesity and type 2 diabetes. Here we demonstrate enhanced metabolic benefits of a combination therapy with retatrutide, a unimolecular GLP-1R/GIPR/GCGR tri-agonist, and cagrilintide, an AMLNR/CALCR co-agonist, in diet-induced obese male rats. Daily co-administration produces dose-dependent reductions in body weight and food intake that exceed both equimolar monotherapies and matched-dose comparator combinations incorporating semaglutide or tirzepatide. The combination therapy also improves circulating markers of metabolic health, including cholesterol, triglycerides and insulin levels. Pair-feeding and weight-matching studies reveal that the enhanced weight loss cannot be explained by reduced food intake alone and enable discrimination between weight-loss-dependent and drug-specific molecular responses. Plasma proteomic profiling highlights enrichment of bioenergetic processes with the combination therapy, whereas brain transcriptomic profiling identifies convergent central neuronal programmes linked to energy balance regulation. Collectively, our preclinical findings support five-receptor polypharmacology as a strategy for efficaciously lowering body weight and provide guidance for the design of next-generation unimolecular multi-receptor agonists.
    DOI:  https://doi.org/10.1038/s42255-026-01603-y
  2. Nature. 2026 Sep 18.
    Cognitive resilience helps to predict Alzheimer's dementia.
      
    Keywords:  Alzheimer's disease
    DOI:  https://doi.org/10.1038/d41586-026-02897-4
  3. J Clin Invest. 2026 Sep 15. pii: e202344. [Epub ahead of print]
    Acute activation of Gq-signaling in pancreatic islet macrophages inhibits insulin secretion through AMPK-sphingolipid axis.
    Simran Singh, Ashish Kumar, Sudipta Paul, Mriganka Sarkar, Santhosh Duraisamy, Ganesh Timalsina, Raashidha Farhath, Harender Yadav, Seema Kuldeep, Soumita Bhaumik, Kunj Kumar Prajapati, Saahiba Thaleshwari, Anuj Gargya, Tamojit Santra, Sonal Amit, Rashmi Parihar, Santosh K Misra, Hamim Zafar, Luiz F Barella, Michael A Kalwat, Dharmaraja Allimuthu, Sai Prasad Pydi.
      Obesity-associated inflammation impairs pancreatic β-cell function, yet the mechanisms by which immune cells acutely regulate insulin secretion remain poorly defined. Here, we identify myeloid Gq signaling as an immunometabolic node linking macrophage lipid sensing to impaired insulin secretion. Using chemogenetic DREADD-mediated activation of myeloid Gq, we show that acute macrophage Gq activation impairs glucose-stimulated insulin secretion (GSIS) in vivo, whereas myeloid Gαq ablation enhances GSIS. Mechanistically, Gq activation rapidly induced AMPK phosphorylation and sphingolipid remodeling independently of canonical inflammatory cytokines. Macrophage-derived sphingolipids impaired β-cell insulin signaling and GSIS through CD36-PKCζ, while inhibition of CD36, AMPK, or sphingolipid metabolism restored β-cell function. We further identified GPR18, a Gq-coupled endocannabinoid-responsive GPCR, as an upstream regulator. GPR18 activation with N-arachidonoyl glycine (NAGly) recapitulated this phenotype, whereas myeloid Gαq deletion or Gpr18/AMPK silencing abolished it. GPR18 signaling predominantly engaged Gq rather than Gi pathways. In human tissues, GPR18 was enriched in islet macrophages, and NAGly suppressed GSIS in primary human islets. Thus, a conserved macrophage GPR18-Gαq-AMPK-sphingolipid axis dynamically regulates β-cell function and represents a potential therapeutic target in obesity and type 2 diabetes.
    Keywords:  Beta cells; Endocrinology; G protein-coupled receptors; Metabolism; Obesity
    DOI:  https://doi.org/10.1172/JCI202344
  4. Nat Commun. 2026 08 19. pii: 9900. [Epub ahead of print]17(1):
    APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics.
    Carla Cuní-López, Jessica T Root, Ying Hao, Niek Blomberg, Sascha J Koppes-den Hertog, Dylan Sacks, Amber E Trujillo, Rodolfo Ghirlando, Isabelle Kowal, Jacob Epstein, Linda G Yang, Mark R Cookson, Elise Marsan, Rik van der Kant, Martin Giera, Yue Andy Qi, Priyanka S Narayan.
      Lipid droplets are dynamic cellular organelles that store neutral lipids and coordinate metabolic and stress-response pathways. In the brain, lipid droplets in glial cells, including astrocytes, have been implicated in Alzheimer's disease, but how genetic risk factors influence their composition and turnover remains poorly understood. APOE is the strongest genetic modulator of late-onset Alzheimer's disease and exists in common variants that confer decreased, neutral, or increased risk. Here we show that APOE genotype shapes the lipid droplet proteome, lipidome, and degradation dynamics in human induced pluripotent stem cell-derived astrocytes. By comparing oleic acid-treated astrocytes carrying APOE2, APOE3, or APOE4, we find that each variant is associated with distinct lipid droplet proteins and lipids. These molecular differences correspond to genotype-dependent changes in lipophagy, an autophagy-mediated pathway for lipid droplet clearance. Lipid droplets in APOE2 astrocytes undergo efficient autophagic turnover, whereas those in APOE4 astrocytes resist degradation. These findings identify impaired lipid droplet clearance as a potential mechanism linking APOE4 to Alzheimer's disease risk.
    DOI:  https://doi.org/10.1038/s41467-026-76565-6
  5. FASEB J. 2026 Sep 30. 40(18): e72313
    AMPK/Autophagy-Dependent Pro-Adipogenic Effect Coupled With Enhanced Lipid Mobilization and Thermogenesis Underlies the Dual Action of Canagliflozin Against Obesity.
    Jingsa Zhang, Yilu Shou, Yaling Tang, Xia Du, Jiajun Chen, He Peng, Die Wu, Yan Li, Chunsheng Xu, Xingya Wang.
      Canagliflozin (CANA) exhibits prominent anti-obesity effects in clinical practice, yet its direct adipocyte-intrinsic functions remain poorly understood. Here, we investigated the regulatory mechanism of CANA in adipogenesis and adipose tissue remodeling. We found that CANA promoted 3 T3-L1 preadipocyte differentiation and lipid accumulation. Mechanistically, CANA facilitated this pro-adipogenic effect via AMPK-dependent autophagy activation. In high-fat diet (HFD)-fed mice, CANA exerted both preventive and therapeutic benefits, reducing body weight gain and fat mass, alleviating hepatic steatosis and dyslipidemia, and improving hyperglycemia despite increased food intake. To resolve the in vitro pro-adipogenic vs. in vivo anti-obesity paradox, we identified stage-specific lipolysis. During differentiation, CANA increased triglycerides (TG) and glycerol release without net lipid loss. In post-differentiated adipocytes, CANA also enhanced glycerol release but markedly reduced intracellular TG, reflecting a switch from lipid-building to lipid-mobilizing. Notably, this lipolytic effect is autophagy-independent. Additionally, CANA enhanced adipocyte thermogenesis and browning, with Seahorse assays confirming elevated mitochondrial proton leak and uncoupled respiration. Importantly, SGLT2 expression was undetectable in 3 T3-L1 adipocytes and white adipose tissues. Collectively, CANA exerts anti-obesity effects by reprogramming adipocytes in an SGLT2-independent manner through AMPK/autophagy-dependent differentiation, coupled with enhanced lipolysis and thermogenesis, synergistically driving healthy lipid turnover.
    Keywords:  SGLT2i; adipogenesis; autophagy; lipolysis; obesity; thermogenesis
    DOI:  https://doi.org/10.1096/fj.202602506R
  6. J Clin Invest. 2026 Sep 15. pii: e207530. [Epub ahead of print]136(18):
    Reverse genetics in humanized mice reveals CARD8-mediated pyroptosis causing pancytopenia in human DPP9 deficiency.
    Tianli Xiao, J Richard Brewer, Maximillian Carlino, Ailin Han, Yamato J Takabe, Chia-Yi Lee, Fengrui Zhang, Mi Chen, Holly Nicole Blackburn, Amin H Nassar, Qiankun Wang, Kristen Brennand, Liang Shan, Esen Sefik, Diane S Krause, Richard A Flavell.
      Loss-of-function mutation in the human gene dipeptidyl peptidase 9 (DPP9) causes Hatipoglu syndrome leading to severe inflammasomopathy. A key feature of the disease is pancytopenia, and patients require bone marrow transplantation, but the mechanism of cell loss is unclear, since Dpp9-mutant mice have normal hematopoiesis, suggesting that a distinct mechanism of disease occurs in humans. Here, we present a model of human DPP9 deficiency leveraging reverse genetics in the MISTRG6 humanized mice. We found that CRISPR editing of human CD34+ hematopoietic stem and progenitor cells (HSPCs) led to very efficient and persistent gene deletion in vivo. Human DPP9 deletion recapitulated cytopenia in peripheral blood and in the bone marrow, and cell loss was cell intrinsic. However, DPP9 deletion led to few transcriptional changes suggesting posttranscriptional regulation in human HSPCs. Mechanistically, DPP9 deficiency led to activation of the CARD8 inflammasome, resulting in HSPC pyroptosis, whereas NLRP1 was dispensable for cell death. Thus, our results reveal a unique human mechanism of disease and offer therapeutic insight for this inflammasomopathy.
    Keywords:  Hematology; Hematopoietic stem cells; Immunology; Innate immunity
    DOI:  https://doi.org/10.1172/JCI207530
  7. Nat Metab. 2026 Sep 18.
    mRNA methylation safeguards pancreatic α-cell identity against cellular plasticity.
      
    DOI:  https://doi.org/10.1038/s42255-026-01594-w
  8. Science. 2026 Sep 17. 393(6817): eady6372
    Multi-organelle signatures map cell-state diversity and metabolic adaptation in tissues.
    Raghabendra Adhikari, Alexander Hillsley, Alana Dowdell Johnson, Shihong Max Gao, Isabel Espinosa-Medina, Jan Funke, Daniel Feliciano.
      Cell-state diversity drives tissue adaptability, repair, and disease resilience, but capturing this complexity is a challenge. Current approaches rely on transcriptional profiling and overlook organelle structure, a key indicator of metabolism and stress. We developed spatial Organellomics (sOrganellomics), an imaging workflow that integrates automated segmentation with machine learning to classify and spatially map cell states from multi-organelle signatures. In liver and pancreas, these signatures distinguished broad cellular classes. In liver, sOrganellomics revealed that zonal position did not fully explain organelle-defined hepatocyte categories. Instead, hepatocytes formed intermixed communities within canonical zones, supporting a refined subzonal diversity model. Nutritional stress reshaped this organization. Intravital imaging linked fasting-induced organelle remodeling with altered mitochondrial membrane potential in vivo, supporting multi-organelle architecture as a structural readout of tissue adaptation.
    DOI:  https://doi.org/10.1126/science.ady6372
  9. Nat Commun. 2026 Aug 14. pii: 9771. [Epub ahead of print]17(1):
    Evolutionary conservation analysis reveals a primordial function of STING as a regulator of lipid metabolism via FADS2.
    Soumyabrata Guha, Joanna Re, Stéphane Grégoire, Morgane Chemarin, Adeline Augereau, Yasmine Messaoud-Nacer, Pierre Le Hars, Hanane Chamma, Victoria Bergas, Collin McNairy, Jenny Nguyen, Jennifer Barrat, Jean-Paul Pais de Barros, Arielle Woznica, Niyazi Acar, Isabelle K Vila, Pierre Boudinot, Nadine Laguette.
      The stimulator of interferon genes (STING) is a pivotal regulator of type I interferon (IFN) responses. Although the IFN system is confined to vertebrates, STING is present across metazoans and in some unicellular eukaryotes, suggesting involvement in distinct functions prior to vertebrate divergence. Here we explore the conservation of STING-mediated regulation of polyunsaturated fatty acid (PUFA) metabolism. We find that STING homologs from vertebrates, invertebrates, and unicellular eukaryotes interact with fatty acid desaturase 2 (FADS2), the rate-limiting enzyme in PUFA metabolism, and influence subsequent functional outputs. Specifically, we show that STING homologs differentially shape cell susceptibility to infection by DNA and RNA viruses independently of the activation of IFN responses, suggesting that STING-mediated metabolic pathway regulation may participate in primitive host defense mechanisms. Thus, we identify STING-mediated metabolic regulation as an evolutionarily conserved feature and a primordial function of STING.
    DOI:  https://doi.org/10.1038/s41467-026-76833-5
  10. Nat Commun. 2026 Aug 20. pii: 9938. [Epub ahead of print]17(1):
    Chromatin decompaction within the nucleus increases plasma membrane tension promoting NETosis execution, independently of transcription.
    Aidan T Cabral, Manasi Sawant, Minwoo Kang, Liangqi Xie, Hawa Racine Thiam.
      Chromatin organizes DNA and regulates nuclear mechanics. However, whether and how chromatin regulates whole-cell mechanics and functions independently of transcription is largely unknown. Here, leveraging transcription-independent NETosis, we show that chromatin decompaction within the nucleus increases plasma membrane tension and cell volume. Mechanistically, we show that chromatin accessibility gradually increases and chromatin binding proteins (CBPs) H1, HP1α, and H3 differentially dissociate from chromatin as it decompacts during NETosis. We posit that dissociated CBPs become osmolytes that alter cellular osmolarity. Consistently, tuning extracellular osmolarity or disrupting regulators of membrane tension and cell volume (mTORC1/2, NHEs, or VRAC ion channels) alters plasma membrane rupture and NETosis execution. In non-NETing U2OS cells, decompacting chromatin increases membrane tension, independently of the cytoskeleton, indicating a causal relationship between chromatin organization and membrane tension. This work shows chromatin as a regulator of whole-cell mechanics, broadening our understanding of the non-genetic roles of chromatin in cell pathophysiology.
    DOI:  https://doi.org/10.1038/s41467-026-76578-1
  11. JAMA. 2026 Sep 18.
    FDA Approves 2 New Alzheimer Disease Blood Tests.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.14721
  12. JAMA. 2026 Sep 18.
    How Do Cardiovascular Risks Vary Across Nicotine Products?
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.14723
  13. JAMA. 2026 Sep 14.
    Weight Loss in Older Adults With Persistent Atrial Fibrillation-Reply.
    Matteo Sclafani, Barbara Casadei, Rohan Wijesurendra.
      
    DOI:  https://doi.org/10.1001/jama.2026.14482
  14. Nat Food. 2026 Sep 16.
    Large nutritional and environmental improvements can be achieved across the product portfolios of major UK food and beverage manufacturers.
    Eleanor Hammond, Lauren Bandy, E J Milner-Gulland, Rachel Pechey, Mike Rayner, Peter Scarborough, Shruti Jain, Michael Clark.
      Food and beverage (F&B) manufacturers can support or hinder the transition towards a more sustainable food system. Yet, there is limited evidence about their potential to improve the nutritiousness and reduce the environmental impact of the F&B sector. Here we develop an approach to estimate the nutritional quality and environmental impact of the product lines of 44 major F&B manufacturers in the UK. We find considerable variation in terms of nutritional quality and environmental impacts across manufacturers operating within the same food retail category and within existing F&B product portfolios. We identify how changing the types of product sold by these manufacturers offers potential for nutritional and environmental benefits. For some of the F&B manufacturers assessed, changes to 10% or less of their product line could deliver more than half of the potential gains in nutritional quality or sustainability.
    DOI:  https://doi.org/10.1038/s43016-026-01420-2
  15. Hepatology. 2026 Sep 14.
    VPS13D protects against alcohol- associated steatohepatitis by regulating organelle contacts and VLDL secretion.
    Chen Zhang, Nicholas Dunn, Yan Xie, Nicholas O Davidson, Wei Zhong, Wen-Xing Ding, Hong-Min Ni.
       BACKGROUND: Organelle contact sites are critical for intracellular signaling, membrane dynamics, and organelle quality control. Here we examined the role of VPS13D, a bridge-like lipid transport protein, in alcohol-induced liver injury and defined the mechanisms by which VPS13D regulates lipid metabolism at organelle contact sites.
    APPROACH AND RESULTS: Liver-specific Vps13d knockout (LKO) mice and matched wild-type (WT) mice were subjected to chronic-plus-binge ethanol feeding. RNA-seq and metabolomic analyses were performed to investigate changes in hepatic gene expression and metabolism. Biochemical, microscopic, and histological analyses were performed to examine organelle contacts and liver injury. Liver samples from patients with alcohol-associated hepatitis (AH) showed decreased VPS13D expression and mitochondrial-ER contact sites. Binge ethanol-fed Vps13d LKO mice developed more severe steatosis, inflammation and liver injury, with increased progenitor cells, compared with WT mice. Ethanol-fed Vps13d LKO mice exhibited decreased mitochondria-ER contact sites and peroxisome content, with increased lysosome damage and ER stress compared with WT mice. Metabolomic analysis revealed altered hepatic phospholipid homeostasis, with increased hepatic phosphatidylethanolamine (PE) and decreased phosphatidylcholine (PC) abundance, along with decreased phosphatidylethanolamine N-methyltransferase (PEMT) expression, resulting in impaired hepatic VLDL secretion in ethanol-fed Vps13d LKO mice. Adenovirus-mediated hepatic PEMT expression increased VLDL secretion and decreased steatosis and liver injury in ethanol-fed Vps13d LKO mice.
    CONCLUSIONS: Loss of hepatic VPS13D disrupts mitochondria-ER contact sites, decreasing hepatic PC content and VLDL secretion, promoting ethanol-induced steatosis, progenitor cell accumulation, and liver injury. ER-mitochondrial contact disruption and altered phospholipid homeostasis may be pathogenic drivers in AH.
    Keywords:  Autophagy; lipid droplet; mitochondria; peroxisome; steatosis
    DOI:  https://doi.org/10.1097/HEP.0000000000001847
  16. Nat Aging. 2026 Sep 18.
    Cytotoxic CD4+ T cells support age-associated myelopoiesis.
      
    DOI:  https://doi.org/10.1038/s43587-026-01241-9
  17. Cell Rep. 2026 Sep 15. pii: S2211-1247(26)01087-9. [Epub ahead of print]45(10): 118009
    ENPP1 buffers extracellular cGAMP in brown adipose tissue to limit insulin resistance.
    Songnan Wang, Yingjie Guo, Weidong An, J Michelle Lee, Yu Li, Valentino Sudaryo, Jacqueline A Carozza, Gabriel Grenot, Gemini Skariah, Saranya C Reghupaty, Sonny Young, Xiaochen Bai, Katrin J Svensson, Lingyin Li.
      The mechanism underlying the role of ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) in metabolic disease remains unsolved. Using a 2'3'-cyclic GMP-AMP (cGAMP)-hydrolysis-deficient mouse (Enpp1H362A), we show that selective loss of this activity exacerbates high-fat diet (HFD)-induced weight gain and insulin resistance. An in vivo glucose-uptake screen identifies brown adipose tissue (BAT) as a key site of metabolic impairment, marked by extracellular cGAMP accumulation and defective insulin-stimulated glucose uptake. Mechanistically, nutrient excess drives mitochondrial DNA leakage in brown adipocytes, triggering cGAMP synthesis and export. Excess extracellular cGAMP directly suppresses glucose uptake in brown adipocytes via stimulator of interferon genes (STING) pathway. Furthermore, impaired cGAMP clearance acts as a paracrine signal that recruits and polarizes BAT macrophages toward a pro-inflammatory M1-like phenotype. Finally, the human ENPP1 K173Q variant associated with obesity and diabetes displays reduced cGAMP hydrolysis activity. Together, these findings establish ENPP1 as an immunometabolic checkpoint that buffers extracellular cGAMP to maintain metabolic homeostasis.
    Keywords:  CP: immunology; CP: metabolism; ENPP1; STING; brown adipose tissue; diabetes; extracellular cGAMP; immune checkpoint; immunometabolism; insulin resistance; obesity
    DOI:  https://doi.org/10.1016/j.celrep.2026.118009
  18. Nat Metab. 2026 Sep 15.
    Cysteine excess triggers a mitochondrial iron-dependent cell death.
    Toshitaka Nakamura, Ayaka Inoki, Nupur K Das, Brandon Chen, Artem Khan, Yuyang Liu, Beste Uygur, Frederick S Yen, Gokhan Unlu, Yatrik M Shah, Kıvanç Birsoy.
      Thiol-containing metabolites are central to cellular redox homeostasis1. Among these, cysteine functions as a proteogenic amino acid, supports redox balance and iron-sulfur cluster biogenesis, and, when depleted, triggers ferroptosis2. Cells nevertheless maintain cysteine at low levels, reflecting its intrinsic toxicity, but the mechanisms by which excess cysteine causes cell death remain unclear3. Here we performed a genome-wide CRISPR screen and identified mitochondrial iron transporters as essential mediators of cysteine toxicity. Limiting mitochondrial iron availability suppresses cysteine-induced cell death and prevents impairment of iron-sulfur cluster proteins and respiration. Mechanistically, cysteine mobilizes iron from ferritin, expands the cytosolic iron pool and drives mitochondrial iron accumulation. Enhancing glutathione reductase activity specifically within mitochondria restores redox balance downstream of iron accumulation and protects cells by maintaining iron-sulfur cluster integrity. Our findings suggest that maintaining low cysteine levels safeguards mitochondrial iron homeostasis, and that excess cysteine triggers a distinct mitochondrial iron-dependent cell death under conditions of thiol imbalance.
    DOI:  https://doi.org/10.1038/s42255-026-01616-7
  19. JAMA. 2026 Sep 14.
    Weight Loss in Older Adults With Persistent Atrial Fibrillation.
    Qifeng Ou, Ding Pan.
      
    DOI:  https://doi.org/10.1001/jama.2026.14479
  20. Nature. 2026 Sep;657(8132): 848
    Why the NIH must resist the metrics trap.
    Kirsten K Davison.
      
    Keywords:  Funding; Research management; Scientific community
    DOI:  https://doi.org/10.1038/d41586-026-02906-6
  21. Aging Cell. 2026 Sep;25(9): e70716
    Synaptic Mitochondrial Oxidative Stress Contributes to Individual Variability in Age-Related Cognitive Inflexibility in Mice.
    Rui Yamada, Hirotaka Nagai, Chisato Numa, Yunhui Zhu, Midori Nagai, Kohei Ota, Yusuke Kawashima, Nobuhiko Ohno, Tomoyuki Furuyashiki.
      Aging is associated with impairments in cognitive flexibility, a key executive function supported by the medial prefrontal cortex (mPFC), yet the biological mechanisms underlying individual variability in age-related decline remain poorly understood. Here we investigated behavioral, ultrastructural, and proteomic correlates of cognitive inflexibility in mice across aging. Using a touchscreen-based attentional set-shifting task, we observed substantial individual variability in cognitive inflexibility among aged C57BL/6J mice. Volume electron microscopy of the mPFC revealed age-related reductions in synaptic density, but these structural changes did not correlate with cognitive performance. Instead, the proportion of synapses containing presynaptic mitochondria was inversely associated with cognitive flexibility in aged mice. To identify molecular correlates, we performed proteomic profiling of mPFC whole tissue and synaptosome fractions. Proteins associated with individual variability in cognitive inflexibility were largely distinct from those associated with chronological aging. Notably, synaptosomal proteins negatively correlated with cognitive performance were strongly enriched for mitochondrial pathways, including oxidative phosphorylation, mitochondrial translation, and the tricarboxylic acid cycle. Consistent with these findings, the mitochondria-targeted antioxidant MitoQ improved attentional set-shifting performance in aged mice without affecting initial learning. Proteomic analyses revealed that MitoQ reduced the abundance of synaptosomal mitochondrial proteins, particularly those involved in mitochondrial apoptotic signaling. Together, these results suggest that synaptic mitochondrial oxidative stress in the mPFC contributes to individual vulnerability to cognitive inflexibility. Targeting synaptic mitochondrial oxidative stress may therefore represent a promising strategy to preserve executive function during aging.
    Keywords:  cognitive aging; mice; mitochondria; oxidative stress; prefrontal cortex; synapse
    DOI:  https://doi.org/10.1111/acel.70716
  22. Aging Cell. 2026 Sep;25(9): e70707
    Natural Killer Cell Dysfunction Is Emerging During Midlife Obesity.
    Ruojia Biao, Xudong Wang, Jiantao Fu, Yifan Guo, Junming He, Juan Du.
      Individuals in the middle-aged demographic are notably more vulnerable to obesity, facing a higher risk of mortality from all causes. However, it remains unclear whether the reduction in life expectancy is related to dysregulated natural killer (NK) cell function triggered by the microenvironment of adiposity in middle age. In the present study, we observed that healthy middle-aged donors and mice displayed compromised NK cell function compared to their younger counterparts, particularly in males. The quantity and maturation of NK cells were significantly diminished in both spleen and white adipose tissues (WATs), coinciding with an increase in WAT volume and a reduced basal metabolic rate in middle-aged mice. We further established that heightened apoptosis coupled with a reduction in cell proliferation might contribute to the diminished NK cell counts in the spleens of middle-aged mice. NK cell function was significantly reduced in the spleen, bone marrow, and adipose tissues of these middle-aged mice. Young mice with diet-induced obesity also exhibited impaired NK cell function. In summary, our findings indicate a reduction in both the quantity and functional efficacy of NK cells, which is associated with the rising prevalence of obesity during middle age.
    Keywords:  NK cells; WAT; dysfunction; middle age; obesity
    DOI:  https://doi.org/10.1111/acel.70707
  23. JAMA. 2026 Sep 14.
    Weight Loss in Older Adults With Persistent Atrial Fibrillation.
    Liang Yan, Wensheng Zhang.
      
    DOI:  https://doi.org/10.1001/jama.2026.14476
  24. Nature. 2026 Sep 18.
    How research funding took me out of the lab and into leadership.
    Anna Sandak.
      
    Keywords:  Business; Careers; Funding; Institutions
    DOI:  https://doi.org/10.1038/d41586-026-02184-2
  25. Sci Immunol. 2026 Sep 18. 11(123): eaeg5223
    In vitro induction of human germinal center B cells.
    David G Priest, Melike Fusun Demir, Wataru Ise, James B Wing.
      During antibody responses, germinal centers (GCs) act as a key site for somatic hypermutation (SHM) and affinity maturation of B cells. However, their lymphoid tissue localization has made experimental manipulation of human germinal center B (GCB) cells difficult. Here, we describe a simple in vitro method, modeling T cell-derived signaling, that converts human naive B cells into BCL6+ induced GCB-like (iGCB) cells. Through side-by-side proteomic and transcriptional single-cell analysis of iGCB and human tonsil GCB cells, we show that iGCB cells recapitulate the surface marker, transcription factor, DNA repair, and glycosylation signatures that define human GCB cells and display ongoing activation-induced cytidine deaminase (AID)-dependent SHM. iGCB cells can be generated from naive B cells and from unswitched memory/circulating marginal zone cells but not class-switched memory B cells. Using this system, we define signals critical for human GCB formation and identify interventions that block their induction, providing a simple and manipulable model of human GCB cell biology.
    DOI:  https://doi.org/10.1126/sciimmunol.aeg5223
  26. JAMA. 2026 Sep 18.
    Earlier Menopause Linked to Faster Cognitive Decline.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.14722
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