bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–05–31
nineteen papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Biobank analysis reveals more than 88,000 genetic associations with metabolic traits.
  2. Hairpin herds corralled at the lipid droplet.
  3. Bespoke immune cells stave off ravages of cirrhosis.
  4. Human haematopoietic stem cells remember inflammatory stress.
  5. When the grid can't keep up: how South African laboratories handle power outages.
  6. Mapping the genetic diversity of Indigenous Americans.
  7. Organ formation in early human embryos captured in spatial cell atlas.
  8. Gene clock predicts time to death in humans - and assesses 'biological' age.
  9. Dual activation of MC3R and MC4R drives weight loss and reduces food intake in male primates with obesity.
  10. A causal link between autoantibodies and neurological symptoms in long COVID.
  11. Dehydration promotes intracellular lipid synthesis and accumulation.
  12. Mechanism of age-related accumulation of mtDNA mutations in human blood.
  13. Daily briefing: Why it's hard to show insight under pressure.
  14. AAAS unveils the AAAS Learning Hub to equip STEMM professionals with skills needed for today's world.
  15. Mapping the GDF15 arm of the integrated stress response in human cells and tissues.
  16. Metabolic and inflammatory biomarker trajectories after a cancer diagnosis and the risk of cardiovascular diseases.
  17. RBP4 Aggravates Diabetic Retinopathy by Inducing Microglial Activation and Endothelial Inflammation.
  18. Genome-wide meta-analysis identifies genetic drivers of bile acid metabolism in intrahepatic cholestasis of pregnancy.
  19. Lifestyle intervention is associated with attenuation of ER stress/inflammation and enhancement of naive immune cell identity in older adults with metabolic disease.
  1. Nature. 2026 May 27.
    Biobank analysis reveals more than 88,000 genetic associations with metabolic traits.
      
    Keywords:  Genetics; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-01571-z
  2. Nat Cell Biol. 2026 May 26.
    Hairpin herds corralled at the lipid droplet.
    Laura Listenberger.
      
    DOI:  https://doi.org/10.1038/s41556-026-01955-3
  3. Nature. 2026 May 29.
    Bespoke immune cells stave off ravages of cirrhosis.
      
    Keywords:  Medical research
    DOI:  https://doi.org/10.1038/d41586-026-01670-x
  4. Nature. 2026 May 27.
    Human haematopoietic stem cells remember inflammatory stress.
    Andy G X Zeng, Murtaza S Nagree, Niels Asger Jakobsen, Sayyam Shah, Angelica Varesi, Jasmine Ryu Won Kang, Alex Murison, Jin-Gyu Cheong, Sven Turkalj, Xuan Zhang, Felix A Radtke, Tsega-Ab Abera, Isabel N X Lim, Liqing Jin, Joana Araújo, Alicia G Aguilar-Navarro, Darrien Parris, Jessica McLeod, Hyerin Kim, Ho Seok Lee, Lin Zhang, Mason Boulanger, Elyssa Bader, Elias Gbeha, Christopher N Parkhurst, Elvin Wagenblast, Eugenia Flores-Figueroa, Bo Wang, Gregory W Schwartz, Leonard D Shultz, Anna S Nam, H Leighton Grimes, Steven Z Josefowicz, Philip Awadalla, Paresh Vyas, John E Dick, Stephanie Z Xie.
      Inflammation activates blood cells, contributing to ageing and malignancy1-3. Haematopoietic stem cells (HSCs) survive a lifetime of infection to sustain life-long haematopoiesis1-9, but how human HSCs respond and adapt to inflammatory stress is largely unknown. Here, to empirically understand this adaptation, we developed xenograft inflammation-recovery models and performed single-cell multiomics on xenografted human HSCs. Two transcriptionally and epigenetically distinct HSC subsets were identified with one, termed HSC inflammatory memory (HSC-iM), retaining a molecular memory of previous inflammatory treatments. The HSC-iM subset exhibited quiescence and restrained haematopoietic output. Molecularly, the HSC-iM program was enriched in HSCs from adult and paediatric samples across conditions ranging from COVID-19 recovery, sickle cell disease, ageing and clonal haematopoiesis, establishing both the validity of our xenograft models and the physiological relevance of HSC-iM. Clonal haematopoiesis mutations in HSC-iM attenuated the effects of inflammatory stress by promoting HSC activation and differentiation. Moreover, transmission of the pro-inflammatory HSC-iM transcriptional program to differentiated immune progeny was demonstrated in xenograft and physiological settings. Finally, HSC-iM program enrichment in circulating blood cells was associated with a heightened risk score for all-cause mortality in population cohort analyses, underscoring the clinical relevance of this newly identified HSC subset in characterizing heterogeneous health outcomes across a lifetime.
    DOI:  https://doi.org/10.1038/s41586-026-10522-7
  5. Nature. 2026 May 26.
    When the grid can't keep up: how South African laboratories handle power outages.
    Max Bennett.
      
    Keywords:  Careers; Energy; Funding; Institutions
    DOI:  https://doi.org/10.1038/d41586-026-00402-5
  6. Nat Med. 2026 May 29.
    Mapping the genetic diversity of Indigenous Americans.
    Karen O'Leary.
      
    Keywords:  Genomics
    DOI:  https://doi.org/10.1038/d41591-026-00028-0
  7. Nature. 2026 May 27.
    Organ formation in early human embryos captured in spatial cell atlas.
    Varun K A Sreenivasan, Malte Spielmann.
      
    Keywords:  Developmental biology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-026-01416-9
  8. Nature. 2026 May 27.
    Gene clock predicts time to death in humans - and assesses 'biological' age.
    Heidi Ledford.
      
    Keywords:  Ageing; Cell biology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-026-01661-y
  9. Nat Commun. 2026 May 29. pii: 4808. [Epub ahead of print]17(1):
    Dual activation of MC3R and MC4R drives weight loss and reduces food intake in male primates with obesity.
    Jillian L Seiler, Anna C Impastato, Emma Xiaoyu Zhang, Kade J Kelley, Thomas L Bennett, Bradley Studnitzer, Claudia R Prindle, Benjamin H Rajewski, Barry A Badeau, Xinjian Jiang, Russell Potterfield, Jordan Y Delev, Daniel L Marks.
      The melanocortin system plays a central role in regulating hunger and satiety, making it an attractive target for treating metabolic disease. However, the limited clinical success of selective melanocortin-4 receptor (MC4R) agonists has prompted investigation into whether concurrent melanocortin-3 receptor (MC3R) and MC4R activation may more effectively engage this pathway for the treatment of general obesity. Here we show that selective MC3R agonism modulates food intake in a state-dependent manner, and that co-agonism of MC3R and MC4R produces greater metabolic effects than selective MC4R agonism alone, consistent with non-redundant and cooperative roles. Using novel peptides in male nonhuman primates and rodents, we develop 710GO, an orally available MC3R/MC4R dual agonist that induces significant weight loss in primates with diet-induced obesity. Oral 710GO demonstrates limited weight rebound, compatibility with GLP-1-based therapies, and a favorable preclinical safety profile. These findings support combined MC3R/MC4R agonism as a promising approach for next-generation obesity therapeutics.
    DOI:  https://doi.org/10.1038/s41467-026-73372-x
  10. Cell. 2026 May 28. pii: S0092-8674(26)00509-X. [Epub ahead of print]189(11): 3214-3235.e37
    A causal link between autoantibodies and neurological symptoms in long COVID.
    Keyla Santos Guedes de Sá, Julio Silva, Rafael Bayarri-Olmos, Christopher A Baker, Zhenni Lu, Wilson Gipson, Daxiang Na, Bandy Chen, Li Wenxue, Delyar Khosroabadi, Ryan Brinda, Robert Alec Rath Constable, Britney Omene, Patricia A Colom Díaz, Dong-Il Kwon, Gisele Rodrigues, Harald Heidecke, Kai Schulze-Forster, Amanda Gross, Tom Shneer, Amanda Clarke, Thomas Linnekin, Ashley Brate, Lev Brown, Henry Buda, Shashi Jatiani, Lenny Moise, Kerrie Greene, Sachin Bhagchandani, Bornali Bhattacharjee, Jeffrey Gehlhausen, Jamie Wood, Laura Tabacof, Carmen Scheibenbogen, Yansheng Liu, Leying Guan, Marc Schneeberger Pane, David Putrino, Tamas L Horvath, Akiko Iwasaki.
      Acute SARS-CoV-2 infection triggers the de novo production of diverse, functional autoantibodies (AABs) that remain elevated in long COVID (LC), but their pathogenic role remains unclear. Using tissue-based immunofluorescence, ELISA, human protein array, and mass spectrometry assays, we identified a broad range of AAB targets among individuals with LC. Individuals with neurocognitive symptoms showed increased AABs against central nervous system (CNS) and peripheral nervous system proteins. Purified immunoglobulin G (IgG) reacted with human locus coeruleus, thalamus, adrenal gland, and thyroid and cross-reacted with mouse sciatic nerve and meninges. CNS-reactive AABs correlated with several neurological symptoms. MED20-targeting IgG from patients with LC showed enhanced antibody-dependent phagocytosis. Passive transfer of IgG from individuals with LC into mice induced fatigue-like behavior, loss of balance/coordination, thermal hyperalgesia, small fiber nerve damage, and increased pain-related neuronal activity, recapitulating patients' symptoms. These findings suggest that targeting AABs might offer therapeutic benefits for this LC subgroup.
    Keywords:  SARS-CoV-2; autoantibodies; behavior; chronic pain; infectious diseases; long COVID; nociceptor; post-acute infection syndrome
    DOI:  https://doi.org/10.1016/j.cell.2026.04.042
  11. Nat Commun. 2026 May 25.
    Dehydration promotes intracellular lipid synthesis and accumulation.
    Joshua S Carty, Jazlyn Selvasingh, Yvonne Zuchowski, Hyuck-Jin Nam, Clothilde Pénalva, Gayani Nanayakkara, Erin Q Jennings, Kelsey Voss, Edith T Adame, John T Tossberg, Wei Sheng Yap, Meiling Melzer, Olga Viquez, A Scott McCall, Elizabeth R Piotrowski, Ryoichi Bessho, Shirong Cao, Katrina L Leaptrot, Alexandra C Schrimpe-Rutledge, Simona G Codreanu, Stacy D Sherrod, John A McLean, Jonathan B Trapani, Matthew A Cottam, Ma Wan, Deepti Shrivastava, Don A Delker, Matthew H Wilson, Clinton M Hasenour, Louise Lantier, Irene Chernova, Jamey D Young, Volker H Haase, Jose Pablo Vazquez-Medina, Dylan K Kosma, Peter K Kim, Jean-Philippe Cartailler, Mingzhi Zhang, Roy Zent, Raymond C Harris, Jason A Watts, Andrew S Terker, Fabian Bock, Jeffrey C Rathmell, Aylin R Rodan, Juan P Arroyo.
      Lipids can be considered a water reservoir used to offset dehydration stress as their oxidation by the mitochondria generates water. However, whether dehydration and the ensuing hypertonic stress directly regulate lipid synthesis is unknown. We show that hypertonic stress decreases cellular oxygen consumption, increases intracellular lipid synthesis, and favors glutamine oxidation as a carbon precursor for lipid synthesis via remodeling mitochondrial metabolism. These findings provide a mechanism whereby cellular dehydration leads to intracellular lipid accumulation, functionally linking water availability to lipid storage.
    DOI:  https://doi.org/10.1038/s41467-026-73534-x
  12. Nature. 2026 May 27.
    Mechanism of age-related accumulation of mtDNA mutations in human blood.
    Rahul Gupta, Timothy J Durham, Grant Chau, Masahiro Kanai, Md Mesbah Uddin, Wenhan Lu, M Austin Argentieri, Konrad J Karczewski, Daniel Howrigan, Pradeep Natarajan, Wei Zhou, Benjamin M Neale, Vamsi K Mootha.
      Accumulation of mutant mitochondrial DNA (mtDNA) heteroplasmy is among the strongest signatures of ageing1. Here we investigated the underlying mechanism by calling mtDNA sequence, mtDNA abundance and mtDNA heteroplasmic variants in human blood using whole-genome sequences from approximately 750,000 individuals. We observed that mtDNA single-nucleotide variants (mtSNVs) accumulate sharply at age 60 years, occur at low levels of heteroplasmy, exhibit little evidence of positive selection and are likely to be predominantly neutral. The mutational spectrum of mtSNVs does not reflect oxidative lesions, as is commonly invoked, but is more consistent with mtDNA replication errors. To understand why mtSNVs become detectable with age, we performed a genome-wide association study for heteroplasmic mtSNV burden, identifying germline variants near TERT, TCL1A and SMC4, all of which have been linked to clonal haematopoiesis (CH)2. Rare-variant analysis also showed that high mtSNV burden is associated with mutations in numerous CH driver genes. These genetic associations persisted even after exclusion of individuals with known CH driver mutations. Our results support a model in which 'cryptic' mtDNA mutations initially arise randomly as replication errors but are undetectable in bulk. They then become apparent only through age-related expansion of cellular clones in blood. We propose that the high copy number and mutation rate of mtDNA make it a sensitive blood-based marker of somatic mosaicism due to CH. Our work mechanistically unifies three prominent signatures of ageing: common germline variants in TERT, CH and observed accrual of mtDNA mutations.
    DOI:  https://doi.org/10.1038/s41586-026-10569-6
  13. Nature. 2026 May 26.
    Daily briefing: Why it's hard to show insight under pressure.
    Jacob Smith.
      
    DOI:  https://doi.org/10.1038/d41586-026-01696-1
  14. Science. 2026 May 28. 392(6801): 992
    AAAS unveils the AAAS Learning Hub to equip STEMM professionals with skills needed for today's world.
    Mary Catherine Longshore, Lili Niederkorn.
      
    DOI:  https://doi.org/10.1126/science.aej1106
  15. Commun Biol. 2026 May 27.
    Mapping the GDF15 arm of the integrated stress response in human cells and tissues.
    Janell L M Smith, Kamaryn T Tanner, Jack Devine, Anna S Monzel, Taivan Batjargal, Maxwell Z Wilson, Alan A Cohen, Martin Picard.
      Mitochondrial stress activates the integrated stress response (ISR) and triggers cell-cell communication through the secretion of the metabokine growth differentiation factor 15 (GDF15). However, the gene network underlying the ISR remains poorly defined across metabolically diverse cellular states and tissues. Using RNAseq data from fibroblasts subjected to eleven metabolic perturbations, including genetic and pharmacological mitochondrial OxPhos defects, we show that the ISR has multiple arms. To quantify the GDF15 arm of ISR activation in human cells, we developed an ISRGDF15 index. We validate the ISRGDF15 index in datasets from optogenetic and small molecule activation of ISR kinases, demonstrating its rapid kinetics preceding to GDF15 gene expression. We then deploy the ISRGDF15 index across 44 postmortem human tissues, confirm its correlation with age, and report that the ISRGDF15 is upregulated in the heart of individuals with acute causes of death in the emergency room, whereas it was upregulated in the brain of individuals who died after protracted hospital inpatient stays. These data highlight distinct arms of the ISR and clarify genes related to the GDF15 ISR arm, yielding an ISRGDF15 index that can be used to investigate tissue-specific and age-related ISR activation in both in vitro cultures and human tissues.
    DOI:  https://doi.org/10.1038/s42003-026-10312-x
  16. Nat Commun. 2026 05 25. pii: 4643. [Epub ahead of print]17(1):
    Metabolic and inflammatory biomarker trajectories after a cancer diagnosis and the risk of cardiovascular diseases.
    Hyemi Park, Quan Wang, Qianwei Liu, Jing Wu, Kelu Yang, Xinyu Zhang, Saro H Armenian, Wenjiang Deng, Niklas Hammar, Maria Feychting, Fang Fang, Kejia Hu, Dang Wei.
      Cancer patients face a high comorbidity burden of cardiovascular diseases (CVD). There is little evidence about stratifying cancer patients for their CVD risk. Here, we conduct a cohort study (1985-2020) to examine post-cancer biomarker trajectories and their associations with subsequent CVD risk. We identify biomarker trajectories after cancer diagnosis for 11 biomarkers using latent class growth modelling. Through Cox regression, we find that cancer patients with initially high and subsequently increasing glucose levels have a 110% higher CVD risk than those with low-stable levels. A low-stable albumin level, even within the normal range, is associated with elevated CVD risk, whereas patients with initially low-stable but subsequently increasing uric acid levels exhibit a 20% reduced risk of CVD. These findings suggest that specific trajectories of glucose, albumin, and uric acid are associated with CVD risk. Further research should elucidate underlying biological mechanisms and validate these associations to improve CVD prevention in cancer patients.
    DOI:  https://doi.org/10.1038/s41467-026-73530-1
  17. Diabetes. 2026 May 28. pii: db250816. [Epub ahead of print]
    RBP4 Aggravates Diabetic Retinopathy by Inducing Microglial Activation and Endothelial Inflammation.
    Ying Shi, Congjuan Mao, Di Zhang, Yanfang Zhu, Yi Lei, Xue Dong, Mengyu Liao, Mei Du.
       ARTICLE HIGHLIGHTS: Retinol-binding protein 4 (RBP4) levels are elevated in the vitreous humor of patients with diabetic retinopathy (DR) and in RBP4 transgenic mice. Elevated vitreous RBP4 exacerbates both vascular and neuronal deficits associated with DR in streptozotocin-induced diabetic mice. Hyperglycemia augments the RBP4-induced inflammatory response in retinal microvascular endothelial cells to exacerbate DR-related vascular pathologies. RBP4 triggers retinal microglial activation and phagocytosis via TLR4/nuclear factor-κB/mitogen-activated protein kinase pathway, and microglial depletion or inhibition alleviates RBP4-induced retinal neurodegeneration.
    DOI:  https://doi.org/10.2337/db25-0816
  18. Nat Commun. 2026 May 25.
    Genome-wide meta-analysis identifies genetic drivers of bile acid metabolism in intrahepatic cholestasis of pregnancy.
    FinnGen
      Intrahepatic cholestasis of pregnancy, which affects 0.2-2% of pregnancies, is characterized by pruritus, increased aminotransferase activity and elevated serum bile acids. Previous studies have implicated liver-enriched genes in intrahepatic cholestasis of pregnancy. We conducted a meta-analysis of intrahepatic cholestasis of pregnancy genome-wide association studies in the FinnGen study, deCODE, Estonian Biobank, the Danish Blood Donor Study and Copenhagen Hospital Biobank with 4,738 women with prior ICP and 436,834 female controls. The analysis found 26 genome-wide significant associations of which 10 were novel. Genes in the associated loci were prioritized using lead SNP expression quantitative trait loci associations and colocalization analysis to assess potential causality. The associated loci implicate bile acid synthesis, LDL cholesterol, and lipid metabolism. Additionally, comorbidity, genetic correlation and polygenic risk score analyses further indicated a link between intrahepatic cholestasis of pregnancy and pancreatitis, suggesting shared genetic underpinnings.
    DOI:  https://doi.org/10.1038/s41467-026-73122-z
  19. bioRxiv. 2026 May 12. pii: 2026.05.08.723786. [Epub ahead of print]
    Lifestyle intervention is associated with attenuation of ER stress/inflammation and enhancement of naive immune cell identity in older adults with metabolic disease.
    Rushil Yerrabelli, Asa Thibodeau, Djamel Nehar-Belaid, Radu Marches, Sathyabaarathi Ravichandran, Yoann Barnouin, Ranjan Sen, Silke Paust, Michael L Stitzel, Luigi Ferrucci, A Phillip West, Jacques Banchereau, Dennis T Villareal, George A Kuchel, Duygu Ucar.
      Chronic inflammation and cellular stress are hallmarks of aging, obesity, and type 2 diabetes (T2D), but whether these programs can be modulated by lifestyle intervention in late life, particularly in the presence of established metabolic disease, remain unknown. We profiled circulating immune cells from older adults with obesity and T2D (ages 66-83 years; n = 9) before and after a 6-month lifestyle intervention combining caloric restriction with exercise training. Participants showed substantial weight loss (∼7%) alongside improvements in glycemic control, insulin sensitivity, and physical performance. Longitudinal single-cell transcriptomic and epigenomic profiling identified two major changes. First, intervention was associated with downregulation of inflammatory and endoplasmic reticulum (ER) stress transcriptional programs, with the most pronounced effects observed in CD14 + monocytes. DDIT3 (CHOP) was transcriptionally and epigenetically downregulated and its inferred regulatory network encompassed multiple inflammatory mediators. Second, naive CD4 + T, naive T reg , and naive B cells exhibited an upregulation of naive cell identity genes, with naiveness scores increasing after intervention, which declines with age in an independent healthy adult cohort. Together, these findings suggest that lifestyle intervention is associated with coordinated remodeling of both innate and adaptive immune compartments in older adults, revealing substantial plasticity of the aging immune system especially targeting ER stress, inflammation, and naive lymphocyte identity programs.
    DOI:  https://doi.org/10.64898/2026.05.08.723786
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