bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–06–22
sixteen papers selected by
Xiong Weng, University of Edinburgh
  1. FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression.
  2. YTHDC1 Is Essential for Postnatal Liver Development and Homeostasis.
  3. Adipocyte RNF20 Knockout Leads to Hyperinsulinemia via the H2Bub-H3K4me3-Slc2a4 Axis.
  4. Shaping the composition of the mitochondrial outer membrane.
  5. Application of human iPSC-derived white, beige, and brown adipocytes for metabolic disease modeling and transplantation therapy.
  6. Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
  7. ATR promotes mTORC1 activity via de novo cholesterol synthesis.
  8. The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.
  9. Mitochondrial dysfunction in the regulation of aging and aging-related diseases.
  10. Mitochondrial innate immune signaling in skeletal muscle adaptation to exercise.
  11. Advancing GWAS of human communication.
  12. Regulation of redox homeostasis by ATF4-MTHFD2 axis during white adipose tissue browning.
  13. Activation of STING pathway by mitochondrial fission negatively regulates adipogenic differentiation of 3 T3-L1 cells.
  14. NIPSNAP1 and NIPSNAP2 facilitate healthy aging independent of mitophagy.
  15. Fighting aging-associated clonal hematopoiesis with microbial metabolite.
  16. Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength.
  1. Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00267-0. [Epub ahead of print]
    FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression.
    Christy M Gliniak, Ruth Gordillo, Yun-Hee Youm, Qian Lin, Clair Crewe, Zhuzhen Zhang, Bianca C Field, Teppei Fujikawa, Megan Virostek, Shangang Zhao, Yi Zhu, Clifford J Rosen, Tamas L Horvath, Vishwa Deep Dixit, Philipp E Scherer.
      Approximately 35% of US adults over 65 are obese, highlighting the need for therapies targeting age-related metabolic issues. Fibroblast growth factor 21 (FGF21), a hormone mainly produced by the liver, improves metabolism and extends lifespan. To explore its effects without developmental confounders, we generated mice with adipocyte-specific FGF21 overexpression beginning in adulthood. When fed a high-fat diet, these mice lived up to 3.3 years, resisted weight gain, improved insulin sensitivity, and showed reduced liver steatosis. Aged transgenic mice also displayed lower levels of inflammatory immune cells and lipotoxic ceramides in visceral adipose tissue, benefits that occurred even in the absence of adiponectin, a hormone known to regulate ceramide breakdown. These results suggest that fat tissue is a central site for FGF21's beneficial effects and point to its potential for treating metabolic syndrome and age-related diseases by promoting a healthier metabolic profile under dietary stress and extending healthspan and lifespan.
    Keywords:  FGF21; adipocytes; adiponectin; adipose tissue; aging; ceramides; inflammation; insulin sensitivity; longevity; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.011
  2. Adv Sci (Weinh). 2025 Jun 19. e05725
    YTHDC1 Is Essential for Postnatal Liver Development and Homeostasis.
    Xinzhi Li, Xueying Li, Chunhong Liu, Zhenzhi Li, Kaixin Ding, Yuxin Wang, Ning Gu, Liwei Xie, Zheng Chen.
      Hepatocytes play a crucial role in liver function, with their maturation occurring during postnatal development. However, the molecular mechanisms underlying this maturation are not yet fully understood. In this study, YTHDC1 is identified as a key positive regulator of hepatocyte maturation and an essential factor in maintaining liver homeostasis. YTHDC1 expression increases in the liver after birth, and hepatocyte-specific deletion of Ythdc1 impairs hepatocyte maturation, leading to reduced liver weight, liver injury, inflammation, and fibrosis. These defects contribute to the development of nonalcoholic steatohepatitis and hepatocellular carcinoma in mice. YTHDC1 supports postnatal hepatocyte maturation and liver function by enhancing the expression of key transcription factors, FOXA1 and FOXA2, at the posttranscriptional level through m6A recognition. Restoring FOXA1 or FOXA2 expression mitigates the phenotypic defects observed in Ythdc1-HKO mice. Mechanistically, YTHDC1 binds to the m6A regions of Foxa1 and Foxa2 mRNAs, promoting their expression. These findings reveal a mechanism by which YTHDC1 regulates hepatocyte maturation.
    Keywords:  FOXA1; FOXA2; YTHDC1; liver; liver injury; m6A modification; postnatal development
    DOI:  https://doi.org/10.1002/advs.202505725
  3. J Cell Mol Med. 2025 Jun;29(11): e70649
    Adipocyte RNF20 Knockout Leads to Hyperinsulinemia via the H2Bub-H3K4me3-Slc2a4 Axis.
    Ying Zhao, Xiaojuan Liang, Jiayu Tang, Chunwei Cao, Chunhuai Yang, Shulin Yang, Jianguo Zhao, Jinxiang Yuan, Meng Zhang, Yanfang Wang.
      The ubiquitin ligase RING finger 20 (RNF20) mediated the monoubiquitination of histone H2B at lysine 120 (H2Bub), an epigenetic modification known to regulate key biological processes such as fat tissue development, tumorigenesis, spermatogenesis and so on. Despite our previous findings showing that mice with adipocyte-specific deletion of Rnf20 (ASKO mice) develop hyperinsulinaemia, the underlying mechanisms remain unclear. In this study, we investigated the role of adipocyte RNF20 in maintaining systemic insulin homoeostasis in ASKO mice. Our results reveal that ASKO mice exhibit an enlarged pancreas, increased islet size and a greater number of pancreatic β-cells. Fat tissue in ASKO mice showed reduced insulin sensitivity, evidenced by diminished AKT phosphorylation under basal and insulin-stimulated conditions, alongside suppressed insulin signalling pathways. Furthermore, the decreased levels of histone modifications, including H2Bub, H3K4me3 and H3K79me3, were observed in both ASKO mice fat tissues and Rnf20-knockdown 3T3-L1 cells. Mechanistically, Rnf20 knockdown in adipocytes reduced H3K4me3 occupancy at the Slc2a4 gene locus, inhibiting GLUT4 expression and inducing adipose-specific insulin resistance. These findings establish a critical role for adipocyte RNF20 in the insulin signalling regulation via the H2Bub-H3K4me3-Slc2a4 axis, highlighting its importance in systemic glucose metabolism.
    Keywords:   Slc2a4 ; H3K4me3; RNF20; adipose tissue; insulin resistance
    DOI:  https://doi.org/10.1111/jcmm.70649
  4. Nat Cell Biol. 2025 Jun;27(6): 890-901
    Shaping the composition of the mitochondrial outer membrane.
    Gayathri Muthukumar, Jonathan S Weissman.
      Mitochondria are critical double-membraned organelles that act as biosynthetic and bioenergetic cellular factories, with the outer membrane providing an interface with the rest of the cell. Mitochondrial outer membrane proteins regulate a variety of processes, including metabolism, innate immunity and apoptosis. Although the biophysical and functional diversity of these proteins is highly documented, the mechanisms of their biogenesis and the integration of that into cellular homeostasis are just starting to take shape. Here, focusing on α-helical outer membrane proteins, we review recent insights into the mechanisms of synthesis and cytosolic chaperoning, insertion and assembly in the lipid bilayer, and quality control of unassembled or mislocalized transmembrane domains. We further discuss the role convergent evolution played in this process, comparing key biogenesis players from lower eukaryotes, including yeast and trypanosomes, with multicellular metazoan systems, and draw comparisons with the endoplasmic reticulum biogenesis system, in which membrane proteins face similar challenges.
    DOI:  https://doi.org/10.1038/s41556-025-01683-0
  5. Cell Transplant. 2025 Jan-Dec;34:34 9636897251346599
    Application of human iPSC-derived white, beige, and brown adipocytes for metabolic disease modeling and transplantation therapy.
    Yamato Keidai, Junji Fujikura, Daisuke Yabe.
      Adipocyte dysfunction plays a critical role in the pathogenesis of metabolic diseases, including type 2 diabetes (T2D). Human induced pluripotent stem cells (hiPSCs) offer a powerful platform for generating white, beige, and brown adipocytes, supporting both disease modeling and therapeutic research. This review provides a comprehensive summary of current differentiation methods to produce three functionally mature adipocyte types from pluripotent stem cells (PSCs), including forced gene expression techniques, developmental biology-inspired approaches, and advanced three-dimensional (3D) culture systems that enhance cellular maturity and functional relevance. PSC-derived white adipocytes contribute to modeling adipocyte dysfunction not only in conditions such as insulin resistance, lipodystrophy, and premature aging but also in more complex metabolic diseases, including T2D, facilitating the investigation of disease mechanisms and the identification of novel therapeutic targets. In addition, iPSC-based models provide a robust platform for exploring genetic regulation by genome-wide association studies (GWAS)-identified variants through population genetics. This review also evaluates the therapeutic potential of iPSC-derived white, beige, and brown adipocytes in cell transplantation therapy for metabolic diseases, with a focus on engraftment potential and metabolic improvement. Enhancing the maturity and subtype specificity of PSC-derived adipocytes is expected to accelerate the development of personalized medicine and innovative therapeutic strategies for metabolic diseases.
    Keywords:  beige adipocytes; brown adipocytes; pluripotent stem cells; transplantation; white adipocytes
    DOI:  https://doi.org/10.1177/09636897251346599
  6. Cell Rep. 2025 Jun 19. pii: S2211-1247(25)00659-X. [Epub ahead of print]44(7): 115888
    Cold-inducible GOT1 activates the malate-aspartate shuttle in brown adipose tissue to support fuel preference for fatty acids.
    Chul-Hong Park, Minsung Park, Miranda E Kelly, Helia Cheng, Sang Ryeul Lee, Cholsoon Jang, Ji Suk Chang.
      Brown adipose tissue (BAT) simultaneously metabolizes fatty acids (FAs) and glucose under cold stress but favors FAs as the primary fuel for heat production. It remains unclear how BAT steers fuel preference toward FAs over glucose. Here, we show that the malate-aspartate shuttle (MAS) is activated by cold in BAT and plays a crucial role in promoting mitochondrial FA utilization. Mechanistically, cold stress selectively induces glutamic-oxaloacetic transaminase (GOT1), a key MAS enzyme, via the β-adrenergic receptor-PKA-PGC-1α axis. The increase in GOT1 activates MAS, transferring reducing equivalents from the cytosol to mitochondria. This process enhances FA oxidation in mitochondria while limiting glucose oxidation. In contrast, loss of MAS activity by GOT1 deficiency reduces FA oxidation, leading to increased glucose oxidation. Together, our work uncovers a unique regulatory mechanism and role for MAS in mitochondrial fuel selection and advances our understanding of how BAT maintains fuel preference for FAs under cold conditions.
    Keywords:  CP: Metabolism; GOT1; NADH shuttle; PGC-1α; brown adipocytes; fatty acid oxidation; glucose oxidation; glutamic oxaloacetic transaminase 1; glycolysis; malate-aspartate shuttle; mitochondrial thermogenesis
    DOI:  https://doi.org/10.1016/j.celrep.2025.115888
  7. EMBO Rep. 2025 Jun 13.
    ATR promotes mTORC1 activity via de novo cholesterol synthesis.
    Naveen Kumar Tangudu, Alexandra N Grumet, Richard Fang, Raquel Buj, Aidan R Cole, Apoorva Uboveja, Amandine Amalric, Baixue Yang, Zhentai Huang, Cassandra Happe, Mai Sun, Stacy L Gelhaus, Matthew L MacDonald, Nadine Hempel, Nathaniel W Snyder, Katarzyna M Kedziora, Alexander J Valvezan, Katherine M Aird.
      DNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback. Key mediators of these pathways include ATR and mTORC1, respectively. Previous studies established ATR as a regulatory upstream factor of mTORC1 during replication stress; however, the precise mechanisms remain poorly defined. Additionally, the activity of this signaling axis in unperturbed cells has not been extensively investigated. We demonstrate that ATR promotes mTORC1 activity across various human cancer cells and both human and mouse normal cells under basal conditions. This effect is enhanced in human cancer cells (SKMEL28, RPMI-7951, HeLa) following knockdown of p16, a cell cycle inhibitor that we have previously found increases mTORC1 activity and here found increases ATR activity. Mechanistically, ATR promotes de novo cholesterol synthesis and mTORC1 activation through the phosphorylation and upregulation of lanosterol synthase (LSS), independently of both CHK1 and the TSC complex. Interestingly, this pathway is distinct from the regulation of mTORC1 by ATM and may be specific to cancer cells. Finally, ATR-mediated increased cholesterol correlates with enhanced localization of mTOR to lysosomes. Collectively, our findings demonstrate a novel connection linking ATR and mTORC1 signaling through the modulation of cholesterol metabolism.
    Keywords:  Cholesterol; Lanosterol Synthase; Lysosome; Metabolism; p16
    DOI:  https://doi.org/10.1038/s44319-025-00451-3
  8. Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00266-9. [Epub ahead of print]
    The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.
    Jesse S S Novak, Lisa Polak, Sanjeethan C Baksh, Douglas W Barrows, Marina Schernthanner, Benjamin T Jackson, Elizabeth A N Thompson, Anita Gola, M Deniz Abdusselamoglu, Alain R Bonny, Kevin A U Gonzales, Julia S Brunner, Anna E Bridgeman, Katie S Stewart, Lynette Hidalgo, June Dela Cruz-Racelis, Ji-Dung Luo, Shiri Gur-Cohen, H Amalia Pasolli, Thomas S Carroll, Lydia W S Finley, Elaine Fuchs.
      Epidermal stem cells produce the skin's barrier that excludes pathogens and prevents dehydration. Hair follicle stem cells (HFSCs) are dedicated to bursts of hair regeneration, but upon injury, they can also reconstruct, and thereafter maintain, the overlying epidermis. How HFSCs balance these fate choices to restore physiologic function to damaged tissue remains poorly understood. Here, we uncover serine as an unconventional, non-essential amino acid that impacts this process. When dietary serine dips, endogenous biosynthesis in HFSCs fails to meet demands (and vice versa), slowing hair cycle entry. Serine deprivation also alters wound repair, further delaying hair regeneration while accelerating re-epithelialization kinetics. Mechanistically, we show that HFSCs sense each fitness challenge by triggering the integrated stress response, which acts as a rheostat of epidermal-HF identity. As stress levels rise, skin barrier restoration kinetics accelerate while hair growth is delayed. Our findings offer potential for dietary and pharmacological intervention to accelerate wound healing.
    Keywords:  dietary intervention; epidermal stem cells; fate selection; hair follicle stem cells; hair regrowth; integrated stress response; serine metabolism; tissue regeneration; tissue repair; wound healing
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.010
  9. Cell Commun Signal. 2025 Jun 19. 23(1): 290
    Mitochondrial dysfunction in the regulation of aging and aging-related diseases.
    Xianhong Zhang, Yue Gao, Siyu Zhang, Yiqi Wang, Xinke Pei, Yufei Chen, Jinhui Zhang, Yichen Zhang, Yitian Du, Shauilin Hao, Yujiong Wang, Ting Ni.
      Aging is an irreversible physiological process that progresses with age, leading to structural disorders and dysfunctions of organs, thereby increasing the risk of chronic diseases such as neurodegenerative diseases, diabetes, hypertension, and cancer. Both organismal and cellular aging are accompanied by the accumulation of damaged organelles and macromolecules, which not only disrupt the metabolic homeostasis of the organism but also trigger the immune response required for physiological repair. Therefore, metabolic remodeling or chronic inflammation induced by damaged tissues, cells, or biomolecules is considered a critical biological factor in the organismal aging process. Notably, mitochondria are essential bioenergetic organelles that regulate both catabolism and anabolism and can respond to specific energy demands and growth repair needs. Additionally, mitochondrial components and metabolites can regulate cellular processes through damage-associated molecular patterns (DAMPs) and participate in inflammatory responses. Furthermore, the accumulation of prolonged, low-grade chronic inflammation can induce immune cell senescence and disrupt immune system function, thereby establishing a vicious cycle of mitochondrial dysfunction, inflammation, and senescence. In this review, we first outline the basic structure of mitochondria and their essential biological functions in cells. We then focus on the effects of mitochondrial metabolites, metabolic remodeling, chronic inflammation, and immune responsesthat are regulated by mitochondrial stress signaling in cellular senescence. Finally, we analyze the various inflammatory responses, metabolites, and the senescence-associated secretory phenotypes (SASP) mediated by mitochondrial dysfunction and their role in senescence-related diseases. Additionally, we analyze the crosstalk between mitochondrial dysfunction-mediated inflammation, metabolites, the SASP, and cellular senescence in age-related diseases. Finally, we propose potential strategies for targeting mitochondria to regulate metabolic remodeling or chronic inflammation through interventions such as dietary restriction or exercise, with the aim of delaying senescence. This reviewprovide a theoretical foundation for organismal antiaging strategies.
    Keywords:  Aging-related diseases; Cellular senescence; Chronic inflammation; Metabolic remodelling; Mitochondria
    DOI:  https://doi.org/10.1186/s12964-025-02308-7
  10. Trends Endocrinol Metab. 2025 Jun 12. pii: S1043-2760(25)00119-5. [Epub ahead of print]
    Mitochondrial innate immune signaling in skeletal muscle adaptation to exercise.
    Jin Ma, Annie Yujin Son, Youlim Son, Ping-Yuan Wang, Paul M Hwang.
      Exercise-induced inflammation is regarded as a response to muscle damage from mechanical stress, but controlled immune signaling can be beneficial by promoting metabolic adaptation which, for example, decreases obesity and lowers the risk of diabetes. In addition to oxidative metabolism, mitochondria play a central role in initiating innate immune signaling. We review recent work that has identified the cGAS-STING-NF-κB signaling pathway, activated by the downregulation of mitochondrial proteins CHCHD4 and TRIAP1, as mediating skeletal muscle adaptation to exercise training as well as potentially promoting cellular resilience to environmental stresses. Notably, CHCHD4 haploinsufficiency prevents obesity in aging mice; therefore, this innate immune signaling pathway could be targeted to achieve some of the health benefits of exercise.
    Keywords:  CHCHD4; TRIAP1; exercise; fiber type; innate immunity; metabolism; mtDNA; obesity
    DOI:  https://doi.org/10.1016/j.tem.2025.05.004
  11. Trends Genet. 2025 Jun 18. pii: S0168-9525(25)00129-5. [Epub ahead of print]
    Advancing GWAS of human communication.
    Rosa S Gisladottir.
      The last decade has seen an explosion in genome-wide association studies (GWAS) on almost any imaginable phenotype. Unfortunately, humanity's most distinctive trait - communication, broadly construed - has been underserved. In this forum article I review recent advances and promising avenues that may help us understand the genetics and evolution of human communication.
    Keywords:  GWAS; archaic humans; communication; language; speech
    DOI:  https://doi.org/10.1016/j.tig.2025.05.009
  12. Redox Biol. 2025 Jun 09. pii: S2213-2317(25)00228-9. [Epub ahead of print]85 103715
    Regulation of redox homeostasis by ATF4-MTHFD2 axis during white adipose tissue browning.
    Rehna Paula Ginting, Hoang-Anh Pham-Bui, Choijamts Munkhzul, Siti Aisyah Fuad, Ahyeon Son, Jong-Seok Moon, Jaeseok Han, Mihye Lee, Min-Woo Lee.
      Maintaining redox balance is crucial for mitochondrial homeostasis. During browning of white adipocytes, both the quality and quantity of mitochondria undergo dramatic changes. However, the mechanisms controlling the redox balance in the mitochondria during this process remain unclear. In this study, we demonstrate that thermogenic activation occurs before mitochondrial biogenesis during cold-induced browning of inguinal white adipose tissue (iWAT) and is accompanied by increased mitochondrial stress and integrated stress response (ISR) signaling. Specifically, cold exposure enhances the expression of ATF4, an ISR effector. Adipocyte-specific deletion of ATF4 results in increased energy expenditure, but paradoxically leads to a lower core body temperature, and heightened pro-inflammation in iWAT after cold exposure, which is restored by the antioxidant, MitoQ. Mechanistically, ATF4 regulates the redox balance through MTHFD2, an enzyme involved in mitochondrial redox homeostasis by NADPH generation. Cold exposure upregulates MTHFD2 expression in an ATF4-dependent manner, and its inhibition by DS18561882 in vivo leads to impaired cold-induced mitochondrial respiration similar to the effects of ATF4 loss. These findings suggest that ATF4 is essential for redox balance via MTHFD2, thereby affecting tissue homeostasis during iWAT browning.
    DOI:  https://doi.org/10.1016/j.redox.2025.103715
  13. Cell Signal. 2025 Jun 16. pii: S0898-6568(25)00363-8. [Epub ahead of print] 111948
    Activation of STING pathway by mitochondrial fission negatively regulates adipogenic differentiation of 3 T3-L1 cells.
    Kai Ma, Haoxuan Sun, Xiaoyun Wu, Jinping Quan, Rong Tang, Weiwei Liu, Toshihiko Hayashi, Kazunori Mizuno, Shunji Hattori, Hitomi Fujisaki, Takashi Ikejima.
      Adipocyte hyperplasia refers to the increase in the number of adipocytes, whereas adipocyte hypertrophy pertains to the enlargement of individual adipocytes resulting from the accumulation of lipid droplets. In this study, we found that activation of the STING signalling pathway occurs during adipogenic differentiation of 3 T3-L1 preadipocytes. Interestingly, inhibiting the STING pathway by using STING antagonist H151 or siRNA targeting STING promotes adipocyte differentiation and increases adipocyte numbers, while activation of STING inhibits adipogenic differentiation. Silencing the STING canonical downstream IRF3, or inhibiting the proton channel activity of STING enhances adipogenic differentiation, confirming the negative modulation of adipogenic differentiation by STING. In vivo, intraperitoneal injection of H151 into mice with a high-fat diet further enhances the adipocyte hyperplasia, as shown by the increased volume of adipose tissues, but consistent sizes of adipocytes. During the adipogenic differentiation of 3 T3-L1 cells, DRP1-mediated mitochondrial fission is enhanced, and causes mitochondrial DNA leakage, which in turn activates the STING pathway. However, inhibition of mitochondrial fission represses adipogenic differentiation of 3 T3-L1 cells in spite of the down-regulation of STING pathway. Therefore, our results indicate that adipogenic differentiation is associated with DRP1-induced mitochondrial fission. However, the leakage of mitochondrial DNA caused by DRP1-induced mitochondrial fission activates the STING signalling pathway, which negatively regulates adipogenic differentiation. Tissue specific reduction of DRP1-associated mitochondrial fission or STING enhancement might be new strategies for the therapy of obesity-associated diseases.
    Keywords:  3 T3-L1 cells; Adipocyte differentiation; DRP1; Mitochondria; STING
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111948
  14. Metabolism. 2025 Jun 13. pii: S0026-0495(25)00193-3. [Epub ahead of print]170 156324
    NIPSNAP1 and NIPSNAP2 facilitate healthy aging independent of mitophagy.
    Jian Lv, Junmei Wang, Qin Chen, Qianhua Zhong, Hongchao Zhan, Qiuxiao Guo, Jiajie Li, Ningning Guo, Yu Fang, Jingjing Tong, Zhihua Wang.
      Mitochondrial dysfunction is a hallmark of aging and has been implicated in aging-related diseases. NIPSNAP1 and NIPSNAP2 are functionally redundant homologs involved in mitochondrial quality control, yet their roles in healthy aging and longevity remain unclear. Here, we generated a Nipsnap1/2 double knockout (DKO) mouse line and examined its impacts on mitochondrial physiology and natural aging. We demonstrated that the loss of Nipsnap1/2 impaired mitochondrial function and enhanced glycolysis activity, but it did not affect mitophagy despite the significant accumulation of Parkin. Compared with wild-type mice, DKO mice exhibited reduced body weight, deteriorated muscle strength, and pronounced fragility at 24 months of age. Moreover, Nipsnap1/2 depletion exacerbates aging-associated fibrosis and inflammation in the heart, liver and kidney. RNA-seq revealed a pro-aging transcriptome reprogramming toward energy exhaustion in DKO mice, eventually leading to cachexia-like adverse metabolic remodeling. Our findings demonstrate an anti-aging role of NIPSNAP1/2 via the surveillance of mitochondrial health.
    Keywords:  Aging; Cardiac aging; Metabolic disorder; Mitochondrial dysfunction; NIPSNAP1/2
    DOI:  https://doi.org/10.1016/j.metabol.2025.156324
  15. Trends Mol Med. 2025 Jun 17. pii: S1471-4914(25)00141-8. [Epub ahead of print]
    Fighting aging-associated clonal hematopoiesis with microbial metabolite.
    Shuqin Zeng, Dezhi Mu, Shaopu Wang.
      Age-related clonal hematopoiesis in the elderly is mediated by expansion of mutant pre-leukemic hematopoietic cells, but the mechanism remains unclear. Recently, Agarwal et al. found elderly individuals exhibit the gut microbial dysbiosis with enriched Gram-negative bacteria that release ADP-heptose into systemic circulation, which promotes pre-leukemic cell expansion through ALPK1-dependent signaling.
    DOI:  https://doi.org/10.1016/j.molmed.2025.06.001
  16. Cell Stem Cell. 2025 Jun 10. pii: S1934-5909(25)00192-4. [Epub ahead of print]
    Multiomic profiling reveals that prostaglandin E2 reverses aged muscle stem cell dysfunction, leading to increased regeneration and strength.
    Yu Xin Wang, Adelaida R Palla, Andrew T V Ho, Daniel C L Robinson, Meenakshi Ravichandran, Glenn J Markov, Thach Mai, Chris Still, Akshay Balsubramani, Surag Nair, Colin A Holbrook, Ann V Yang, Peggy E Kraft, Shiqi Su, David M Burns, Nora D Yucel, Lei S Qi, Anshul Kundaje, Helen M Blau.
      Repair of muscle damage declines with age due to the accumulation of dysfunctional muscle stem cells (MuSCs). Here, we uncover that aged MuSCs have blunted prostaglandin E2 (PGE2)-EP4 receptor signaling, which causes precocious commitment and mitotic catastrophe. Treatment with PGE2 alters chromatin accessibility and overcomes the dysfunctional aged MuSC fate trajectory, increasing viability and triggering cell cycle re-entry. We employ neural network models to learn the complex logic of transcription factors driving the change in accessibility. After PGE2 treatment, we detect increased transcription factor binding at sites with CRE and E-box motifs and reduced binding at sites with AP1 motifs, overcoming the changes that occur with age. We find that short-term exposure of aged MuSCs to PGE2 augments their long-term regenerative capacity upon transplantation. Strikingly, PGE2 injections following myotoxin- or exercise-induced injury overcome the aged niche, leading to enhanced regenerative function of endogenous tissue-resident MuSCs and an increase in strength.
    Keywords:  Prostaglandin E2; aging; epigenetic remodeling; inflammaging; molecular memory; muscle stem cells; neural network analysis; regeneration; rejuvenation; sarcopenia
    DOI:  https://doi.org/10.1016/j.stem.2025.05.012
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