bims-obesme Biomed News
on Obesity metabolism
Issue of 2025–06–29
fifteen papers selected by
Xiong Weng, University of Edinburgh
  1. Cysteine deficiency induces rapid weight loss via adipose tissue browning.
  2. Glucagon controls obesity-specific energy expenditure via persistent cAMP/PKA signaling.
  3. Sarcosine decreases in sarcopenia and enhances muscle regeneration and adipose thermogenesis by activating anti-inflammatory macrophages.
  4. Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.
  5. RIPK1 senses S-adenosylmethionine scarcity to drive cell death and inflammation.
  6. GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity.
  7. SENP2 regulates UCP1-dependent thermogenesis in brown adipocytes via deSUMOylation of ERRα.
  8. Age-dependent accumulation of mitochondrial tRNA mutations in mouse kidneys linked to mitochondrial kidney diseases.
  9. The mitochondrial methylation potential gates mitoribosome assembly.
  10. Perspectives on the essence and drivers of aging.
  11. Mettl7a alleviated bone loss in osteoporosis mice by targeting the O-GlcNAcylation of Bsp via m6A methylation.
  12. Generation of a set of genetically modified long QT syndrome induced pluripotent stem cell lines carrying knock-in variants rs120074178 (KCNQ1 c.569G > A; p.Arg190Gln) and rs137854600 (SCN5A c.4865G > A; p.Arg1622Gln) and isogenic control lines.
  13. Creatine kinase B mediates Ucp1-independent beige fat thermogenesis in mice.
  14. Adipose tissue ageing: implications for metabolic health and lifespan.
  15. Hallmarks of stem cell aging.
  1. Nat Rev Endocrinol. 2025 Jun 24.
    Cysteine deficiency induces rapid weight loss via adipose tissue browning.
    Olivia Tysoe.
      
    DOI:  https://doi.org/10.1038/s41574-025-01146-4
  2. J Hepatol. 2025 Jun 21. pii: S0168-8278(25)02278-0. [Epub ahead of print]
    Glucagon controls obesity-specific energy expenditure via persistent cAMP/PKA signaling.
    Fen Long, Tenagne Delessa Challa, Lianggong Ding, Anand Kumar Sharma, Chunyan Wu, Adhideb Ghosh, Falko Noé, Carla Horvath, Gerhard Liebisch, Marcus Höring, Tongtong Wang, Manuel Klug, Tina Zimmermann, Mafalda Maria Azevedo Pereira, Wolfgang Rist, Benjamin Strobel, Anton Pekcec, Heike Neubauer, Christian Wolfrum.
       BACKGROUND & AIMS: Glucagon (GCG) analogues are gaining attention as promising components in incretin-based therapeutics for obesity and metabolic dysfunction-associated steatohepatitis. However, the biology of chronic glucagon treatment, particularly the molecular underpinnings of GCG-induced energy expenditure and lipid metabolism, remains poorly defined.
    METHODS: We utilized a long-acting GCG analogue (LA-GCG) in conjunction with hepatic and adipose glucagon receptor knockout mouse models. Through an integrative approach that combined metabolic, biochemical, and omics techniques, we investigated the molecular mechanisms underlying GCG-induced energy expenditure and metabolic benefits.
    RESULTS: We demonstrate that the LA-GCG enhances energy expenditure in diet-induced obese mice with an essential role of hepatic, but not adipose, glucagon receptor (GCGR) signaling. Intriguingly, the enhancement in energy expenditure is observed only in obese but not in lean mice. The preferential efficacy is plausibly found in a prolonged activation of cAMP/PKA signaling through PDE4B/4D downregulation by LA-GCG. Conversely, the cAMP/PKA signaling is promptly attenuated by the PDE4B/4D activity in lean mice. Interestingly, unlike the EE phenotype, the lipid-clearing capacity of LA-GCG is independent of the PDE4/cAMP/PKA axis.
    CONCLUSIONS: These findings provide the molecular basis for GCG-induced energy expenditure and metabolic benefits and suggest the phenotypic segregation of cAMP/PKA-dependent and independent effects.
    IMPACT AND IMPLICATIONS: This study provides fundamental mechanistic insights into GCG pharmacology with direct clinical implications. The obesity-specific enhancement of energy expenditure by GCGR agonist substantiates the superior efficacy of GCGR/glucagon-like peptide-1 receptor (GLP-1R) dual agonists in individuals with obesity compared to GLP-1R mono-agonists. Importantly, differential PDE4 expression patterns may provide a molecular basis for the variable weight-loss responses to GCG-based agonists, identifying PDE4 inhibition as a potential strategy to restore efficacy in GCG-non-responders. Furthermore, the PDE4-overexpression model preserved the lipid-clearing capacity of GCGR agonist while attenuating hyperglycemic risk, demonstrating a translatable strategy to optimize the safety-efficacy profile of GCG-based therapies for cardio-renal-metabolic diseases such as obesity and MASH.
    Keywords:  PDE4; PKA; adipose tissue; cAMP; energy expenditure; glucagon; lipid metabolism; liver; obesity; weight loss
    DOI:  https://doi.org/10.1016/j.jhep.2025.06.011
  3. Nat Aging. 2025 Jun 23.
    Sarcosine decreases in sarcopenia and enhances muscle regeneration and adipose thermogenesis by activating anti-inflammatory macrophages.
    Yu Liu, Meiling Ge, Xina Xiao, Ying Lu, Wanyu Zhao, Kun Zheng, Kexin Yu, Yanting He, Qian Zhong, Lixing Zhou, Shan Hai, Xiaohui Liu, Na Jiang, Dan Du, Yan Zhang, Guo Cheng, Zhenmei An, Yi Zhao, Heng Xu, Biao Dong, Shuangqing Li, Binwu Ying, Huiyuan Zhang, Jirong Yue, Birong Dong, Lunzhi Dai.
      Age-related changes in circulating metabolites influence systemic physiology and may contribute to diseases such as sarcopenia. Although metabolic dysregulation is closely linked to sarcopenia, the roles of specific metabolites remain unclear. In this study, we performed comprehensive plasma metabolomic and lipidomic analyses across two cohorts comprising 1,013 individuals, uncovering the metabolic characteristics of sarcopenia, including a notable decline in plasma sarcosine levels in both aging patients and those with sarcopenia. Functional studies in mice showed that sarcosine helps maintain muscle mass homeostasis during aging, promotes adipose thermogenesis and enhances muscle regeneration. We demonstrate here that sarcosine activated the GCN2 signaling pathway to enhance anti-inflammatory macrophage polarization, promoting adipose thermogenesis and muscle regeneration. These effects may increase energy expenditure and restore metabolic balance to reduce chronic inflammation and improve insulin sensitivity, which are crucial for managing sarcopenia. This study underscores the potential of sarcosine supplementation as an adjunctive strategy via macrophage modulation for preventing sarcopenia in older adults.
    DOI:  https://doi.org/10.1038/s43587-025-00900-7
  4. Nat Metab. 2025 Jun 27.
    Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.
    Marcus J Tol, Yuta Shimanaka, Alexander H Bedard, Jennifer Sapia, Liujuan Cui, Mariana Colaço-Gaspar, Peter Hofer, Alessandra Ferrari, Kevin Qian, John P Kennelly, Stephen D Lee, Yajing Gao, Xu Xiao, Jie Gao, Julia J Mack, Thomas A Weston, Kevin J Williams, Baolong Su, Calvin Pan, Aldons J Lusis, Daniel P Pike, Alex Reed, Natalia Milosevich, Benjamin F Cravatt, Makoto Arita, Stephen G Young, David A Ford, Rudolf Zechner, Stefano Vanni, Peter Tontonoz.
      Genetic and dietary cues are known drivers of obesity, yet how they converge at the molecular level is incompletely understood. Here we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, an endoplasmic reticulum (ER)-resident O-acyltransferase that selectively enriches diet-derived omega-6 polyunsaturated fatty acids (n-6 PUFAs) in the membrane lipidome. In mice fed a high-fat diet, lowering membrane n-6 PUFA levels through genetic or dietary interventions results in aberrant adipose triglyceride (TG) turnover, ectopic fat deposition and insulin resistance. Additionally, we detail a non-canonical adaptive response in 'lipodystrophic' Lpcat3-/- adipose tissues that engages a futile lipid cycle to increase metabolic rate and offset lipid overflow to ectopic sites. Live-cell imaging, lipidomics and molecular dynamics simulations reveal that adipocyte LPCAT3 activity enriches n-6 arachidonate in the phosphatidylethanolamine (PE)-dense ER-lipid droplet interface. Functionally, this localized PE remodelling optimizes TG storage by driving the formation of large droplets that exhibit greater resistance to adipose TG lipase activity. These findings highlight the PPARγ-LPCAT3 axis as a mechanistic link between dietary n-6 PUFA intake, adipose expandability and systemic energy balance.
    DOI:  https://doi.org/10.1038/s42255-025-01320-y
  5. Cell Metab. 2025 Jun 19. pii: S1550-4131(25)00294-3. [Epub ahead of print]
    RIPK1 senses S-adenosylmethionine scarcity to drive cell death and inflammation.
    Zezhao Chen, Xiaosong Gu, Hongbo Chen, Huijing Zhang, Jianping Liu, Xiaohua Yang, Yuping Cai, Mengmeng Zhang, Lingjie Yan, Yuanxin Yang, Bing Shan, Zheng-Jiang Zhu, Yixiao Zhang, Jinyang Gu, Daichao Xu.
      The capacity of cells to sense and respond to nutrient availability is essential for metabolic homeostasis. Failure in this process may cause cell death and associated diseases. While nutrient sensing in metabolic pathways is well understood, the mechanisms linking nutrient signals to cell death remain unclear. Here, we show that RIPK1, a key mediator of cell death and inflammation, senses methionine and its metabolite, S-adenosylmethionine (SAM), to dictate cell survival and death. SAM-mediated symmetrical dimethylation at RIPK1 Arg606 by PRMT5 functions as a physiological protective brake against RIPK1 activation. Metabolic perturbations, such as methionine restriction or disrupted one-carbon flux, reduce SAM levels and unmask Arg606, promoting RIPK1 self-association and trans-activation, thereby triggering apoptosis and inflammation. Thus, RIPK1 is a physiological SAM sensor linking methionine and one-carbon metabolism to the control of life-or-death decisions. Our findings suggest that RIPK1 could be a potential target for diseases associated with disrupted SAM availability.
    Keywords:  PRMT5; RIPK1; S-adenosylmethionine; TNF signaling; apoptosis; death domain; inflammation; methionine; methylation; one-carbon metabolism
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.014
  6. Cell. 2025 Jun 23. pii: S0092-8674(25)00630-0. [Epub ahead of print]
    GRK-biased adrenergic agonists for the treatment of type 2 diabetes and obesity.
    Aikaterini Motso, Benjamin Pelcman, Anastasia Kalinovich, Nour Aldin Kahlous, Muhammad Hamza Bokhari, Nodi Dehvari, Carina Halleskog, Erik Waara, Jasper de Jong, Elizabeth Cheesman, Christine Kallenberg, Gopala Krishna Yakala, Praerona Murad, Erika Wetterdal, Pia Andersson, Sten van Beek, Anna Sandström, Diane Natacha Alleluia, Emanuela Talamonti, Sonia Youhanna, Pierre Sabatier, Claire Koenig, Sabine Willems, Aurino M Kemas, Dana S Hutchinson, Seungmin Ham, Lukas Grätz, Jan Voss, Jose G Marchan-Alvarez, Martins Priede, Krista Jaunsleine, Jana Spura, Vadims Kovada, Linda Supe, Leigh A Stoddart, Nicholas D Holliday, Phillip T Newton, Nicolas J Pillon, Gunnar Schulte, Roger J Summers, Ilga Mutule, Edgars Suna, Jesper V Olsen, Peter Molenaar, Jens Carlsson, Volker M Lauschke, Shane C Wright, Tore Bengtsson.
      Biased agonism of G protein-coupled receptors (GPCRs) offers potential for safer medications. Current efforts have explored the balance between G proteins and β-arrestin; however, other transducers like GPCR kinases (GRKs) remain understudied. GRK2 is essential for β2 adrenergic receptor (β2AR)-mediated glucose uptake, but β2AR agonists are considered poor clinical candidates for glycemic management due to Gs/cyclic AMP (cAMP)-induced cardiac side effects and β-arrestin-dependent desensitization. Using ligand-based virtual screening and chemical evolution, we developed pathway-selective agonists of β2AR that prefer GRK coupling. These compounds perform well in preclinical models of hyperglycemia and obesity and demonstrate a lower potential for cardiac and muscular side effects compared with standard β2-receptor agonists and incretin mimetics, respectively. Furthermore, the lead candidate showed favorable pharmacokinetics and was well tolerated in a placebo-controlled clinical trial. GRK-biased β2AR partial agonists are thus promising oral alternatives to injectable incretin mimetics used in the treatment of type 2 diabetes and obesity.
    Keywords:  BRET; GLP-1; GPCR; GRK; beta-2 agonists; biased agonism; diabetes; metabolism; obesity; skeletal muscle
    DOI:  https://doi.org/10.1016/j.cell.2025.05.042
  7. Exp Mol Med. 2025 Jun 27.
    SENP2 regulates UCP1-dependent thermogenesis in brown adipocytes via deSUMOylation of ERRα.
    Hun Jee Choe, Ji Seon Lee, Jong Yoen Park, Seung-Ah Lee, Young Joo Park, Sung Soo Chung, Kyong Soo Park.
      Brown adipose tissue (BAT) is responsible for energy homeostasis and adaptive thermogenesis. SUMO-specific protease 2 (SENP2) plays an essential role in adipogenesis; however, the role of SENP2 in BAT metabolism has not been explored. Here we investigated the role of SENP2 in mature brown adipocytes with a brown adipocyte-specific SENP2 knockout (Senp2-BKO) mouse model generated using the uncoupling protein 1 (Ucp1)-Cre. High-fat diet-induced insulin resistance was aggravated in Senp2-BKO mice compared with control mice. In Senp2-BKO mice, adaptive thermogenesis upon acute cold exposure was impaired and UCP1 expression was barely induced upon cold or β-adrenergic stimulation. SENP2-mediated deSUMOylation of estrogen-related receptor alpha (ERRα) significantly enhanced Ucp1 promoter activity through activation of the ERRα/PGC1α complex. The absence of SENP2 inhibited formation of ERRα, cAMP-response element-binding protein (CREB) and RNA Polymerase II transcriptional complex at the Ucp1 promoter following β3-adrenergic stimulation. In addition, SUMOylation of ERRα severely interfered with binding of ERRα to its DNA-binding site (ERRE) in the promoter of Ucp1. Our findings revealed that SENP2 plays a role in the metabolic flexibility and thermogenic efficiency of BAT, particularly in response to β3-adrenergic activation.
    DOI:  https://doi.org/10.1038/s12276-025-01458-5
  8. Nat Aging. 2025 Jun 27.
    Age-dependent accumulation of mitochondrial tRNA mutations in mouse kidneys linked to mitochondrial kidney diseases.
    Leping Zhang, Zhe Xu, Jia Jing, Guoshi Chai, Guanglei Xie, Yanfei Ru, Qunyu Lv, Xiang Zuo, Qian Zhang, Jiatong Chen, He Jin, Ning Liu, Minghua Kong, Bin Shen, Mingxi Liu, Lei Jiang, Xi Wang, Yanxiao Zhang, Min Jiang.
      Heteroplasmic pathogenic mitochondrial DNA (mtDNA) mutations are key drivers of mitochondrial diseases, yet their tissue-specific and cell-specific accumulation patterns during aging and the mechanistic links to pathology remain poorly understood. In this study, we employed DddA-derived cytosine base editor technology to generate three mouse models harboring distinct pathogenic mitochondrial tRNA mutations. These mutations exhibited age-dependent accumulation in the kidneys, leading to severe kidney defects that well recapitulate human mitochondrial kidney disease. Mitochondrial single-cell assay for transposase-accessible chromatin with sequencing (mtscATAC-seq) revealed unique heteroplasmy dynamics across different kidney cell types: podocytes exhibited a positive selection for mutant mtDNA, whereas tubular epithelial cells displayed neutral drift of mutations during aging. Integrative analyses combining mtscATAC-seq, single-cell RNA sequencing and spatially enhanced resolution omics sequencing further identified molecular changes in high-mutant defective cells, including increased AP-1 family transcription factor activity, tubular epithelial cell proliferation and immune activation, which contribute to disease progression. Our study underscores the importance of kidney function monitoring in patients with mitochondrial disease, particularly in older adults, and establishes robust preclinical models to facilitate the development of therapeutic strategies.
    DOI:  https://doi.org/10.1038/s43587-025-00909-y
  9. Nat Commun. 2025 Jun 25. 16(1): 5388
    The mitochondrial methylation potential gates mitoribosome assembly.
    Ruth I C Glasgow, Vivek Singh, Lucía Peña-Pérez, Alissa Wilhalm, Marco F Moedas, David Moore, Florian A Rosenberger, Xinping Li, Ilian Atanassov, Mira Saba, Miriam Cipullo, Joanna Rorbach, Anna Wedell, Christoph Freyer, Alexey Amunts, Anna Wredenberg.
      S-adenosylmethionine (SAM) is the principal methyl donor in cells and is essential for mitochondrial gene expression, influencing RNA modifications, translation, and ribosome biogenesis. Using direct long-read RNA sequencing in mouse tissues and embryonic fibroblasts, we show that processing of the mitochondrial ribosomal gene cluster fails in the absence of mitochondrial SAM, leading to an accumulation of unprocessed precursors. Proteomic analysis of ribosome fractions revealed these precursors associated with processing and assembly factors, indicating stalled biogenesis. Structural analysis by cryo-electron microscopy demonstrated that SAM-dependent methylation is required for peptidyl transferase centre formation during mitoribosome assembly. Our findings identify a critical role for SAM in coordinating mitoribosomal RNA processing and large subunit maturation, linking cellular methylation potential to mitochondrial translation capacity.
    DOI:  https://doi.org/10.1038/s41467-025-60977-x
  10. Life Med. 2025 Apr;4(2): lnaf006
    Perspectives on the essence and drivers of aging.
    Haim Y Cohen, Vera Gorbunova, Steve Horvath, Brian K Kennedy, Wei Li, João Pedro de Magalhães, Andrei Seluanov, Moshi Song, Keiichiro Suzuki.
      
    DOI:  https://doi.org/10.1093/lifemedi/lnaf006
  11. Stem Cells Transl Med. 2025 Jun 25. pii: szaf024. [Epub ahead of print]14(7):
    Mettl7a alleviated bone loss in osteoporosis mice by targeting the O-GlcNAcylation of Bsp via m6A methylation.
    Yantong Wang, Yangyang Cao, Zhipeng Fan.
      Postmenopausal osteoporosis, a prevalent metabolic bone disease, elevates susceptibility to fragility fractures while imposing substantial healthcare costs and public health challenges. The profound interplay between BMSCs and surrounding extracellular matrix (ECM) proteins, which are highly rich in O-GlcNAcylation, play pivotal roles in the process of osteoporosis. M6A methylation plays a crucial regulatory role in the development of osteoporosis, while the crosstalk between m6A methylation and ECM O-GlcNAcylation remains mechanistically undefined. Here we found Mettl7a overexpression improved the impaired osteogenic capability of OVX-mBMSCs in vitro. Conditional knockout of Mettl7a in the mesenchyme (Prx1-cre;Mettl7af/f) accelerated bone loss of OVX mice. Mechanistically, Mettl7a promoted mBMSCs osteogenic differentiation by targeting the O-GlcNAcylation of Bsp, an ECM protein. Mettl7a regulated the expression and O-GlcNAcylation of Bsp through m6A methylation of Oga. We further demonstrated that Mettl7a-AAV treatment alleviated bone loss phenotype in osteoporosis mice via the O-GlcNAcylation of Bsp. Collectively, our findings reveal novel mechanistic intersections between ECM protein O-GlcNAcylation and m6A methylation, advancing the understanding of osteoporotic regulation.
    Keywords:  Mettl7a; O-GlcNAcylation; extracellular matrix (ECM); m6A methylation; osteoporosis
    DOI:  https://doi.org/10.1093/stcltm/szaf024
  12. Stem Cell Res. 2025 Jun 18. pii: S1873-5061(25)00105-9. [Epub ahead of print]87 103755
    Generation of a set of genetically modified long QT syndrome induced pluripotent stem cell lines carrying knock-in variants rs120074178 (KCNQ1 c.569G > A; p.Arg190Gln) and rs137854600 (SCN5A c.4865G > A; p.Arg1622Gln) and isogenic control lines.
    Nayara Sousa da Silva, Agnieszka D'Antonio-Chronowska, Reyna Hernandez-Benitez, Angelina Rose McCarron, Esra Karaca, Kai Fang, Juan Carlos Izpisua Belmonte, Athanasia D Panopoulos, Keiichiro Suzuki, Kelly A Frazer.
      Long QT syndrome (LQTS) is an inherited channelopathy characterized by life-threatening arrhythmias. LQTS has many subtypes defined by the gene that contains the mutation, including LQT1 (KCNQ1), LQT2 (KCNH2), and LQT3 (SCN5A). Here, we used CRISPR/Cas9 technology to generate five isogenic human induced pluripotent stem cell (iPSC) lines, one line harboring an LQT1 variant rs120074178 (KCNQ1 c.569G > A), two lines harboring an LQT3 variant rs137854600 (SCN5A c.4865G > A), and two derived control lines.
    DOI:  https://doi.org/10.1016/j.scr.2025.103755
  13. Mol Metab. 2025 Jun 23. pii: S2212-8778(25)00100-0. [Epub ahead of print] 102193
    Creatine kinase B mediates Ucp1-independent beige fat thermogenesis in mice.
    Jakub Bunk, Mina Ersin, Mohammed F Hussain, Bozena Samborska, Maria Guerra-Martinez, Drishti Soni, Lawrence Kazak.
       OBJECTIVE: Creatine kinase B (CKB) is the main isoenzyme driving creatine kinase (CK) activity in classical brown adipocytes. However, the specific CK isoenzyme active in beige adipocytes remains unknown. This study aimed to identify the predominant CK isoenzyme expressed and functionally active in beige adipocytes.
    METHODS: CK activity was tracked using D3-creatine tracing in inguinal adipocytes from mice with adipocyte-specific Ckb deletion and their littermate controls, across in vivo, in vitro, and ex vivo settings.
    RESULTS: CKB was essential for CK activity in protein lysates and intact white and beige adipocytes isolated from inguinal fat and drives thermogenesis through the Futile Creatine Cycle.
    CONCLUSIONS: Similar to classical brown adipocytes, CKB is the key functional CK isoenzyme in white and beige adipocytes from the inguinal depot.
    DOI:  https://doi.org/10.1016/j.molmet.2025.102193
  14. Nat Rev Endocrinol. 2025 Jun 23.
    Adipose tissue ageing: implications for metabolic health and lifespan.
    Guan Wang, Anying Song, Qiong A Wang.
      Adipose tissue, a pivotal player in whole-body energy homeostasis and insulin sensitivity, undergoes considerable remodelling throughout the ageing process, a facet that has garnered little attention until the past decade. This Review comprehensively summarizes the dynamic metabolic, cellular and functional changes that occur in white and thermogenic adipose tissue during distinct ageing stages, across different adipose tissue depots. We emphasize the influence of ageing on different cell types within adipose tissue, including adipocytes, adipocyte progenitors, immune cells and senescent cells, and their collective effect on adipose tissue function and systemic metabolism. We also decipher the correlation between adipose tissue ageing and prevalent age-related conditions such as metabolic dysfunction-associated fatty liver disease and cardiovascular diseases. Finally, the Review delves into the potential of current anti-ageing interventions to beneficially affect adipose tissue, encompassing caloric restriction, metformin, glucagon-like peptide 1 receptor agonists and senolytics. The discussion extends to the exploration of whether targeting adipose tissue through such interventions could emerge as a prominent therapeutic strategy for mitigating age-related diseases and enhancing the healthspan and lifespan of the ageing population.
    DOI:  https://doi.org/10.1038/s41574-025-01142-8
  15. Cell Stem Cell. 2025 Jun 17. pii: S1934-5909(25)00226-7. [Epub ahead of print]
    Hallmarks of stem cell aging.
    Thomas A Rando, Anne Brunet, Margaret A Goodell.
      As organisms age, somatic stem cells progressively lose their ability to sustain tissue homeostasis and support regeneration. Although stem cells are relatively shielded from some cellular aging mechanisms compared with their differentiated progeny, they remain vulnerable to both intrinsic and extrinsic stressors. In this review, we delineate five cardinal features that characterize aged stem cells and examine how these alterations underlie functional decline across well-studied stem cell compartments. These hallmarks not only provide insight into the aging process but also serve as promising targets for therapeutic strategies aimed at rejuvenating stem cell function and extending tissue health span.
    Keywords:  aging; differentiation; hematopoietic stem cells; heterogeneity; muscle stem cells; neural stem cells; quiescence; stem cells
    DOI:  https://doi.org/10.1016/j.stem.2025.06.004
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