Aging Cell最新文献

{"title":"Metabolic Kinases as Regulators of Inter-Organelle Communication in Aging and Age-Related Diseases.","authors":"Md Riad Chowdhury, Jae-Han Jeon, Dipanjan Chanda","doi":"10.1111/acel.70624","DOIUrl":"10.1111/acel.70624","url":null,"abstract":"<p><p>Cellular aging is accompanied by progressive alterations in metabolic homeostasis, stress adaptation, and organelle function. Increasing evidence suggests that functional coordination among membrane-bound organelles, including mitochondria, the endoplasmic reticulum (ER), lysosomes, peroxisomes, and the Golgi apparatus, contributes to cellular homeostasis during aging. However, the mechanisms linking kinase signaling to specific inter-organelle contact sites or communication pathways remain incompletely defined. In this review, we discuss current evidence linking major metabolic and stress-responsive kinases, including AMPK, pyruvate dehydrogenase kinases (PDKs), mTOR, AKT, and PERK, to organelle coordination in aging and age-related diseases. These kinases regulate mitochondrial dynamics, metabolic flux, calcium and lipid handling, autophagy, lysosomal function, proteostasis, and vesicular trafficking. In some contexts, kinase signaling intersects with defined organelle interfaces, such as mitochondria-associated ER membranes, whereas in many cases the effects on inter-organelle communication are indirect or inferred from broader changes in organelle function. We further discuss how kinase dysregulation may contribute to age-associated defects in mitochondria-ER, mitochondria-lysosome, mitochondria-peroxisome, and ER-Golgi coordination in neurodegeneration, cardiometabolic disease, cellular senescence, and inflammaging. By distinguishing direct contact-site regulation from indirect functional coordination, this review highlights kinase-regulated organelle communication as an emerging, but still incompletely resolved, framework for understanding cellular decline during aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70624"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13333541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"EGR1 Mediates Ursodeoxycholic Acid-Promoted Mitophagy to Prevent Postovulatory Aging of Porcine Oocytes.","authors":"Ying Zhang, Qianru Han, Yongchao Liu, Wei Shen, Shunfeng Cheng, Xiaoya Li","doi":"10.1111/acel.70612","DOIUrl":"10.1111/acel.70612","url":null,"abstract":"<p><p>Postovulatory oocyte aging (POA) is a key factor contributing to the decline in female fertility and the success rate of assisted reproductive technology. Currently, most studies on POA have focused on downstream phenotypes such as mitochondrial dysfunction and oxidative stress, while little is known about its key upstream regulatory factors. Here, we show that the downregulation of transcription factor Early Growth Response 1 (EGR1) is a key upstream event driving porcine oocyte aging. Microtranscriptome sequencing combined with experimental validation verified a notable reduction in EGR1 protein abundance in aged oocytes. We found that Ursodeoxycholic Acid (UDCA) upregulated EGR1, which in turn promoted the expression of the autophagy-related protein LC3B and the lysosomal protein LAMP1, while reducing P62 accumulation. Furthermore, UDCA enhanced the expression of mitophagy core proteins PINK1, VDAC1 and promoted mitochondrial-lysosomal colocalization, thereby improving mitophagy and restoring the quality of aged oocytes. Crucially, treatment with the EGR1 inhibitor plicamycin completely blocked UDCA's ability to enhance the developmental potential of aged oocytes, confirming that EGR1-mediated mitophagy was the core pathway underlying UDCA's effects. Collectively, this study innovatively identified EGR1 as a key bridge linking oocyte aging and decreased mitophagy, and clarified the novel mechanism by which UDCA exerts its protective effects through the \"UDCA-EGR1-mitophagy\" axis. Our findings advanced the research on oocyte aging from phenotypic observation to the upstream transcriptional regulation level, providing a novel theoretical target and experimental basis for fundamentally intervening in reproductive aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70612"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13330137/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148373944","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Traditional Disease Risk Factors Outperform Epigenetic Clocks as Predictors of Non-Communicable Disease Morbidity in a Middle-Aged Cohort.","authors":"Daria Kostiniuk, Flóra Székely, Leo-Pekka Lyytikäinen, Jo Ciantar, Sonja Rajić, Pashupati P Mishra, Terho Lehtimäki, Katja Pahkala, Suvi Rovio, Juha Mykkänen, Olli Raitakari, Emma Raitoharju, Saara Marttila","doi":"10.1111/acel.70626","DOIUrl":"10.1111/acel.70626","url":null,"abstract":"<p><p>DNA methylation-based epigenetic clocks have been highlighted as promising biomarkers of ageing, and they have been shown to robustly predict morbidity and mortality. However, current literature is lacking a formal analysis of the increased prediction accuracy, or the added value, of the epigenetic clocks over traditional risk factors, such as body composition, smoking, or alcohol consumption, in predicting common chronic diseases. Here, we have compared the most commonly used epigenetic clocks and traditional risk factors as predictors of incidence of ageing-associated non-communicable chronic disease in a 7-to-9-year follow-up in a middle-aged population cohort (n = 1108, aged 34 to 49 years at baseline). In our cohort, a statistical model consisting of a combination of traditional risk factors (age, sex, smoking, alcohol consumption, WHR, BMI) outperforms any model including an epigenetic clock. The added value of epigenetic clock measurements over simple and affordable traditional risk factors should be clearly established if epigenetic clocks are to be used in clinical settings or as tools of personal health monitoring.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70626"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13347623/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148409699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Gut to Fat: Intestinal Epithelial Exosomes Target PDGFRα⁺ Progenitors to Promote Lipogenesis and Counteract Subcutaneous Adipose Tissue Atrophy in Aging.","authors":"Tingting Huang, Ye Huang, Yin Zhou, Xuanbei Lu, Lijun Yang, Jing Yu, Yunlu Sheng, Fan Xia, Guoxian Ding, Yifan Lv, Shan Lv","doi":"10.1111/acel.70625","DOIUrl":"10.1111/acel.70625","url":null,"abstract":"<p><p>Age-related subcutaneous adipose tissue (SAT) atrophy is a hallmark of aging, contributing to metabolic dysfunction and systemic aging. The mechanisms underlying SAT atrophy and potential therapeutic strategies remain poorly understood. Here, we report that small intestinal epithelium-derived exosomes (SI-Exos) mediate gut-adipose communication and play a pivotal role in age-related SAT remodeling. We found that the miRNA cargo of SI-Exos undergoes significant age-related changes. Administration of young SI-Exos to aged mice enhanced lipid droplet formation, reversed SAT atrophy, and reduced inflammation in visceral adipose tissue (VAT). These beneficial effects were mediated by young SI-Exos targeting PDGFRα⁺ progenitor cells, the major adipocyte precursors in SAT. Mechanistically, young SI-Exos were enriched with miR-379-5p, which targeted Usp34, a negative regulator of lipogenesis. Inhibition of Usp34 downregulated the Wnt/β-catenin pathway, promoting lipid droplet formation and differentiation of PDGFRα⁺ progenitor cells. Single-cell RNA sequencing analysis further confirmed that young SI-Exos enhanced lipid transport and synthesis in SAT cell populations. Additionally, NK cells were increased. Our findings reveal a previously unrecognized role of SI-Exos in regulating SAT progenitor cell dynamics through the miR-379-5p/Usp34/Wnt/β-catenin axis, offering a potential therapeutic strategy for combating age-associated SAT atrophy and promoting healthy aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70625"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13357384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429382","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptomic Evidence of Mitochondrial Double-Stranded RNA Accumulation in Brain Aging and Alzheimer's Disease.","authors":"Rachel L Doser, Thomas J LaRocca","doi":"10.1111/acel.70616","DOIUrl":"10.1111/acel.70616","url":null,"abstract":"<p><p>Mitochondria and inflammation are tightly linked in aging and Alzheimer's disease (AD), and recent evidence implicates mitochondrial double-stranded RNA (mt-dsRNA) as a potential trigger of inflammation. We examined mt-dsRNA accumulation and dsRNA signaling in brain aging and AD using complementary human brain tissue and in vitro transcriptomic datasets by quantifying mitochondrial transcripts, dsRNA editing, and related gene expression patterns. We found that mt-dsRNA signatures increased after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt-dsRNA-driven inflammation. In AD brains, mt-dsRNA signatures were further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin-dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt-dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age- and AD-related neurodegeneration and identify mt-dsRNA as a potential driver of chronic inflammation in the brain.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70616"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13349986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"High Intrinsic Aerobic Capacity Is Associated With a Distinct Epigenetic and Signaling Profile in the Aged Rat Brain.","authors":"Lei Zhou, Soroosh Mozaffaritabar, Erika Koltai, Takuji Kawamura, Mitsuru Higuchi, Sylwester Kujach, Yaodong Gu, Lauren Gerard Koch, Steven Loyal Britton, Zsolt Radák","doi":"10.1111/acel.70622","DOIUrl":"10.1111/acel.70622","url":null,"abstract":"<p><p>Exercise is a powerful non-pharmacological strategy for preserving brain health during aging. However, whether intrinsic exercise capacity is associated with a distinct molecular phenotype in the aged brain, independent of training intervention, remains unclear. Aged selectively bred low-capacity runner (LCR) and high-capacity runner (HCR) rats were studied. Hippocampal DNA methylation was profiled by reduced representation bisulfite sequencing (RRBS), and differentially methylated regions (DMRs) were annotated and functionally enriched. Spatial learning, aerobic capacity, and cortical protein signaling were assessed by Morris water maze, VO₂max testing, and Western blotting. RRBS identified 6452 significant DMRs, most of which were hypermethylated in HCR rats (82.4%) and enriched in open-sea and gene-body regions. Genes linked to hypermethylated DMRs showed context-dependent enrichment, particularly in intronic and exonic regions, highlighting MAPK, PI3K-Akt, TNF, calcium, and synaptic signaling pathways. Core methylation-related enzymes TET1/2 and DNMT3A/B were unchanged. Cortical protein profiling showed higher phosphorylation of ERK1/2, AKT, mTOR, S6, and synapsin in HCR rats, together with higher JNK2, p38, NF-κB, TNF-α, and OGG1 abundance, whereas protein carbonylation and selected exercise-responsive neurotrophic and metabolic/mitochondrial markers were unchanged. Exploratory correlation analysis identified a subset of DMRs associated with individual VO₂max values. Morris water maze performance did not differ significantly between groups. High intrinsic exercise capacity in aged rats is associated with distinct hippocampal DNA methylation patterns that align with cortical protein profiles involving MAPK, AKT-mTOR-S6, synaptic, and inflammation-related signaling. These findings suggest a distinct molecular phenotype linked to intrinsic aerobic capacity in the aged brain.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70622"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13366406/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic Aging of Critical Illness Survivors Assessed by the Muscle-Specific \"Clock\" and Its Relationship With Reduced Long-Term Muscle Strength.","authors":"Ceren Uzun Ayar, Inge Derese, Greet Van den Berghe, Ilse Vanhorebeek","doi":"10.1111/acel.70629","DOIUrl":"10.1111/acel.70629","url":null,"abstract":"<p><p>Critically ill patients requiring treatment in the intensive care unit (ICU) suffer from muscle weakness that persists for years. As compared with healthy subjects, skeletal muscle of patients biopsied five years post-ICU revealed an abnormal transcriptome partially associated with poor muscle strength. We now hypothesized that skeletal muscle of long-term ICU survivors is \"epigenetically aged\", as determined by a muscle-specific epigenetic clock, and that such accelerated epigenetic aging contributes to their long-term muscle weakness. Muscle DNA-methylation data from former ICU patients at 5-year follow-up (N = 118) and healthy controls (N = 160), aged 18-89 years, were analyzed by the MEATv2 epigenetic clock. First, epigenetic age (DNAmAge), epigenetic minus chronological age (AADiff) and epigenetic age acceleration (AAResid) were compared between 97 former patients and 97 controls, propensity score-matched for age and sex. Next, the impact of any muscle-specific epigenetic aging of ICU survivors was investigated, via multivariable models, as a potential contributor to the altered transcriptome and reduced muscle strength. Former ICU patients showed a significantly higher muscle DNAmAge, AADiff, and AAResid than matched controls. In adjusted models, higher muscle DNAmAge, AADiff, or AAResid did not substantially contribute to differentially expressed muscle RNAs in former patients as compared with controls and was not associated with the poor long-term muscle strength. In conclusion, five years after ICU discharge, former patients showed accelerated epigenetic aging in skeletal muscle. However, the muscle-specific epigenetic clock did not capture molecular changes that are associated with long-term muscle weakness, which highlights the need for other muscle-specific biological predictors of age-related physical impairment. Trail Registration: ClinicalTrials.gov: NCT00512122.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70629"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356824/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circular RNAs-Stress Granule Interplay Drives Aging-Related Proteostasis Loss.","authors":"José M Izquierdo","doi":"10.1111/acel.70641","DOIUrl":"10.1111/acel.70641","url":null,"abstract":"<p><p>Aging involves a gradual loss of cellular balance, leading to reduced function and increased disease risk. While impaired proteostasis is a key hallmark of aging, more evidence shows the importance of RNA homeostasis (ribostasis), particularly the regulation of circular RNAs (circRNAs). CircRNAs are stable RNA molecules that build up over time and are linked to age-related cellular dysfunctions. In this regard, Kim et al. 2026 provide new insights into the impact of circRNA turnover on aging and lifespan. Their findings indicate that the accumulation of circRNAs is partly due to a decline in ribonuclease K (RNASEK), an enzyme that breaks down circRNAs. Using models such as worms, mice, and human cells, they show that RNASEK is crucial for healthy aging and longevity, suggesting its role is conserved across species. The research also shows that circRNAs gather in stress granules (SGs), which are ribonucleoprotein complexes formed during cell stress. RNASEK collaborates with heat shock protein 90 to prevent harmful RNA-rich aggregates, maintaining cellular dynamics in balance. These findings suggest a link between ribostasis and proteostasis, identifying circRNA clearance as a potential factor in longevity. The study also points to RNASEK as a promising target for treating age-related diseases. However, key questions remain, such as how RNASEK specifically degrades circRNAs, whether specific circRNAs or overall circRNA levels drive aging traits, and whether circRNA buildup is a cause or result of cell aging. Further research is needed to evaluate the conservation, safety, and therapeutic potential of this proteostasis-ribostasis axis in human biology.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70641"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13373772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Suppression of Ciliogenesis Alleviates Cellular Senescence via AKT Signaling in Gingival Aging.","authors":"Wenjun Shao, Huihui Yang, Chenghu Yin, Yunjie Zhang, Yixing Xu, Wakam Chang, Haibin Xia, Min Wang, Liangliang Fu, Kaiyao Huang","doi":"10.1111/acel.70627","DOIUrl":"10.1111/acel.70627","url":null,"abstract":"<p><p>Aging, as an intrinsic risk factor, accelerates gingival inflammation and periodontal diseases. However, the cellular and molecular mechanisms underlying gingival aging remain unclear, hindering the development of targeted therapies. In this study, we performed the first single-cell transcriptomic analysis of aging human gingiva, identifying primary cilia as potential regulators of gingival fibroblast senescence. We demonstrated that aged gingival tissues exhibit increased fibroblast senescence and enhanced ciliogenesis compared to young tissues. Suppression of ciliogenesis significantly reduced senescence markers and alleviated DNA damage in aged fibroblasts accompanied by increased AKT activation. In addition, FOXO1 inactivation and enhanced expression of DNA repair-related genes were found after suppression of ciliogenesis in aged gingival fibroblasts. Importantly, inhibition of AKT partially reversed the anti-senescent phenotypes induced by ciliogenesis suppression. Functionally, adeno-associated virus-mediated suppression of ciliogenesis in aged mice mitigated gingival fibroblast senescence, reduced inflammation, and diminished tissue fibrosis. These findings highlight that primary cilia may contribute to the regulation of gingival fibroblast senescence and identify ciliary dynamics and AKT signaling downstream of cilia as potential therapeutic targets for managing aging-related gingival diseases, providing a potential strategy to improve periodontal health in the elderly.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70627"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13354758/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148417146","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GW9508-Induced Activation of GPR40 in Thymic Epithelial Cells: A Therapeutic Strategy to Delay Thymic Aging.","authors":"Qingqing Li, Ping Zhu, Lihong Cui, Fenghua Luo, Yongqin Zhou, Yuanyuan Hu, Chunyan Luo, Shanshan Han, Xie Ding, Maoxi Yao, Honggang Yuan, Yinhong Song","doi":"10.1111/acel.70630","DOIUrl":"10.1111/acel.70630","url":null,"abstract":"<p><p>Age-associated thymic involution leads to a reduction of T-cell production, which constitutes a primary factor in immunosenescence, thereby increasing vulnerability to cancer, infections, and autoimmune disorders. Thymic epithelial cells (TECs), essential for T-cell development, exhibit progressive senescence with aging. The development of strategies to mitigate TECs senescence and delay thymic degeneration has emerged as a significant research focus. Here, aged C57BL/6J mice and immortalized thymic epithelial cells (iTECs) were hired. The marked reduction of GPR40 expression was observed in TECs from aged mice and in senescent iTECs induced by doxorubicin in vitro. Administration of the GPR40 agonist GW9508, antagonist GW1100, or their combination to aged mice or senescent iTECs demonstrated that GPR40 activation effectively restored thymic function in aged mice. Mechanistically, GW9508 targeted GPR40 to elevate intracellular calcium ion levels, thereby activating the AMPK signaling pathway and inhibiting the hyperactivation of the ERK1/2-MAPK pathway in senescent cells, ultimately enhancing the activity of aged iTECs. Collectively, these findings suggest that the exogenous activation of GPR40 by GW9508 may represent a viable strategy to alleviate thymic senescence and enhance immune function in aged individuals.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":"25 7","pages":"e70630"},"PeriodicalIF":7.1,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13365366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}