Aging Cell最新文献

{"title":"A Deep-Learning Based Biomarker of Systemic Cellular Senescence Burden to Predict Mortality and Health Outcomes","authors":"Shangshu Zhao,&nbsp;Chia-Ling Kuo,&nbsp;Eric J. Lenze,&nbsp;Julie L. Wetherell,&nbsp;Laura Haynes,&nbsp;Perla El-Ahmad,&nbsp;Richard Fortinsky,&nbsp;George Kuchel,&nbsp;Trevor Harris,&nbsp;Breno S. Diniz","doi":"10.1111/acel.70737","DOIUrl":"https://doi.org/10.1111/acel.70737","url":null,"abstract":"<p>The accumulation of senescent cells is a recognized hallmark of biological aging and is associated with the onset of multiple chronic medical conditions. Senescent cells exhibit a distinct secretory profile, known as the senescence-associated secretory phenotype (SASP), which can propagate cellular senescence to neighboring and distant tissues. Measuring SASP factors in blood serves as a practical proxy for cellular senescence burden and may help track disease states and intervention outcomes. We developed and validated a composite SASP Score by integrating large-scale population proteomics data with a semi-supervised deep learning framework. The analytical workflow included: (1) selection of biologically curated SASP proteins; (2) development of a Guided autoencoder with Transformer (GAET) model using data from the UK Biobank Pharma Proteomics Project (UKB-PPP); (3) internal evaluation and association analyses within the UK Biobank; and (4) external validation and longitudinal assessment in an independent randomized clinical trial cohort. The deep learning-based SASP Score was a strong, independent predictor of mortality risk and incident serious, chronic medical conditions (e.g., dementia, COPD, myocardial infarction, stroke). In an independent cohort, multimodal exercise significantly changed the SASP Score trajectory over 18 months. Our findings support the potential of a deep learning-derived SASP Score as a biomarker for systemic cellular senescence burden. Our statistical approach can offer enhanced interpretability and cross-platform utility, providing a valuable tool for aging research and the evaluation of geroscience-guided interventions.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70737","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048428","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":"Correction to “Impaired Cytokine Secretion Contributes to Age-Dependent Immune Dysfunction in SARS Coronavirus Response and Is Restored by Young CD11b-Positive Cell Transfer”","authors":"","doi":"10.1111/acel.70744","DOIUrl":"https://doi.org/10.1111/acel.70744","url":null,"abstract":"<p>\u0000 <span>Wu, Y.-X.</span>, <span>C.-W. Hu</span>, <span>J.-Y. Chang</span>, et al. (<span>2025</span>), <span>Impaired Cytokine Secretion Contributes to Age-Dependent Immune Dysfunction in SARS Coronavirus Response and Is Restored by Young CD11b-Positive Cell Transfer</span>. <i>Aging Cell</i>, <span>24</span>: e70154. https://doi.org/10.1111/acel.70154.\u0000 </p><p>In Figure 6c, the lung section shown for Mouse #3 in the CoV2 column (Vein) is the same field as the section shown in Figure 2b (Old, CoV2); it appears in Figure 6c as a crop of that field presented at a larger size. Both panels show an aged mouse 7 days after CoV2 ssRNA administration, stained with hematoxylin and eosin. The re-use of this image was not declared in the figure's legend.</p><p>Accordingly, in the legend to Figure 6, the text “(c) Representative lung histology (H&amp;E staining) from aged mice and treatment (Tx) groups 7 days post-ssRNA administration.” was incomplete.</p><p>This should have read as: “(c) Representative lung histology (H&amp;E staining) from aged mice and treatment (Tx) groups 7 days post-ssRNA administration. The section shown for Mouse #3 in the CoV2 column (Vein) is the same field as that shown in Figure 2b (Old, CoV2), reproduced here as a crop presented at a larger size.”</p><p>Figure 6 along with its corrected legend is provided below. The image itself is unchanged, and the results, interpretation and conclusions of the article are unaffected.</p><p>In addition, in the legend to Figure 6 the significance markers were printed as “<i>p</i> &lt; 0.05, **<i>p</i> &lt; 0.01, ***<i>p</i> &lt; 0.001”; this should have read as “*<i>p</i> &lt; 0.05, **<i>p</i> &lt; 0.01, ***<i>p</i> &lt; 0.001”. The corrected legend below incorporates both changes.</p><p>We apologize for these errors.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70744","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048429","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":"Hepatocyte Growth Hormone Receptor Ablation Is Associated With Aging Phenotypes and Hepatic Mitochondrial Dysfunction","authors":"Kangkang Yang,&nbsp;Yuli Jian,&nbsp;Fusheng Pang,&nbsp;Ming Ying,&nbsp;Qian Yang,&nbsp;Nian Liu,&nbsp;Shujing Wang,&nbsp;Yingjie Wu","doi":"10.1111/acel.70741","DOIUrl":"https://doi.org/10.1111/acel.70741","url":null,"abstract":"<p>Aging drives physiological decline and predisposes individuals to multiple age-related pathologies, constituting a major global health challenge. Growth hormone receptor (GHR), a critical regulator of growth, development, and metabolism, has emerged as a potential therapeutic target. However, its precise role in aging and age-related diseases remains incompletely defined. Here, we demonstrate that hepatocyte-specific GHR knockout mice display accelerated aging-related phenotypes, characterized by shortened lifespan, enhanced cellular senescence, reduced metabolic stress resilience, cognitive decline, impaired bone mineralization, and exacerbated inflammaging. Elevated circulating GH following hepatocyte-specific GHR ablation mediates adipose-liver crosstalk that promotes adipose lipolysis and CD36-dependent hepatic steatosis. Hepatocyte-specific GHR deficiency also promotes liver aging and aggravates age-related hepatic pathologies in both naturally aged and high-fat diet (HFD)-fed mice. Mechanistically, loss of hepatic GHR impairs STAT5b phosphorylation while upregulating PPARγ expression. Enhanced nuclear translocation of PPARγ activates transcription of <i>Pdk4</i> and <i>Cd36</i>, leading to mitochondrial damage and ectopic lipid accumulation. Together, dysregulated lipid metabolism and mitochondrial dysfunction establish a self-amplifying vicious cycle that accelerates aging and its pathophysiology. Pharmacological inhibition of PDK4 in vivo effectively ameliorates the age-related pathologies induced by hepatocyte-specific GHR ablation. These findings identify hepatic GHR signaling as an important contributor to age-related hepatic pathology and a candidate node within the broader network of factors driving systemic aging phenotypes, highlighting hepatocyte GHR signaling as a promising therapeutic target for age-related liver disorders.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70741","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149048430","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":"Organ-Specific Proteomic Aging Clocks Reveal Complexities Underlying the Healthy Drinking Paradox","authors":"Gabin Drouard","doi":"10.1111/acel.70743","DOIUrl":"10.1111/acel.70743","url":null,"abstract":"<p>The “healthy drinking” paradox refers to situations where alcohol consumption is misleadingly associated with better health outcomes, a pattern frequently observed in observational studies that are prone to a range of confounding factors. Some recent studies developing organ-specific proteomic aging clocks report that alcohol consumption is linked to slower aging in select organs, even as it accelerates aging in others, thus echoing this paradox, with substantial discrepancies across such studies. In this Perspective, I summarize findings to date, discuss potential reasons for these contradictory results, such as differences in clock construction, alcohol phenotyping, and confounding control across studies, and highlight both the limitations and promise of organ-specific clocks for studying epidemiologically challenging traits such as alcohol consumption. Taken together, these findings call for careful interpretation of observational studies linking alcohol consumption to systemic and organ-specific biological aging, which may, if taken at face value, understate the known damage that alcohol causes to human health. Further work comparing organ-specific clocks developed across different studies from a biological standpoint is needed to fully decipher the true effects of alcohol consumption, alongside research applying aging clocks to alcohol consumption within more advanced epidemiological designs and across different dimensions of aging (chronological age vs. mortality).</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70743","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149035598","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":"Inhibition of Abnormal Elevated α-Synuclein Ameliorates Dopaminergic Neuron Degeneration in Parkinson's Disease Mouse Model","authors":"Xuenan Wang,&nbsp;Yiru Ding,&nbsp;Lujuan He,&nbsp;Xizhi Kang,&nbsp;Xiwen Geng,&nbsp;Fumika Sakaue,&nbsp;Takanori Yokota,&nbsp;Liang-wen Zhang,&nbsp;Wei Yao,&nbsp;Ji-chun Zhang","doi":"10.1111/acel.70717","DOIUrl":"https://doi.org/10.1111/acel.70717","url":null,"abstract":"<p>Parkinson's disease (PD) is characterized by the accumulation of Lewy bodies (LBs) in the brain, predominantly consisting of aggregated and phosphorylated α-synuclein (α-Syn). Consequently, strategies to suppress α-Syn expression offer substantial therapeutic potential for PD. This study explores heteroduplex oligonucleotides (HDOs), an innovative gene-silencing technology utilizing DNA/RNA or DNA/DNA hybrids. We designed two HDOs targeting α-Syn: α-Syn-HDO-1 (DNA/RNA) and α-Syn-HDO-2 (DNA/DNA). Both demonstrated robust silencing of α-Syn expression in mice. In AAV-hSyn-human SNCA-treated mice, these α-Syn-HDOs exerted neuroprotective effects on dopaminergic neurons. Furthermore, they reduced aberrant α-Syn accumulation in α-Syn-HEK293 cells and in mice treated with α-Syn preformed fibrils (PFFs). The neuroprotective effects of α-Syn-HDOs were linked to activation of the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway. Moreover, BDNF overexpression diminished abnormal α-Syn aggregation in both PFFs-treated α-Syn-HEK293 cells and PFFs-treated mice. These results highlight the capacity of α-Syn-HDOs to protect dopaminergic neurons by enhancing BDNF–TrkB signaling through the inhibition of abnormal elevated α-Syn. Our findings position α-Syn-HDOs as promising therapeutic candidates for PD and suggest BDNF as a potential diagnostic biomarker or indicator of treatment efficacy.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70717","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149014696","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":"Thymic Involution and Function in People With HIV and General Population Controls: A Cross-Sectional Analysis From Two Danish Cohort Studies","authors":"Manon C. Vanbellinghen,&nbsp;Anders Boyd,&nbsp;Andreas Ohrt Johansen,&nbsp;Moises Alberto Suarez-Zdunek,&nbsp;Andreas Dehlbæk Knudsen,&nbsp;Thomas Skårup Kristensen,&nbsp;Jørgen Tobias Kühl,&nbsp;Per Ejlstrup Sigvardsen,&nbsp;Michael Huy Cuong Pham,&nbsp;Andreas Fuchs Larsen,&nbsp;Klaus Fuglsang Kofoed,&nbsp;Børge Grønne Nordestgaard,&nbsp;Shoaib Afzal,&nbsp;Neeltje Kootstra,&nbsp;Susanne Dam Nielsen,&nbsp;Peter Reiss","doi":"10.1111/acel.70723","DOIUrl":"https://doi.org/10.1111/acel.70723","url":null,"abstract":"<p>Thymic involution, the age-related replacement of thymic soft tissue by fat, has been linked to immunosenescence and chronic inflammation, processes implicated in aging-associated comorbidities. Untreated HIV infection is associated with thymic atrophy and reduced thymic output. Although thymic function may normalize after initiation of antiretroviral therapy, the long-term consequences of HIV infection on thymic involution in people with HIV (PWH) remain unknown. We investigated whether thymic involution differs between PWH and population controls, and how its association with markers of T-cell differentiation and inflammation in PWH. We conducted a cross-sectional analysis including 654 PWH aged ≥ 40 years from the Copenhagen Comorbidity in HIV Infection study and 637 age- and sex-matched population controls from the Copenhagen General Population Study. Thymic tissue was graded on a 4-point scale based on adipose-to-soft tissue proportion on chest CT scans, with higher grades reflecting more soft tissue (i.e., less involution). Thymic output was assessed by signal joint T-cell receptor excision circle (sjTREC) content in buffy coats. PWH had higher odds of a higher thymus grade compared to population controls (adjusted-OR = 1.75, 95% CI = 1.31–2.33), after adjustment for age, sex, pack-years, BMI, waist-to-hip ratio, physical activity, and alcohol intake. Higher thymus grade was associated with greater sjTREC content, and among PWH with higher proportions of naïve CD4⁺ and CD8⁺ T cells, lower proportions of senescent T cells, and lower IL-6 and hs-CRP levels. Our findings indicate thymic involution may be attenuated in some PWH on long-term treatment, and that the preserved thymic output may help mitigate chronic inflammation.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70723","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149014800","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":"Therapeutic Immune Reprogramming by Rapamycin Attenuates Plaque Inflammation and Lymphoid Immune Responses in Aged Atherosclerotic Mice","authors":"Jill de Mol,&nbsp;Daphne H. de Korte,&nbsp;Marie A. C. Depuydt,&nbsp;Virginia Smit,&nbsp;Mireia N. A. Bernabé Kleijn,&nbsp;Peter J. van Santbrink,&nbsp;Christoph J. Binder,&nbsp;Florentina Porsch,&nbsp;Frank H. Schaftenaar,&nbsp;Amanda C. Foks","doi":"10.1111/acel.70730","DOIUrl":"https://doi.org/10.1111/acel.70730","url":null,"abstract":"<p>Aging is a major risk factor for atherosclerosis and is accompanied by profound changes in the immune system, including effector T cell expansion, senescent cell accumulation, and increased pro-inflammatory signaling. Rapamycin, a promising rejuvenation therapeutic that inhibits mTORC1 and modulates immune aging, was investigated for its potential to attenuate pro-atherogenic immune responses in aged atherosclerotic mice. 80- to 90-week-old male <i>Ldlr</i>^{<i>−/−</i>} mice with established atherosclerotic lesions were treated intraperitoneally with rapamycin or control triweekly for 8 weeks. Systemic and plaque immunity was assessed by flow cytometry or single-cell RNA-sequencing. Plaque morphology was evaluated by histology. Rapamycin treatment reduced plaque macrophage content (0.73 ± 0.07 × 10⁵ μm²) compared to control (ctrl: 0.95 ± 0.09 × 10⁵ μm², <i>p</i> &lt; 0.05) and decreased total T cell numbers in vascular and lymphoid tissues. This was accompanied by a shift from effector to central memory phenotypes, particularly within the CD8⁺ compartment, and a relative enrichment of regulatory CD4⁺ T cells (Tregs). Single-cell transcriptomics of aortic Tregs revealed increased expression of suppressive genes (<i>Foxp3</i>, <i>Tgfb1</i>) upon rapamycin. Rapamycin also reduced T follicular helper cells, IL-21 expression, germinal center B cells, plasma cells, and total and oxidation-specific epitope-specific immunoglobulin levels. Additionally, age-associated B cells were diminished in spleen and lymph nodes, reflecting a broader anti-inflammatory effect on B cell immunity. Finally, aortic leukocytes displayed profoundly reduced senescent enrichment scores. Rapamycin remodels the immune landscape in aged atherosclerotic mice, promoting regulatory lymphocyte subsets and suppressing antigen-driven and inflammatory immune responses. These findings highlight the potential of immune-targeted rejuvenation to mitigate age-related atherogenic inflammation.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70730","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149014801","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":"The Role of EVs in the Aging Hematopoietic System","authors":"Esra G. Kosebent,&nbsp;Nathalie Havranek,&nbsp;Karoline Kollmann,&nbsp;Kristina Kirschner,&nbsp;Eszter Doma,&nbsp;Kavya Gupta","doi":"10.1111/acel.70715","DOIUrl":"10.1111/acel.70715","url":null,"abstract":"<p>Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that mediate intercellular communication by transferring proteins, nucleic acids, and lipids. Within the hematopoietic system, EVs orchestrate critical signaling between bone marrow (BM) niche cells and hematopoietic stem and progenitor cells (HSPCs) to regulate quiescence, proliferation, and lineage commitment. During aging, senescence and telomere attrition drive a profound remodeling of EV biogenesis and cargo. Aged EVs, particularly those released from senescent mesenchymal stromal cells (MSCs) and osteoblasts, exhibit altered microRNA profiles and reduced protective antioxidants. These changes perpetuate niche dysfunction, induce senescence in recipient cells, and promote myeloid-biased hematopoiesis. Importantly, this communication is a selective process governed by vesicle-intrinsic surface signatures, such as tetraspanins and integrins, which interact with specific receptors on distinct hematopoietic subsets to regulate signaling fidelity. Conversely, EVs from young or pluripotent stem cells deliver rejuvenating signals that can restore aged HSPC function and attenuate inflammaging. Elucidating these mechanisms of selective targeting and stress-responsive cargo remodeling provides vital insights for developing EV-based diagnostic tools and rejuvenation strategies to prevent age-related immune imbalances and hematologic malignancies.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70715","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029328","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":"Motor Cortex Hyperexcitability Is Coupled to Neuromuscular Dysfunction in Aged Mice","authors":"Jose A. Viteri,&nbsp;Nathan R. Kerr,&nbsp;Fereshteh B. Darvishi,&nbsp;Anna Roshani Dashtmian,&nbsp;Charles D. Brennan,&nbsp;Sindhuja N. Ayyagari,&nbsp;Peter J. Moore,&nbsp;Meifang Wang,&nbsp;Harper Snyder,&nbsp;Baocong Yu,&nbsp;Joseph M. Santin,&nbsp;W. David Arnold","doi":"10.1111/acel.70731","DOIUrl":"https://doi.org/10.1111/acel.70731","url":null,"abstract":"<p>Age-related weakness is strongly associated with disability and mortality in older adults. While muscle atrophy contributes to weakness, strength declines at a faster rate than muscle mass, implicating neural mechanisms such as changes at the spinal cord and neuromuscular junction. Yet, the role of the motor cortex in age-related weakness remains largely unexplored. We previously identified layer V pyramidal neurons (LVPNs) of the primary motor cortex as hyperexcitable in aged mice, but whether this phenotype was coupled to neuromuscular dysfunction was unknown. Here, we show that aged mice exhibit impaired strength, coordination, and neuromuscular excitability. However, cortical motor output to muscle measured in vivo was enhanced, with patch-clamp recordings from the same aged animals confirming LVPN hyperexcitability. This was accompanied by altered excitatory and inhibitory synaptic responses evoked by layer II/III stimulation, and by transcriptional changes in excitability-related genes of aged LVPNs. Statistical analysis across 250 cortical–neuromuscular/behavioral pairwise relationships revealed that greater cortical excitability is broadly and consistently correlated with worse whole-animal neuromuscular and behavioral outcomes. Most strikingly, LVPN firing frequency emerged as the single strongest correlate of neuromuscular dysfunction and statistically accounted for 75% of the age effect on neuromuscular function, while the reverse analysis showed that neuromuscular dysfunction accounted for 42.2% of the age effect on LVPN firing frequency. These findings identify the motor cortex as a potential contributor to age-related weakness—a finding with broader significance given that hyperexcitability of LVPNs is a shared feature of motor dysfunction across neurodegenerative disease contexts.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70731","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149014799","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":"Mitochondrial Transplantation Rejuvenates Aging Heart by Restoring Mitophagy Flux via the HIF-3α-BNIP3 Axis","authors":"Ning Jin,&nbsp;Li Zhou,&nbsp;Haixia Gui,&nbsp;Jingjing Tang,&nbsp;Xiaozhen Huang,&nbsp;Wenting Wang,&nbsp;Guorong Jin,&nbsp;Haiqin Cheng,&nbsp;Yuxiang Liang,&nbsp;Xinyi Geng,&nbsp;Zhiwei Peng,&nbsp;Hong Zhao,&nbsp;Zhizhen Liu,&nbsp;Jun Xie","doi":"10.1111/acel.70720","DOIUrl":"https://doi.org/10.1111/acel.70720","url":null,"abstract":"<p>Mitochondrial quality control is severely impaired in the aging heart, largely attributed to disrupted mitophagy homeostasis. However, the key molecular drivers remain poorly defined, and the translational value of mitochondria-targeted therapy for cardiac aging is still underexplored. Here, we report prominent mitophagy flux congestion in aged cardiac tissue and confirm that mitochondrial transplantation efficiently rescues impaired mitophagy, ultimately rejuvenating the aging heart. Mechanistically, we identify a novel HIF-3α-BNIP3 signaling axis in the aging heart: HIF-3α, conventionally recognized as a transcriptional repressor, is aberrantly upregulated in senescent cardiomyocytes and directly regulates excessive BNIP3 expression to trigger mitophagy congestion. Notably, we establish an innovative translational strategy that mitochondrial transplantation restrains pathological overactivation of the HIF-3α-BNIP3 axis via improving intracellular ATP homeostasis, thereby reconstructing normal mitophagy flux and reversing cardiac aging. Our findings uncover an unrecognized upstream regulator of age-related mitophagy defects and provide a mitochondrial-based intervention approach for the treatment of aging-associated cardiac dysfunction.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"25 10","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.70720","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149014698","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}