Aging Cell最新文献

{"title":"Senescence Cell Induction Methods Display Diverse Metabolic Reprogramming and Reveal an Underpinning Serine/Taurine Reductive Metabolic Phenotype.","authors":"Domenica Berardi, Gillian Farrell, Abdullah AlSultan, Ashley McCulloch, Nicole M Hall, Rui Pedro Pereira Sousa, Melanie Jimenez, Colin Selman, Ilaria Bellantuono, Caroline H Johnson, Zahra Rattray, Nicholas J W Rattray","doi":"10.1111/acel.70127","DOIUrl":"https://doi.org/10.1111/acel.70127","url":null,"abstract":"<p><p>The relationship between in vitro senescence cell induction and intracellular biomolecular dysregulation is still poorly understood. In this study, we have found that a range of metabolic subphenotypes exists and is dependent on the induction method that is used. To develop understanding of these subphenotypes, we developed and employed a novel bioanalytical pipeline integrating untargeted metabolomics, label-free proteomics, and stable isotope tracing alongside cellular deformability measurements and established senescence biomarkers. Initially, standard senescent markers indicated all induction methods were consistent by showing elevated SA-β-Gal expression, p21 levels, and γH2AX DNA damage markers alongside a decrease in Ki67 and an increase in shape, volume, and deformability. However, when probed at the metabolic and protein levels, all senescence models indicated both shared and unique biomolecular responses. A metabolic shift toward reductive pathways (driven by serine and taurine rewiring) and impaired proteostasis was an observed shared response. These findings suggest that targeting metabolic redox circuits, alongside serine and taurine metabolic processes, presents novel therapeutic strategies for addressing senescence and aging. But importantly, alongside this general shift, we found that significant metabolic and proteomic heterogeneity also exists across different senescence induction methods. This demonstrates that the method of senescence induction significantly influences cell metabolic and proteomic profiles. Critically, methods of senescence induction are not interchangeable, and careful consideration is needed when choosing between different induction methods and when comparing cellular phenotypes across different in vitro senescence experiments.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70127"},"PeriodicalIF":8.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323946","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rapamycin, Not Metformin, Mirrors Dietary Restriction-Driven Lifespan Extension in Vertebrates: A Meta-Analysis.","authors":"Edward R Ivimey-Cook, Zahida Sultanova, Alexei A Maklakov","doi":"10.1111/acel.70131","DOIUrl":"https://doi.org/10.1111/acel.70131","url":null,"abstract":"<p><p>Dietary restriction (DR) robustly increases lifespan across taxa. However, in humans, long-term DR is difficult to maintain, leading to the search for compounds that regulate metabolism and increase lifespan without reducing caloric intake. The magnitude of lifespan extension from two such compounds, rapamycin and metformin, remains inconclusive, particularly in vertebrates. Here, we conducted a meta-analysis comparing lifespan extension conferred by rapamycin and metformin to DR-mediated lifespan extension across vertebrates. We assessed whether these effects were sex- and, when considering DR, treatment-specific. In total, we analysed 911 effect sizes from 167 papers covering eight different vertebrate species. We find that DR robustly extends lifespan across log-response means and medians and, importantly, rapamycin-but not metformin-produced a significant lifespan extension. We also observed no consistent effect of sex across all treatments and log-response measures. Furthermore, we found that the effect of DR was robust to differences in the type of DR methodology used. However, high heterogeneity and significant publication bias influenced results across all treatments. Additionally, results were sensitive to how lifespan was reported, although some consistent patterns still emerged. Overall, this study suggests that rapamycin and DR confer comparable lifespan extension across a broad range of vertebrates.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70131"},"PeriodicalIF":8.0,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144323945","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic Cellular NAD Depletion Activates a Viral Infection-Like Interferon Response Through Mitochondrial DNA Leakage.","authors":"Claudia C S Chini, Laura Colman, Eduardo Palmieri, Jessica L Strange, Sonu Kashyap, Bing Han, Andres Benitez-Rosendo, Gina L Ciccio Lopez, Sara Peixoto Rabelo, Shreyartha Mukherjee, Gustavo H de Souza, John Varga, Ralph G Meyer, Mirella L Meyer-Ficca, Eduardo N Chini","doi":"10.1111/acel.70135","DOIUrl":"10.1111/acel.70135","url":null,"abstract":"<p><p>Nicotinamide adenine dinucleotide (NAD) is a key coenzyme involved in energy metabolism, DNA repair, and cellular signaling. While the effects of acute NAD depletion have been better characterized, the consequences of chronic NAD deficiency remain unclear. Here, we investigated the impact of chronic NAD depletion in cultured cells by removing the availability of nicotinamide (NAM), a key precursor for NAD synthesis, from the culture media. In NIH3T3 fibroblasts, NAM depletion caused a dramatic drop in intracellular NAD levels within 2 days. Remarkably, the cells remained viable even after 7-14 days of NAM depletion, despite NAD⁺ levels falling to less than 10% of control conditions. This chronic NAD depletion led to distinct metabolic alterations. Mitochondrial basal respiration remained unchanged, but cells exhibited reduced spare respiratory and maximal capacities, along with significantly impaired glycolysis. Notably, NAD depletion triggered an interferon-dependent inflammatory response, resembling viral infections. This was driven by cytosolic leakage of mitochondrial DNA (mtDNA) through voltage-dependent anion channel 1 (VDAC1), which activated the cGAS-STING signaling pathway. Inhibition of VDAC oligomerization with VBIT-4, STING signaling with H-151, or mtDNA depletion blocked the upregulation of interferon genes induced by NAM depletion. Similar interferon responses triggered by NAD depletion were observed in IMR90 human fibroblasts and HS5 stromal cells. Our findings reveal a novel link between chronic NAD deficiency, VDAC-mediated mtDNA release to the cytoplasm, and the activation of the inflammatory response, providing new insight into how NAD decline affects cellular metabolic and inflammatory processes.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70135"},"PeriodicalIF":8.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Short-Term Severe Energy Restriction Promotes Molecular Health and Reverses Aging Signatures in Adults With Prediabetes in the PREVIEW Study.","authors":"Maria Lastra Cagigas, Andrius Masedunskas, Yao Lin, Samantha J Emery-Corbin, Jumana M Yousef, Laura F Dagley, Sam Olechnowicz, Rory Bowden, Rachael Hayward, Gary Low, Roslyn Muirhead, Jennie Brand-Miller, Mikael Fogeltholm, Anne Raben, Marco Demaria, Stephen J Fuller, Luigi Fontana","doi":"10.1111/acel.70123","DOIUrl":"https://doi.org/10.1111/acel.70123","url":null,"abstract":"<p><p>Prediabetes, characterized by impaired fasting glucose and/or glucose tolerance, is associated with organ damage, increased mortality, and accelerated aging, even before diabetes onset. Severe short-term energy restriction while maintaining essential nutrient intake is among the most effective strategies for weight loss, metabolic health improvement, and delaying type 2 diabetes progression. Extracellular vesicles contribute to these metabolic benefits; however, the impact of energy-restriction-induced weight loss on the extracellular vesicle proteome remains incompletely understood. This study employed targeted and untargeted proteomics to investigate the effect of an 8-week severely energy-restricted diet on the plasma proteome in adults with prediabetes from Sydney, Australia, as part of the PREVIEW study. Circulating extracellular vesicles were enriched in plasma using an immunoaffinity-based protocol. A total of 44 participants who achieved at least a 12% weight loss and provided informed consent were included in the study. Paired changes in over 2000 proteins between baseline and week 8 were analyzed. Following the intervention, multiple proteins associated with inflammation and senescence were significantly reduced, reversing the increase commonly associated with aging. The decline in inflammatory and senescence markers may have been mediated by extracellular vesicles, as indicated by significantly lower circulating levels of several vesicular markers. Additionally, several markers of protein synthesis downstream of mTORC1 and protein degradation were significantly reduced in vesicle-enriched plasma, suggesting decreased intercellular secretion and/or trafficking. Overall, this study identifies a diet-induced proteomic signature suggestive of reduced inflammation, lower senescence, and enhanced vesicle-associated proteostasis, potentially conferring health benefits beyond glycemic control.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70123"},"PeriodicalIF":8.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309232","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting CA2 Perineuronal Nets Restores Recognition Memory and Theta Oscillations in Aged Mice.","authors":"Sonam Fathima Mehak, Apoorva Bettagere Shivakumar, Feyba Jijimon, Amritanshu Gupta, Vikram Gopalakrishna Pillai, Gireesh Gangadharan","doi":"10.1111/acel.70139","DOIUrl":"https://doi.org/10.1111/acel.70139","url":null,"abstract":"<p><p>Remembering familiar versus novel stimuli is fundamental to survival, but it is compromised in several neurodegenerative disorders where aging is a key factor. Although the components of the extracellular matrix (ECM) have been suggested to be implicated in memory maintenance, the mechanistic and behavioral roles of ECM during the aging process remain unclear. Here, we employed an accelerated mouse model of aging to elucidate the causal link between ECM dynamics and recognition memory during aging. Aged mice exhibited impaired social and non-social recognition memory, accompanied by increased intensity of perineuronal nets (PNNs), specialized ECM structures in the hippocampal dorsal CA2 (dCA2). A reduction in the power of theta oscillations (3-7 Hz) in the dCA2 of aged mice was also observed. Notably, selective degradation of PNNs in the dCA2 using chondroitinase ABC (ChABC) rescued recognition memory deficits and restored theta oscillations. Together, our findings identify abnormal PNN in the CA2 as a critical factor for age-related deficits in hippocampal-dependent recognition memory and network rhythmicity. These insights raise the possibility that targeting CA2 PNNs could facilitate the development of diagnostic and therapeutic strategies to address age-associated cognitive frailty.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70139"},"PeriodicalIF":8.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebral Metabolic Rate of Oxygen and Accelerometry-Based Fatigability in Community-Dwelling Older Adults.","authors":"Emma L Gay, Caterina Rosano, Paul M Coen, Nicholaas Bohnen, Theodore Huppert, Yujia Susanna Qiao, Nancy W Glynn","doi":"10.1111/acel.70121","DOIUrl":"10.1111/acel.70121","url":null,"abstract":"<p><p>Alterations in energy metabolism may drive fatigue in older age, but prior research primarily focused on skeletal muscle energetics without assessing other systems and utilized self-reported measures of fatigue. We tested the association between energy metabolism in the brain and an objective measure of fatigability in the Study of Muscle, Mobility and Aging (N = 119, age 76.8 ± 4.0 years, 59.7% women). Total brain cerebral metabolic rate of oxygen (CMRO₂) was measured using arterial spin labeling and T₂-relaxation under spin tagging MRI protocols. Accelerometry-based fatigability status during a fast-paced 400 m walk was determined using the Pittsburgh Performance Fatigability Index (PPFI, higher = worse). Confounders included skeletal muscle energetics, measured in vivo using spectroscopy and ex vivo using respirometry, cardiorespiratory fitness (VO₂peak), weight, medication count, and multimorbidity. Multivariable logistic regression models were used to estimate the association (odds ratio (OR)) of CMRO₂ with PPFI > 0 compared to the referent group PPFI = 0. Models were first adjusted for age and sex and further adjusted for confounders. In this sample, 41.2% had PPFI > 0 (median 3.3% [0.4%-8.0%]). Higher CMRO₂ was associated with exhibiting performance fatigability (age- and sex-adjusted OR = 1.61, 95% CI: 1.06, 2.45, p = 0.03). This association remained significant after adjusting for in vivo skeletal muscle energetics and VO₂peak, suggesting that performance fatigability is associated with multi-system impairments in older adults.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70121"},"PeriodicalIF":8.0,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144289364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain DNA Methylation Age, Lifestyle Factors and Dementia in the Swedish Twin Registry.","authors":"Christopher E McMurran, Ida K Karlsson, Shayan Mostafaei, Yunzhang Wang, Lotte Gerritsen, Nancy L Pedersen, Sara Hägg","doi":"10.1111/acel.70117","DOIUrl":"https://doi.org/10.1111/acel.70117","url":null,"abstract":"<p><p>Advanced age is the most important risk factor for dementia. Measures of biological ageing such as DNA methylation age (DNAmAge) can give more information about the accumulation of age-related molecular damage in different organs than chronological age alone. Using post-mortem brain tissue from Swedish Twin Registry participants, we explored the relationship between lifestyle factors, dementia and DNAmAge measures from prefrontal cortex and cerebellum (n = 27 individuals) and paired blood samples (n = 20 individuals). We observed that smoking was associated with a higher DNAmAge deviation (PCBrainAge + 6.4 years in prefrontal cortex, CI [2.5, 10.3], p = 0.004). Conversely, a longer time spent in formal education was associated with a lower DNAmAge deviation (DNAmClock_Cortical - 4.8 years in prefrontal cortex, CI [-7.9, -1.8], p = 0.007). We found no significant differences between DNAmAge deviation of dementia cases versus controls, though among dementia cases there was a tendency towards higher DNAmClock_Cortical deviation in prefrontal cortex for those with a more advanced Braak stage on histopathological assessment (+ 3.4 years, CI [-0.68, 7.50], p = 0.13). There were no clear associations between DNAmAge from brain and blood samples collected prior to death. In summary, these data highlight the impact of smoking and education on biomarkers of brain ageing and emphasise the role for organ-specific biomarkers of ageing.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70117"},"PeriodicalIF":8.0,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144256831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Organ Specificity and Commonality of Epigenetic Aging in Low- and High-Running Capacity Rats.","authors":"Takuji Kawamura, Csaba Kerepesi, Juliet Polok Sarkar, Ferenc Torma, Zoltan Bori, Lei Zhou, Peter Bakonyi, Attila Kolonics, Laszlo Balogh, Mitsuru Higuchi, Vivien Pillár, Karolina Pircs, Lauren Gerard Koch, Steven Loyal Britton, Erika Koltai, Zsolt Radak","doi":"10.1111/acel.70110","DOIUrl":"https://doi.org/10.1111/acel.70110","url":null,"abstract":"<p><p>Epigenetic drift, which is gradual age-related changes in DNA methylation patterns, plays a significant role in aging and age-related diseases. However, the relationship between exercise, epigenetics, and aging, and the molecular mechanisms underlying their interactions are poorly understood. Here, we investigated the relationship between cardiorespiratory fitness (CRF), epigenetic aging, and promoter methylation of individual genes across multiple organs in selectively bred low- and high-capacity runner (LCR and HCR) aged rats. Epigenetic clocks, trained on available rat blood-derived reduced representation bisulfite sequencing data, did not reflect differences in CRF between LCR and HCR rats across all four organs. However, we observed organ-specific differences in global mean DNA methylation and mean methylation entropy between LCR and HCR rats, and the direction of these differences was the opposite compared to the age-related changes in the rat blood. Notably, the soleus muscle exhibited the most pronounced differences in promoter methylation due to CRF. We also identified seven genes whose promoter methylation was consistently influenced by CRF in all four organs. Moreover, we found that age acceleration of the soleus muscle was significantly higher compared to the heart and the hippocampus, and significantly lower compared to the large intestine. Finally, we found that the age acceleration was not consistent across organs. Our data suggest that CRF associates with epigenetic aging in an organ-specific and organ-common manner. Our findings provide important insights into the biology of aging and emphasize the need to validate rejuvenation strategies in the context of the organ-specific nature of epigenetic aging.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70110"},"PeriodicalIF":8.0,"publicationDate":"2025-06-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Type-Specific Single-Neuron Analysis Reveals Mitochondrial DNA Maintenance Failure Affecting Atrophying Pontine Neurons Differentially in Lewy Body Dementia Syndromes.","authors":"Eloise J Stephenson, Laura J Bailey, Stephen Gentleman, Helen Tuppen, Istvan Bodi, Claire Troakes, Christopher M Morris, Tony M Carr, Sarah Guthrie, Joanna L Elson, Ilse S Pienaar","doi":"10.1111/acel.70125","DOIUrl":"https://doi.org/10.1111/acel.70125","url":null,"abstract":"<p><p>The age-associated neurodegenerative disorder, Lewy body dementia (LBD), encompasses neuropsychiatric symptom-overlapping Dementia with Lewy bodies (DLB) and Parkinson's Disease with Dementia (PDD). We characterised how differential mitochondrial DNA (mtDNA) profiles contribute to neurotype-specific neurodegeneration and thereby clinicopathological heterogeneity, between LBD's syndromes. We further characterised key nuclear-encoding genes' recalibrations in response to such mtDNA changes. In post-mortem 'single-cell' acetylcholine- and noradrenaline-producing neurons, respectively of the pedunculopontine nucleus (PPN) and locus coeruleus (LC) from DLB, PDD and neurological-control brains, we quantified 'major arc'-locating mtDNA deletions (mtDels) and -copy number (mtCN), and measured mRNA levels of nuclear-encoding genes regulating mtDNA maintenance, -biogenesis and mitophagy. DLB cases' OXPHOS defect instigating mtDel burden was higher in both neurotypes than PDD. In DLB, mtCN was reduced for both neurotypes, but PDD cases revealed mtDNA depletion in LC-noradrenergic neurons only. DLB patients' shorter survival correlated with PPN-cholinergic neurons' mtDel levels, inversely with wild-type mtCN, implying that such neurons' inability to maintain sufficient wild-type mtDNA content drive DLBs' rapid psycho-cognitive manifestations. Contrastingly, PDD's longer disease duration allowed compensation against mtDels' clonal expansion in PPN-cholinergic neurons. Moreover, PDD induced mRNA depletion of a mitochondrial genome maintenance gene in PPN-cholinergic neurons, whilst LC-noradrenergic neurons displayed reduced expression of a mitophagy regulating gene. Here we identify mitochondrial genome maintenance and mitophagy pathway enrichment as therapeutic targets to offset defective mtDNA within pontine cholinergic and noradrenergic neurons of PDD patients. The pronounced LBD subtype-related mitochondria-nuclear genetic differences question the consensus that pathology converges at disease end-stage, calling for LBD subtype and neurotype-specific therapeutics.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70125"},"PeriodicalIF":8.0,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel GH Deficient Rat Model Reveals Cross-Species Insights Into Aging.","authors":"Soe Maung Maung Phone Myint, Alexander Tate Lasher, Kaimao Liu, Aron M Geurts, Steven N Austad, Liou Y Sun","doi":"10.1111/acel.70126","DOIUrl":"https://doi.org/10.1111/acel.70126","url":null,"abstract":"<p><p>Multiple studies in mice with genetically disrupted growth hormone (GH) signaling have demonstrated that such disruption results in reduced body size, robustly increased longevity (> 50% in some cases), and improvements across multiple health parameters. However, it remains unclear how generalizable these findings are across mammals. Evidence in rats is limited and inconsistent. These conflicting results highlight the need for further investigation into the role of GH signaling in longevity across species. To address this gap, we developed a novel GH-deficient rat model using CRISPR/Cas9 technology to introduce a 10 bp deletion in exon 3 of the gene encoding rat GH-releasing hormone (GHRH) yielding a non-functional GHRH product. Physiological characterization of GHRH knockout (KO) rats revealed that they were half the body weight of wild-type controls. Additionally, relative to controls, they displayed an increased percent body fat, enhanced insulin sensitivity, reduced circulating insulin-like growth factor I (IGF-I) concentration, and a decreased reliance on glucose oxidation for energy metabolism, as determined by indirect calorimetry. Analysis of the gut microbial community in adult GHRH-KO rats further revealed a less diverse male microbiome, but a more diverse female KO microbiome compared to controls. Collectively, these findings demonstrate that multiple aspects of the GH activity-deficient phenotype, well-documented in mice, are faithfully recapitulated in our rat model. Therefore, the GHRH-deficient rat model represents a valuable new tool for advancing our understanding of the role of GH signaling in aging processes.</p>","PeriodicalId":119,"journal":{"name":"Aging Cell","volume":" ","pages":"e70126"},"PeriodicalIF":8.0,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}