Aging CellPub Date : 2024-06-06DOI: 10.1111/acel.14196
Yiyang Wang, Yunyan Ye, Shengyi Shi, Kehang Mao, Haonan Zheng, Xuguang Chen, Hanting Yan, Yiming Lu, Yong Zhou, Weimin Ye, Jing Ye, Jing-Dong J. Han
{"title":"Prediagnosis recognition of acute ischemic stroke by artificial intelligence from facial images","authors":"Yiyang Wang, Yunyan Ye, Shengyi Shi, Kehang Mao, Haonan Zheng, Xuguang Chen, Hanting Yan, Yiming Lu, Yong Zhou, Weimin Ye, Jing Ye, Jing-Dong J. Han","doi":"10.1111/acel.14196","DOIUrl":"10.1111/acel.14196","url":null,"abstract":"<p>Stroke is a major threat to life and health in modern society, especially in the aging population. Stroke may cause sudden death or severe sequela-like hemiplegia. Although computed tomography (CT) and magnetic resonance imaging (MRI) are standard diagnosis methods, and artificial intelligence models have been built based on these images, shortage in medical resources and the time and cost of CT/MRI imaging hamper fast detection, thus increasing the severity of stroke. Here, we developed a convolutional neural network model by integrating four networks, Xception, ResNet50, VGG19, and EfficientNetb1, to recognize stroke based on 2D facial images with a cross-validation area under curve (AUC) of 0.91 within the training set of 185 acute ischemic stroke patients and 551 age- and sex-matched controls, and AUC of 0.82 in an independent data set regardless of age and sex. The model computed stroke probability was quantitatively associated with facial features, various clinical parameters of blood clotting indicators and leukocyte counts, and, more importantly, stroke incidence in the near future. Our real-time facial image artificial intelligence model can be used to rapidly screen and prediagnose stroke before CT scanning, thus meeting the urgent need in emergency clinics, potentially translatable to routine monitoring.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14196","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141282406","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":"Pip5k1γ promotes anabolism of nucleus pulposus cells and intervertebral disc homeostasis by activating CaMKII-Ampk pathway in aged mice","authors":"Mingjue Chen, Feiyun Li, Minghao Qu, Xiaowan Jin, Tailin He, Shuangshuang He, Sheng Chen, Qing Yao, Lin Wang, Di Chen, Xiaohao Wu, Guozhi Xiao","doi":"10.1111/acel.14237","DOIUrl":"10.1111/acel.14237","url":null,"abstract":"<p>Degenerative disc disease (DDD) represents a significant global health challenge, yet its underlying molecular mechanisms remain elusive. This study aimed to investigate the role of type 1 phosphatidylinositol 4-phosphate 5-kinase (Pip5k1) in intervertebral disc (IVD) homeostasis and disease. All three Pip5k1 isoforms, namely Pip5k1α, Pip5k1β, and Pip5k1γ, were detectable in mouse and human IVD tissues, with Pip5k1γ displaying a highest expression in nucleus pulposus (NP) cells. The expression of Pip5k1γ was significantly down-regulated in the NP cells of aged mice and patients with severe DDD. To determine whether Pip5k1γ expression is required for disc homeostasis, we generated a <i>Pip5k1γ</i><sup><i>fl</i>/<i>fl</i></sup>; <i>Aggrecan</i><sup><i>CreERT2</i></sup> mouse model for the conditional knockout of the <i>Pip5k1γ</i> gene in aggrecan-expressing IVD cells. Our findings revealed that the conditional deletion of Pip5k1γ did not affect the disc structure or cellular composition in 5-month-old adult mice. However, in aged (15-month-old) mice, this deletion led to several severe degenerative disc defects, including decreased NP cellularity, spontaneous fibrosis and cleft formation, and a loss of the boundary between NP and annulus fibrosus. At the molecular level, the absence of Pip5k1γ reduced the anabolism of NP cells without markedly affecting their catabolic or anti-catabolic activities. Moreover, the loss of Pip5k1γ significantly dampened the activation of the protective Ampk pathway in NP cells, thereby accelerating NP cell senescence. Notably, Pip5k1γ deficiency blunted the effectiveness of metformin, a potent Ampk activator, in activating the Ampk pathway and mitigating lumbar spine instability (LSI)-induced disc lesions in mice. Overall, our study unveils a novel role for Pip5k1γ in promoting anabolism and maintaining disc homeostasis, suggesting it as a potential therapeutic target for DDD.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 9","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14237","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260087","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":"Identification of nicotinamide N-methyltransferase as a promising therapeutic target for sarcopenia","authors":"Rui Liang, Qiao Xiang, Miao Dai, Taiping Lin, Dongmei Xie, Quhong Song, Yu Liu, Jirong Yue","doi":"10.1111/acel.14236","DOIUrl":"10.1111/acel.14236","url":null,"abstract":"<p>Sarcopenia is a significant geriatric syndrome that involves the loss of skeletal muscle mass and strength. Due to its substantial endocrine role, the metabolic microenvironment of skeletal muscle undergoes changes with age. Examining the pathogenesis of sarcopenia through focusing on metabolic dysregulation could offer insights for developing more effective intervention strategies. In this study, we analyzed the transcriptomics data to identify specific genes involved in the regulation of metabolism in skeletal muscle during the development of sarcopenia. Three machine learning algorithms were employed to screen key target genes exhibiting strong correlations with metabolism, which were further validated using RNA-sequencing data and publicly accessible datasets. Among them, the metabolic enzyme nicotinamide N-methyltransferase (NNMT) was elevated in sarcopenia, and predicted sarcopenia with an area under the curve exceeding 0.7, suggesting it as a potential therapeutic target for sarcopenia. As expected, inhibition of NNMT improved the grip strength in aging mice and alleviated age-related decline in the mass index of the quadriceps femoris muscles and whole-body lean mass index. Additionally, the NNMTi treatment increased the levels of nicotinamide adenine dinucleotide (NAD<sup>+</sup>) content, as well as PGC1α and p-AMPK expression in the muscles of both the D-galactose-treated mouse model and naturally aging mouse model. Overall, this work demonstrates NNMT as a promising target for preventing age-related decline in muscle mass and strength.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 9","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14236","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141260086","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}
Aging CellPub Date : 2024-06-03DOI: 10.1111/acel.14114
Gregory J. Tranah, Haley N. Barnes, Peggy M. Cawthon, Paul M. Coen, Karyn A. Esser, Russell T. Hepple, Zhiguang Huo, Philip A. Kramer, Frederico G. S. Toledo, Xiping Zhang, Kevin Wu, Christopher A. Wolff, Daniel S. Evans, Steven R. Cummings
{"title":"Expression of mitochondrial oxidative stress response genes in muscle is associated with mitochondrial respiration, physical performance, and muscle mass in the Study of Muscle, Mobility, and Aging","authors":"Gregory J. Tranah, Haley N. Barnes, Peggy M. Cawthon, Paul M. Coen, Karyn A. Esser, Russell T. Hepple, Zhiguang Huo, Philip A. Kramer, Frederico G. S. Toledo, Xiping Zhang, Kevin Wu, Christopher A. Wolff, Daniel S. Evans, Steven R. Cummings","doi":"10.1111/acel.14114","DOIUrl":"10.1111/acel.14114","url":null,"abstract":"<p>Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility, and Aging. Expression levels of 21 protein-coding RNAs related to the oxidative stress response were analyzed in relation to six phenotypic measures, including maximal mitochondrial respiration from muscle biopsies (Max OXPHOS), physical performance (VO<sub>2</sub> peak, 400-m walking speed, and leg strength), and muscle size (thigh muscle volume and whole-body D3Cr muscle mass). The mRNA level of the oxidative stress response genes most consistently associated across outcomes are preferentially expressed within the mitochondria. Higher expression of mRNAs that encode generally mitochondria located proteins <i>SOD2</i>, <i>TRX2</i>, <i>PRX3</i>, <i>PRX5</i>, and <i>GRX2</i> were associated with higher levels of mitochondrial respiration and VO<sub>2</sub> peak. In addition, greater <i>SOD2, PRX3,</i> and <i>GRX2</i> expression was associated with higher physical performance and muscle size. Identifying specific mechanisms associated with high functioning across multiple performance and physical domains may lead to targeted antioxidant interventions with greater impacts on mobility and independence.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 6","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14114","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236541","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}
Aging CellPub Date : 2024-06-03DOI: 10.1111/acel.14115
Cole J. Lukasiewicz, Gregory J. Tranah, Daniel S. Evans, Paul M. Coen, Haley N. Barnes, Zhiguang Huo, Karyn A. Esser, Xiping Zhang, Christopher Wolff, Kevin Wu, Nancy E. Lane, Steven B. Kritchevsky, Anne B. Newman, Steven R. Cummings, Peggy M. Cawthon, Russell T. Hepple
{"title":"Higher expression of denervation-responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA)","authors":"Cole J. Lukasiewicz, Gregory J. Tranah, Daniel S. Evans, Paul M. Coen, Haley N. Barnes, Zhiguang Huo, Karyn A. Esser, Xiping Zhang, Christopher Wolff, Kevin Wu, Nancy E. Lane, Steven B. Kritchevsky, Anne B. Newman, Steven R. Cummings, Peggy M. Cawthon, Russell T. Hepple","doi":"10.1111/acel.14115","DOIUrl":"10.1111/acel.14115","url":null,"abstract":"<p>With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility, and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation-responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation-responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO<sub>2peak</sub>), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calciumdependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (CHRNA1, CHRND, CHRNE), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO<sub>2peak</sub> and maximal respiration had the strongest negative associations with 15 and 19 denervation-responsive genes, respectively. In conclusion, the abundance of denervationresponsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 6","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14115","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236542","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}
Aging CellPub Date : 2024-06-03DOI: 10.1111/acel.14229
Mengxia Shen, Jiafeng Fu, Yunna Zhang, Yanfen Chang, Xiaohong Li, Haipeng Cheng, Yujia Qiu, Min Shao, Yang Han, Yan Zhou, Ziqiang Luo
{"title":"A novel senolytic drug for pulmonary fibrosis: BTSA1 targets apoptosis of senescent myofibroblasts by activating BAX","authors":"Mengxia Shen, Jiafeng Fu, Yunna Zhang, Yanfen Chang, Xiaohong Li, Haipeng Cheng, Yujia Qiu, Min Shao, Yang Han, Yan Zhou, Ziqiang Luo","doi":"10.1111/acel.14229","DOIUrl":"10.1111/acel.14229","url":null,"abstract":"<p>Idiopathic pulmonary fibrosis is a progressive and age-related disease that results from impaired lung repair following injury. Targeting senescent myofibroblasts with senolytic drugs attenuates pulmonary fibrosis, revealing a detrimental role of these cells in pulmonary fibrosis. The mechanisms underlying the occurrence and persistence of senescent myofibroblasts in fibrotic lung tissue require further clarification. In this study, we demonstrated that senescent myofibroblasts are resistant to apoptosis by upregulating the proapoptotic protein BAX and antiapoptotic protein BCL-2 and BCL-XL, leading to BAX inactivation. We further showed that high levels of inactive BAX-mediated minority mitochondrial outer membrane permeabilization (minority MOMP) promoted DNA damage and myofibroblasts senescence after insult by a sublethal stimulus. Intervention of minority MOMP via the inhibition of caspase activity by quinolyl-valyl-O-methylaspartyl-[2,6-difluorophenoxy]-methyl ketone (QVD-OPH) or BAX knockdown significantly reduced DNA damage and ultimately delayed the progression of senescence. Moreover, the BAX activator BTSA1 selectively promoted the apoptosis of senescent myofibroblasts, as BTSA1-activated BAX converted minority MOMP to complete MOMP while not injuring other cells with low levels of BAX. Furthermore, therapeutic activation of BAX with BTSA1 effectively reduced the number of senescent myofibroblasts in the lung tissue and alleviated both reversible and irreversible pulmonary fibrosis. These findings advance the understanding of apoptosis resistance and cellular senescence mechanisms in senescent myofibroblasts in pulmonary fibrosis and demonstrate a novel senolytic drug for pulmonary fibrosis treatment.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 9","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14229","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141236539","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":"Sevoflurane-induced overexpression of extrasynaptic α5-GABAAR via the RhoA/ROCK2 pathway impairs cognitive function in aged mice","authors":"Zhun Wang, Jinpeng Dong, Mengxue Zhang, Sixuan Wang, Jiangnan Wu, Shengran Wang, Yuan Luo, Yongan Wang, Yiqing Yin","doi":"10.1111/acel.14209","DOIUrl":"10.1111/acel.14209","url":null,"abstract":"<p>Perioperative neurocognitive disorder (PND) is a serious neurologic complication in aged patients and might be associated with sevoflurane exposure. However, the specific pathogenesis is still unclear. The distribution of α5-GABA<sub>A</sub>R, a γ-aminobutyric acid type A receptor (GABA<sub>A</sub>R) subtype, at extrasynaptic sites is influenced by the anchor protein radixin, whose phosphorylation is regulated via the RhoA/ROCK2 signaling pathway and plays a crucial role in cognition. However, whether sevoflurane affects the ability of radixin phosphorylation to alter extrasynaptic receptor expression is unknown. Aged mice were exposed to sevoflurane to induce cognitive impairment. Both total proteins and membrane proteins were extracted for analysis. Cognitive function was evaluated using the Morris water maze and fear conditioning test. Western blotting was used to determine the expression of ROCK2 and the phosphorylation of radixin. Furthermore, the colocalization of p-radixin and α5-GABA<sub>A</sub>R was observed. To inhibit ROCK2 activity, either an adeno-associated virus (AAV) or fasudil hydrochloride was administered. Aged mice treated with sevoflurane exhibited significant cognitive impairment accompanied by increased membrane expression of α5-GABA<sub>A</sub>R. Moreover, the colocalization of α5-GABA<sub>A</sub>R and p-radixin increased after treatment with sevoflurane, and this change was accompanied by an increase in ROCK2 expression and radixin phosphorylation. Notably, inhibiting the RhoA/ROCK2 pathway significantly decreased the distribution of extrasynaptic α5-GABA<sub>A</sub>R and improved cognitive function. Sevoflurane activates the RhoA/ROCK2 pathway and increases the phosphorylation of radixin. Excess α5-GABA<sub>A</sub>R is anchored to extrasynaptic sites and impairs cognitive ability in aged mice. Fasudil hydrochloride administration improves cognitive function.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 9","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14209","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141198680","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}
Aging CellPub Date : 2024-06-02DOI: 10.1111/acel.14212
Daniel Clark, Sloane Brazina, Ted Miclau, Sangmin Park, Christine L. Hsieh, Mary Nakamura, Ralph Marcucio
{"title":"Age-related changes to macrophage subpopulations and TREM2 dysregulation characterize attenuated fracture healing in old mice","authors":"Daniel Clark, Sloane Brazina, Ted Miclau, Sangmin Park, Christine L. Hsieh, Mary Nakamura, Ralph Marcucio","doi":"10.1111/acel.14212","DOIUrl":"10.1111/acel.14212","url":null,"abstract":"<p>Fracture healing complications increase with age, with higher rates of delayed unions and nonunions and an associated increase in morbidity and mortality in older adults. Macrophages have a dynamic role in fracture healing, and we have previously demonstrated that age-related changes in macrophages are associated with attenuated fracture repair in old mice. Here, we provide a single cell characterization of the immune cells involved in the early phase of fracture healing. We show that there were multiple transcriptionally distinct macrophage subpopulations present simultaneously within the healing tissue. Fracture healing was attenuated in old mice compared to young, and macrophages from the fracture callus of old mice demonstrated a pro-inflammatory phenotype compared to young. Interestingly, Trem2 expression was decreased in old macrophages compared to young. Young mice lacking Trem2 demonstrated attenuated fracture healing and inflammatory dysregulation similar to old mice. Trem2 dysregulation has previously been implicated in other age-related diseases, but its role in fracture healing is unknown. This work provides a robust characterization of the macrophage subpopulations involved in fracture healing, and further reveals the important role of Trem2 in fracture healing and may be a potential driver of age-related inflammatory dysregulation. Future work may further examine macrophages and Trem2 as potential therapeutic targets for management of fracture repair in older adults.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 9","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14212","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141198671","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}
Aging CellPub Date : 2024-06-02DOI: 10.1111/acel.14197
Cristobal F. Rivera, Yasmeen M. Farra, Michele Silvestro, Steven Medvedovsky, Jacqueline Matz, Muhammad Yogi Pratama, John Vlahos, Bhama Ramkhelawon, Chiara Bellini
{"title":"Mapping the unicellular transcriptome of the ascending thoracic aorta to changes in mechanosensing and mechanoadaptation during aging","authors":"Cristobal F. Rivera, Yasmeen M. Farra, Michele Silvestro, Steven Medvedovsky, Jacqueline Matz, Muhammad Yogi Pratama, John Vlahos, Bhama Ramkhelawon, Chiara Bellini","doi":"10.1111/acel.14197","DOIUrl":"10.1111/acel.14197","url":null,"abstract":"<p>Aortic stiffening is an inevitable manifestation of chronological aging, yet the mechano-molecular programs that orchestrate region- and layer-specific adaptations along the length and through the wall of the aorta are incompletely defined. Here, we show that the decline in passive cyclic distensibility is more pronounced in the ascending thoracic aorta (ATA) compared to distal segments of the aorta and that collagen content increases in both the medial and adventitial compartments of the ATA during aging. The single-cell RNA sequencing of aged ATA tissues reveals altered cellular senescence, remodeling, and inflammatory responses accompanied by enrichment of T-lymphocytes and rarefaction of vascular smooth muscle cells, compared to young samples. T lymphocyte clusters accumulate in the adventitia, while the activation of mechanosensitive Piezo-1 enhances vasoconstriction and contributes to the overall functional decline of ATA tissues. These results portray the immuno-mechanical aging of the ATA as a process that culminates in a stiffer conduit permissive to the accrual of multi-gerogenic signals priming to disease development.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14197","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141198676","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}
Aging CellPub Date : 2024-05-29DOI: 10.1111/acel.14194
Edwina Yeung, Richard J. Biedrzycki, Laura C. Gómez Herrera, Prachand Issarapu, John Dou, Irene Fontes Marques, Sohail Rafik Mansuri, Christian Magnus Page, Justin Harbs, Dennis Khodasevich, Eric Poisel, Zhongzheng Niu, Catherine Allard, Emma Casey, Fernanda Morales Berstein, Giulia Mancano, Hannah R. Elliott, Rebecca Richmond, Yiyan He, Justiina Ronkainen, Sylvain Sebert, Erin M. Bell, Gemma Sharp, Sunni L. Mumford, Enrique F. Schisterman, Giriraj R. Chandak, Caroline H. D. Fall, Sirazul A. Sahariah, Matt J. Silver, Andrew M. Prentice, Luigi Bouchard, Magnus Domellof, Christina West, Nina Holland, Andres Cardenas, Brenda Eskenazi, Lea Zillich, Stephanie H. Witt, Tabea Send, Carrie Breton, Kelly M. Bakulski, M. Daniele Fallin, Rebecca J. Schmidt, Dan J. Stein, Heather J. Zar, Vincent W. V. Jaddoe, John Wright, Regina Grazuleviciene, Kristine Bjerve Gutzkow, Jordi Sunyer, Anke Huels, Martine Vrijheid, Sophia Harlid, Stephanie London, Marie-France Hivert, Janine Felix, Mariona Bustamante, Weihua Guan
{"title":"Maternal age is related to offspring DNA methylation: A meta-analysis of results from the PACE consortium","authors":"Edwina Yeung, Richard J. Biedrzycki, Laura C. Gómez Herrera, Prachand Issarapu, John Dou, Irene Fontes Marques, Sohail Rafik Mansuri, Christian Magnus Page, Justin Harbs, Dennis Khodasevich, Eric Poisel, Zhongzheng Niu, Catherine Allard, Emma Casey, Fernanda Morales Berstein, Giulia Mancano, Hannah R. Elliott, Rebecca Richmond, Yiyan He, Justiina Ronkainen, Sylvain Sebert, Erin M. Bell, Gemma Sharp, Sunni L. Mumford, Enrique F. Schisterman, Giriraj R. Chandak, Caroline H. D. Fall, Sirazul A. Sahariah, Matt J. Silver, Andrew M. Prentice, Luigi Bouchard, Magnus Domellof, Christina West, Nina Holland, Andres Cardenas, Brenda Eskenazi, Lea Zillich, Stephanie H. Witt, Tabea Send, Carrie Breton, Kelly M. Bakulski, M. Daniele Fallin, Rebecca J. Schmidt, Dan J. Stein, Heather J. Zar, Vincent W. V. Jaddoe, John Wright, Regina Grazuleviciene, Kristine Bjerve Gutzkow, Jordi Sunyer, Anke Huels, Martine Vrijheid, Sophia Harlid, Stephanie London, Marie-France Hivert, Janine Felix, Mariona Bustamante, Weihua Guan","doi":"10.1111/acel.14194","DOIUrl":"10.1111/acel.14194","url":null,"abstract":"<p>Worldwide trends to delay childbearing have increased parental ages at birth. Older parental age may harm offspring health, but mechanisms remain unclear. Alterations in offspring DNA methylation (DNAm) patterns could play a role as aging has been associated with methylation changes in gametes of older individuals. We meta-analyzed epigenome-wide associations of parental age with offspring blood DNAm of over 9500 newborns and 2000 children (5–10 years old) from the Pregnancy and Childhood Epigenetics consortium. In newborns, we identified 33 CpG sites in 13 loci with DNAm associated with maternal age (P<sub>FDR</sub> < 0.05). Eight of these CpGs were located near/in the <i>MTNR1B</i> gene, coding for a melatonin receptor. Regional analysis identified them together as a differentially methylated region consisting of 9 CpGs in/near <i>MTNR1B</i>, at which higher DNAm was associated with greater maternal age (P<sub>FDR</sub> = 6.92 × 10<sup>−8</sup>) in newborns. In childhood blood samples, these differences in blood DNAm of <i>MTNR1B</i> CpGs were nominally significant (<i>p</i> < 0.05) and retained the same positive direction, suggesting persistence of associations. Maternal age was also positively associated with higher DNA methylation at three CpGs in <i>RTEL1-TNFRSF6B</i> at birth (P<sub>FDR</sub> < 0.05) and nominally in childhood (<i>p</i> < 0.0001). Of the remaining 10 CpGs also persistent in childhood, methylation at cg26709300 in <i>YPEL3/BOLA2B</i> in external data was associated with expression of <i>ITGAL</i>, an immune regulator. While further study is needed to establish causality, particularly due to the small effect sizes observed, our results potentially support offspring DNAm as a mechanism underlying associations of maternal age with child health.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14194","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141160044","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}