Aging CellPub Date : 2024-08-26DOI: 10.1111/acel.14296
Antentor O. Hinton Jr., Zer Vue, Estevão Scudese, Kit Neikirk, Annet Kirabo, Monty Montano
{"title":"Mitochondrial heterogeneity and crosstalk in aging: Time for a paradigm shift?","authors":"Antentor O. Hinton Jr., Zer Vue, Estevão Scudese, Kit Neikirk, Annet Kirabo, Monty Montano","doi":"10.1111/acel.14296","DOIUrl":"10.1111/acel.14296","url":null,"abstract":"<p>The hallmarks of aging have been influential in guiding the biology of aging research, with more recent and growing recognition of the interdependence of these hallmarks on age-related health outcomes. However, a current challenge is personalizing aging trajectories to promote healthy aging, given the diversity of genotypes and lived experience. We suggest that incorporating heterogeneity—including intrinsic (e.g., genetic and structural) and extrinsic (e.g., environmental and exposome) factors and their interdependence of hallmarks—may move the dial. This editorial perspective will focus on one hallmark, namely mitochondrial dysfunction, to exemplify how consideration of heterogeneity and interdependence or crosstalk may reveal new perspectives and opportunities for personalizing aging research. To this end, we highlight heterogeneity within mitochondria as a model.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142071504","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 : 2024-08-23DOI: 10.1111/acel.14298
Ramkumar Thiyagarajan, Lixia Zhang, Omar D. Glover, Kyu Hwan Kwack, Sara Ahmed, Emma Murray, Nanda Kumar Yellapu, Jonathan Bard, Kenneth L. Seldeen, Spencer R. Rosario, Bruce R. Troen, Keith L. Kirkwood
{"title":"Age-related increase of CD38 directs osteoclastogenic potential of monocytic myeloid-derived suppressor cells through mitochondrial dysfunction in male mice","authors":"Ramkumar Thiyagarajan, Lixia Zhang, Omar D. Glover, Kyu Hwan Kwack, Sara Ahmed, Emma Murray, Nanda Kumar Yellapu, Jonathan Bard, Kenneth L. Seldeen, Spencer R. Rosario, Bruce R. Troen, Keith L. Kirkwood","doi":"10.1111/acel.14298","DOIUrl":"10.1111/acel.14298","url":null,"abstract":"<p>An aged immune system undergoes substantial changes where myelopoiesis dominates within the bone marrow. Monocytic-MDSCs (M-MDSCs) have been found to play an important role in osteoclastogenesis and bone resorption. In this study, we sought to provide a more comprehensive understanding of the osteoclastogenic potential of bone marrow M-MDSCs during normal aging through transcriptomic and metabolic changes. Using young mature and aged mice, detailed immunophenotypic analyses of myeloid cells revealed that the M-MDSCs were not increased in bone marrow, however M-MDSCS were significantly expanded in peripheral tissues. Although aged mice exhibited a similar number of M-MDSCs in bone marrow, these M-MDSCs had significantly higher osteoclastogenic potential and greater demineralization activity. Intriguingly, osteoclast progenitors from aged bone marrow M-MDSCs exhibited greater mitochondrial respiration rate and glucose metabolism. Further, transcriptomic analyses revealed the upregulation of mitochondrial oxidative phosphorylation and glucose metabolism genes. Interestingly, there was 8-fold increase in <i>Cd38</i> mRNA gene expression, consistent with the Mouse Aging Cell Atlas transcriptomic database, and confirmed by qRT-PCR. CD38 regulates NAD<sup>+</sup> availability, and 78c, a small molecule inhibitor of CD38, reduced the mitochondrial oxygen consumption rate and glucose metabolism and inhibited the osteoclastogenic potential of aged mice bone marrow-derived M-MDSCs. These results indicate that the age-related increase in <i>Cd38</i> expression in M-MDSCs bias the transcriptome of M-MDSCs towards osteoclastogenesis. This enhanced understanding of the mechanistic underpinnings of M-MDSCs and their osteoclastogenesis during aging could lead to new therapeutic approaches for age-related bone loss and promote healthy aging.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 11","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561650/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142045982","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 : 2024-08-18DOI: 10.1111/acel.14317
Tingting Xia, Ying Zhou, Jiayao An, Zhi Cui, Xinqin Zhong, Tianyi Cui, Bin Lv, Xin Zhao, Xiumei Gao
{"title":"Benefit delayed immunosenescence by regulating CD4+T cells: A promising therapeutic target for aging-related diseases","authors":"Tingting Xia, Ying Zhou, Jiayao An, Zhi Cui, Xinqin Zhong, Tianyi Cui, Bin Lv, Xin Zhao, Xiumei Gao","doi":"10.1111/acel.14317","DOIUrl":"10.1111/acel.14317","url":null,"abstract":"<p>CD4<sup>+</sup>T cells play a notable role in immune protection at different stages of life. During aging, the interaction between the body's internal and external environment and CD4<sup>+</sup>T cells results in a series of changes in the CD4<sup>+</sup>T cells pool making it involved in immunosenescence. Many studies have extensively examined the subsets and functionality of CD4<sup>+</sup>T cells within the immune system, highlighted their pivotal role in disease pathogenesis, progression, and therapeutic interventions. However, the underlying mechanism of CD4<sup>+</sup>T cells senescence and its intricate association with diseases remains to be elucidated and comprehensively understood. By summarizing the immunosenescent progress and network of CD4<sup>+</sup>T cell subsets, we reveal the crucial role of CD4<sup>+</sup>T cells in the occurrence and development of age-related diseases. Furthermore, we provide new insights and theoretical foundations for diseases targeting CD4<sup>+</sup>T cell subsets aging as a treatment focus, offering novel approaches for therapy, especially in infections, cancers, autoimmune diseases, and other diseases in the elderly.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141998924","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 connection between aging, cellular senescence and gut microbiome alterations: A comprehensive review","authors":"Dong-Hyun Jang, Ji-Won Shin, Eunha Shim, Naoko Ohtani, Ok Hee Jeon","doi":"10.1111/acel.14315","DOIUrl":"10.1111/acel.14315","url":null,"abstract":"<p>The intricate interplay between cellular senescence and alterations in the gut microbiome emerges as a pivotal axis in the aging process, increasingly recognized for its contribution to systemic inflammation, physiological decline, and predisposition to age-associated diseases. Cellular senescence, characterized by a cessation of cell division in response to various stressors, induces morphological and functional changes within tissues. The complexity and heterogeneity of senescent cells, alongside the secretion of senescence-associated secretory phenotype, exacerbate the aging process through pro-inflammatory pathways and influence the microenvironment and immune system. Concurrently, aging-associated changes in gut microbiome diversity and composition contribute to dysbiosis, further exacerbating systemic inflammation and undermining the integrity of various bodily functions. This review encapsulates the burgeoning research on the reciprocal relationship between cellular senescence and gut dysbiosis, highlighting their collective impact on age-related musculoskeletal diseases, including osteoporosis, sarcopenia, and osteoarthritis. It also explores the potential of modulating the gut microbiome and targeting cellular senescence as innovative strategies for healthy aging and mitigating the progression of aging-related conditions. By exploring targeted interventions, including the development of senotherapeutic drugs and probiotic therapies, this review aims to shed light on novel therapeutic avenues. These strategies leverage the connection between cellular senescence and gut microbiome alterations to advance aging research and development of interventions aimed at extending health span and improving the quality of life in the older population.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 10","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11464129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986950","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 : 2024-08-15DOI: 10.1111/acel.14270
João P. Novo, Lucy Gee, Carolina A. Caetano, Inês Tomé, Andreia Vilaça, Thomas von Zglinicki, Irina S. Moreira, Diana Jurk, Susana Rosa, Lino Ferreira
{"title":"Blood–brain barrier dysfunction in aging is mediated by brain endothelial senescence","authors":"João P. Novo, Lucy Gee, Carolina A. Caetano, Inês Tomé, Andreia Vilaça, Thomas von Zglinicki, Irina S. Moreira, Diana Jurk, Susana Rosa, Lino Ferreira","doi":"10.1111/acel.14270","DOIUrl":"10.1111/acel.14270","url":null,"abstract":"<p>BBB dysfunction during aging is characterized by an increase in its permeability and phenotypic alterations of brain endothelial cells (BECs) including dysregulation of tight junction's expression. Here we have investigated the role of BEC senescence in the dysfunction of the BBB. Our results suggest that the transition from young to aged BBB is mediated, at least in part by BEC senescence.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 9","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14270","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981270","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 : 2024-08-14DOI: 10.1111/acel.14287
K. L. Whytock, A. Divoux, Y. Sun, M. F. Pino, G. Yu, C. A. Jin, J. J. Robino, A. Plekhanov, O. Varlamov, S. R. Smith, M. J. Walsh, L. M. Sparks
{"title":"Aging human abdominal subcutaneous white adipose tissue at single cell resolution","authors":"K. L. Whytock, A. Divoux, Y. Sun, M. F. Pino, G. Yu, C. A. Jin, J. J. Robino, A. Plekhanov, O. Varlamov, S. R. Smith, M. J. Walsh, L. M. Sparks","doi":"10.1111/acel.14287","DOIUrl":"10.1111/acel.14287","url":null,"abstract":"<p>White adipose tissue (WAT) is a robust energy storage and endocrine organ critical for maintaining metabolic health as we age. Our aim was to identify cell-specific transcriptional aberrations that occur in WAT with aging. We leveraged full-length snRNA-Seq and histology to characterize the cellular landscape of human abdominal subcutaneous WAT in a prospective cohort of 10 younger (≤30 years) and 10 older individuals (≥65 years) balanced for sex and body mass index (BMI). The older group had greater cholesterol, very-low-density lipoprotein, triglycerides, thyroid stimulating hormone, and aspartate transaminase compared to the younger group (<i>p</i> < 0.05). We highlight that aging WAT is associated with adipocyte hypertrophy, increased proportions of lipid-associated macrophages and mast cells, an upregulation of immune responses linked to fibrosis in pre-adipocyte, adipocyte, and vascular populations, and highlight CXCL14 as a biomarker of these processes. We show that older WAT has elevated levels of senescence marker p16 in adipocytes and identify the adipocyte subpopulation driving this senescence profile. We confirm that these transcriptional and phenotypical changes occur without overt fibrosis and in older individuals that have comparable WAT insulin sensitivity to the younger individuals.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 11","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981269","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":"Dysregulation of choline metabolism and therapeutic potential of citicoline in Huntington's disease","authors":"Kuo-Hsuan Chang, Mei-Ling Cheng, Hsiang-Yu Tang, Chung-Yin Lin, Chiung-Mei Chen","doi":"10.1111/acel.14302","DOIUrl":"10.1111/acel.14302","url":null,"abstract":"<p>Huntington's disease (HD) is associated with dysregulated choline metabolism, but the underlying mechanisms remain unclear. This study investigated the expression of key enzymes in this pathway in R6/2 HD mice and human HD postmortem brain tissues. We further explored the therapeutic potential of modulating choline metabolism for HD. Both R6/2 mice and HD patients exhibited reduced expression of glycerophosphocholine phosphodiesterase 1 (GPCPD1), a key enzyme in choline metabolism, in the striatum and cortex. The striatum of R6/2 mice also showed decreased choline and phosphorylcholine, and increased glycerophosphocholine, suggesting disruption in choline metabolism due to GPCPD1 deficiency. Treatment with citicoline significantly improved motor performance, upregulated anti-apoptotic Bcl2 expression, and reduced oxidative stress marker malondialdehyde in both brain regions. Metabolomic analysis revealed partial restoration of disrupted metabolic patterns in the striatum and cortex following citicoline treatment. These findings strongly suggest the role of GPCPD1 deficiency in choline metabolism dysregulation in HD. The therapeutic potential of citicoline in R6/2 mice highlights the choline metabolic pathway as a promising target for future HD therapies.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 11","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981271","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 : 2024-08-14DOI: 10.1111/acel.14297
Kotb Abdelmohsen, Krystyna Mazan-Mamczarz, Rachel Munk, Dimitrios Tsitsipatis, Qiong Meng, Martina Rossi, Apala Pal, Chang Hoon Shin, Jennifer L. Martindale, Yulan Piao, Jinshui Fan, Hagai Yanai, Supriyo De, Isabel Beerman, Myriam Gorospe
{"title":"Identification of senescent cell subpopulations by CITE-seq analysis","authors":"Kotb Abdelmohsen, Krystyna Mazan-Mamczarz, Rachel Munk, Dimitrios Tsitsipatis, Qiong Meng, Martina Rossi, Apala Pal, Chang Hoon Shin, Jennifer L. Martindale, Yulan Piao, Jinshui Fan, Hagai Yanai, Supriyo De, Isabel Beerman, Myriam Gorospe","doi":"10.1111/acel.14297","DOIUrl":"10.1111/acel.14297","url":null,"abstract":"<p>Cellular senescence, a state of persistent growth arrest, is closely associated with aging and age-related diseases. Deciphering the heterogeneity within senescent cell populations and identifying therapeutic targets are paramount for mitigating senescence-associated pathologies. In this study, proteins on the surface of cells rendered senescent by replicative exhaustion and by exposure to ionizing radiation (IR) were identified using mass spectrometry analysis, and a subset of them was further studied using single-cell CITE-seq (Cellular Indexing of Transcriptomes and Epitopes by Sequencing) analysis. Based on the presence of proteins on the cell surface, we identified two distinct IR-induced senescent cell populations: one characterized by high levels of CD109 and CD112 (cluster 3), the other characterized by high levels of CD112, CD26, CD73, HLA-ABC, CD54, CD49A, and CD44 (cluster 0). We further found that cluster 0 represented proliferating and senescent cells in the G1 phase of the division cycle, and CITE-seq detection of cell surface proteins selectively discerned those in the senescence group. Our study highlights the heterogeneity of senescent cells and underscores the value of cell surface proteins as tools for distinguishing senescent cell programs and subclasses, paving the way for targeted therapeutic strategies in disorders exacerbated by senescence.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 11","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141981272","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 : 2024-08-13DOI: 10.1111/acel.14277
Shweta Yadav, Aidan Graham, Farazdaq Al Hammood, Chris Garbark, Deepika Vasudevan, Udai Pandey, John M. Asara, Dhivyaa Rajasundaram, Andrey A. Parkhitko
{"title":"Unique tau- and synuclein-dependent metabolic reprogramming in neurons distinct from normal aging","authors":"Shweta Yadav, Aidan Graham, Farazdaq Al Hammood, Chris Garbark, Deepika Vasudevan, Udai Pandey, John M. Asara, Dhivyaa Rajasundaram, Andrey A. Parkhitko","doi":"10.1111/acel.14277","DOIUrl":"10.1111/acel.14277","url":null,"abstract":"<p>Neuronal cells are highly specialized cells and have a specific metabolic profile to support their function. It has been demonstrated that the metabolic profiles of different cells/tissues undergo significant reprogramming with advancing age, which has often been considered a contributing factor towards aging-related diseases including Alzheimer's (AD) and Parkinson's (PD) diseases. However, it is unclear if the metabolic changes associated with normal aging predispose neurons to disease conditions or a distinct set of metabolic alterations happen in neurons in AD or PD which might contribute to disease pathologies. To decipher the changes in neuronal metabolism with age, in AD, or in PD, we performed high-throughput steady-state metabolite profiling on heads in wildtype <i>Drosophila</i> and in <i>Drosophila</i> models relevant to AD and PD. Intriguingly, we found that the spectrum of affected metabolic pathways is dramatically different between normal aging, Tau, or Synuclein overexpressing neurons. Genetic targeting of the purine and glutamate metabolism pathways, which were dysregulated in both old age and disease conditions partially rescued the neurodegenerative phenotype associated with the overexpression of wildtype and mutant tau. Our findings support a “two-hit model” to explain the pathological manifestations associated with AD where both aging- and Tau/Synuclein- driven metabolic reprogramming events cooperate with each other, and targeting both could be a potent therapeutic strategy.</p>","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 11","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974558","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 : 2024-08-13DOI: 10.1111/acel.14307
{"title":"Anatomical Society Research Studentships 2024/25","authors":"","doi":"10.1111/acel.14307","DOIUrl":"https://doi.org/10.1111/acel.14307","url":null,"abstract":"","PeriodicalId":55543,"journal":{"name":"Aging Cell","volume":"23 8","pages":""},"PeriodicalIF":7.8,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/acel.14307","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141980405","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}