Pub Date : 2024-06-07DOI: 10.1038/s43587-024-00635-x
Ana Ortega-Molina, Cristina Lebrero-Fernández, Alba Sanz, Miguel Calvo-Rubio, Nerea Deleyto-Seldas, Lucía de Prado-Rivas, Ana Belén Plata-Gómez, Elena Fernández-Florido, Patricia González-García, Yurena Vivas-García, Elena Sánchez García, Osvaldo Graña-Castro, Nathan L. Price, Alejandra Aroca-Crevillén, Eduardo Caleiras, Daniel Monleón, Consuelo Borrás, María Casanova-Acebes, Rafael de Cabo, Alejo Efeyan
The mechanistic target of rapamycin complex 1 controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan. Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity. Ortega-Molina et al. demonstrate that mouse models with mild, genetic overactivation of mTOR signaling develop chronic myeloid inflammation, causing reduced healthspan and lifespan, without an increase in tumor incidence.
{"title":"A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan","authors":"Ana Ortega-Molina, Cristina Lebrero-Fernández, Alba Sanz, Miguel Calvo-Rubio, Nerea Deleyto-Seldas, Lucía de Prado-Rivas, Ana Belén Plata-Gómez, Elena Fernández-Florido, Patricia González-García, Yurena Vivas-García, Elena Sánchez García, Osvaldo Graña-Castro, Nathan L. Price, Alejandra Aroca-Crevillén, Eduardo Caleiras, Daniel Monleón, Consuelo Borrás, María Casanova-Acebes, Rafael de Cabo, Alejo Efeyan","doi":"10.1038/s43587-024-00635-x","DOIUrl":"10.1038/s43587-024-00635-x","url":null,"abstract":"The mechanistic target of rapamycin complex 1 controls cellular anabolism in response to growth factor signaling and to nutrient sufficiency signaled through the Rag GTPases. Inhibition of mTOR reproducibly extends longevity across eukaryotes. Here we report that mice that endogenously express active mutant variants of RagC exhibit multiple features of parenchymal damage that include senescence, expression of inflammatory molecules, increased myeloid inflammation with extensive features of inflammaging and a ~30% reduction in lifespan. Through bone marrow transplantation experiments, we show that myeloid cells are abnormally activated by signals emanating from dysfunctional RagC-mutant parenchyma, causing neutrophil extravasation that inflicts additional inflammatory damage. Therapeutic suppression of myeloid inflammation in aged RagC-mutant mice attenuates parenchymal damage and extends survival. Together, our findings link mildly increased nutrient signaling to limited lifespan in mammals, and support a two-component process of parenchymal damage and myeloid inflammation that together precipitate a time-dependent organ deterioration that limits longevity. Ortega-Molina et al. demonstrate that mouse models with mild, genetic overactivation of mTOR signaling develop chronic myeloid inflammation, causing reduced healthspan and lifespan, without an increase in tumor incidence.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00635-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141289062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-05DOI: 10.1038/s43587-024-00630-2
Marie Sarazin, Julien Lagarde, Inès El Haddad, Leonardo Cruz de Souza, Bertrand Bellier, Marie-Claude Potier, Michel Bottlaender, Guillaume Dorothée
The cautious optimism following recent anti-amyloid therapeutic trials for Alzheimer’s disease (AD) provides a glimmer of hope after years of disappointment. Although these encouraging results represent discernible progress, they also highlight the need to enhance further the still modest clinical efficacy of current disease-modifying immunotherapies. Here, we highlight crucial milestones essential for advancing precision medicine in AD. These include reevaluating the choice of therapeutic targets by considering the key role of both central neuroinflammation and peripheral immunity in disease pathogenesis, refining patient stratification by further defining the inflammatory component within the forthcoming ATN(I) (amyloid, tau and neurodegeneration (and inflammation)) classification of AD biomarkers and defining more accurate clinical outcomes and prognostic biomarkers that better reflect disease heterogeneity. Next-generation immunotherapies will need to go beyond the current antibody-only approach by simultaneously targeting pathological proteins together with innate neuroinflammation and/or peripheral–central immune crosstalk. Such innovative immunomodulatory combination therapy approaches should be evaluated in appropriately redesigned clinical therapeutic trials, which must carefully integrate the neuroimmune component. Looking beyond anti-amyloid immunotherapy in Alzheimer’s disease, the authors discuss innovative next-generation immunomodulatory combination therapies jointly targeting pathogenic proteins and peripheral–central immune crosstalk.
{"title":"The path to next-generation disease-modifying immunomodulatory combination therapies in Alzheimer’s disease","authors":"Marie Sarazin, Julien Lagarde, Inès El Haddad, Leonardo Cruz de Souza, Bertrand Bellier, Marie-Claude Potier, Michel Bottlaender, Guillaume Dorothée","doi":"10.1038/s43587-024-00630-2","DOIUrl":"10.1038/s43587-024-00630-2","url":null,"abstract":"The cautious optimism following recent anti-amyloid therapeutic trials for Alzheimer’s disease (AD) provides a glimmer of hope after years of disappointment. Although these encouraging results represent discernible progress, they also highlight the need to enhance further the still modest clinical efficacy of current disease-modifying immunotherapies. Here, we highlight crucial milestones essential for advancing precision medicine in AD. These include reevaluating the choice of therapeutic targets by considering the key role of both central neuroinflammation and peripheral immunity in disease pathogenesis, refining patient stratification by further defining the inflammatory component within the forthcoming ATN(I) (amyloid, tau and neurodegeneration (and inflammation)) classification of AD biomarkers and defining more accurate clinical outcomes and prognostic biomarkers that better reflect disease heterogeneity. Next-generation immunotherapies will need to go beyond the current antibody-only approach by simultaneously targeting pathological proteins together with innate neuroinflammation and/or peripheral–central immune crosstalk. Such innovative immunomodulatory combination therapy approaches should be evaluated in appropriately redesigned clinical therapeutic trials, which must carefully integrate the neuroimmune component. Looking beyond anti-amyloid immunotherapy in Alzheimer’s disease, the authors discuss innovative next-generation immunomodulatory combination therapies jointly targeting pathogenic proteins and peripheral–central immune crosstalk.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141254999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-04DOI: 10.1038/s43587-024-00647-7
Taralynn M. Mack, Michael A. Raddatz, Yash Pershad, Daniel C. Nachun, Kent D. Taylor, Xiuqing Guo, Alan R. Shuldiner, Jeffrey R. O’Connell, Eimear E. Kenny, Ruth J. F. Loos, Susan Redline, Brian E. Cade, Bruce M. Psaty, Joshua C. Bis, Jennifer A. Brody, Edwin K. Silverman, Jeong H. Yun, Michael H. Cho, Dawn L. DeMeo, Daniel Levy, Andrew D. Johnson, Rasika A. Mathias, Lisa R. Yanek, Susan R. Heckbert, Nicholas L. Smith, Kerri L. Wiggins, Laura M. Raffield, April P. Carson, Jerome I. Rotter, Stephen S. Rich, Ani W. Manichaikul, C. Charles Gu, Yii-Der Ida Chen, Wen-Jane Lee, M. Benjamin Shoemaker, Dan M. Roden, Charles Kooperberg, Paul L. Auer, Pinkal Desai, Thomas W. Blackwell, Albert V. Smith, Alexander P. Reiner, Siddhartha Jaiswal, Joshua S. Weinstock, Alexander G. Bick
Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion. Exploring the clonal expansion of somatically mutated hematopoietic stem cells with aging, Mack, Raddatz et al. quantify rates of clonal expansion in 4,370 individuals in the Trans-Omics for Precision Medicine cohort, observing epigenetic and proteomic patterns associated with clonal hematopoiesis of indeterminate potential.
{"title":"Epigenetic and proteomic signatures associate with clonal hematopoiesis expansion rate","authors":"Taralynn M. Mack, Michael A. Raddatz, Yash Pershad, Daniel C. Nachun, Kent D. Taylor, Xiuqing Guo, Alan R. Shuldiner, Jeffrey R. O’Connell, Eimear E. Kenny, Ruth J. F. Loos, Susan Redline, Brian E. Cade, Bruce M. Psaty, Joshua C. Bis, Jennifer A. Brody, Edwin K. Silverman, Jeong H. Yun, Michael H. Cho, Dawn L. DeMeo, Daniel Levy, Andrew D. Johnson, Rasika A. Mathias, Lisa R. Yanek, Susan R. Heckbert, Nicholas L. Smith, Kerri L. Wiggins, Laura M. Raffield, April P. Carson, Jerome I. Rotter, Stephen S. Rich, Ani W. Manichaikul, C. Charles Gu, Yii-Der Ida Chen, Wen-Jane Lee, M. Benjamin Shoemaker, Dan M. Roden, Charles Kooperberg, Paul L. Auer, Pinkal Desai, Thomas W. Blackwell, Albert V. Smith, Alexander P. Reiner, Siddhartha Jaiswal, Joshua S. Weinstock, Alexander G. Bick","doi":"10.1038/s43587-024-00647-7","DOIUrl":"10.1038/s43587-024-00647-7","url":null,"abstract":"Clonal hematopoiesis of indeterminate potential (CHIP), whereby somatic mutations in hematopoietic stem cells confer a selective advantage and drive clonal expansion, not only correlates with age but also confers increased risk of morbidity and mortality. Here, we leverage genetically predicted traits to identify factors that determine CHIP clonal expansion rate. We used the passenger-approximated clonal expansion rate method to quantify the clonal expansion rate for 4,370 individuals in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) cohort and calculated polygenic risk scores for DNA methylation aging, inflammation-related measures and circulating protein levels. Clonal expansion rate was significantly associated with both genetically predicted and measured epigenetic clocks. No associations were identified with inflammation-related lab values or diseases and CHIP expansion rate overall. A proteome-wide search identified predicted circulating levels of myeloid zinc finger 1 and anti-Müllerian hormone as associated with an increased CHIP clonal expansion rate and tissue inhibitor of metalloproteinase 1 and glycine N-methyltransferase as associated with decreased CHIP clonal expansion rate. Together, our findings identify epigenetic and proteomic patterns associated with the rate of hematopoietic clonal expansion. Exploring the clonal expansion of somatically mutated hematopoietic stem cells with aging, Mack, Raddatz et al. quantify rates of clonal expansion in 4,370 individuals in the Trans-Omics for Precision Medicine cohort, observing epigenetic and proteomic patterns associated with clonal hematopoiesis of indeterminate potential.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141249198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Oxidative phosphorylation, essential for energy metabolism and linked to the regulation of longevity, involves mitochondrial and nuclear genes. The functions of these genes and their evolutionary rate covariation (ERC) have been extensively studied, but little is known about whether other nuclear genes not targeted to mitochondria evolutionarily and functionally interact with mitochondrial genes. Here we systematically examined the ERC of mitochondrial and nuclear benchmarking universal single-copy ortholog (BUSCO) genes from 472 insects, identifying 75 non-mitochondria-targeted nuclear genes. We found that the uncharacterized gene CG11837—a putative ortholog of human DIMT1—regulates insect lifespan, as its knockdown reduces median lifespan in five diverse insect species and Caenorhabditis elegans, whereas its overexpression extends median lifespans in fruit flies and C. elegans and enhances oxidative phosphorylation gene activity. Additionally, DIMT1 overexpression protects human cells from cellular senescence. Together, these data provide insights into the ERC of mito-nuclear genes and suggest that CG11837 may regulate longevity across animals. By analyzing co-evolution of mitochondrial and nuclear genomes across insect species, the authors uncover the evolutionary covariation of a group of non-mitochondrially targeted nuclear genes with mitochondrial genes, including the uncharacterized gene CG11837, which regulates insect lifespan.
{"title":"Identification of a longevity gene through evolutionary rate covariation of insect mito-nuclear genomes","authors":"Mei Tao, Jiani Chen, Chunlai Cui, Yandong Xu, Jingxiu Xu, Zheyi Shi, Jiaqi Yun, Junwei Zhang, Guo-Zheng Ou, Chao Liu, Yun Chen, Zeng-Rong Zhu, Ronghui Pan, Suhong Xu, Xue-xin Chen, Antonis Rokas, Yang Zhao, Sibao Wang, Jianhua Huang, Xing-Xing Shen","doi":"10.1038/s43587-024-00641-z","DOIUrl":"10.1038/s43587-024-00641-z","url":null,"abstract":"Oxidative phosphorylation, essential for energy metabolism and linked to the regulation of longevity, involves mitochondrial and nuclear genes. The functions of these genes and their evolutionary rate covariation (ERC) have been extensively studied, but little is known about whether other nuclear genes not targeted to mitochondria evolutionarily and functionally interact with mitochondrial genes. Here we systematically examined the ERC of mitochondrial and nuclear benchmarking universal single-copy ortholog (BUSCO) genes from 472 insects, identifying 75 non-mitochondria-targeted nuclear genes. We found that the uncharacterized gene CG11837—a putative ortholog of human DIMT1—regulates insect lifespan, as its knockdown reduces median lifespan in five diverse insect species and Caenorhabditis elegans, whereas its overexpression extends median lifespans in fruit flies and C. elegans and enhances oxidative phosphorylation gene activity. Additionally, DIMT1 overexpression protects human cells from cellular senescence. Together, these data provide insights into the ERC of mito-nuclear genes and suggest that CG11837 may regulate longevity across animals. By analyzing co-evolution of mitochondrial and nuclear genomes across insect species, the authors uncover the evolutionary covariation of a group of non-mitochondrially targeted nuclear genes with mitochondrial genes, including the uncharacterized gene CG11837, which regulates insect lifespan.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141249240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-04DOI: 10.1038/s43587-024-00645-9
Sven Wischnewski, Thomas Thäwel, Chiseko Ikenaga, Anna Kocharyan, Celia Lerma-Martin, Amel Zulji, Hans-Werner Rausch, David Brenner, Leonie Thomas, Michael Kutza, Brittney Wick, Tim Trobisch, Corinna Preusse, Maximilian Haeussler, Jan Leipe, Albert Ludolph, Angela Rosenbohm, Ahmet Hoke, Michael Platten, Jochen H. Weishaupt, Clemens J. Sommer, Werner Stenzel, Thomas E. Lloyd, Lucas Schirmer
Inclusion body myositis (IBM) is the most prevalent inflammatory muscle disease in older adults with no effective therapy available. In contrast to other inflammatory myopathies such as subacute, immune-mediated necrotizing myopathy (IMNM), IBM follows a chronic disease course with both inflammatory and degenerative features of pathology. Moreover, causal factors and molecular drivers of IBM progression are largely unknown. Therefore, we paired single-nucleus RNA sequencing with spatial transcriptomics from patient muscle biopsies to map cell-type-specific drivers underlying IBM pathogenesis compared with IMNM muscles and noninflammatory skeletal muscle samples. In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and conventional type 1 dendritic cells. IBM myofibers were characterized by either upregulation of cell stress markers featuring GADD45A and NORAD or protein degradation markers including RNF7 associated with p62 aggregates. GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation. We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways. Inclusion body myositis (IBM) is a progressive inflammatory muscle disease of unknown cause, prevalent in older adults. Through spatial and single nuclear profiling, the authors identify a selective type 2 myofiber pathology in IBM, linked to genomic stress and denervation.
包涵体肌炎（IBM）是老年人最常见的炎症性肌肉疾病，目前尚无有效的治疗方法。与亚急性免疫介导坏死性肌病（IMNM）等其他炎症性肌病不同，IBM 的病程为慢性，病理特征既有炎症性，也有退行性。此外，IBM 进展的致病因素和分子驱动因素在很大程度上尚属未知。因此，我们将单核 RNA 测序与来自患者肌肉活检组织的空间转录组学进行配对，以绘制出与 IMNM 肌肉和非炎症骨骼肌样本相比，IBM 发病机制背后的细胞特异性驱动因素。在 IBM 肌肉中，我们观察到 2 型肌核选择性缺失，同时细胞毒性 T 细胞和常规 1 型树突状细胞水平升高。IBM肌纤维的特点是细胞应激标志物（包括GADD45A和NORAD）或蛋白质降解标志物（包括与p62聚集体相关的RNF7）上调。GADD45A 上调主要出现在与严重组织炎症相关的 2A 型肌纤维中。我们还注意到编码乙酰胆碱酯酶的 ACHE 的 IBM 特异性上调，该酶可受 NORAD 活性调控，并导致肌纤维的功能性去神经化。我们的研究结果为了解 IBM 肌纤维变性的可能机制提供了前景广阔的见解，并表明 2 型纤维的选择性脆弱性与基因组应激和去神经支配途径有关。
{"title":"Cell type mapping of inflammatory muscle diseases highlights selective myofiber vulnerability in inclusion body myositis","authors":"Sven Wischnewski, Thomas Thäwel, Chiseko Ikenaga, Anna Kocharyan, Celia Lerma-Martin, Amel Zulji, Hans-Werner Rausch, David Brenner, Leonie Thomas, Michael Kutza, Brittney Wick, Tim Trobisch, Corinna Preusse, Maximilian Haeussler, Jan Leipe, Albert Ludolph, Angela Rosenbohm, Ahmet Hoke, Michael Platten, Jochen H. Weishaupt, Clemens J. Sommer, Werner Stenzel, Thomas E. Lloyd, Lucas Schirmer","doi":"10.1038/s43587-024-00645-9","DOIUrl":"10.1038/s43587-024-00645-9","url":null,"abstract":"Inclusion body myositis (IBM) is the most prevalent inflammatory muscle disease in older adults with no effective therapy available. In contrast to other inflammatory myopathies such as subacute, immune-mediated necrotizing myopathy (IMNM), IBM follows a chronic disease course with both inflammatory and degenerative features of pathology. Moreover, causal factors and molecular drivers of IBM progression are largely unknown. Therefore, we paired single-nucleus RNA sequencing with spatial transcriptomics from patient muscle biopsies to map cell-type-specific drivers underlying IBM pathogenesis compared with IMNM muscles and noninflammatory skeletal muscle samples. In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and conventional type 1 dendritic cells. IBM myofibers were characterized by either upregulation of cell stress markers featuring GADD45A and NORAD or protein degradation markers including RNF7 associated with p62 aggregates. GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation. We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways. Inclusion body myositis (IBM) is a progressive inflammatory muscle disease of unknown cause, prevalent in older adults. Through spatial and single nuclear profiling, the authors identify a selective type 2 myofiber pathology in IBM, linked to genomic stress and denervation.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00645-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141249197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-06-01DOI: 10.1038/s43587-024-00634-y
Christopher G Bell
{"title":"Quantifying stochasticity in the aging DNA methylome.","authors":"Christopher G Bell","doi":"10.1038/s43587-024-00634-y","DOIUrl":"10.1038/s43587-024-00634-y","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140961273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium–glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells. Katsuumi, Shimizu, Suda et al. report that SGLT2 inhibition reduces the senescence burden and alleviates aging traits in mice. The authors demonstrate an indirect mechanism of senescent cell removal, through enhancing immunosurveillance.
{"title":"SGLT2 inhibition eliminates senescent cells and alleviates pathological aging","authors":"Goro Katsuumi, Ippei Shimizu, Masayoshi Suda, Yohko Yoshida, Takaaki Furihata, Yusuke Joki, Chieh-Lun Hsiao, Liang Jiaqi, Shinya Fujiki, Manabu Abe, Masataka Sugimoto, Tomoyoshi Soga, Tohru Minamino","doi":"10.1038/s43587-024-00642-y","DOIUrl":"10.1038/s43587-024-00642-y","url":null,"abstract":"It has been reported that accumulation of senescent cells in various tissues contributes to pathological aging and that elimination of senescent cells (senolysis) improves age-associated pathologies. Here, we demonstrate that inhibition of sodium–glucose co-transporter 2 (SGLT2) enhances clearance of senescent cells, thereby ameliorating age-associated phenotypic changes. In a mouse model of dietary obesity, short-term treatment with the SGLT2 inhibitor canagliflozin reduced the senescence load in visceral adipose tissue and improved adipose tissue inflammation and metabolic dysfunction, but normalization of plasma glucose by insulin treatment had no effect on senescent cells. Canagliflozin extended the lifespan of mice with premature aging even when treatment was started in middle age. Metabolomic analyses revealed that short-term treatment with canagliflozin upregulated 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside, enhancing immune-mediated clearance of senescent cells by downregulating expression of programmed cell death-ligand 1. These findings suggest that inhibition of SGLT2 has an indirect senolytic effect by enhancing endogenous immunosurveillance of senescent cells. Katsuumi, Shimizu, Suda et al. report that SGLT2 inhibition reduces the senescence burden and alleviates aging traits in mice. The authors demonstrate an indirect mechanism of senescent cell removal, through enhancing immunosurveillance.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00642-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141181762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-30DOI: 10.1038/s43587-024-00631-1
Shihong Max Gao, Yanyan Qi, Qinghao Zhang, Youchen Guan, Yi-Tang Lee, Lang Ding, Lihua Wang, Aaron S. Mohammed, Hongjie Li, Yusi Fu, Meng C. Wang
Organismal aging involves functional declines in both somatic and reproductive tissues. Multiple strategies have been discovered to extend lifespan across species. However, how age-related molecular changes differ among various tissues and how those lifespan-extending strategies slow tissue aging in distinct manners remain unclear. Here we generated the transcriptomic Cell Atlas of Worm Aging (CAWA, http://mengwanglab.org/atlas ) of wild-type and long-lived strains. We discovered cell-specific, age-related molecular and functional signatures across all somatic and germ cell types. We developed transcriptomic aging clocks for different tissues and quantitatively determined how three different pro-longevity strategies slow tissue aging distinctively. Furthermore, through genome-wide profiling of alternative polyadenylation (APA) events in different tissues, we discovered cell-type-specific APA changes during aging and revealed how these changes are differentially affected by the pro-longevity strategies. Together, this study offers fundamental molecular insights into both somatic and reproductive aging and provides a valuable resource for in-depth understanding of the diversity of pro-longevity mechanisms. This comprehensive resource offers new insights into how different types of cell and tissue change with age in C. elegans and unveils the distinctive anti-aging effects of various pro-longevity strategies in a cell-type-specific manner.
生物衰老涉及体细胞和生殖组织的功能衰退。目前已发现多种延长物种寿命的策略。然而，与年龄相关的分子变化在不同组织间有何差异，以及这些延长寿命的策略如何以不同的方式延缓组织衰老，目前仍不清楚。在这里，我们生成了野生型和长寿命菌株的转录组细胞老化图谱（CAWA，http://mengwanglab.org/atlas ）。我们在所有体细胞和生殖细胞类型中发现了细胞特异性的、与年龄相关的分子和功能特征。我们开发了不同组织的转录组衰老时钟，并定量确定了三种不同的长寿策略如何不同地减缓组织衰老。此外，通过对不同组织中的替代多腺苷酸化（APA）事件进行全基因组剖析，我们发现了衰老过程中细胞类型特异性的 APA 变化，并揭示了这些变化如何受到益寿策略的不同影响。总之，这项研究为体细胞衰老和生殖衰老提供了基本的分子见解，并为深入了解促长寿机制的多样性提供了宝贵的资源。
{"title":"Aging atlas reveals cell-type-specific effects of pro-longevity strategies","authors":"Shihong Max Gao, Yanyan Qi, Qinghao Zhang, Youchen Guan, Yi-Tang Lee, Lang Ding, Lihua Wang, Aaron S. Mohammed, Hongjie Li, Yusi Fu, Meng C. Wang","doi":"10.1038/s43587-024-00631-1","DOIUrl":"10.1038/s43587-024-00631-1","url":null,"abstract":"Organismal aging involves functional declines in both somatic and reproductive tissues. Multiple strategies have been discovered to extend lifespan across species. However, how age-related molecular changes differ among various tissues and how those lifespan-extending strategies slow tissue aging in distinct manners remain unclear. Here we generated the transcriptomic Cell Atlas of Worm Aging (CAWA, http://mengwanglab.org/atlas ) of wild-type and long-lived strains. We discovered cell-specific, age-related molecular and functional signatures across all somatic and germ cell types. We developed transcriptomic aging clocks for different tissues and quantitatively determined how three different pro-longevity strategies slow tissue aging distinctively. Furthermore, through genome-wide profiling of alternative polyadenylation (APA) events in different tissues, we discovered cell-type-specific APA changes during aging and revealed how these changes are differentially affected by the pro-longevity strategies. Together, this study offers fundamental molecular insights into both somatic and reproductive aging and provides a valuable resource for in-depth understanding of the diversity of pro-longevity mechanisms. This comprehensive resource offers new insights into how different types of cell and tissue change with age in C. elegans and unveils the distinctive anti-aging effects of various pro-longevity strategies in a cell-type-specific manner.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00631-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141181761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-30DOI: 10.1038/s43587-024-00650-y
Small extracellular vesicles (sEVs) derived from the blood of young mice are shown to have the potential to extend lifespan and rejuvenate physiological functions in aged mice. Mechanistically, microRNA (miRNA) cargoes within these sEVs alleviated age-related dysfunction by promoting the expression of PGC1α and enhancing mitochondrial energy metabolism.
{"title":"Small extracellular vesicles are rejuvenating factors in young blood","authors":"","doi":"10.1038/s43587-024-00650-y","DOIUrl":"10.1038/s43587-024-00650-y","url":null,"abstract":"Small extracellular vesicles (sEVs) derived from the blood of young mice are shown to have the potential to extend lifespan and rejuvenate physiological functions in aged mice. Mechanistically, microRNA (miRNA) cargoes within these sEVs alleviated age-related dysfunction by promoting the expression of PGC1α and enhancing mitochondrial energy metabolism.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141181763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-05-27DOI: 10.1038/s43587-024-00639-7
Thomas R. Austin, Maria Nethander, Howard A. Fink, Anna E. Törnqvist, Diana I. Jalal, Petra Buzkova, Joshua I. Barzilay, Laura Carbone, Maiken E. Gabrielsen, Louise Grahnemo, Tianyuan Lu, Kristian Hveem, Christian Jonasson, Jorge R. Kizer, Arnulf Langhammer, Kenneth J. Mukamal, Robert E. Gerszten, Bruce M. Psaty, John A. Robbins, Yan V. Sun, Anne Heidi Skogholt, John A. Kanis, Helena Johansson, Bjørn Olav Åsvold, Rodrigo J. Valderrabano, Jie Zheng, J. Brent Richards, Eivind Coward, Claes Ohlsson
As there are effective treatments to reduce hip fractures, identification of patients at high risk of hip fracture is important to inform efficient intervention strategies. To obtain a new tool for hip fracture prediction, we developed a protein-based risk score in the Cardiovascular Health Study using an aptamer-based proteomic platform. The proteomic risk score predicted incident hip fractures and improved hip fracture discrimination in two Trøndelag Health Study validation cohorts using the same aptamer-based platform. When transferred to an antibody-based proteomic platform in a UK Biobank validation cohort, the proteomic risk score was strongly associated with hip fractures (hazard ratio per s.d. increase, 1.64; 95% confidence interval 1.53–1.77). The proteomic risk score, but not available polygenic risk scores for fractures or bone mineral density, improved the C-index beyond the fracture risk assessment tool (FRAX), which integrates information from clinical risk factors (C-index, FRAX 0.735 versus FRAX + proteomic risk score 0.776). The developed proteomic risk score constitutes a new tool for stratifying patients according to hip fracture risk; however, its improvement in hip fracture discrimination is modest and its clinical utility beyond FRAX with information on femoral neck bone mineral density remains to be determined. The authors developed a proteomic risk score that improved the prediction of hip fractures in three validation cohorts analyzed by two different proteomic platforms. This risk score constitutes a new tool to stratify patients by hip fracture risk.
{"title":"A plasma protein-based risk score to predict hip fractures","authors":"Thomas R. Austin, Maria Nethander, Howard A. Fink, Anna E. Törnqvist, Diana I. Jalal, Petra Buzkova, Joshua I. Barzilay, Laura Carbone, Maiken E. Gabrielsen, Louise Grahnemo, Tianyuan Lu, Kristian Hveem, Christian Jonasson, Jorge R. Kizer, Arnulf Langhammer, Kenneth J. Mukamal, Robert E. Gerszten, Bruce M. Psaty, John A. Robbins, Yan V. Sun, Anne Heidi Skogholt, John A. Kanis, Helena Johansson, Bjørn Olav Åsvold, Rodrigo J. Valderrabano, Jie Zheng, J. Brent Richards, Eivind Coward, Claes Ohlsson","doi":"10.1038/s43587-024-00639-7","DOIUrl":"10.1038/s43587-024-00639-7","url":null,"abstract":"As there are effective treatments to reduce hip fractures, identification of patients at high risk of hip fracture is important to inform efficient intervention strategies. To obtain a new tool for hip fracture prediction, we developed a protein-based risk score in the Cardiovascular Health Study using an aptamer-based proteomic platform. The proteomic risk score predicted incident hip fractures and improved hip fracture discrimination in two Trøndelag Health Study validation cohorts using the same aptamer-based platform. When transferred to an antibody-based proteomic platform in a UK Biobank validation cohort, the proteomic risk score was strongly associated with hip fractures (hazard ratio per s.d. increase, 1.64; 95% confidence interval 1.53–1.77). The proteomic risk score, but not available polygenic risk scores for fractures or bone mineral density, improved the C-index beyond the fracture risk assessment tool (FRAX), which integrates information from clinical risk factors (C-index, FRAX 0.735 versus FRAX + proteomic risk score 0.776). The developed proteomic risk score constitutes a new tool for stratifying patients according to hip fracture risk; however, its improvement in hip fracture discrimination is modest and its clinical utility beyond FRAX with information on femoral neck bone mineral density remains to be determined. The authors developed a proteomic risk score that improved the prediction of hip fractures in three validation cohorts analyzed by two different proteomic platforms. This risk score constitutes a new tool to stratify patients by hip fracture risk.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11333168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141159360","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：