Pub Date : 2026-01-02DOI: 10.1038/s43587-025-01047-1
We developed scMORE (single-cell multiomics regulon enrichment), a computational framework that integrates single-cell multiomics with genome-wide association study summary statistics to identify transcription factor–chromatin–gene regulatory networks (eRegulons) that underlie complex diseases. Applying scMORE to 31 traits (including Parkinson’s disease), we investigated immune- and aging-associated eRegulons, and revealed how genetic variants shape cell-type-specific regulatory programs.
{"title":"Linking single-cell multiomics with GWAS to reveal key regulators of disease risk","authors":"","doi":"10.1038/s43587-025-01047-1","DOIUrl":"10.1038/s43587-025-01047-1","url":null,"abstract":"We developed scMORE (single-cell multiomics regulon enrichment), a computational framework that integrates single-cell multiomics with genome-wide association study summary statistics to identify transcription factor–chromatin–gene regulatory networks (eRegulons) that underlie complex diseases. Applying scMORE to 31 traits (including Parkinson’s disease), we investigated immune- and aging-associated eRegulons, and revealed how genetic variants shape cell-type-specific regulatory programs.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"36-37"},"PeriodicalIF":19.4,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145893034","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}
Lung aging is a multifactorial series of molecular alterations that leads to gradual deterioration of lung function and increased vulnerability to cancer. Tumor communicates with host organs partially through extracellular vesicles; however, the mechanistic drivers and consequences of lung aging in the context of cancer remain unclear. Here we identify cancer cell-secreted dimethylarginine dimethylaminohydrolase-1 (DDAH1) protein induces citrulline accumulation and promotes lung fibrosis and aging. Mechanistically, our single-cell sequencing and genetic knockout mice evidence that citrulline availability elevation inhibits peptidyl arginine deiminase 4-mediated transforming growth factor-β1 (TGF-β1) citrullination, thereby inducing the TGF-β1/Smad3 signaling pathway in lung fibroblasts. Notably, vacuolar protein sorting assists the packaging of DDAH1 into the late endosomes. The administration of DDAH1 inhibitor reduces fibrosis and alleviates lung aging. Conclusively, our findings reveal tumor-derived DDAH1 protein contributes to citrulline accumulation to promote lung aging, shedding light on the treatment and diagnosis of tumors by inhibiting senescent lung fibroblasts. Liu et al. show that tumor-secreted dimethylarginine dimethylaminohydrolase-1 protein induces citrulline accumulation and promotes lung fibrosis and aging, shedding light on the cancer treatment and diagnosis by inhibiting senescent lung fibroblasts.
{"title":"Cancer-cell-secreted DDAH1 induces TGF-β1/Smad3 signaling pathway to promote fibrosis and aging in lung","authors":"Liu Liu, Qianyue Wang, Meng Chen, Haifeng Zhou, Xu Li, Ziqi Yuan, Yong Hu, Chaoqun Wang, Xiaohui Zhang, Sheng Hu, Xiaoting Wu, Meixin Li, Juanjuan Li, Aijun Chen, Wei Yan","doi":"10.1038/s43587-025-01024-8","DOIUrl":"10.1038/s43587-025-01024-8","url":null,"abstract":"Lung aging is a multifactorial series of molecular alterations that leads to gradual deterioration of lung function and increased vulnerability to cancer. Tumor communicates with host organs partially through extracellular vesicles; however, the mechanistic drivers and consequences of lung aging in the context of cancer remain unclear. Here we identify cancer cell-secreted dimethylarginine dimethylaminohydrolase-1 (DDAH1) protein induces citrulline accumulation and promotes lung fibrosis and aging. Mechanistically, our single-cell sequencing and genetic knockout mice evidence that citrulline availability elevation inhibits peptidyl arginine deiminase 4-mediated transforming growth factor-β1 (TGF-β1) citrullination, thereby inducing the TGF-β1/Smad3 signaling pathway in lung fibroblasts. Notably, vacuolar protein sorting assists the packaging of DDAH1 into the late endosomes. The administration of DDAH1 inhibitor reduces fibrosis and alleviates lung aging. Conclusively, our findings reveal tumor-derived DDAH1 protein contributes to citrulline accumulation to promote lung aging, shedding light on the treatment and diagnosis of tumors by inhibiting senescent lung fibroblasts. Liu et al. show that tumor-secreted dimethylarginine dimethylaminohydrolase-1 protein induces citrulline accumulation and promotes lung fibrosis and aging, shedding light on the cancer treatment and diagnosis by inhibiting senescent lung fibroblasts.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"143-161"},"PeriodicalIF":19.4,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145829443","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 : 2025-12-19DOI: 10.1038/s43587-025-01026-6
Kai Zhuang, Liu Zi, Xiao Su, Chen Hu, Xinrui Li, Shuzhong Wang, Yujun Xia, Bo Wu, Yuemin Su, Shaokun Chen, Haojie Li, Siqi Wang, Mengdan Wang, Jieyin Li, Wenting Xie, Yanbing Chen, Lige Leng, Huifang Li, Li Zhong, Jiechao Zhou, Yan Liu, Qingsong Liu, Karl Herrup, Jie Zhang
Progressive neuronal loss and brain atrophy are principal determinants of cognitive decline in Alzheimer’s disease (AD), yet most mouse models fail to recapitulate these features. Here we identify cyclin-dependent kinase 3 (CDK3) as a key driver of neurodegeneration in AD. CDK3 is elevated in human AD brains and correlates with disease severity. As laboratory mice carry a nonfunctional Cdk3 mutation, we generated two models with restored CDK3 activity and then crossed to AD backgrounds. Both models exhibited substantial neuronal loss, hippocampal atrophy, and cognitive deficits. Single-nucleus RNA sequencing revealed neurons simultaneously activating cell cycle and cell death pathways, indicating cell cycle reentry-induced death. Proteomics implicated synaptic proteins as CDK3 substrates. Finally, we developed BMX330, an inhibitor of CDK3, which mitigated neuronal death and rescued cognitive decline in CDK3-restored AD mice. These findings position CDK3 as a therapeutic target and provide pathologically relevant AD models. Zhuang, Zi et al. identify cyclin-dependent kinase 3 (CDK3) as a driver of neuron loss in Alzheimer’s disease that is associated with brain atrophy and memory decline in mice. Inhibition of CDK3 (BMX330) is shown to limit neuronal loss and improve cognition.
{"title":"CDK3 induces neuronal death and brain atrophy in Alzheimer’s disease","authors":"Kai Zhuang, Liu Zi, Xiao Su, Chen Hu, Xinrui Li, Shuzhong Wang, Yujun Xia, Bo Wu, Yuemin Su, Shaokun Chen, Haojie Li, Siqi Wang, Mengdan Wang, Jieyin Li, Wenting Xie, Yanbing Chen, Lige Leng, Huifang Li, Li Zhong, Jiechao Zhou, Yan Liu, Qingsong Liu, Karl Herrup, Jie Zhang","doi":"10.1038/s43587-025-01026-6","DOIUrl":"10.1038/s43587-025-01026-6","url":null,"abstract":"Progressive neuronal loss and brain atrophy are principal determinants of cognitive decline in Alzheimer’s disease (AD), yet most mouse models fail to recapitulate these features. Here we identify cyclin-dependent kinase 3 (CDK3) as a key driver of neurodegeneration in AD. CDK3 is elevated in human AD brains and correlates with disease severity. As laboratory mice carry a nonfunctional Cdk3 mutation, we generated two models with restored CDK3 activity and then crossed to AD backgrounds. Both models exhibited substantial neuronal loss, hippocampal atrophy, and cognitive deficits. Single-nucleus RNA sequencing revealed neurons simultaneously activating cell cycle and cell death pathways, indicating cell cycle reentry-induced death. Proteomics implicated synaptic proteins as CDK3 substrates. Finally, we developed BMX330, an inhibitor of CDK3, which mitigated neuronal death and rescued cognitive decline in CDK3-restored AD mice. These findings position CDK3 as a therapeutic target and provide pathologically relevant AD models. Zhuang, Zi et al. identify cyclin-dependent kinase 3 (CDK3) as a driver of neuron loss in Alzheimer’s disease that is associated with brain atrophy and memory decline in mice. Inhibition of CDK3 (BMX330) is shown to limit neuronal loss and improve cognition.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"200-220"},"PeriodicalIF":19.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145795751","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}
Black rice diets are enriched with unsaturated fatty acids that are thought to be beneficial for neurodegenerative disorders in aging. Here we find that α-linolenic acid (ALA) and 11,14-eicosadienoic acid (EDA), which are naturally enriched in black rice, inhibit amyloid pathology, rescue cognition and extend lifespan in mouse preclinical models of Alzheimer’s disease via allosteric activation of G protein-coupled receptor 120 (GPR120) in plaque-associated macrophages and activated microglia. We generate the structures of GPR120 bound to ALA and EDA. We demonstrate that ALA and EDA allosterically modulate and synergistically activate GPR120 for macrophagic phagocytosis and clearance of β-amyloid aggregates in Alzheimer’s disease mice. A cell-type-specific deletion of GPR120, or Gαi1, completely abrogates the therapeutic effects of ALA and EDA. This deletion can be rescued by a constitutive active Gαi1–Q204L. These findings show a cell-type-specific function of GPR120 in the brain and provide an enriched allosteric mechanism of GPR120 activation for the treatment of Alzheimer’s disease. He, Wang, Shen, Dong and colleagues find that unsaturated fatty acids enriched in a black rice diet inhibit amyloid pathology, rescue cognition and restore physiological lifespan in mouse models of Alzheimer’s disease via allosteric activation of GPR120.
{"title":"Allosteric activation of a cell-type-specific GPR120 inhibits amyloid pathology of Alzheimer’s disease","authors":"Aodi He, Yue Wang, Yuhang Shen, Zhiqiang Dong, Lingli Luo, Xiangyu Ge, Xinlu Liu, Yue Mao, Tongmei Zhang, Xinyan Li, Hao Li, Wei Jing, Ling-Qiang Zhu, Qifa Zhang, Youming Lu","doi":"10.1038/s43587-025-01028-4","DOIUrl":"10.1038/s43587-025-01028-4","url":null,"abstract":"Black rice diets are enriched with unsaturated fatty acids that are thought to be beneficial for neurodegenerative disorders in aging. Here we find that α-linolenic acid (ALA) and 11,14-eicosadienoic acid (EDA), which are naturally enriched in black rice, inhibit amyloid pathology, rescue cognition and extend lifespan in mouse preclinical models of Alzheimer’s disease via allosteric activation of G protein-coupled receptor 120 (GPR120) in plaque-associated macrophages and activated microglia. We generate the structures of GPR120 bound to ALA and EDA. We demonstrate that ALA and EDA allosterically modulate and synergistically activate GPR120 for macrophagic phagocytosis and clearance of β-amyloid aggregates in Alzheimer’s disease mice. A cell-type-specific deletion of GPR120, or Gαi1, completely abrogates the therapeutic effects of ALA and EDA. This deletion can be rescued by a constitutive active Gαi1–Q204L. These findings show a cell-type-specific function of GPR120 in the brain and provide an enriched allosteric mechanism of GPR120 activation for the treatment of Alzheimer’s disease. He, Wang, Shen, Dong and colleagues find that unsaturated fatty acids enriched in a black rice diet inhibit amyloid pathology, rescue cognition and restore physiological lifespan in mouse models of Alzheimer’s disease via allosteric activation of GPR120.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"181-199"},"PeriodicalIF":19.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01028-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145795689","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 : 2025-12-19DOI: 10.1038/s43587-025-01029-3
Marwan N. Sabbagh, Jeffrey L. Cummings, Clive Ballard, Wiesje M. van der Flier, Michael T. Heneka, Jens Juul Holst, Lotte Bjerre Knudsen, Stephen Salloway, Malú Gámez Tansey, Daniel J. Drucker
With therapeutic progress in Alzheimer’s disease (AD), more molecular and mechanistic targets are coming into focus. Beyond amyloid, emerging targets include tau, neuroinflammation and neurotransmitters. Targeting neuroinflammation in neurodegenerative diseases has been explored using cyclooxygenase inhibitors, but it has mostly been unsuccessful. Among the drug classes under investigation for AD are the glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are approved for the treatment of type 2 diabetes (T2D), obesity and cardiovascular disease. GLP-1RAs are candidate treatments for AD based on several concepts. First, epidemiological data reveal that patients with T2D and cardiovascular disease receiving GLP-1RAs have substantial reductions in the risk of developing all-cause dementia. Second, GLP-1RAs reduce neuroinflammatory changes in preclinical models. Clinical trials have not yet shown that GLP-1RAs can slow the rate of cognitive decline in mild cognitive impairment and mild dementia due to AD. Here, we summarize data supporting the use of GLP-1RAs for the treatment of neurodegenerative diseases, with a focus on AD. The authors discuss the preclinical literature and emerging clinical evidence that support the rationale for investigating the use of glucagon-like peptide-1 receptor agonists to prevent and treat several neurodegenerative diseases of aging, with a focus on Alzheimer’s disease.
{"title":"Repurposing glucagon-like peptide-1 receptor agonists for the treatment of neurodegenerative disorders","authors":"Marwan N. Sabbagh, Jeffrey L. Cummings, Clive Ballard, Wiesje M. van der Flier, Michael T. Heneka, Jens Juul Holst, Lotte Bjerre Knudsen, Stephen Salloway, Malú Gámez Tansey, Daniel J. Drucker","doi":"10.1038/s43587-025-01029-3","DOIUrl":"10.1038/s43587-025-01029-3","url":null,"abstract":"With therapeutic progress in Alzheimer’s disease (AD), more molecular and mechanistic targets are coming into focus. Beyond amyloid, emerging targets include tau, neuroinflammation and neurotransmitters. Targeting neuroinflammation in neurodegenerative diseases has been explored using cyclooxygenase inhibitors, but it has mostly been unsuccessful. Among the drug classes under investigation for AD are the glucagon-like peptide-1 receptor agonists (GLP-1RAs), which are approved for the treatment of type 2 diabetes (T2D), obesity and cardiovascular disease. GLP-1RAs are candidate treatments for AD based on several concepts. First, epidemiological data reveal that patients with T2D and cardiovascular disease receiving GLP-1RAs have substantial reductions in the risk of developing all-cause dementia. Second, GLP-1RAs reduce neuroinflammatory changes in preclinical models. Clinical trials have not yet shown that GLP-1RAs can slow the rate of cognitive decline in mild cognitive impairment and mild dementia due to AD. Here, we summarize data supporting the use of GLP-1RAs for the treatment of neurodegenerative diseases, with a focus on AD. The authors discuss the preclinical literature and emerging clinical evidence that support the rationale for investigating the use of glucagon-like peptide-1 receptor agonists to prevent and treat several neurodegenerative diseases of aging, with a focus on Alzheimer’s disease.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"56-67"},"PeriodicalIF":19.4,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145795822","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}
Single-cell multiomics provides critical insights into how disease-associated variants identified through genome-wide association studies (GWASs) influence transcription factor eRegulons within a specific cellular context; however, the regulatory roles of genetic variants in aging and disease remain unclear. Here, we present scMORE, a method that integrates single-cell transcriptomes and chromatin accessibility with GWAS summary statistics to identify cell-type-specific eRegulons associated with diseases. scMORE effectively captures trait-relevant cellular features and demonstrates robust performance across simulated and real single-cell datasets, and GWASs for 31 immune- and aging-related traits, including Parkinson’s disease (PD). In the human midbrain, scMORE identifies 77 aging-relevant eRegulons implicated in PD across seven brain cell types and reveals sex-dependent dysregulation of these eRegulons in PD neurons compared to both young and aged groups. By linking genetic variation to cell type-resolved eRegulon activity, scMORE illuminates how variants shape trait-relevant regulatory networks and provides a practical framework for mechanistic interpretation of GWAS signals. In this technical report Ma et al. present scMORE, a polygenic method integrating single-cell multiomics and GWAS to prioritize cell-type-specific, trait-relevant eRegulons. scMORE revealed regulators underlying 31 immune and aging traits, including Parkinson’s disease.
{"title":"Integrating polygenic signals and single-cell multiomics identifies cell-type-specific regulomes critical for immune- and aging-related diseases","authors":"Yunlong Ma, Yinghao Yao, Yijun Zhou, Wei Dai, Jingjing Li, Yuanyuan Gui, Haojun Sun, Zhengbiao Zhu, Dingping Jiang, Cheng Chen, Chunyu Deng, Yizhou Huang, Haijun Han, Jianhong Zhou, Jianzhong Su","doi":"10.1038/s43587-025-01027-5","DOIUrl":"10.1038/s43587-025-01027-5","url":null,"abstract":"Single-cell multiomics provides critical insights into how disease-associated variants identified through genome-wide association studies (GWASs) influence transcription factor eRegulons within a specific cellular context; however, the regulatory roles of genetic variants in aging and disease remain unclear. Here, we present scMORE, a method that integrates single-cell transcriptomes and chromatin accessibility with GWAS summary statistics to identify cell-type-specific eRegulons associated with diseases. scMORE effectively captures trait-relevant cellular features and demonstrates robust performance across simulated and real single-cell datasets, and GWASs for 31 immune- and aging-related traits, including Parkinson’s disease (PD). In the human midbrain, scMORE identifies 77 aging-relevant eRegulons implicated in PD across seven brain cell types and reveals sex-dependent dysregulation of these eRegulons in PD neurons compared to both young and aged groups. By linking genetic variation to cell type-resolved eRegulon activity, scMORE illuminates how variants shape trait-relevant regulatory networks and provides a practical framework for mechanistic interpretation of GWAS signals. In this technical report Ma et al. present scMORE, a polygenic method integrating single-cell multiomics and GWAS to prioritize cell-type-specific, trait-relevant eRegulons. scMORE revealed regulators underlying 31 immune and aging traits, including Parkinson’s disease.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"270-289"},"PeriodicalIF":19.4,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01027-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145770405","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 : 2025-12-17DOI: 10.1038/s43587-025-01025-7
Vrinda Kalia, Dolly Reyes-Dumeyer, Saurabh Dubey, Hanisha Udhani, Renu Nandakumar, Annie J. Lee, Rafael Lantigua, Martin Medrano, Diones Rivera, Lawrence S. Honig, Richard Mayeux, Gary W. Miller, Badri N. Vardarajan
Circulating metabolites can identify biochemical risk factors related to Alzheimer’s disease (AD). We measured plasma metabolites in 1,068 participants of Caribbean Hispanic ancestry (250 patients with AD and 818 healthy controls) across 2 cohorts and analyzed their relationship with clinical AD, biomarker-supported AD and plasma biomarkers (P-tau181, P-tau217, P-tau231 and Aβ42:Aβ40). Amino acid metabolism pathways were enriched among metabolites associated with P-tau biomarkers, whereas sialic acid and N-glycan pathways were associated with Aβ42:Aβ40. Through several dimensionality reduction approaches, we identified an APOE-ε4 dependent relationship between lysophosphatidylcholines (lysoPCs) carrying polyunsaturated fatty acids and biomarker-supported AD and P-tau biomarkers. In an independent dataset of 110 postmortem brain tissues from non-Hispanic white participants, lysoPCs in the brain were also associated with AD neuropathological features. Our results show that biomarker-based diagnostic criteria identified an APOE-ε4 dependent association with lysoPCs, which play a critical role in the transport of neuroprotective polyunsaturated fatty acids into the brain, and AD. Kalia et al. investigate metabolic changes in Alzheimer’s disease (AD) using blood metabolomics, and show that lysophosphatidylcholines are associated with early amyloidosis in AD as measured by P-tau181 and P-tau217.
{"title":"Lysophosphatidylcholines are associated with amyloidosis in early stages of Alzheimer’s disease","authors":"Vrinda Kalia, Dolly Reyes-Dumeyer, Saurabh Dubey, Hanisha Udhani, Renu Nandakumar, Annie J. Lee, Rafael Lantigua, Martin Medrano, Diones Rivera, Lawrence S. Honig, Richard Mayeux, Gary W. Miller, Badri N. Vardarajan","doi":"10.1038/s43587-025-01025-7","DOIUrl":"10.1038/s43587-025-01025-7","url":null,"abstract":"Circulating metabolites can identify biochemical risk factors related to Alzheimer’s disease (AD). We measured plasma metabolites in 1,068 participants of Caribbean Hispanic ancestry (250 patients with AD and 818 healthy controls) across 2 cohorts and analyzed their relationship with clinical AD, biomarker-supported AD and plasma biomarkers (P-tau181, P-tau217, P-tau231 and Aβ42:Aβ40). Amino acid metabolism pathways were enriched among metabolites associated with P-tau biomarkers, whereas sialic acid and N-glycan pathways were associated with Aβ42:Aβ40. Through several dimensionality reduction approaches, we identified an APOE-ε4 dependent relationship between lysophosphatidylcholines (lysoPCs) carrying polyunsaturated fatty acids and biomarker-supported AD and P-tau biomarkers. In an independent dataset of 110 postmortem brain tissues from non-Hispanic white participants, lysoPCs in the brain were also associated with AD neuropathological features. Our results show that biomarker-based diagnostic criteria identified an APOE-ε4 dependent association with lysoPCs, which play a critical role in the transport of neuroprotective polyunsaturated fatty acids into the brain, and AD. Kalia et al. investigate metabolic changes in Alzheimer’s disease (AD) using blood metabolomics, and show that lysophosphatidylcholines are associated with early amyloidosis in AD as measured by P-tau181 and P-tau217.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"221-234"},"PeriodicalIF":19.4,"publicationDate":"2025-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01025-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145776958","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 : 2025-12-15DOI: 10.1038/s43587-025-01034-6
In Hwa Jang, Anna Carey, Victor Kruglov, Katie Nguyen, Jeffrey R. Misialek, Stephanie H. Cholensky, Declan M. Smith, Suxia Bai, Timothy Nottoli, David A. Bernlohr, Pamela L. Lutsey, Christina D. Camell
Aging is characterized by amplified inflammation, including proinflammatory macrophages and increased susceptibility to endotoxemia. Here we uncover a mechanism by which macrophages maintain their inflammatory phenotype through autocrine GDF3–SMAD2/3 signaling, which ultimately exacerbates endotoxemia. We show that inflammatory adipose tissue macrophages display an age-dependent increase in GDF3, a TGFβ-family cytokine. Lifelong systemic or myeloid-specific Gdf3 deletion leads to reduced endotoxic inflammation. Using pharmacological interventions to modulate the GDF3–SMAD2/3 axis, we demonstrate its role in regulating the inflammatory adipose tissue macrophage phenotype and endotoxemia lethality in old mice. Mechanistically, single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses suggest that GDF3 induces a shift toward an inflammatory state by limiting methylation-dependent chromatin compaction. Leveraging human adipose tissue samples and 11,084 participants from the atherosclerosis risk in communities study, we validate the relevance of GDF3 to aging in humans. These findings position the GDF3–SMAD2/3 axis as a critical driver of age-associated chromatin remodeling and a promising therapeutic target for mitigating macrophage-related inflammation in aging. Jang and colleagues demonstrate that GDF3 reshapes the chromatin landscape of inflammatory adipose tissue macrophages and drives endotoxic inflammation with age. Pharmacological inhibition of the GDF3–SMAD2/3 axis alleviates endotoxemia lethality in old mice.
{"title":"GDF3 promotes adipose tissue macrophage-mediated inflammation via altered chromatin accessibility during aging","authors":"In Hwa Jang, Anna Carey, Victor Kruglov, Katie Nguyen, Jeffrey R. Misialek, Stephanie H. Cholensky, Declan M. Smith, Suxia Bai, Timothy Nottoli, David A. Bernlohr, Pamela L. Lutsey, Christina D. Camell","doi":"10.1038/s43587-025-01034-6","DOIUrl":"10.1038/s43587-025-01034-6","url":null,"abstract":"Aging is characterized by amplified inflammation, including proinflammatory macrophages and increased susceptibility to endotoxemia. Here we uncover a mechanism by which macrophages maintain their inflammatory phenotype through autocrine GDF3–SMAD2/3 signaling, which ultimately exacerbates endotoxemia. We show that inflammatory adipose tissue macrophages display an age-dependent increase in GDF3, a TGFβ-family cytokine. Lifelong systemic or myeloid-specific Gdf3 deletion leads to reduced endotoxic inflammation. Using pharmacological interventions to modulate the GDF3–SMAD2/3 axis, we demonstrate its role in regulating the inflammatory adipose tissue macrophage phenotype and endotoxemia lethality in old mice. Mechanistically, single-cell RNA sequencing and assay for transposase-accessible chromatin with sequencing analyses suggest that GDF3 induces a shift toward an inflammatory state by limiting methylation-dependent chromatin compaction. Leveraging human adipose tissue samples and 11,084 participants from the atherosclerosis risk in communities study, we validate the relevance of GDF3 to aging in humans. These findings position the GDF3–SMAD2/3 axis as a critical driver of age-associated chromatin remodeling and a promising therapeutic target for mitigating macrophage-related inflammation in aging. Jang and colleagues demonstrate that GDF3 reshapes the chromatin landscape of inflammatory adipose tissue macrophages and drives endotoxic inflammation with age. Pharmacological inhibition of the GDF3–SMAD2/3 axis alleviates endotoxemia lethality in old mice.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"6 1","pages":"127-142"},"PeriodicalIF":19.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s43587-025-01034-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764786","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 : 2025-12-15DOI: 10.1038/s43587-025-01050-6
David H Meyer, Alexei A Maklakov, Björn Schumacher
{"title":"Addendum: Aging by the clock and yet without a program.","authors":"David H Meyer, Alexei A Maklakov, Björn Schumacher","doi":"10.1038/s43587-025-01050-6","DOIUrl":"10.1038/s43587-025-01050-6","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":" ","pages":""},"PeriodicalIF":19.4,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145764773","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 : 2025-12-12DOI: 10.1038/s43587-025-01013-x
Arokiasamy Perianayagam, Ritu Sadana, Matthew Prina, Y Selvamani, Aravinda Meera Guntupalli, David E. Bloom, Jinkook Lee, Yu-Tzu Wu
Intrinsic capacity (IC), which comprises all physical and mental capacities of individuals, is a key component in the World Health Organization’s healthy aging framework. A validated IC measure is lacking in India, the most populous country in the world. The aim of this study is to develop an IC measure in older Indian adults using 60,591 participants aged ≥45 years from the Longitudinal Ageing Study in India. Confirmatory factor analysis incorporated 14 items of cognitive, locomotor, psychological, sensory and vitality capacities in a bifactor structure and estimated IC scores (range 0–100). The mean score was 69.7 (95% confidence interval of 69.6 to 69.8) and varied across the 36 states and union territories (range 63.4–77.8). A higher IC score had protective associations with poor self-rated health and functioning limitations after adjusting for demographic factors, socioeconomic status and chronic conditions. The score provides a comprehensive indicator that can be implemented in future aging research and practices in India. Intrinsic capacity (IC) was introduced by the World Health Organization to promote healthy aging. Here, using data from the Longitudinal Ageing Study in India, the authors develop an IC measure for older Indian adults. Their analysis shows that higher IC scores are associated with better health and functioning and reveals regional and sociodemographic variations.
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