Pub Date : 2024-11-22DOI: 10.1038/s43587-024-00768-z
We used single-cell and high-resolution spatial transcriptomics to investigate age-related decline in mouse skeletal muscle regeneration. Using a transfer learning-based scoring approach, we identified a population of senescent-like muscle stem cells that increases with age and is induced by muscle injury. This highlights that halted stem cell self-renewal underlies the muscle regenerative dysfunction in mouse aging.
{"title":"Mapping aged stem cell states associated with decline in skeletal muscle regeneration","authors":"","doi":"10.1038/s43587-024-00768-z","DOIUrl":"10.1038/s43587-024-00768-z","url":null,"abstract":"We used single-cell and high-resolution spatial transcriptomics to investigate age-related decline in mouse skeletal muscle regeneration. Using a transfer learning-based scoring approach, we identified a population of senescent-like muscle stem cells that increases with age and is induced by muscle injury. This highlights that halted stem cell self-renewal underlies the muscle regenerative dysfunction in mouse aging.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"4 12","pages":"1680-1681"},"PeriodicalIF":17.0,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142694007","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 : 2024-11-21DOI: 10.1038/s43587-024-00760-7
Elaine GY Chew, Zhehao Liu, Zheng Li, Sun Ju Chung, Michelle M. Lian, Moses Tandiono, Yue Jing Heng, Ebonne Y. Ng, Louis CS Tan, Wee Ling Chng, Tiak Ju Tan, Esther KL Peh, Ying Swan Ho, Xiao Yin Chen, Erin YT Lim, Chu Hua Chang, Jonavan J. Leong, Ting Xuan Peh, Ling Ling Chan, Yinxia Chao, Wing-Lok Au, Kumar M. Prakash, Jia Lun Lim, Yi Wen Tay, Vincent Mok, Anne YY Chan, Juei-Jueng Lin, Beom S. Jeon, Kyuyoung Song, Clement C. Tham, Chi Pui Pang, Jeeyun Ahn, Kyu Hyung Park, Janey L. Wiggs, Tin Aung, Ai Huey Tan, Azlina Ahmad Annuar, Mary B. Makarious, Cornelis Blauwendraat, Mike A. Nalls, Laurie A. Robak, Roy N. Alcalay, Ziv Gan-Or, Richard Reynolds, Shen-Yang Lim, Yun Xia, Chiea Chuen Khor, Eng-King Tan, Zhenxun Wang, Jia Nee Foo
Parkinson’s disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (<44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10−15) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10−8). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease. Using whole-exome sequencing followed by in vitro enzymatic assays, Chew, Liu, Li, Chung et al. identified rare protein-coding variants in GBA1 and SMPD1 that significantly associate with risk of Parkinson’s disease across cohorts of Asian descent.
{"title":"Exome sequencing in Asian populations identifies low-frequency and rare coding variation influencing Parkinson’s disease risk","authors":"Elaine GY Chew, Zhehao Liu, Zheng Li, Sun Ju Chung, Michelle M. Lian, Moses Tandiono, Yue Jing Heng, Ebonne Y. Ng, Louis CS Tan, Wee Ling Chng, Tiak Ju Tan, Esther KL Peh, Ying Swan Ho, Xiao Yin Chen, Erin YT Lim, Chu Hua Chang, Jonavan J. Leong, Ting Xuan Peh, Ling Ling Chan, Yinxia Chao, Wing-Lok Au, Kumar M. Prakash, Jia Lun Lim, Yi Wen Tay, Vincent Mok, Anne YY Chan, Juei-Jueng Lin, Beom S. Jeon, Kyuyoung Song, Clement C. Tham, Chi Pui Pang, Jeeyun Ahn, Kyu Hyung Park, Janey L. Wiggs, Tin Aung, Ai Huey Tan, Azlina Ahmad Annuar, Mary B. Makarious, Cornelis Blauwendraat, Mike A. Nalls, Laurie A. Robak, Roy N. Alcalay, Ziv Gan-Or, Richard Reynolds, Shen-Yang Lim, Yun Xia, Chiea Chuen Khor, Eng-King Tan, Zhenxun Wang, Jia Nee Foo","doi":"10.1038/s43587-024-00760-7","DOIUrl":"10.1038/s43587-024-00760-7","url":null,"abstract":"Parkinson’s disease (PD) is an incurable, progressive and common movement disorder that is increasing in incidence globally because of population aging. We hypothesized that the landscape of rare, protein-altering variants could provide further insights into disease pathogenesis. Here we performed whole-exome sequencing followed by gene-based tests on 4,298 PD cases and 5,512 controls of Asian ancestry. We showed that GBA1 and SMPD1 were significantly associated with PD risk, with replication in a further 5,585 PD cases and 5,642 controls. We further refined variant classification using in vitro assays and showed that SMPD1 variants with reduced enzymatic activity display the strongest association (<44% activity, odds ratio (OR) = 2.24, P = 1.25 × 10−15) with PD risk. Moreover, 80.5% of SMPD1 carriers harbored the Asian-specific p.Pro332Arg variant (OR = 2.16; P = 4.47 × 10−8). Our findings highlight the utility of performing exome sequencing in diverse ancestry groups to identify rare protein-altering variants in genes previously unassociated with disease. Using whole-exome sequencing followed by in vitro enzymatic assays, Chew, Liu, Li, Chung et al. identified rare protein-coding variants in GBA1 and SMPD1 that significantly associate with risk of Parkinson’s disease across cohorts of Asian descent.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 2","pages":"205-218"},"PeriodicalIF":17.0,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00760-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142690165","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 : 2024-11-20DOI: 10.1038/s43587-024-00759-0
Jill A. Kreiling
A study by Mao, Zhang, Zhuang and colleagues defines a specific class of endogenous retroviruses that are upregulated with age and in cellular senescence by the stress-induced transcription factor ATF3. The expression of endogenous retroviral elements has implications for the development of inflammation that may drive the onset of aging pathologies.
{"title":"Dysregulation of endogenous retroviruses triggers aging and senescence","authors":"Jill A. Kreiling","doi":"10.1038/s43587-024-00759-0","DOIUrl":"10.1038/s43587-024-00759-0","url":null,"abstract":"A study by Mao, Zhang, Zhuang and colleagues defines a specific class of endogenous retroviruses that are upregulated with age and in cellular senescence by the stress-induced transcription factor ATF3. The expression of endogenous retroviral elements has implications for the development of inflammation that may drive the onset of aging pathologies.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"4 12","pages":"1670-1672"},"PeriodicalIF":17.0,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684083","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 : 2024-11-20DOI: 10.1038/s43587-024-00765-2
Loss of nicotinamide adenine dinucleotide (NAD+) with aging may contribute to chronic obstructive pulmonary disease (COPD). In a randomized controlled trial, we show that six weeks of boosting NAD+ levels in patients with COPD reduces airway inflammation and might affect biological aging, possibly through a reduction in cellular senescence.
{"title":"Boosting NAD+ in patients with COPD reduces airway inflammation","authors":"","doi":"10.1038/s43587-024-00765-2","DOIUrl":"10.1038/s43587-024-00765-2","url":null,"abstract":"Loss of nicotinamide adenine dinucleotide (NAD+) with aging may contribute to chronic obstructive pulmonary disease (COPD). In a randomized controlled trial, we show that six weeks of boosting NAD+ levels in patients with COPD reduces airway inflammation and might affect biological aging, possibly through a reduction in cellular senescence.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"4 12","pages":"1676-1677"},"PeriodicalIF":17.0,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684080","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 : 2024-11-15DOI: 10.1038/s43587-024-00758-1
Kristoffer L. Norheim, Michael Ben Ezra, Indra Heckenbach, Louise Munkholm Andreasson, Lise Lotte Eriksen, Nanna Dyhre-Petersen, Mads Vargas Damgaard, Magnus Berglind, Luca Pricolo, Dayle Sampson, Ryan W. Dellinger, Asger Sverrild, Jonas T. Treebak, Sisse Bolm Ditlev, Celeste Porsbjerg, Morten Scheibye-Knudsen
Chronic obstructive pulmonary disease (COPD) is a progressive, incurable disease associated with smoking and advanced age, ranking as the third leading cause of death worldwide. DNA damage and loss of the central metabolite nicotinamide adenine dinucleotide (NAD+) may contribute to both aging and COPD, presenting a potential avenue for interventions. In this randomized, double-blind, placebo-controlled clinical trial, we treated patients with stable COPD (n = 40) with the NAD+ precursor nicotinamide riboside (NR) for 6 weeks and followed-up 12 weeks later. The primary outcome was change in sputum interleukin-8 (IL-8) from baseline to week 6. The estimated treatment difference between NR and placebo in IL-8 after 6 weeks was −52.6% (95% confidence interval (CI): −75.7% to −7.6%; P = 0.030). This effect persisted until the follow-up 12 weeks after the end of treatment (−63.7%: 95% CI −85.7% to −7.8%; P = 0.034). For secondary outcomes, NR treatment increased NAD+ levels by more than twofold in whole blood, whereas IL-6 levels in plasma remained unchanged. In exploratory analyses, treatment with NR showed indications of upregulated gene pathways related to genomic integrity in the airways and reduced epigenetic aging, possibly through a reduction in cellular senescence. These exploratory analyses need to be confirmed in future trials. ClinicalTrials.gov identifier: NCT04990869 . Drivers of physiological aging are also linked to the etiology of chronic obstructive pulmonary disease (COPD), including inflammation and senescence, both influenced by nicotinamide adenine dinucleotide (NAD+) metabolism. Norheim et al. performed a randomized controlled trial in patients with COPD, testing whether boosting NAD+ levels reduces airway inflammation.
{"title":"Effect of nicotinamide riboside on airway inflammation in COPD: a randomized, placebo-controlled trial","authors":"Kristoffer L. Norheim, Michael Ben Ezra, Indra Heckenbach, Louise Munkholm Andreasson, Lise Lotte Eriksen, Nanna Dyhre-Petersen, Mads Vargas Damgaard, Magnus Berglind, Luca Pricolo, Dayle Sampson, Ryan W. Dellinger, Asger Sverrild, Jonas T. Treebak, Sisse Bolm Ditlev, Celeste Porsbjerg, Morten Scheibye-Knudsen","doi":"10.1038/s43587-024-00758-1","DOIUrl":"10.1038/s43587-024-00758-1","url":null,"abstract":"Chronic obstructive pulmonary disease (COPD) is a progressive, incurable disease associated with smoking and advanced age, ranking as the third leading cause of death worldwide. DNA damage and loss of the central metabolite nicotinamide adenine dinucleotide (NAD+) may contribute to both aging and COPD, presenting a potential avenue for interventions. In this randomized, double-blind, placebo-controlled clinical trial, we treated patients with stable COPD (n = 40) with the NAD+ precursor nicotinamide riboside (NR) for 6 weeks and followed-up 12 weeks later. The primary outcome was change in sputum interleukin-8 (IL-8) from baseline to week 6. The estimated treatment difference between NR and placebo in IL-8 after 6 weeks was −52.6% (95% confidence interval (CI): −75.7% to −7.6%; P = 0.030). This effect persisted until the follow-up 12 weeks after the end of treatment (−63.7%: 95% CI −85.7% to −7.8%; P = 0.034). For secondary outcomes, NR treatment increased NAD+ levels by more than twofold in whole blood, whereas IL-6 levels in plasma remained unchanged. In exploratory analyses, treatment with NR showed indications of upregulated gene pathways related to genomic integrity in the airways and reduced epigenetic aging, possibly through a reduction in cellular senescence. These exploratory analyses need to be confirmed in future trials. ClinicalTrials.gov identifier: NCT04990869 . Drivers of physiological aging are also linked to the etiology of chronic obstructive pulmonary disease (COPD), including inflammation and senescence, both influenced by nicotinamide adenine dinucleotide (NAD+) metabolism. Norheim et al. performed a randomized controlled trial in patients with COPD, testing whether boosting NAD+ levels reduces airway inflammation.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"4 12","pages":"1772-1781"},"PeriodicalIF":17.0,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00758-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142640304","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 : 2024-11-14DOI: 10.1038/s43587-024-00745-6
Jian Mao, Qian Zhang, Yang Zhuang, Yinyu Zhang, Linmeng Li, Juan Pan, Lu Xu, Yuxuan Ding, Miao Wang, Yu-Sheng Cong
Reactivation of endogenous retroviruses (ERVs) has been proposed to be involved in aging. However, the mechanism of reactivation and contribution to aging and age-associated diseases is largely unexplored. In this study, we identified a subclass of ERVs reactivated in senescent cells (termed senescence-associated ERVs (SA-ERVs)). These SA-ERVs can be bidirectional transcriptionally activated by activating transcription factor 3 (ATF3) to generate double-stranded RNAs (dsRNAs), which activate the RIG-I/MDA5–MAVS signaling pathway and trigger a type I interferon (IFN-I) response in senescent fibroblasts. Consistently, we found a concerted increased expression of ATF3 and SA-ERVs and enhanced IFN-I response in several tissues of healthy aged individuals and patients with Hutchinson–Gilford progeria syndrome. Moreover, we observed an accumulation of dsRNAs derived from SA-ERVs and higher levels of IFNβ in blood of aged individuals. Together, these results reveal a previously unknown mechanism for reactivation of SA-ERVs by ATF3 and illustrate SA-ERVs as an important component and hallmark of aging. Mao, Zhang, Zhuang et al. identified a subclass of endogenous retroviruses that become activated by ATF3 in senescence, generating dsRNAs that activate RIG-I signaling and drive a type I interferon response in normal and premature aging.
{"title":"Reactivation of senescence-associated endogenous retroviruses by ATF3 drives interferon signaling in aging","authors":"Jian Mao, Qian Zhang, Yang Zhuang, Yinyu Zhang, Linmeng Li, Juan Pan, Lu Xu, Yuxuan Ding, Miao Wang, Yu-Sheng Cong","doi":"10.1038/s43587-024-00745-6","DOIUrl":"10.1038/s43587-024-00745-6","url":null,"abstract":"Reactivation of endogenous retroviruses (ERVs) has been proposed to be involved in aging. However, the mechanism of reactivation and contribution to aging and age-associated diseases is largely unexplored. In this study, we identified a subclass of ERVs reactivated in senescent cells (termed senescence-associated ERVs (SA-ERVs)). These SA-ERVs can be bidirectional transcriptionally activated by activating transcription factor 3 (ATF3) to generate double-stranded RNAs (dsRNAs), which activate the RIG-I/MDA5–MAVS signaling pathway and trigger a type I interferon (IFN-I) response in senescent fibroblasts. Consistently, we found a concerted increased expression of ATF3 and SA-ERVs and enhanced IFN-I response in several tissues of healthy aged individuals and patients with Hutchinson–Gilford progeria syndrome. Moreover, we observed an accumulation of dsRNAs derived from SA-ERVs and higher levels of IFNβ in blood of aged individuals. Together, these results reveal a previously unknown mechanism for reactivation of SA-ERVs by ATF3 and illustrate SA-ERVs as an important component and hallmark of aging. Mao, Zhang, Zhuang et al. identified a subclass of endogenous retroviruses that become activated by ATF3 in senescence, generating dsRNAs that activate RIG-I signaling and drive a type I interferon response in normal and premature aging.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"4 12","pages":"1794-1812"},"PeriodicalIF":17.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634969","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 : 2024-11-14DOI: 10.1038/s43587-024-00730-z
Ting Zhang, Yunfeng Li, Liuliu Pan, Jihui Sha, Michael Bailey, Emmanuelle Faure-Kumar, Christopher Kazu Williams, James Wohlschlegel, Shino Magaki, Chao Niu, Yoojin Lee, Yu-chyuan Su, Xinmin Li, Harry V. Vinters, Daniel H. Geschwind
Understanding the pathophysiology of neurological symptoms observed after severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection is essential to optimizing outcomes and therapeutics. To date, small sample sizes and narrow molecular profiling have limited the generalizability of findings. In this study, we profiled multiple cortical and subcortical regions in postmortem brains of patients with coronavirus disease 2019 (COVID-19) and controls with matched pulmonary pathology (total n = 42) using spatial transcriptomics, bulk gene expression and proteomics. We observed a multi-regional antiviral response without direct active SARS-CoV2 infection. We identified dysregulation of mitochondrial and synaptic pathways in deep-layer excitatory neurons and upregulation of neuroinflammation in glia, consistent across both mRNA and protein. Remarkably, these alterations overlapped substantially with changes in age-related neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease. Our work, combining multiple experimental and analytical methods, demonstrates the brain-wide impact of severe acute/subacute COVID-19, involving both cortical and subcortical regions, shedding light on potential therapeutic targets within pathways typically associated with pathological aging and neurodegeneration. Zhang et al. performed a multi-regional multi-omics study, identifying brain-wide mitochondrial and synaptic defects in neurons and glial inflammation as key mechanisms underlying central nervous system impairment in COVID-19, potentially triggering neurodegeneration.
{"title":"Brain-wide alterations revealed by spatial transcriptomics and proteomics in COVID-19 infection","authors":"Ting Zhang, Yunfeng Li, Liuliu Pan, Jihui Sha, Michael Bailey, Emmanuelle Faure-Kumar, Christopher Kazu Williams, James Wohlschlegel, Shino Magaki, Chao Niu, Yoojin Lee, Yu-chyuan Su, Xinmin Li, Harry V. Vinters, Daniel H. Geschwind","doi":"10.1038/s43587-024-00730-z","DOIUrl":"10.1038/s43587-024-00730-z","url":null,"abstract":"Understanding the pathophysiology of neurological symptoms observed after severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection is essential to optimizing outcomes and therapeutics. To date, small sample sizes and narrow molecular profiling have limited the generalizability of findings. In this study, we profiled multiple cortical and subcortical regions in postmortem brains of patients with coronavirus disease 2019 (COVID-19) and controls with matched pulmonary pathology (total n = 42) using spatial transcriptomics, bulk gene expression and proteomics. We observed a multi-regional antiviral response without direct active SARS-CoV2 infection. We identified dysregulation of mitochondrial and synaptic pathways in deep-layer excitatory neurons and upregulation of neuroinflammation in glia, consistent across both mRNA and protein. Remarkably, these alterations overlapped substantially with changes in age-related neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease. Our work, combining multiple experimental and analytical methods, demonstrates the brain-wide impact of severe acute/subacute COVID-19, involving both cortical and subcortical regions, shedding light on potential therapeutic targets within pathways typically associated with pathological aging and neurodegeneration. Zhang et al. performed a multi-regional multi-omics study, identifying brain-wide mitochondrial and synaptic defects in neurons and glial inflammation as key mechanisms underlying central nervous system impairment in COVID-19, potentially triggering neurodegeneration.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"4 11","pages":"1598-1618"},"PeriodicalIF":17.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634973","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 : 2024-11-13DOI: 10.1038/s43587-024-00755-4
Nathan S. Gasek, Pengyi Yan, Junyu Zhu, K-Raman Purushothaman, Taewan Kim, Lichao Wang, Binsheng Wang, William F. Flynn, Mingda Sun, Chun Guo, Billy Huggins, Roshanak Sharafieh, Yueying Zhou, Vojtech Parizek, Tamar Tchkonia, James L. Kirkland, Saranya P. Wyles, Ming Xu
While senescent cells have detrimental roles in several contexts, they are highly heterogeneous. p16 highly expressing senescent cells have been reported to exert beneficial functions in wound healing. Here we use Xenium spatial transcriptomics to identify a distinct p21 highly expressing senescent population induced on wounding, with a pro-inflammatory profile. We find that clearing p21 highly expressing cells expedites wound closure and is partially mediated by NF-κB inhibition, thus enhancing our understanding of the multifaceted functions of senescence in tissue remodeling. Senescent cells can exert detrimental effects, yet beneficial roles of p16 highly expressing cells have been reported in contexts such as wound healing. Enhancing our understanding of the heterogeneity of senescence in vivo, Gasek et al. identify a distinct and detrimental p21 highly expressing cell population induced upon wound healing.
{"title":"Clearance of p21 highly expressing senescent cells accelerates cutaneous wound healing","authors":"Nathan S. Gasek, Pengyi Yan, Junyu Zhu, K-Raman Purushothaman, Taewan Kim, Lichao Wang, Binsheng Wang, William F. Flynn, Mingda Sun, Chun Guo, Billy Huggins, Roshanak Sharafieh, Yueying Zhou, Vojtech Parizek, Tamar Tchkonia, James L. Kirkland, Saranya P. Wyles, Ming Xu","doi":"10.1038/s43587-024-00755-4","DOIUrl":"10.1038/s43587-024-00755-4","url":null,"abstract":"While senescent cells have detrimental roles in several contexts, they are highly heterogeneous. p16 highly expressing senescent cells have been reported to exert beneficial functions in wound healing. Here we use Xenium spatial transcriptomics to identify a distinct p21 highly expressing senescent population induced on wounding, with a pro-inflammatory profile. We find that clearing p21 highly expressing cells expedites wound closure and is partially mediated by NF-κB inhibition, thus enhancing our understanding of the multifaceted functions of senescence in tissue remodeling. Senescent cells can exert detrimental effects, yet beneficial roles of p16 highly expressing cells have been reported in contexts such as wound healing. Enhancing our understanding of the heterogeneity of senescence in vivo, Gasek et al. identify a distinct and detrimental p21 highly expressing cell population induced upon wound healing.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 1","pages":"21-27"},"PeriodicalIF":17.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634961","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 : 2024-11-12DOI: 10.1038/s43587-024-00731-y
Joseph Therriault, Shorena Janelidze, Andréa Lessa Benedet, Nicholas J. Ashton, Javier Arranz Martínez, Armand Gonzalez-Escalante, Bruna Bellaver, Daniel Alcolea, Agathe Vrillon, Helmet Karim, Michelle M. Mielke, Chang Hyung Hong, Hyun Woong Roh, José Contador, Albert Puig Pijoan, Alicia Algeciras-Schimnich, Prashanthi Vemuri, Jonathan Graff-Radford, Val J. Lowe, Thomas K. Karikari, Erin Jonaitis, Wagner Brum, Cécile Tissot, Stijn Servaes, Nesrine Rahmouni, Arthur C. Macedo, Jenna Stevenson, Jaime Fernandez-Arias, Yi-Ting Wang, Marcel S. Woo, Manuel A. Friese, Wan Lu Jia, Julien Dumurgier, Claire Hourregue, Emmanuel Cognat, Pamela Lukasewicz Ferreira, Paolo Vitali, Sterling Johnson, Tharick A. Pascoal, Serge Gauthier, Alberto Lleó, Claire Paquet, Ronald C. Petersen, David Salmon, Niklas Mattsson-Carlgren, Sebastian Palmqvist, Erik Stomrud, Douglas Galasko, Sang Joon Son, Henrik Zetterberg, Juan Fortea, Marc Suárez-Calvet, Clifford R. Jack Jr, Kaj Blennow, Oskar Hansson, Pedro Rosa-Neto
Recently approved anti-amyloid immunotherapies for Alzheimer’s disease (AD) require evidence of amyloid-β pathology from positron emission tomography (PET) or cerebrospinal fluid (CSF) before initiating treatment. Blood-based biomarkers promise to reduce the need for PET or CSF testing; however, their interpretation at the individual level and the circumstances requiring confirmatory testing are poorly understood. Individual-level interpretation of diagnostic test results requires knowledge of disease prevalence in relation to clinical presentation (clinical pretest probability). Here, in a study of 6,896 individuals evaluated from 11 cohort studies from six countries, we determined the positive and negative predictive value of five plasma biomarkers for amyloid-β pathology in cognitively impaired individuals in relation to clinical pretest probability. We observed that p-tau217 could rule in amyloid-β pathology in individuals with probable AD dementia (positive predictive value above 95%). In mild cognitive impairment, p-tau217 interpretation depended on patient age. Negative p-tau217 results could rule out amyloid-β pathology in individuals with non-AD dementia syndromes (negative predictive value between 90% and 99%). Our findings provide a framework for the individual-level interpretation of plasma biomarkers, suggesting that p-tau217 combined with clinical phenotyping can identify patients where amyloid-β pathology can be ruled in or out without the need for PET or CSF confirmatory testing. Therriault et al. provide a framework for the individual-level interpretation of plasma biomarkers by determining their positive and negative predictive values for amyloid positron emission tomography status in relation to patient age and clinical symptoms.
{"title":"Diagnosis of Alzheimer’s disease using plasma biomarkers adjusted to clinical probability","authors":"Joseph Therriault, Shorena Janelidze, Andréa Lessa Benedet, Nicholas J. Ashton, Javier Arranz Martínez, Armand Gonzalez-Escalante, Bruna Bellaver, Daniel Alcolea, Agathe Vrillon, Helmet Karim, Michelle M. Mielke, Chang Hyung Hong, Hyun Woong Roh, José Contador, Albert Puig Pijoan, Alicia Algeciras-Schimnich, Prashanthi Vemuri, Jonathan Graff-Radford, Val J. Lowe, Thomas K. Karikari, Erin Jonaitis, Wagner Brum, Cécile Tissot, Stijn Servaes, Nesrine Rahmouni, Arthur C. Macedo, Jenna Stevenson, Jaime Fernandez-Arias, Yi-Ting Wang, Marcel S. Woo, Manuel A. Friese, Wan Lu Jia, Julien Dumurgier, Claire Hourregue, Emmanuel Cognat, Pamela Lukasewicz Ferreira, Paolo Vitali, Sterling Johnson, Tharick A. Pascoal, Serge Gauthier, Alberto Lleó, Claire Paquet, Ronald C. Petersen, David Salmon, Niklas Mattsson-Carlgren, Sebastian Palmqvist, Erik Stomrud, Douglas Galasko, Sang Joon Son, Henrik Zetterberg, Juan Fortea, Marc Suárez-Calvet, Clifford R. Jack Jr, Kaj Blennow, Oskar Hansson, Pedro Rosa-Neto","doi":"10.1038/s43587-024-00731-y","DOIUrl":"10.1038/s43587-024-00731-y","url":null,"abstract":"Recently approved anti-amyloid immunotherapies for Alzheimer’s disease (AD) require evidence of amyloid-β pathology from positron emission tomography (PET) or cerebrospinal fluid (CSF) before initiating treatment. Blood-based biomarkers promise to reduce the need for PET or CSF testing; however, their interpretation at the individual level and the circumstances requiring confirmatory testing are poorly understood. Individual-level interpretation of diagnostic test results requires knowledge of disease prevalence in relation to clinical presentation (clinical pretest probability). Here, in a study of 6,896 individuals evaluated from 11 cohort studies from six countries, we determined the positive and negative predictive value of five plasma biomarkers for amyloid-β pathology in cognitively impaired individuals in relation to clinical pretest probability. We observed that p-tau217 could rule in amyloid-β pathology in individuals with probable AD dementia (positive predictive value above 95%). In mild cognitive impairment, p-tau217 interpretation depended on patient age. Negative p-tau217 results could rule out amyloid-β pathology in individuals with non-AD dementia syndromes (negative predictive value between 90% and 99%). Our findings provide a framework for the individual-level interpretation of plasma biomarkers, suggesting that p-tau217 combined with clinical phenotyping can identify patients where amyloid-β pathology can be ruled in or out without the need for PET or CSF confirmatory testing. Therriault et al. provide a framework for the individual-level interpretation of plasma biomarkers by determining their positive and negative predictive values for amyloid positron emission tomography status in relation to patient age and clinical symptoms.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"4 11","pages":"1529-1537"},"PeriodicalIF":17.0,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00731-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142635093","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 : 2024-11-11DOI: 10.1038/s43587-024-00743-8
Carey E. Lyons, Jean Pierre Pallais, Seth McGonigle, Rachel P. Mansk, Charles W. Collinge, Matthew J. Yousefzadeh, Darren J. Baker, Patricia R. Schrank, Jesse W. Williams, Laura J. Niedernhofer, Jan M. van Deursen, Maria Razzoli, Alessandro Bartolomucci
Life stress can shorten lifespan and increase risk for aging-related diseases, but the biology underlying this phenomenon remains unclear. Here we assessed the effect of chronic stress on cellular senescence—a hallmark of aging. Exposure to restraint stress, a psychological non-social stress model, increased p21Cip1 exclusively in the brains of male, but not female mice, and in a p16Ink4a-independent manner. Conversely, exposure to chronic subordination stress (only males were tested) increased key senescent cell markers in peripheral blood mononuclear cells, adipose tissue and brain, in a p16Ink4a-dependent manner. p16Ink4a-positive cells in the brain of chronic subordination stress-exposed mice were primarily hippocampal and cortical neurons with evidence of DNA damage that could be reduced by p16Ink4a cell clearance. Clearance of p16Ink4a-positive cells was not sufficient to ameliorate the adverse effects of social stress on measured metrics of healthspan. Overall, our findings indicate that social stress induces an organ-specific and p16Ink4a-dependent accumulation of senescent cells, illuminating a fundamental way by which the social environment can contribute to aging. Exploring the molecular consequences of exposing mice to social stress, Lyons et al. identify that hippocampal and cortical neurons acquire features of senescence, identifying a mechanism through which the social environment may contribute to aging.
{"title":"Chronic social stress induces p16-mediated senescent cell accumulation in mice","authors":"Carey E. Lyons, Jean Pierre Pallais, Seth McGonigle, Rachel P. Mansk, Charles W. Collinge, Matthew J. Yousefzadeh, Darren J. Baker, Patricia R. Schrank, Jesse W. Williams, Laura J. Niedernhofer, Jan M. van Deursen, Maria Razzoli, Alessandro Bartolomucci","doi":"10.1038/s43587-024-00743-8","DOIUrl":"10.1038/s43587-024-00743-8","url":null,"abstract":"Life stress can shorten lifespan and increase risk for aging-related diseases, but the biology underlying this phenomenon remains unclear. Here we assessed the effect of chronic stress on cellular senescence—a hallmark of aging. Exposure to restraint stress, a psychological non-social stress model, increased p21Cip1 exclusively in the brains of male, but not female mice, and in a p16Ink4a-independent manner. Conversely, exposure to chronic subordination stress (only males were tested) increased key senescent cell markers in peripheral blood mononuclear cells, adipose tissue and brain, in a p16Ink4a-dependent manner. p16Ink4a-positive cells in the brain of chronic subordination stress-exposed mice were primarily hippocampal and cortical neurons with evidence of DNA damage that could be reduced by p16Ink4a cell clearance. Clearance of p16Ink4a-positive cells was not sufficient to ameliorate the adverse effects of social stress on measured metrics of healthspan. Overall, our findings indicate that social stress induces an organ-specific and p16Ink4a-dependent accumulation of senescent cells, illuminating a fundamental way by which the social environment can contribute to aging. Exploring the molecular consequences of exposing mice to social stress, Lyons et al. identify that hippocampal and cortical neurons acquire features of senescence, identifying a mechanism through which the social environment may contribute to aging.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":"5 1","pages":"48-64"},"PeriodicalIF":17.0,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142634960","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}
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