Pub Date : 2024-07-08DOI: 10.1038/s43587-024-00664-6
Daniel Thiele, Nicole L. La Gruta
A study demonstrates the efficacy of immune-checkpoint blockade in prolonging survival and boosting CD8+ T cell function in aged mice after pathogen exposure. These findings highlight how aging-related immune changes may lead to augmented CD8+ T cell responses to checkpoint blockade, which results in improved protection from infection. The findings also highlight the importance of understanding immune aging in future efforts to target immunotherapies to older adults.
一项研究表明，免疫检查点阻断剂能有效延长病原体暴露后老年小鼠的存活时间并增强CD8+ T细胞的功能。这些发现强调了与衰老相关的免疫变化如何可能导致 CD8+ T 细胞对检查点阻断的反应增强，从而改善对感染的保护。这些发现还强调了了解免疫衰老对未来针对老年人的免疫疗法的重要性。
{"title":"Immune-checkpoint blockade protects aged mice from infection","authors":"Daniel Thiele, Nicole L. La Gruta","doi":"10.1038/s43587-024-00664-6","DOIUrl":"10.1038/s43587-024-00664-6","url":null,"abstract":"A study demonstrates the efficacy of immune-checkpoint blockade in prolonging survival and boosting CD8+ T cell function in aged mice after pathogen exposure. These findings highlight how aging-related immune changes may lead to augmented CD8+ T cell responses to checkpoint blockade, which results in improved protection from infection. The findings also highlight the importance of understanding immune aging in future efforts to target immunotherapies to older adults.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141560658","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 : 2024-07-02DOI: 10.1038/s43587-024-00665-5
A deep learning model accurately predicts 1-year mortality for the entire Finnish population. Despite robust performance and potential as a digital marker of aging, fairness analyses reveal prediction disparities, so integration into public health should be approached cautiously.
{"title":"A deep learning model accurately predicts 1-year mortality but at the risk of unfairness","authors":"","doi":"10.1038/s43587-024-00665-5","DOIUrl":"10.1038/s43587-024-00665-5","url":null,"abstract":"A deep learning model accurately predicts 1-year mortality for the entire Finnish population. Despite robust performance and potential as a digital marker of aging, fairness analyses reveal prediction disparities, so integration into public health should be approached cautiously.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494655","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 : 2024-07-01DOI: 10.1038/s43587-024-00663-7
Sara Zumerle, Miles Sarill, Miriam Saponaro, Manuel Colucci, Liliana Contu, Edoardo Lazzarini, Roberta Sartori, Camilla Pezzini, Anna Rinaldi, Anna Scanu, Jacopo Sgrignani, Patrizia Locatelli, Marianna Sabbadin, Aurora Valdata, Daniela Brina, Isabella Giacomini, Beatrice Rizzo, Alessandra Pierantoni, Saman Sharifi, Silvia Bressan, Claudia Altomare, Yulia Goshovska, Chiara Giraudo, Roberto Luisetto, Luca Iaccarino, Cristina Torcasio, Simone Mosole, Emiliano Pasquini, Andrea Rinaldi, Laura Pellegrini, Gregorio Peron, Matteo Fassan, Stefano Masiero, Andrea Maria Giori, Stefano Dall’Acqua, Johan Auwerx, Pietro Cippà, Andrea Cavalli, Marco Bolis, Marco Sandri, Lucio Barile, Monica Montopoli, Andrea Alimonti
Accumulating senescent cells within tissues contribute to the progression of aging and age-related diseases. Botanical extracts, rich in phytoconstituents, present a useful resource for discovering therapies that could target senescence and thus improve healthspan. Here, we show that daily oral administration of a standardized extract of Salvia haenkei (Haenkenium (HK)) extended lifespan and healthspan of naturally aged mice. HK treatment inhibited age-induced inflammation, fibrosis and senescence markers across several tissues, as well as increased muscle strength and fur thickness compared with age-matched controls. We also found that HK treatment reduced acutely induced senescence by the chemotherapeutic agent doxorubicin, using p16LUC reporter mice. We profiled the constituent components of HK by mass spectrometry, and identified luteolin—the most concentrated flavonoid in HK—as a senomorphic compound. Mechanistically, by performing surface plasmon resonance and in situ proximity ligation assay, we found that luteolin disrupted the p16–CDK6 interaction. This work demonstrates that administration of HK promotes longevity in mice, possibly by modulating cellular senescence and by disrupting the p16–CDK6 interaction. Botanical extracts offer a valuable resource for identifying therapies. Zumerle, Sarill et al. show that a standardized extract of Salvia haenkei extends lifespan and healthspan in naturally aged mice by modulating inflammation and cellular senescence, and identify the constituent component luteolin as a senomorphic that disrupts the p16–CDK6 interaction.
组织内衰老细胞的积累会导致衰老和与年龄有关的疾病。植物萃取物富含植物成分，是发现针对衰老从而改善健康寿命的疗法的有用资源。在这里，我们发现，每天口服丹参的标准化提取物（Haenkenium (HK)）可延长自然衰老小鼠的寿命和健康寿命。与年龄匹配的对照组相比，海金沙能抑制年龄诱导的炎症、纤维化和多个组织的衰老标志物，并增加肌肉力量和皮毛厚度。我们还利用 p16LUC 报告小鼠发现，HK 治疗可减少化疗药物多柔比星急性诱导的衰老。我们通过质谱分析了 HK 的组成成分，并确定了木犀草素（HK 中含量最高的黄酮类化合物）是一种衰老化合物。从机理上讲，通过表面等离子体共振和原位近接实验，我们发现木犀草素破坏了 p16-CDK6 的相互作用。这项研究表明，服用 HK 可促进小鼠的长寿，这可能是通过调节细胞衰老和破坏 p16-CDK6 的相互作用实现的。
{"title":"Targeting senescence induced by age or chemotherapy with a polyphenol-rich natural extract improves longevity and healthspan in mice","authors":"Sara Zumerle, Miles Sarill, Miriam Saponaro, Manuel Colucci, Liliana Contu, Edoardo Lazzarini, Roberta Sartori, Camilla Pezzini, Anna Rinaldi, Anna Scanu, Jacopo Sgrignani, Patrizia Locatelli, Marianna Sabbadin, Aurora Valdata, Daniela Brina, Isabella Giacomini, Beatrice Rizzo, Alessandra Pierantoni, Saman Sharifi, Silvia Bressan, Claudia Altomare, Yulia Goshovska, Chiara Giraudo, Roberto Luisetto, Luca Iaccarino, Cristina Torcasio, Simone Mosole, Emiliano Pasquini, Andrea Rinaldi, Laura Pellegrini, Gregorio Peron, Matteo Fassan, Stefano Masiero, Andrea Maria Giori, Stefano Dall’Acqua, Johan Auwerx, Pietro Cippà, Andrea Cavalli, Marco Bolis, Marco Sandri, Lucio Barile, Monica Montopoli, Andrea Alimonti","doi":"10.1038/s43587-024-00663-7","DOIUrl":"10.1038/s43587-024-00663-7","url":null,"abstract":"Accumulating senescent cells within tissues contribute to the progression of aging and age-related diseases. Botanical extracts, rich in phytoconstituents, present a useful resource for discovering therapies that could target senescence and thus improve healthspan. Here, we show that daily oral administration of a standardized extract of Salvia haenkei (Haenkenium (HK)) extended lifespan and healthspan of naturally aged mice. HK treatment inhibited age-induced inflammation, fibrosis and senescence markers across several tissues, as well as increased muscle strength and fur thickness compared with age-matched controls. We also found that HK treatment reduced acutely induced senescence by the chemotherapeutic agent doxorubicin, using p16LUC reporter mice. We profiled the constituent components of HK by mass spectrometry, and identified luteolin—the most concentrated flavonoid in HK—as a senomorphic compound. Mechanistically, by performing surface plasmon resonance and in situ proximity ligation assay, we found that luteolin disrupted the p16–CDK6 interaction. This work demonstrates that administration of HK promotes longevity in mice, possibly by modulating cellular senescence and by disrupting the p16–CDK6 interaction. Botanical extracts offer a valuable resource for identifying therapies. Zumerle, Sarill et al. show that a standardized extract of Salvia haenkei extends lifespan and healthspan in naturally aged mice by modulating inflammation and cellular senescence, and identify the constituent component luteolin as a senomorphic that disrupts the p16–CDK6 interaction.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00663-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141478273","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 : 2024-06-28DOI: 10.1038/s43587-024-00662-8
Junhao Wen, Ye Ella Tian, Ioanna Skampardoni, Zhijian Yang, Yuhan Cui, Filippos Anagnostakis, Elizabeth Mamourian, Bingxin Zhao, Arthur W. Toga, Andrew Zalesky, Christos Davatzikos
Investigating the genetic underpinnings of human aging is essential for unraveling the etiology of and developing actionable therapies for chronic diseases. Here, we characterize the genetic architecture of the biological age gap (BAG; the difference between machine learning-predicted age and chronological age) across nine human organ systems in 377,028 participants of European ancestry from the UK Biobank. The BAGs were computed using cross-validated support vector machines, incorporating imaging, physical traits and physiological measures. We identify 393 genomic loci–BAG pairs (P < 5 × 10–8) linked to the brain, eye, cardiovascular, hepatic, immune, metabolic, musculoskeletal, pulmonary and renal systems. Genetic variants associated with the nine BAGs are predominantly specific to the respective organ system (organ specificity) while exerting pleiotropic links with other organ systems (interorgan cross-talk). We find that genetic correlation between the nine BAGs mirrors their phenotypic correlation. Further, a multiorgan causal network established from two-sample Mendelian randomization and latent causal variance models revealed potential causality between chronic diseases (for example, Alzheimer’s disease and diabetes), modifiable lifestyle factors (for example, sleep duration and body weight) and multiple BAGs. Our results illustrate the potential for improving human organ health via a multiorgan network, including lifestyle interventions and drug repurposing strategies. Using machine learning techniques applied to multimodal UK Biobank data, Wen et al. characterize the genetic basis of the biological age gaps of individual organs, uncovering interorgan cross-talk and links between chronic diseases, lifestyle factors and biological age gaps.
研究人类衰老的遗传基础对于揭示慢性疾病的病因和开发可行的疗法至关重要。在这里，我们描述了英国生物库中 377,028 名具有欧洲血统的参与者的九个人体器官系统的生物年龄差距（BAG，即机器学习预测年龄与计时年龄之间的差异）的遗传结构。BAG 是通过交叉验证的支持向量机计算得出的，并结合了成像、身体特征和生理指标。我们确定了与大脑、眼睛、心血管、肝脏、免疫、新陈代谢、肌肉骨骼、肺部和肾脏系统相关的 393 个基因组位点-BAG 对（P -8）。与这九个 BAG 相关的基因变异主要针对各自的器官系统（器官特异性），同时与其他器官系统存在多效应联系（器官间交叉作用）。我们发现，九个 BAG 之间的遗传相关性反映了它们的表型相关性。此外，通过双样本孟德尔随机化和潜在因果方差模型建立的多器官因果网络揭示了慢性疾病（如阿尔茨海默病和糖尿病）、可改变的生活方式因素（如睡眠时间和体重）和多个 BAG 之间的潜在因果关系。我们的研究结果说明了通过多器官网络（包括生活方式干预和药物再利用策略）改善人体器官健康的潜力。
{"title":"The genetic architecture of biological age in nine human organ systems","authors":"Junhao Wen, Ye Ella Tian, Ioanna Skampardoni, Zhijian Yang, Yuhan Cui, Filippos Anagnostakis, Elizabeth Mamourian, Bingxin Zhao, Arthur W. Toga, Andrew Zalesky, Christos Davatzikos","doi":"10.1038/s43587-024-00662-8","DOIUrl":"10.1038/s43587-024-00662-8","url":null,"abstract":"Investigating the genetic underpinnings of human aging is essential for unraveling the etiology of and developing actionable therapies for chronic diseases. Here, we characterize the genetic architecture of the biological age gap (BAG; the difference between machine learning-predicted age and chronological age) across nine human organ systems in 377,028 participants of European ancestry from the UK Biobank. The BAGs were computed using cross-validated support vector machines, incorporating imaging, physical traits and physiological measures. We identify 393 genomic loci–BAG pairs (P < 5 × 10–8) linked to the brain, eye, cardiovascular, hepatic, immune, metabolic, musculoskeletal, pulmonary and renal systems. Genetic variants associated with the nine BAGs are predominantly specific to the respective organ system (organ specificity) while exerting pleiotropic links with other organ systems (interorgan cross-talk). We find that genetic correlation between the nine BAGs mirrors their phenotypic correlation. Further, a multiorgan causal network established from two-sample Mendelian randomization and latent causal variance models revealed potential causality between chronic diseases (for example, Alzheimer’s disease and diabetes), modifiable lifestyle factors (for example, sleep duration and body weight) and multiple BAGs. Our results illustrate the potential for improving human organ health via a multiorgan network, including lifestyle interventions and drug repurposing strategies. Using machine learning techniques applied to multimodal UK Biobank data, Wen et al. characterize the genetic basis of the biological age gaps of individual organs, uncovering interorgan cross-talk and links between chronic diseases, lifestyle factors and biological age gaps.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474153","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 : 2024-06-28DOI: 10.1038/s43587-024-00666-4
Natalia Gomes Gonçalves, Leandro Teixeira Cacau, Naomi Vidal Ferreira, Paulo Andrade Lotufo, Alessandra Carvalho Goulart, Maria Carmen Viana, Sandhi Maria Barreto, Isabela Martins Bensenor, Dirce Maria Marchioni, Claudia Kimie Suemoto
The EAT-Lancet Commission proposed a planetary health diet to improve human health within planetary boundaries; however, little is known about the association between adherence to this diet and cognitive decline. We used data from three waves of the Brazilian Longitudinal Study of Adult Health to evaluate the association between the planetary health diet and cognitive decline using linear mixed-effects models. Here we show that in 11,737 participants (mean (s.d.) age 51.6 (9.0) years, 54% women and 53% white), higher adherence to the planetary health diet was associated with slower memory decline (P = 0.046) and that income was a modifier in this association (P < 0.001). Adherence to the planetary health diet was associated with slower decline of memory (P = 0.040) and global cognition (P = 0.009) in high-income participants. No association was found among low-income participants. The results of our study highlight that the promotion of healthy dietary patterns should take into consideration income barriers as well as differences in dietary habits to achieve high adherence.
{"title":"Adherence to the planetary health diet and cognitive decline: findings from the ELSA-Brasil study.","authors":"Natalia Gomes Gonçalves, Leandro Teixeira Cacau, Naomi Vidal Ferreira, Paulo Andrade Lotufo, Alessandra Carvalho Goulart, Maria Carmen Viana, Sandhi Maria Barreto, Isabela Martins Bensenor, Dirce Maria Marchioni, Claudia Kimie Suemoto","doi":"10.1038/s43587-024-00666-4","DOIUrl":"10.1038/s43587-024-00666-4","url":null,"abstract":"<p><p>The EAT-Lancet Commission proposed a planetary health diet to improve human health within planetary boundaries; however, little is known about the association between adherence to this diet and cognitive decline. We used data from three waves of the Brazilian Longitudinal Study of Adult Health to evaluate the association between the planetary health diet and cognitive decline using linear mixed-effects models. Here we show that in 11,737 participants (mean (s.d.) age 51.6 (9.0) years, 54% women and 53% white), higher adherence to the planetary health diet was associated with slower memory decline (P = 0.046) and that income was a modifier in this association (P < 0.001). Adherence to the planetary health diet was associated with slower decline of memory (P = 0.040) and global cognition (P = 0.009) in high-income participants. No association was found among low-income participants. The results of our study highlight that the promotion of healthy dietary patterns should take into consideration income barriers as well as differences in dietary habits to achieve high adherence.</p>","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141474152","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 : 2024-06-26DOI: 10.1038/s43587-024-00654-8
Older age is associated with metabolic stress and increases the risk of degeneration of organs that maintain metabolic homeostasis, including the liver. We discovered that aging promotes ferroptosis in hepatocytes, that ferroptotic stress is generally increased in degenerating organs, and that reducing ferroptosis reverses aging-related metabolic dysfunction and liver damage.
{"title":"Ferroptotic stress drives liver aging and metabolic dysfunction","authors":"","doi":"10.1038/s43587-024-00654-8","DOIUrl":"10.1038/s43587-024-00654-8","url":null,"abstract":"Older age is associated with metabolic stress and increases the risk of degeneration of organs that maintain metabolic homeostasis, including the liver. We discovered that aging promotes ferroptosis in hepatocytes, that ferroptotic stress is generally increased in degenerating organs, and that reducing ferroptosis reverses aging-related metabolic dysfunction and liver damage.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141461445","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 : 2024-06-25DOI: 10.1038/s43587-024-00652-w
Kuo Du, Liuyang Wang, Ji Hye Jun, Rajesh K. Dutta, Raquel Maeso-Díaz, Seh Hoon Oh, Dennis C. Ko, Anna Mae Diehl
Susceptibility to the biological consequences of aging varies among organs and individuals. We analyzed hepatocyte transcriptomes of healthy young and aged male mice to generate an aging hepatocyte gene signature, used it to deconvolute transcriptomic data from humans and mice with metabolic dysfunction-associated liver disease, validated findings with functional studies in mice and applied the signature to transcriptomic data from other organs to determine whether aging-sensitive degenerative mechanisms are conserved. We discovered that the signature enriches in diseased livers in parallel with degeneration. It is also enriched in failing human hearts, diseased kidneys and pancreatic islets from individuals with diabetes. The signature includes genes that control ferroptosis. Aged mice develop more hepatocyte ferroptosis and liver degeneration than young mice when fed diets that induce metabolic stress. Inhibiting ferroptosis shifts the liver transcriptome of old mice toward that of young mice and reverses aging-exacerbated liver damage, identifying ferroptosis as a tractable, conserved mechanism for aging-related tissue degeneration. The mechanisms underlying susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD) in aging are incompletely understood. Here the authors show that an aging hepatocyte gene signature is enriched in MASLD liver tissue and contains ferroptosis genes. Experiments in mice show that metabolic stress increases ferroptosis in liver tissue in old compared to young animals and that blocking ferroptosis in old animals reduces the susceptibility to metabolic stress.
{"title":"Aging promotes metabolic dysfunction-associated steatotic liver disease by inducing ferroptotic stress","authors":"Kuo Du, Liuyang Wang, Ji Hye Jun, Rajesh K. Dutta, Raquel Maeso-Díaz, Seh Hoon Oh, Dennis C. Ko, Anna Mae Diehl","doi":"10.1038/s43587-024-00652-w","DOIUrl":"10.1038/s43587-024-00652-w","url":null,"abstract":"Susceptibility to the biological consequences of aging varies among organs and individuals. We analyzed hepatocyte transcriptomes of healthy young and aged male mice to generate an aging hepatocyte gene signature, used it to deconvolute transcriptomic data from humans and mice with metabolic dysfunction-associated liver disease, validated findings with functional studies in mice and applied the signature to transcriptomic data from other organs to determine whether aging-sensitive degenerative mechanisms are conserved. We discovered that the signature enriches in diseased livers in parallel with degeneration. It is also enriched in failing human hearts, diseased kidneys and pancreatic islets from individuals with diabetes. The signature includes genes that control ferroptosis. Aged mice develop more hepatocyte ferroptosis and liver degeneration than young mice when fed diets that induce metabolic stress. Inhibiting ferroptosis shifts the liver transcriptome of old mice toward that of young mice and reverses aging-exacerbated liver damage, identifying ferroptosis as a tractable, conserved mechanism for aging-related tissue degeneration. The mechanisms underlying susceptibility to metabolic dysfunction-associated steatotic liver disease (MASLD) in aging are incompletely understood. Here the authors show that an aging hepatocyte gene signature is enriched in MASLD liver tissue and contains ferroptosis genes. Experiments in mice show that metabolic stress increases ferroptosis in liver tissue in old compared to young animals and that blocking ferroptosis in old animals reduces the susceptibility to metabolic stress.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141452543","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 : 2024-06-25DOI: 10.1038/s43587-024-00644-w
Beatrice Dallan, Davide Proietto, Martina De Laurentis, Eleonora Gallerani, Mara Martino, Sara Ghisellini, Amedeo Zurlo, Stefano Volpato, Benedetta Govoni, Michela Borghesi, Valentina Albanese, Victor Appay, Stefano Bonnini, Sian Llewellyn-Lacey, Salvatore Pacifico, Laura Grumiro, Martina Brandolini, Simona Semprini, Vittorio Sambri, Kristin Ladell, Helen M. Parry, Paul A. H. Moss, David A. Price, RIV Study Group, Antonella Caputo, Riccardo Gavioli, Francesco Nicoli
Adenoviral and mRNA vaccines encoding the viral spike (S) protein have been deployed globally to contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Older individuals are particularly vulnerable to severe infection, probably reflecting age-related changes in the immune system, which can also compromise vaccine efficacy. It is nonetheless unclear to what extent different vaccine platforms are impacted by immunosenescence. Here, we evaluated S protein-specific immune responses elicited by vaccination with two doses of BNT162b2 or ChAdOx1-S and subsequently boosted with a single dose of BNT162b2 or mRNA-1273, comparing age-stratified participants with no evidence of previous infection with SARS-CoV-2. We found that aging profoundly compromised S protein-specific IgG titers and further limited S protein-specific CD4+ and CD8+ T cell immunity as a probable function of progressive erosion of the naive lymphocyte pool in individuals vaccinated initially with BNT162b2. Our results demonstrate that primary vaccination with ChAdOx1-S and subsequent boosting with BNT162b2 or mRNA-1273 promotes sustained immunological memory in older adults and potentially confers optimal protection against coronavirus disease 2019. Age-related immune dysfunction can compromise immune responses to infection and vaccine efficacy. Across two cohorts, Dallan et al. demonstrate that protective immunity against severe acute respiratory syndrome coronavirus is optimally maintained in older adults after primary adenoviral immunization (ChAdOx1-S) and subsequent mRNA vaccine boosting (BNT162b2 or mRNA-1273).
编码病毒尖峰（S）蛋白的腺病毒疫苗和 mRNA 疫苗已在全球范围内用于遏制严重急性呼吸系统综合征冠状病毒 2（SARS-CoV-2）。老年人特别容易受到严重感染，这可能反映了与年龄有关的免疫系统变化，这种变化也会影响疫苗的效力。然而，目前还不清楚不同的疫苗平台在多大程度上会受到免疫衰老的影响。在这里，我们评估了接种两剂 BNT162b2 或 ChAdOx1-S 疫苗后，再接种一剂 BNT162b2 或 mRNA-1273 疫苗所引起的 S 蛋白特异性免疫反应，并与既往未感染过 SARS-CoV-2 的年龄分层参与者进行了比较。我们发现，老龄化严重影响了 S 蛋白特异性 IgG 滴度，并进一步限制了 S 蛋白特异性 CD4+ 和 CD8+ T 细胞免疫力，这可能是最初接种 BNT162b2 的个体的幼稚淋巴细胞池逐渐受到侵蚀的结果。我们的研究结果表明，用 ChAdOx1-S 进行初次接种，随后再用 BNT162b2 或 mRNA-1273 进行强化接种，可促进老年人的持续免疫记忆，并有可能在 2019 年冠状病毒疾病面前获得最佳保护。
{"title":"Age differentially impacts adaptive immune responses induced by adenoviral versus mRNA vaccines against COVID-19","authors":"Beatrice Dallan, Davide Proietto, Martina De Laurentis, Eleonora Gallerani, Mara Martino, Sara Ghisellini, Amedeo Zurlo, Stefano Volpato, Benedetta Govoni, Michela Borghesi, Valentina Albanese, Victor Appay, Stefano Bonnini, Sian Llewellyn-Lacey, Salvatore Pacifico, Laura Grumiro, Martina Brandolini, Simona Semprini, Vittorio Sambri, Kristin Ladell, Helen M. Parry, Paul A. H. Moss, David A. Price, RIV Study Group, Antonella Caputo, Riccardo Gavioli, Francesco Nicoli","doi":"10.1038/s43587-024-00644-w","DOIUrl":"10.1038/s43587-024-00644-w","url":null,"abstract":"Adenoviral and mRNA vaccines encoding the viral spike (S) protein have been deployed globally to contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Older individuals are particularly vulnerable to severe infection, probably reflecting age-related changes in the immune system, which can also compromise vaccine efficacy. It is nonetheless unclear to what extent different vaccine platforms are impacted by immunosenescence. Here, we evaluated S protein-specific immune responses elicited by vaccination with two doses of BNT162b2 or ChAdOx1-S and subsequently boosted with a single dose of BNT162b2 or mRNA-1273, comparing age-stratified participants with no evidence of previous infection with SARS-CoV-2. We found that aging profoundly compromised S protein-specific IgG titers and further limited S protein-specific CD4+ and CD8+ T cell immunity as a probable function of progressive erosion of the naive lymphocyte pool in individuals vaccinated initially with BNT162b2. Our results demonstrate that primary vaccination with ChAdOx1-S and subsequent boosting with BNT162b2 or mRNA-1273 promotes sustained immunological memory in older adults and potentially confers optimal protection against coronavirus disease 2019. Age-related immune dysfunction can compromise immune responses to infection and vaccine efficacy. Across two cohorts, Dallan et al. demonstrate that protective immunity against severe acute respiratory syndrome coronavirus is optimally maintained in older adults after primary adenoviral immunization (ChAdOx1-S) and subsequent mRNA vaccine boosting (BNT162b2 or mRNA-1273).","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141452542","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 : 2024-06-24DOI: 10.1038/s43587-024-00657-5
Andrius Vabalas, Tuomo Hartonen, Pekka Vartiainen, Sakari Jukarainen, Essi Viippola, Rodosthenis S. Rodosthenous, Aoxing Liu, Sara Hägg, Markus Perola, Andrea Ganna
Short-term mortality risk, which is indicative of individual frailty, serves as a marker for aging. Previous age clocks focused on predicting either chronological age or longer-term mortality. Aging clocks predicting short-term mortality are lacking and their algorithmic fairness remains unexamined. We developed a deep learning model to predict 1-year mortality using nationwide longitudinal data from the Finnish population (FinRegistry; n = 5.4 million), incorporating more than 8,000 features spanning up to 50 years. We achieved an area under the curve (AUC) of 0.944, outperforming a baseline model that included only age and sex (AUC = 0.897). The model generalized well to different causes of death (AUC > 0.800 for 45 of 50 causes), including coronavirus disease 2019, which was absent in the training data. Performance varied among demographics, with young females exhibiting the best and older males the worst results. Extensive prediction fairness analyses highlighted disparities among disadvantaged groups, posing challenges to equitable integration into public health interventions. Our model accurately identified short-term mortality risk, potentially serving as a population-wide aging marker. Here the authors show that deep learning accurately predicts one-year mortality using nationwide Finnish data. Despite robust performance and potential as an aging marker, fairness analyses reveal prediction disparities, urging cautious integration into public health.
{"title":"Deep learning-based prediction of one-year mortality in Finland is an accurate but unfair aging marker","authors":"Andrius Vabalas, Tuomo Hartonen, Pekka Vartiainen, Sakari Jukarainen, Essi Viippola, Rodosthenis S. Rodosthenous, Aoxing Liu, Sara Hägg, Markus Perola, Andrea Ganna","doi":"10.1038/s43587-024-00657-5","DOIUrl":"10.1038/s43587-024-00657-5","url":null,"abstract":"Short-term mortality risk, which is indicative of individual frailty, serves as a marker for aging. Previous age clocks focused on predicting either chronological age or longer-term mortality. Aging clocks predicting short-term mortality are lacking and their algorithmic fairness remains unexamined. We developed a deep learning model to predict 1-year mortality using nationwide longitudinal data from the Finnish population (FinRegistry; n = 5.4 million), incorporating more than 8,000 features spanning up to 50 years. We achieved an area under the curve (AUC) of 0.944, outperforming a baseline model that included only age and sex (AUC = 0.897). The model generalized well to different causes of death (AUC > 0.800 for 45 of 50 causes), including coronavirus disease 2019, which was absent in the training data. Performance varied among demographics, with young females exhibiting the best and older males the worst results. Extensive prediction fairness analyses highlighted disparities among disadvantaged groups, posing challenges to equitable integration into public health interventions. Our model accurately identified short-term mortality risk, potentially serving as a population-wide aging marker. Here the authors show that deep learning accurately predicts one-year mortality using nationwide Finnish data. Despite robust performance and potential as an aging marker, fairness analyses reveal prediction disparities, urging cautious integration into public health.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00657-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141447922","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 : 2024-06-21DOI: 10.1038/s43587-024-00640-0
Francesco Limone, Daniel A. Mordes, Alexander Couto, Brian J. Joseph, Jana M. Mitchell, Martine Therrien, Sulagna Dia Ghosh, Daniel Meyer, Yingying Zhang, Melissa Goldman, Laura Bortolin, Inma Cobos, Beth Stevens, Steven A. McCarroll, Irena Kadiu, Aaron Burberry, Olli Pietiläinen, Kevin Eggan
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls. In both patients and unaffected individuals, we found significantly higher expression of ALS risk genes in THY1+ ETNs, regardless of diagnosis. In patients, this was accompanied by the induction of genes involved in protein homeostasis and stress responses that were significantly induced in a wide collection of ETNs. Examination of oligodendroglial and microglial nuclei revealed patient-specific downregulation of myelinating genes in oligodendrocytes and upregulation of an endolysosomal reactive state in microglia. Our findings suggest that selective vulnerability of extratelencephalic neurons is partly connected to their intrinsic molecular properties sensitizing them to genetics and mechanisms of degeneration. Using single-nucleus RNA sequencing data from patients with sporadic amyotrophic lateral sclerosis (ALS) cortices, the authors find that higher expression of ALS risk genes is accompanied by upregulation of stress responses in groups of extratelencephalic neurons. Analyses of glial nuclei revealed a downregulation of myelination genes in oligodendrocytes and upregulation of reactive state genes in microglia.
肌萎缩性脊髓侧索硬化症（ALS）是一种神经退行性疾病，其特征是进行性运动功能丧失，这与脑外神经元/贝茨细胞（ETNs）的退化有关。这些神经元受到选择性影响的原因仍不清楚。在此，为了了解可能使 ETNs 对 ALS 敏感的独特分子特性，我们对来自患者和对照组大脑皮层的 79,169 个单核细胞进行了 RNA 测序。在患者和未受影响的个体中，我们发现无论诊断与否，THY1+ ETNs 中的 ALS 风险基因表达量都明显较高。在患者中，与蛋白质稳态和应激反应相关的基因也被诱导，这些基因在大量的 ETNs 中被显著诱导。对少突胶质细胞和小胶质细胞核的检查显示，患者特有的少突胶质细胞髓鞘化基因下调，而小胶质细胞内溶酶体反应状态基因上调。我们的研究结果表明，脑外神经元的选择性易损性在一定程度上与它们的内在分子特性有关，这些特性使它们对遗传学和变性机制敏感。
{"title":"Single-nucleus sequencing reveals enriched expression of genetic risk factors in extratelencephalic neurons sensitive to degeneration in ALS","authors":"Francesco Limone, Daniel A. Mordes, Alexander Couto, Brian J. Joseph, Jana M. Mitchell, Martine Therrien, Sulagna Dia Ghosh, Daniel Meyer, Yingying Zhang, Melissa Goldman, Laura Bortolin, Inma Cobos, Beth Stevens, Steven A. McCarroll, Irena Kadiu, Aaron Burberry, Olli Pietiläinen, Kevin Eggan","doi":"10.1038/s43587-024-00640-0","DOIUrl":"10.1038/s43587-024-00640-0","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by a progressive loss of motor function linked to degenerating extratelencephalic neurons/Betz cells (ETNs). The reasons why these neurons are selectively affected remain unclear. Here, to understand the unique molecular properties that may sensitize ETNs to ALS, we performed RNA sequencing of 79,169 single nuclei from cortices of patients and controls. In both patients and unaffected individuals, we found significantly higher expression of ALS risk genes in THY1+ ETNs, regardless of diagnosis. In patients, this was accompanied by the induction of genes involved in protein homeostasis and stress responses that were significantly induced in a wide collection of ETNs. Examination of oligodendroglial and microglial nuclei revealed patient-specific downregulation of myelinating genes in oligodendrocytes and upregulation of an endolysosomal reactive state in microglia. Our findings suggest that selective vulnerability of extratelencephalic neurons is partly connected to their intrinsic molecular properties sensitizing them to genetics and mechanisms of degeneration. Using single-nucleus RNA sequencing data from patients with sporadic amyotrophic lateral sclerosis (ALS) cortices, the authors find that higher expression of ALS risk genes is accompanied by upregulation of stress responses in groups of extratelencephalic neurons. Analyses of glial nuclei revealed a downregulation of myelination genes in oligodendrocytes and upregulation of reactive state genes in microglia.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00640-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437976","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}
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