Pub Date : 2024-06-19DOI: 10.1038/s43587-024-00646-8
Sheng Fong, Kamil Pabis, Djakim Latumalea, Nomuundari Dugersuren, Maximilian Unfried, Nicholas Tolwinski, Brian Kennedy, Jan Gruber
Clocks that measure biological age should predict all-cause mortality and give rise to actionable insights to promote healthy aging. Here we applied dimensionality reduction by principal component analysis to clinical data to generate a clinical aging clock (PCAge) identifying signatures (principal components) separating healthy and unhealthy aging trajectories. We found signatures of metabolic dysregulation, cardiac and renal dysfunction and inflammation that predict unsuccessful aging, and we demonstrate that these processes can be impacted using well-established drug interventions. Furthermore, we generated a streamlined aging clock (LinAge), based directly on PCAge, which maintains equivalent predictive power but relies on substantially fewer features. Finally, we demonstrate that our approach can be tailored to individual datasets, by re-training a custom clinical clock (CALinAge), for use in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study of caloric restriction. Our analysis of CALERIE participants suggests that 2 years of mild caloric restriction significantly reduces biological age. Altogether, we demonstrate that this dimensionality reduction approach, through integrating different biological markers, can provide targets for preventative medicine and the promotion of healthy aging. Using a dimensionality reduction approach, Fong et al. generated a clinical aging clock (PCAge) that delineates healthy and unhealthy aging trajectories. They provide a streamlined version (LinAge) that maintains predictive power, and they demonstrate how the clock can be tailored to available data using the CALERIE study.
{"title":"Principal component-based clinical aging clocks identify signatures of healthy aging and targets for clinical intervention","authors":"Sheng Fong, Kamil Pabis, Djakim Latumalea, Nomuundari Dugersuren, Maximilian Unfried, Nicholas Tolwinski, Brian Kennedy, Jan Gruber","doi":"10.1038/s43587-024-00646-8","DOIUrl":"10.1038/s43587-024-00646-8","url":null,"abstract":"Clocks that measure biological age should predict all-cause mortality and give rise to actionable insights to promote healthy aging. Here we applied dimensionality reduction by principal component analysis to clinical data to generate a clinical aging clock (PCAge) identifying signatures (principal components) separating healthy and unhealthy aging trajectories. We found signatures of metabolic dysregulation, cardiac and renal dysfunction and inflammation that predict unsuccessful aging, and we demonstrate that these processes can be impacted using well-established drug interventions. Furthermore, we generated a streamlined aging clock (LinAge), based directly on PCAge, which maintains equivalent predictive power but relies on substantially fewer features. Finally, we demonstrate that our approach can be tailored to individual datasets, by re-training a custom clinical clock (CALinAge), for use in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) study of caloric restriction. Our analysis of CALERIE participants suggests that 2 years of mild caloric restriction significantly reduces biological age. Altogether, we demonstrate that this dimensionality reduction approach, through integrating different biological markers, can provide targets for preventative medicine and the promotion of healthy aging. Using a dimensionality reduction approach, Fong et al. generated a clinical aging clock (PCAge) that delineates healthy and unhealthy aging trajectories. They provide a streamlined version (LinAge) that maintains predictive power, and they demonstrate how the clock can be tailored to available data using the CALERIE study.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00646-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141428550","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 : 2024-06-18DOI: 10.1038/s43587-024-00656-6
We reveal considerable heterogeneity in risk factors for healthy aging in Latin America, which underscores the limitations of existing, unharmonized research models for diverse populations. Our results emphasize the urgent need for region-specific studies that describe particular risks for Latin American aging to develop tailored preventive models and interventions.
{"title":"Latin American brain-health research requires regional data and tailored models","authors":"","doi":"10.1038/s43587-024-00656-6","DOIUrl":"10.1038/s43587-024-00656-6","url":null,"abstract":"We reveal considerable heterogeneity in risk factors for healthy aging in Latin America, which underscores the limitations of existing, unharmonized research models for diverse populations. Our results emphasize the urgent need for region-specific studies that describe particular risks for Latin American aging to develop tailored preventive models and interventions.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141422352","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 : 2024-06-17DOI: 10.1038/s43587-024-00660-w
George Andrew S. Inglis
{"title":"Slowing early Parkinson’s disease","authors":"George Andrew S. Inglis","doi":"10.1038/s43587-024-00660-w","DOIUrl":"10.1038/s43587-024-00660-w","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141422353","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 : 2024-06-17DOI: 10.1038/s43587-024-00648-6
Agustin Ibanez, Marcelo Maito, Felipe Botero-Rodríguez, Sol Fittipaldi, Carlos Coronel, Joaquin Migeot, Andrea Lacroix, Brian Lawlor, Claudia Duran-Aniotz, Sandra Baez, Hernando Santamaria-Garcia
Models of healthy aging are typically based on the United States and Europe and may not apply to diverse and heterogeneous populations. In this study, our objectives were to conduct a meta-analysis to assess risk factors of cognition and functional ability across aging populations in Latin America and a scoping review focusing on methodological procedures. Our study design included randomized controlled trials and cohort, case–control and cross-sectional studies using multiple databases, including MEDLINE, the Virtual Health Library and Web of Science. From an initial pool of 455 studies, our meta-analysis included 38 final studies (28 assessing cognition and 10 assessing functional ability, n = 146,000 participants). Our results revealed significant but heterogeneous effects for cognition (odds ratio (OR) = 1.20, P = 0.03, confidence interval (CI) = (1.0127, 1.42); heterogeneity: I2 = 92.1%, CI = (89.8%, 94%)) and functional ability (OR = 1.20, P = 0.01, CI = (1.04, 1.39); I2 = 93.1%, CI = (89.3%, 95.5%)). Specific risk factors had limited effects, especially on functional ability, with moderate impacts for demographics and mental health and marginal effects for health status and social determinants of health. Methodological issues, such as outliers, inter-country differences and publication bias, influenced the results. Overall, we highlight the specific profile of risk factors associated with healthy aging in Latin America. The heterogeneity in results and methodological approaches in studying healthy aging call for greater harmonization and further regional research to understand healthy aging in Latin America. Ibanez et al. performed a scoping review and meta-analysis of healthy aging studies across Latin America and report substantial heterogeneity in how risk factors affect cognitive and functional ability, underscoring the need for further regional research.
{"title":"Healthy aging meta-analyses and scoping review of risk factors across Latin America reveal large heterogeneity and weak predictive models","authors":"Agustin Ibanez, Marcelo Maito, Felipe Botero-Rodríguez, Sol Fittipaldi, Carlos Coronel, Joaquin Migeot, Andrea Lacroix, Brian Lawlor, Claudia Duran-Aniotz, Sandra Baez, Hernando Santamaria-Garcia","doi":"10.1038/s43587-024-00648-6","DOIUrl":"10.1038/s43587-024-00648-6","url":null,"abstract":"Models of healthy aging are typically based on the United States and Europe and may not apply to diverse and heterogeneous populations. In this study, our objectives were to conduct a meta-analysis to assess risk factors of cognition and functional ability across aging populations in Latin America and a scoping review focusing on methodological procedures. Our study design included randomized controlled trials and cohort, case–control and cross-sectional studies using multiple databases, including MEDLINE, the Virtual Health Library and Web of Science. From an initial pool of 455 studies, our meta-analysis included 38 final studies (28 assessing cognition and 10 assessing functional ability, n = 146,000 participants). Our results revealed significant but heterogeneous effects for cognition (odds ratio (OR) = 1.20, P = 0.03, confidence interval (CI) = (1.0127, 1.42); heterogeneity: I2 = 92.1%, CI = (89.8%, 94%)) and functional ability (OR = 1.20, P = 0.01, CI = (1.04, 1.39); I2 = 93.1%, CI = (89.3%, 95.5%)). Specific risk factors had limited effects, especially on functional ability, with moderate impacts for demographics and mental health and marginal effects for health status and social determinants of health. Methodological issues, such as outliers, inter-country differences and publication bias, influenced the results. Overall, we highlight the specific profile of risk factors associated with healthy aging in Latin America. The heterogeneity in results and methodological approaches in studying healthy aging call for greater harmonization and further regional research to understand healthy aging in Latin America. Ibanez et al. performed a scoping review and meta-analysis of healthy aging studies across Latin America and report substantial heterogeneity in how risk factors affect cognitive and functional ability, underscoring the need for further regional research.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00648-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141422351","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 : 2024-06-14DOI: 10.1038/s43587-024-00661-9
Yahyah Aman
{"title":"Addressing gender disparities in global health","authors":"Yahyah Aman","doi":"10.1038/s43587-024-00661-9","DOIUrl":"10.1038/s43587-024-00661-9","url":null,"abstract":"","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141322262","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 : 2024-06-12DOI: 10.1038/s43587-024-00649-5
Tian Mi, Andrew G. Soerens, Shanta Alli, Tae Gun Kang, Anoop Babu Vasandan, Zhaoming Wang, Vaiva Vezys, Shunsuke Kimura, Ilaria Iacobucci, Stephen B. Baylin, Peter A. Jones, Christopher Hiner, April Mueller, Harris Goldstein, Charles G. Mullighan, Caitlin C. Zebley, David Masopust, Ben Youngblood
Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such ‘epigenetic clocks’ appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue ‘counting’ beyond species lifespan. Here we found that memory T cell epigenetic clocks tick independently of host age and continue through four lifetimes. Instead of recording chronological time, T cells recorded proliferative experience through modification of cell cycle regulatory genes. Applying this epigenetic profile across a range of human T cell contexts, we found that naive T cells appeared ‘young’ regardless of organism age, while in pediatric patients, T cell acute lymphoblastic leukemia appeared to have epigenetically aged for up to 200 years. Thus, T cell epigenetic clocks measure replicative history and can continue to accumulate well-beyond organismal lifespan. Using an iterative boost and transplantation model to generate multilifetime T cells, Mi et al. show that cellular epigenetic age can be uncoupled from organism age. While naive T cells appear epigenetically young, memory T cells and T-ALL leukemia can exhibit epigenetic ages exceeding the organismal lifespan.
时间衰老与特定位点的表观遗传修饰相关，并与物种寿命校准。这种 "表观遗传时钟 "在哺乳动物中似乎是保守的，但它们是否独立于细胞并受限于生物体的最大寿命仍是未知数。我们利用重复接种疫苗和记忆性 T 细胞移植的多寿命小鼠模型来检验表观遗传学衰老是否与细胞复制同步，以及这种时钟是否在物种寿命之后继续 "计数"。在这里，我们发现记忆 T 细胞表观遗传时钟的滴答声不受宿主年龄的影响，并可持续四次寿命。T细胞不记录时间，而是通过细胞周期调控基因的改变来记录增殖经历。将这种表观遗传学特征应用于一系列人类 T 细胞时，我们发现，无论机体年龄如何，天真 T 细胞都显得 "年轻"，而在儿科患者中，T 细胞急性淋巴细胞白血病的表观遗传学年龄似乎长达 200 年。因此，T细胞表观遗传时钟可测量复制历史，并可在生物体寿命之外继续积累。
{"title":"Conserved epigenetic hallmarks of T cell aging during immunity and malignancy","authors":"Tian Mi, Andrew G. Soerens, Shanta Alli, Tae Gun Kang, Anoop Babu Vasandan, Zhaoming Wang, Vaiva Vezys, Shunsuke Kimura, Ilaria Iacobucci, Stephen B. Baylin, Peter A. Jones, Christopher Hiner, April Mueller, Harris Goldstein, Charles G. Mullighan, Caitlin C. Zebley, David Masopust, Ben Youngblood","doi":"10.1038/s43587-024-00649-5","DOIUrl":"10.1038/s43587-024-00649-5","url":null,"abstract":"Chronological aging correlates with epigenetic modifications at specific loci, calibrated to species lifespan. Such ‘epigenetic clocks’ appear conserved among mammals, but whether they are cell autonomous and restricted by maximal organismal lifespan remains unknown. We used a multilifetime murine model of repeat vaccination and memory T cell transplantation to test whether epigenetic aging tracks with cellular replication and if such clocks continue ‘counting’ beyond species lifespan. Here we found that memory T cell epigenetic clocks tick independently of host age and continue through four lifetimes. Instead of recording chronological time, T cells recorded proliferative experience through modification of cell cycle regulatory genes. Applying this epigenetic profile across a range of human T cell contexts, we found that naive T cells appeared ‘young’ regardless of organism age, while in pediatric patients, T cell acute lymphoblastic leukemia appeared to have epigenetically aged for up to 200 years. Thus, T cell epigenetic clocks measure replicative history and can continue to accumulate well-beyond organismal lifespan. Using an iterative boost and transplantation model to generate multilifetime T cells, Mi et al. show that cellular epigenetic age can be uncoupled from organism age. While naive T cells appear epigenetically young, memory T cells and T-ALL leukemia can exhibit epigenetic ages exceeding the organismal lifespan.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s43587-024-00649-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141312624","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 : 2024-06-10DOI: 10.1038/s43587-024-00651-x
Guangran Guo, Corina Amor
Inhibitors of sodium glucose co-transporter 2 (SGLT2) have long been used in the treatment of diabetes and cardiovascular disease, owing to their modulation of glucose levels. Katsuumi and colleagues now show that, in addition to their glycemic effects, SGLT2 inhibitors modulate senescence immune surveillance by downregulating PD-L1 expression on senescent cells.
{"title":"SGLT2 regulates immune-mediated senolysis","authors":"Guangran Guo, Corina Amor","doi":"10.1038/s43587-024-00651-x","DOIUrl":"10.1038/s43587-024-00651-x","url":null,"abstract":"Inhibitors of sodium glucose co-transporter 2 (SGLT2) have long been used in the treatment of diabetes and cardiovascular disease, owing to their modulation of glucose levels. Katsuumi and colleagues now show that, in addition to their glycemic effects, SGLT2 inhibitors modulate senescence immune surveillance by downregulating PD-L1 expression on senescent cells.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141302341","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 : 2024-06-10DOI: 10.1038/s43587-024-00633-z
Jooman Park, Ruoci Hu, Yanyu Qian, Shaolei Xiong, Asma Sana El-Sabbagh, Meram Ibrahim, Jaden Wang, Ziqiao Xu, Zhengjia Chen, Qing Song, Zhenyuan Song, Gege Yan, Abeer M. Mahmoud, Yanlin He, Brian T. Layden, Jiwang Chen, Sang-Ging Ong, Pingwen Xu, Yuwei Jiang
Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages that they offer are compromised with aging. Here we show that treating mice with estrogen (E2), a hormone that decreases with age, can counteract the age-related decline in beige adipogenesis when exposed to cold temperature while concurrently enhancing energy expenditure and improving glucose tolerance in mice. Mechanistically, we found that nicotinamide phosphoribosyl transferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related endoplasmic reticulum (ER) stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. Together, our findings shed light on the mechanisms regulating the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT-controlled ER stress pathway as a key regulator of this process. Thermogenic beige adipose tissue can enhance energy expenditure and improve metabolism, but its formation declines with age. Park, Hu et al. show that replenishing estrogen can restore cold-induced beige adipogenesis by regulating NAMPT-controlled ER stress.
{"title":"Estrogen counteracts age-related decline in beige adipogenesis through the NAMPT-regulated ER stress response","authors":"Jooman Park, Ruoci Hu, Yanyu Qian, Shaolei Xiong, Asma Sana El-Sabbagh, Meram Ibrahim, Jaden Wang, Ziqiao Xu, Zhengjia Chen, Qing Song, Zhenyuan Song, Gege Yan, Abeer M. Mahmoud, Yanlin He, Brian T. Layden, Jiwang Chen, Sang-Ging Ong, Pingwen Xu, Yuwei Jiang","doi":"10.1038/s43587-024-00633-z","DOIUrl":"10.1038/s43587-024-00633-z","url":null,"abstract":"Thermogenic beige adipocytes are recognized as potential therapeutic targets for combating metabolic diseases. However, the metabolic advantages that they offer are compromised with aging. Here we show that treating mice with estrogen (E2), a hormone that decreases with age, can counteract the age-related decline in beige adipogenesis when exposed to cold temperature while concurrently enhancing energy expenditure and improving glucose tolerance in mice. Mechanistically, we found that nicotinamide phosphoribosyl transferase (NAMPT) plays a pivotal role in facilitating the formation of E2-induced beige adipocytes, which subsequently suppresses the onset of age-related endoplasmic reticulum (ER) stress. Furthermore, we found that targeting NAMPT signaling, either genetically or pharmacologically, can restore the formation of beige adipocytes by increasing the number of perivascular adipocyte progenitor cells. Conversely, the absence of NAMPT signaling prevents this process. Together, our findings shed light on the mechanisms regulating the age-dependent impairment of beige adipocyte formation and underscore the E2-NAMPT-controlled ER stress pathway as a key regulator of this process. Thermogenic beige adipose tissue can enhance energy expenditure and improve metabolism, but its formation declines with age. Park, Hu et al. show that replenishing estrogen can restore cold-induced beige adipogenesis by regulating NAMPT-controlled ER stress.","PeriodicalId":94150,"journal":{"name":"Nature aging","volume":null,"pages":null},"PeriodicalIF":17.0,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141302340","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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