NPJ Aging and Mechanisms of Disease最新文献

{"title":"NQO1 protects obese mice through improvements in glucose and lipid metabolism.","authors":"Andrea Di Francesco, Youngshim Choi, Michel Bernier, Yingchun Zhang, Alberto Diaz-Ruiz, Miguel A Aon, Krystle Kalafut, Margaux R Ehrlich, Kelsey Murt, Ahmed Ali, Kevin J Pearson, Sophie Levan, Joshua D Preston, Alejandro Martin-Montalvo, Jennifer L Martindale, Kotb Abdelmohsen, Cole R Michel, Diana M Willmes, Christine Henke, Placido Navas, Jose Manuel Villalba, David Siegel, Myriam Gorospe, Kristofer Fritz, Shyam Biswal, David Ross, Rafael de Cabo","doi":"10.1038/s41514-020-00051-6","DOIUrl":"10.1038/s41514-020-00051-6","url":null,"abstract":"<p><p>Chronic nutrient excess leads to metabolic disorders and insulin resistance. Activation of stress-responsive pathways via Nrf2 activation contributes to energy metabolism regulation. Here, inducible activation of Nrf2 in mice and transgenesis of the Nrf2 target, NQO1, conferred protection from diet-induced metabolic defects through preservation of glucose homeostasis, insulin sensitivity, and lipid handling with improved physiological outcomes. NQO1-RNA interaction mediated the association with and inhibition of the translational machinery in skeletal muscle of NQO1 transgenic mice. NQO1-Tg mice on high-fat diet had lower adipose tissue macrophages and enhanced expression of lipogenic enzymes coincident with reduction in circulating and hepatic lipids. Metabolomics data revealed a systemic metabolic signature of improved glucose handling, cellular redox, and NAD⁺ metabolism while label-free quantitative mass spectrometry in skeletal muscle uncovered a distinct diet- and genotype-dependent acetylation pattern of SIRT3 targets across the core of intermediary metabolism. Thus, under nutritional excess, NQO1 transgenesis preserves healthful benefits.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 1","pages":"13"},"PeriodicalIF":5.0,"publicationDate":"2020-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38693394","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}

{"title":"Fenofibrate prevents iron induced activation of canonical Wnt/β-catenin and oxidative stress signaling in the retina.","authors":"Ashok Mandala,&nbsp;Austin Armstrong,&nbsp;Becky Girresch,&nbsp;Jiyao Zhu,&nbsp;Aruna Chilakala,&nbsp;Sanmathi Chavalmane,&nbsp;Kapil Chaudhary,&nbsp;Pratim Biswas,&nbsp;Judith Ogilvie,&nbsp;Jaya P Gnana-Prakasam","doi":"10.1038/s41514-020-00050-7","DOIUrl":"https://doi.org/10.1038/s41514-020-00050-7","url":null,"abstract":"<p><p>Accumulating evidence strongly implicates iron in the pathogenesis of aging and disease. Iron levels have been found to increase with age in both the human and mouse retinas. We and others have shown that retinal diseases such as age-related macular degeneration and diabetic retinopathy are associated with disrupted iron homeostasis, resulting in retinal iron accumulation. In addition, hereditary disorders due to mutation in one of the iron regulatory genes lead to age dependent retinal iron overload and degeneration. However, our knowledge on whether iron toxicity contributes to the retinopathy is limited. Recently, we reported that iron accumulation is associated with the upregulation of retinal and renal renin-angiotensin system (RAS). Evidences indicate that multiple genes/components of the RAS are targets of Wnt/β-catenin signaling. Interestingly, aberrant activation of Wnt/β-catenin signaling is observed in several degenerative diseases. In the present study, we explored whether iron accumulation regulates canonical Wnt signaling in the retina. We found that in vitro and in vivo iron treatment resulted in the upregulation of Wnt/β-catenin signaling and its downstream target genes including renin-angiotensin system in the retina. We confirmed further that iron activates canonical Wnt signaling in the retina using TOPFlash T-cell factor/lymphoid enhancer factor promoter assay and Axin2-LacZ reporter mouse. The presence of an iron chelator or an antioxidant reversed the iron-mediated upregulation of Wnt/β-catenin signaling in retinal pigment epithelial (RPE) cells. In addition, treatment of RPE cells with peroxisome proliferator-activated receptor (PPAR) α-agonist fenofibrate prevented iron-induced activation of oxidative stress and Wnt/β-catenin signaling by chelating the iron. The role of fenofibrate, an FDA-approved drug for hyperlipidemia, as an iron chelator has potentially significant therapeutic impact on iron associated degenerative diseases.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"12"},"PeriodicalIF":5.0,"publicationDate":"2020-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-020-00050-7","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38668087","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}

{"title":"Molecular phenotyping of oxidative stress in diabetes mellitus with point-of-care NMR system.","authors":"Weng Kung Peng, Lan Chen, Bernhard O Boehm, Jongyoon Han, Tze Ping Loh","doi":"10.1038/s41514-020-00049-0","DOIUrl":"10.1038/s41514-020-00049-0","url":null,"abstract":"<p><p>Diabetes mellitus is one of the fastest-growing health burdens globally. Oxidative stress, which has been implicated in the pathogenesis of diabetes complication (e.g., cardiovascular event), remains poorly understood. We report a new approach to rapidly manipulate and evaluate the redox states of blood using a point-of-care NMR system. Various redox states of the hemoglobin were mapped out using the newly proposed (pseudo) two-dimensional map known as <i>T</i>₁-<i>T</i>₂ magnetic state diagram. We exploit the fact that oxidative stress changes the subtle molecular motion of water proton in the blood, and thus inducing a measurable shift in magnetic resonance relaxation properties. We demonstrated the clinical utilities of this technique to rapidly stratify diabetes subjects based on their oxidative status in conjunction to the traditional glycemic level to improve the patient stratification and thus the overall outcome of clinical diabetes care and management.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"11"},"PeriodicalIF":5.0,"publicationDate":"2020-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-020-00049-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38516931","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}

{"title":"Assessing the cognitive status of Drosophila by the value-based feeding decision","authors":"C. Yu, Ferng-Chang Chang, Yong-Huei Hong, Jian-Chiuan Li, Po-Lin Chen, Chun-Hong Chen, Tzai-Wen Chiu, Tsai‐Te Lu, Yun-Ming Wang, Chih-Fei Kao","doi":"10.1101/2020.08.27.267955","DOIUrl":"https://doi.org/10.1101/2020.08.27.267955","url":null,"abstract":"Decision-making is considered an important aspect of cognitive function. Impaired decision-making is a consequence of cognitive decline caused by various physiological conditions, such as aging and neurodegenerative diseases. Here we exploited the value-based feeding decision (VBFD) assay, which is a simple sensory–motor task, to determine the cognitive status of Drosophila . Our results indicated the deterioration of VBFD is notably correlated with aging and neurodegenerative disorders. Restriction of the mushroom body (MB) neuronal activity partly blunted the proper VBFD. Furthermore, using the Drosophila polyQ disease model, we demonstrated the impaired VBFD is ameliorated by the dinitrosyl iron complex (DNIC-1), a novel and steady nitric oxide (NO)-releasing compound. Therefore we propose that the VBFD assay provides a robust assessment of Drosophila cognition and can be used to characterize additional neuroprotective interventions.","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"7 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2020-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46832229","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}

{"title":"Targeting of intracellular Ca²⁺ stores as a therapeutic strategy against age-related neurotoxicities.","authors":"Joshua Goldberg,&nbsp;Antonio Currais,&nbsp;Gamze Ates,&nbsp;Ling Huang,&nbsp;Maxim Shokhirev,&nbsp;Pamela Maher,&nbsp;David Schubert","doi":"10.1038/s41514-020-00048-1","DOIUrl":"https://doi.org/10.1038/s41514-020-00048-1","url":null,"abstract":"<p><p>Calcium dysregulation often underlies pathologies associated with aging and age-associated neurodegenerative diseases. Cells express a unique pattern of Ca²⁺ channels and pumps geared to fulfill specific physiological requirements and there is a decline in the fidelity of these processes with age and age-associated diseases. J147 is an Alzheimer's disease (AD) drug candidate that was identified using a phenotypic screening platform based upon age-related brain toxicities that are mediated by changes in calcium metabolism. The molecular target for J147 is the α-F1-ATP synthase (ATP5A). J147 has therapeutic efficacy in multiple mouse models of AD and accelerated aging and extends life span in flies. A bioinformatics analysis of gene expression in rapidly aging SAMP8 mice during the last quadrant of their life span shows that J147 has a significant effect on ion transport pathways that are changed with aging, making their expression look more like that of younger animals. The molecular basis of these changes was then investigated in cell culture neurotoxicity assays that were the primary screen in the development of J147. Here we show that J147 and its molecular target, ATP synthase, regulate the maintenance of store-operated calcium entry (SOCE) and cell death during acute neurotoxicity.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"10"},"PeriodicalIF":5.0,"publicationDate":"2020-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-020-00048-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38439418","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}

{"title":"Short-term calorie restriction enhances DNA repair by non-homologous end joining in mice.","authors":"Zhonghe Ke, Denis Firsanov, Brianna Spencer, Andrei Seluanov, Vera Gorbunova","doi":"10.1038/s41514-020-00047-2","DOIUrl":"10.1038/s41514-020-00047-2","url":null,"abstract":"<p><p>Calorie restriction (CR) improves health, reduces cancer incidence and extends lifespan in multiple organisms including mice. CR was shown to enhance base excision repair and nucleotide excision repair pathways of DNA repair, however, whether CR improves repair of DNA double-strand breaks has not been examined in in vivo system. Here we utilize non-homologous end joining (NHEJ) reporter mice to show that short-term CR strongly enhances DNA repair by NHEJ, which is associated with elevated levels of DNA-PK and SIRT6.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"9"},"PeriodicalIF":5.4,"publicationDate":"2020-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38325665","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}

{"title":"Elucidating the mechanisms by which disulfiram protects against obesity and metabolic syndrome.","authors":"Michel Bernier, Dylan Harney, Yen Chin Koay, Antonio Diaz, Abhishek Singh, Devin Wahl, Tamara Pulpitel, Ahmed Ali, Vince Guiterrez, Sarah J Mitchell, Eun-Young Kim, John Mach, Nathan L Price, Miguel A Aon, David G LeCouteur, Victoria C Cogger, Carlos Fernandez-Hernando, John O'Sullivan, Mark Larance, Ana Maria Cuervo, Rafael de Cabo","doi":"10.1038/s41514-020-0046-6","DOIUrl":"10.1038/s41514-020-0046-6","url":null,"abstract":"<p><p>There is an unmet need and urgency to find safe and effective anti-obesity interventions. Our recent study in mice fed on obesogenic diet found that treatment with the alcohol aversive drug disulfiram reduced feeding efficiency and led to a decrease in body weight and an increase in energy expenditure. The intervention with disulfiram improved glucose tolerance and insulin sensitivity, and mitigated metabolic dysfunctions in various organs through poorly defined mechanisms. Here, integrated analysis of transcriptomic and proteomic data from mouse and rat livers unveiled comparable signatures in response to disulfiram, revealing pathways associated with lipid and energy metabolism, redox, and detoxification. In cell culture, disulfiram was found to be a potent activator of autophagy, the malfunctioning of which has negative consequences on metabolic regulation. Thus, repurposing disulfiram may represent a potent strategy to combat obesity.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"8"},"PeriodicalIF":5.0,"publicationDate":"2020-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374720/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38203182","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}

{"title":"Age-dependent hormesis-like effects of the synthetic cannabinoid CP55940 in C57BL/6 mice.","authors":"Erik L Hodges, Jessica P Marshall, Nicole M Ashpole","doi":"10.1038/s41514-020-0045-7","DOIUrl":"10.1038/s41514-020-0045-7","url":null,"abstract":"<p><p>Use of cannabis and cannabinoid-containing substances is increasing among geriatric patients, despite relatively sparse preclinical evidence in aged models. To better understand the effects of exogenous cannabinoids on aging male and female rodents, we compared the age- and dose-dependent physiological and behavioral effects of the synthetic cannabinoid CP55940 in young-adult and aged C57BL/6 mice. Locomotion, body temperature, thermal nociception, and fecal output were measured following CP55940 administration. Our findings indicate that CP55940 is more potent and efficacious in older mice, evidenced by exaggerated antinociception and locomotor inhibition when compared to younger adult mice. In addition, we report that low doses of CP55940 paradoxically stimulate locomotion in young-adult (4 m) mice; however, this hormesis-like response is not as evident in aged animals (21-24 m). These bidirectional effects appear to be mediated via the endocannabinoid CB1 and CB2 receptors.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"7"},"PeriodicalIF":5.0,"publicationDate":"2020-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38144535","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}

{"title":"Lifespan and healthspan benefits of exogenous H₂S in <i>C. elegans</i> are independent from effects downstream of <i>eat-2</i> mutation.","authors":"Li Theng Ng,&nbsp;Li Fang Ng,&nbsp;Richard Ming Yi Tang,&nbsp;Diogo Barardo,&nbsp;Barry Halliwell,&nbsp;Philip Keith Moore,&nbsp;Jan Gruber","doi":"10.1038/s41514-020-0044-8","DOIUrl":"https://doi.org/10.1038/s41514-020-0044-8","url":null,"abstract":"<p><p>Caloric restriction (CR) is one of the most effective interventions to prolong lifespan and promote health. Recently, it has been suggested that hydrogen sulfide (H₂S) may play a pivotal role in mediating some of these CR-associated benefits. While toxic at high concentrations, H₂S at lower concentrations can be biologically advantageous. H₂S levels can be artificially elevated <i>via</i> H₂S-releasing donor drugs. In this study, we explored the function of a novel, slow-releasing H₂S donor drug (FW1256) and used it as a tool to investigate H₂S in the context of CR and as a potential CR mimetic. We show that exposure to FW1256 extends lifespan and promotes health in <i>Caenorhabditis elegans</i> (<i>C. elegans</i>) more robustly than some previous H₂S-releasing compounds, including GYY4137. We looked at the extent to which FW1256 reproduces CR-associated physiological effects in normal-feeding <i>C. elegans</i>. We found that FW1256 promoted healthy longevity to a similar degree as CR but with fewer fitness costs. In contrast to CR, FW1256 actually enhanced overall reproductive capacity and did not reduce adult body length. FW1256 further extended the lifespan of already long-lived <i>eat-2</i> mutants without further detriments in developmental timing or fertility, but these lifespan and healthspan benefits required H₂S exposure to begin early in development. Taken together, these observations suggest that FW1256 delivers exogenous H₂S efficiently and supports a role for H₂S in mediating longevity benefits of CR. Delivery of H₂S <i>via</i> FW1256, however, does not mimic CR perfectly, suggesting that the role of H₂S in CR-associated longevity is likely more complex than previously described.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"6"},"PeriodicalIF":5.0,"publicationDate":"2020-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-020-0044-8","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38068398","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}

{"title":"The aging human body shape.","authors":"Alexander Frenzel,&nbsp;Hans Binder,&nbsp;Nadja Walter,&nbsp;Kerstin Wirkner,&nbsp;Markus Loeffler,&nbsp;Henry Loeffler-Wirth","doi":"10.1038/s41514-020-0043-9","DOIUrl":"https://doi.org/10.1038/s41514-020-0043-9","url":null,"abstract":"<p><p>Body shape and composition are heterogeneous among humans with possible impact for health. Anthropometric methods and data are needed to better describe the diversity of the human body in human populations, its age dependence, and associations with health risk. We applied whole-body laser scanning to a cohort of 8499 women and men of age 40-80 years within the frame of the LIFE (Leipzig Research Center for Civilization Diseases) study aimed at discovering health risk in a middle European urban population. Body scanning delivers multidimensional anthropometric data, which were further processed by machine learning to stratify the participants into body types. We here applied this body typing concept to describe the diversity of body shapes in an aging population and its association with physical activity and selected health and lifestyle factors. We find that aging results in similar reshaping of female and male bodies despite the large diversity of body types observed in the study. Slim body shapes remain slim and partly tend to become even more lean and fragile, while obese body shapes remain obese. Female body shapes change more strongly than male ones. The incidence of the different body types changes with characteristic Life Course trajectories. Physical activity is inversely related to the body mass index and decreases with age, while self-reported incidence for myocardial infarction shows overall the inverse trend. We discuss health risks factors in the context of body shape and its relation to obesity. Body typing opens options for personalized anthropometry to better estimate health risk in epidemiological research and future clinical applications.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"5"},"PeriodicalIF":5.0,"publicationDate":"2020-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-020-0043-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37777936","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}