NPJ Aging and Mechanisms of Disease最新文献

{"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}

{"title":"Organotypic human skin culture models constructed with senescent fibroblasts show hallmarks of skin aging.","authors":"Regina Weinmüllner, Barbara Zbiral, Adnan Becirovic, Elena Maria Stelzer, Fabian Nagelreiter, Markus Schosserer, Ingo Lämmermann, Lisa Liendl, Magdalena Lang, Lucia Terlecki-Zaniewicz, Orestis Andriotis, Michael Mildner, Bahar Golabi, Petra Waidhofer-Söllner, Karl Schedle, Gerhard Emsenhuber, Philipp J Thurner, Erwin Tschachler, Florian Gruber, Johannes Grillari","doi":"10.1038/s41514-020-0042-x","DOIUrl":"10.1038/s41514-020-0042-x","url":null,"abstract":"<p><p>Skin aging is driven by intrinsic and extrinsic factors impacting on skin functionality with progressive age. One factor of this multifaceted process is cellular senescence, as it has recently been identified to contribute to a declining tissue functionality in old age. In the skin, senescent cells have been found to markedly accumulate with age, and thus might impact directly on skin characteristics. Especially the switch from young, extracellular matrix-building fibroblasts to a senescence-associated secretory phenotype (SASP) could alter the microenvironment in the skin drastically and therefore promote skin aging. In order to study the influence of senescence in human skin, 3D organotypic cultures are a well-suited model system. However, only few \"aged\" skin- equivalent (SE) models are available, requiring complex and long-term experimental setups. Here, we adapted a previously published full-thickness SE model by seeding increasing ratios of stress-induced premature senescent versus normal fibroblasts into the collagen matrix, terming these SE \"senoskin\". Immunohistochemistry stainings revealed a shift in the balance between proliferation (Ki67) and differentiation (Keratin 10 and Filaggrin) of keratinocytes within our senoskin equivalents, as well as partial impairment of skin barrier function and changed surface properties. Monitoring of cytokine levels of known SASP factors confirmedly showed an upregulation in 2D cultures of senescent cells and at the time of seeding into the skin equivalent. Surprisingly, we find a blunted response of cytokines in the senoskin equivalent over time during 3D differentiation.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"4"},"PeriodicalIF":5.4,"publicationDate":"2020-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37757506","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":"CMV-independent increase in CD27-CD28+ CD8+ EMRA T cells is inversely related to mortality in octogenarians.","authors":"Carmen Martin-Ruiz, Jedrzej Hoffmann, Evgeniya Shmeleva, Thomas von Zglinicki, Gavin Richardson, Lilia Draganova, Rachael Redgrave, Joanna Collerton, Helen Arthur, Bernard Keavney, Ioakim Spyridopoulos","doi":"10.1038/s41514-019-0041-y","DOIUrl":"10.1038/s41514-019-0041-y","url":null,"abstract":"<p><p>Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of CD27-CD28+ CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51-0.86). In addition, CD27-CD28+ CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"3"},"PeriodicalIF":5.4,"publicationDate":"2020-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6972903/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37588675","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":"Repository of proposed pathways and protein-protein interaction networks in age-related macular degeneration.","authors":"Fran M Pool,&nbsp;Christina Kiel,&nbsp;Luis Serrano,&nbsp;Philip J Luthert","doi":"10.1038/s41514-019-0039-5","DOIUrl":"https://doi.org/10.1038/s41514-019-0039-5","url":null,"abstract":"<p><p>Age-related macular degeneration (AMD) is one of the commonest causes of sight loss in the elderly population and to date there is no intervention that slows or prevents early AMD disease progressing to blinding neovascularization or geographic atrophy. AMD is a complex disease and factors proposed to contribute to the development and progression of disease include aging, genetics, epigenetics, oxidative stress, pro-inflammatory state, and life-style factors such as smoking, alcohol, and high fat diet. Here, we generate a knowledge repository of pathways and protein-protein interaction (PPI) networks likely to be implicated in AMD pathogenesis, such as complement activation, lipid trafficking and metabolism, vitamin A cycle, oxidative stress, proteostasis, bioenergetics, autophagy/mitophagy, extracellular matrix (ECM) turnover, and choroidal vascular dropout. Two disctinct clusters ermerged from the networks for parainflamation and ECM homeostasis, which may represent two different disease modules underlying AMD pathology. Our analyses also suggest that the disease manifests primarily in RPE/choroid and less in neural retina. The use of standardized syntax when generating maps of these biological processes (SBGN standard) and networks (PSI standard) enables visualization of complex information in graphical programs such as CellDesigner and Cytoscape and enhances reusability and extension of data. The ability to focus onto subnetworks, multiple visualizations and simulation options will enable the AMD research community to computationally model subnetworks or to test experimentally new hypotheses arising from connectivities in the AMD pathway map.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"2"},"PeriodicalIF":5.0,"publicationDate":"2020-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-019-0039-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37539750","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 NAD⁺ supplementation prevents hearing loss in mouse models of Cockayne syndrome.","authors":"Mustafa N Okur, Beatrice Mao, Risako Kimura, Scott Haraczy, Tracy Fitzgerald, Kamren Edwards-Hollingsworth, Jane Tian, Wasif Osmani, Deborah L Croteau, Matthew W Kelley, Vilhelm A Bohr","doi":"10.1038/s41514-019-0040-z","DOIUrl":"10.1038/s41514-019-0040-z","url":null,"abstract":"<p><p>Age-related hearing loss (ARHL) is one of the most common disorders affecting elderly individuals. There is an urgent need for effective preventive measures for ARHL because none are currently available. Cockayne syndrome (CS) is a premature aging disease that presents with progressive hearing loss at a young age, but is otherwise similar to ARHL. There are two human genetic complementation groups of CS, A and B. While the clinical phenotypes in patients are similar, the proteins have very diverse functions, and insight into their convergence is of great interest. Here, we use mouse models for CS (<i>CSA</i> ^-<i>/-</i> and <i>CSB</i> ^<i>m/m</i> ) that recapitulate the hearing loss in human CS patients. We previously showed that NAD⁺, a key metabolite with various essential functions, is reduced in CS and associated with multiple CS phenotypes. In this study, we report that NAD⁺ levels are reduced in the cochlea of <i>CSB</i> ^<i>m/m</i> mice and that short-term treatment (10 days) with the NAD⁺ precursor nicotinamide riboside (NR), prevents hearing loss, restores outer hair cell loss, and improves cochlear health in <i>CSB</i> ^<i>m/m</i> mice. Similar, but more modest effects were observed in <i>CSA</i> ^-<i>/-</i> mice. Remarkably, we observed a reduction in synaptic ribbon counts in the presynaptic zones of inner hair cells in both <i>CSA</i> ^<i>-/-</i> and <i>CSB</i> ^<i>m/m</i> mice, pointing to a converging mechanism for cochlear defects in CS. Ribbon synapses facilitate rapid and sustained synaptic transmission over long periods of time. Ribeye, a core protein of synaptic ribbons, possesses an NAD(H) binding pocket which regulates its activity. Intriguingly, NAD⁺ supplementation rescues reduced synaptic ribbon formation in both <i>CSA</i> ^<i>-/-</i> and <i>CSB</i> ^<i>m/m</i> mutant cochleae. These findings provide valuable insight into the mechanism of CS- and ARHL-associated hearing loss, and suggest a possible intervention.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":"6 ","pages":"1"},"PeriodicalIF":5.4,"publicationDate":"2020-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946667/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37539749","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":"Daily blue-light exposure shortens lifespan and causes brain neurodegeneration in Drosophila","authors":"Trevor R. Nash, Eileen S. Chow, Alexander D. Law, Samuel D. Fu, E. Fuszara, A. Bilska, P. Bebas, D. Kretzschmar, J. Giebultowicz","doi":"10.1038/s41514-019-0038-6","DOIUrl":"https://doi.org/10.1038/s41514-019-0038-6","url":null,"abstract":"","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2019-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1038/s41514-019-0038-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49090221","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}