NPJ Aging and Mechanisms of Disease最新文献

{"title":"EPB41L4A-AS1 is required to maintain basal autophagy to modulates Aβ clearance","authors":"Ziqiang Wang, Ruomei Wang, Lixin Niu, Xiaoyan Zhou, Jinxiang Han, Kun Li","doi":"10.1038/s41514-024-00152-6","DOIUrl":"https://doi.org/10.1038/s41514-024-00152-6","url":null,"abstract":"<p>Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by the deposition of β-amyloid (Aβ) plaques. Aβ is generated from the cleavage of the amyloid precursor protein by β and γ-secretases and cleared by neuroglial cells mediated autophagy. The imbalance of the intracellular Aβ generation and clearance is the causative factor for AD pathogenesis. However, the exact underlying molecular mechanisms remain unclear. Our previous study reported that EPB41L4A-AS1 is an aging-related long non-coding RNA (lncRNA) that is repressed in patients with AD. In this study, we found that downregulated EPB41L4A-AS1 in AD inhibited neuroglial cells mediated-Aβ clearance by decreasing the expression levels of multiple autophagy-related genes. We found that EPB41L4A-AS1 regulates the expression of general control of amino acid synthesis 5-like 2, an important histone acetyltransferase, thus affecting histone acetylation, crotonylation, and lactylation near the transcription start site of autophagy-related genes, ultimately influencing their transcription. Collectively, this study reveals EPB41L4A-AS1 as an AD-related lncRNA via mediating Aβ clearance and provides insights into the epigenetic regulatory mechanism of EPB41L4A-AS1 in gene expression and AD pathogenesis.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140830834","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":"Dynamics of Wnt/β-catenin reporter activity throughout whole life in a naturally short-lived vertebrate","authors":"Shohei Ogamino, Moeko Yamamichi, Ken Sato, Tohru Ishitani","doi":"10.1038/s41514-024-00149-1","DOIUrl":"https://doi.org/10.1038/s41514-024-00149-1","url":null,"abstract":"<p>Wnt/β-catenin signaling plays a major role in regulation of embryogenesis, organogenesis, and adult tissue homeostasis and regeneration. However, the roles played by Wnt/β-catenin and the spatiotemporal regulation of its activity throughout life, including during aging, are not fully understood. To address these issues, we introduced a Wnt/β-catenin signaling sensitive reporter into African turquoise killifish (<i>Nothobranchius furzeri</i>), a naturally ultra-short-lived fish that allows for the analysis of its whole life within a short period of time. Using this reporter killifish, we unraveled the previously unidentified dynamics of Wnt/β-catenin signaling during development and aging. Using the reporter strain, we detected Wnt/β-catenin activity in actively developing tissues as reported in previous reports, but also observed activation and attenuation of Wnt/β-catenin activity during embryonic reaggregation and diapause, respectively. During the aging process, the reporter was activated in the choroidal layer and liver, but its expression decreased in the kidneys. In addition, the reporter also revealed that aging disrupts the spatial regulation and intensity control of Wnt/β-catenin activity seen during fin regeneration, which interferes with precise regeneration. Thus, the employed reporter killifish is a highly useful model for investigating the dynamics of Wnt/β-catenin signaling during both the developmental and aging process.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140841940","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":"Healthcare on the brink: navigating the challenges of an aging society in the United States","authors":"Charles H. Jones, Mikael Dolsten","doi":"10.1038/s41514-024-00148-2","DOIUrl":"https://doi.org/10.1038/s41514-024-00148-2","url":null,"abstract":"<p>The US healthcare system is at a crossroads. With an aging population requiring more care and a strained system facing workforce shortages, capacity issues, and fragmentation, innovative solutions and policy reforms are needed. This paper aims to spark dialogue and collaboration among healthcare stakeholders and inspire action to meet the needs of the aging population. Through a comprehensive analysis of the impact of an aging society, this work highlights the urgency of addressing this issue and the importance of restructuring the healthcare system to be more efficient, equitable, and responsive.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140564545","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":"Oxidative damage in the gastrocnemius predicts long-term survival in patients with peripheral artery disease","authors":"Panagiotis Koutakis, Hernan Hernandez, Dimitrios Miserlis, Jonathan R. Thompson, Evlampia Papoutsi, Constance J. Mietus, Gleb Haynatzki, Julian K. Kim, George P. Casale, Iraklis I. Pipinos","doi":"10.1038/s41514-024-00147-3","DOIUrl":"https://doi.org/10.1038/s41514-024-00147-3","url":null,"abstract":"<p>Patients with peripheral artery disease (PAD) have increased mortality rates and a myopathy in their affected legs which is characterized by increased oxidative damage, reduced antioxidant enzymatic activity and defective mitochondrial bioenergetics. This study evaluated the hypothesis that increased levels of oxidative damage in gastrocnemius biopsies from patients with PAD predict long-term mortality rates. Oxidative damage was quantified as carbonyl adducts in myofibers of the gastrocnemius of PAD patients. The oxidative stress data were grouped into tertiles and the 5-year, all-cause mortality for each tertile was determined by Kaplan-Meier curves and compared by the Modified Peto test. A Cox-regression model was used to control the effects of clinical characteristics. Results were adjusted for age, sex, race, body mass index, ankle-brachial index, smoking, physical activity, and comorbidities. Of the 240 study participants, 99 died during a mean follow up of 37.8 months. Patients in the highest tertile of oxidative damage demonstrated the highest 5-year mortality rate. The mortality hazard ratios (HR) from the Cox analysis were statistically significant for oxidative damage (lowest <i>vs</i> middle tertile; HR = 6.33; <i>p</i> = 0.0001 and lowest <i>vs</i> highest; HR = 8.37; <i>p</i> &lt; 0.0001). Survival analysis of a contemporaneous population of PAD patients identifies abundance of carbonyl adducts in myofibers of their gastrocnemius as a predictor of mortality rate independently of ankle-brachial index, disease stage and other clinical and myopathy-related covariates.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140564705","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":"The use of a systems approach to increase NAD+ in human participants","authors":"John D. Henderson, Sophia N. Z. Quigley, Shruti S. Chachra, Nichola Conlon, Dianne Ford","doi":"10.1038/s41514-023-00134-0","DOIUrl":"https://doi.org/10.1038/s41514-023-00134-0","url":null,"abstract":"<p>Reversal or mitigation against an age-related decline in NAD⁺ has likely benefits, and this premise has driven academic and commercial endeavour to develop dietary supplements that achieve this outcome. We used a systems-based approach to improve on current supplements by targeting multiple points in the NAD⁺ salvage pathway. In a double-blind, randomised, crossover trial, the supplement – Nuchido TIME+® (NT) - increased NAD⁺ concentration in whole blood. This was associated with an increase in SIRT1 and an increase in nicotinamide phosphoribosyltransferase (NAMPT) in peripheral blood mononucleocytes, lower concentrations of pro-inflammatory cytokines in plasma, including a reduction in interleukin 2 (IL2), a reduction in glycated serum protein and a shift in the glycosylation profile of immunoglobulin G (IgG) toward a younger biological age, all of which are likely to promote a healthier ageing trajectory.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139661455","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":"The HLA-DRB1*09:01-DQB1*03:03 haplotype is associated with the risk for late-onset Alzheimer’s disease in APOE $${{varepsilon }}$$ 4–negative Japanese adults","authors":"Daichi Shigemizu, Koya Fukunaga, Akiko Yamakawa, Mutsumi Suganuma, Kosuke Fujita, Tetsuaki Kimura, Ken Watanabe, Taisei Mushiroda, Takashi Sakurai, Shumpei Niida, Kouichi Ozaki","doi":"10.1038/s41514-023-00131-3","DOIUrl":"https://doi.org/10.1038/s41514-023-00131-3","url":null,"abstract":"<p>Late-onset Alzheimer’s disease (LOAD) is the most common cause of dementia among those older than 65 years. The onset of LOAD is influenced by neuroinflammation. The human leukocyte antigen (HLA) system is involved in regulating inflammatory responses. Numerous HLA alleles and their haplotypes have shown varying associations with LOAD in diverse populations, yet their impact on the Japanese population remains to be elucidated. Here, we conducted a comprehensive investigation into the associations between LOAD and HLA alleles within the Japanese population. Using whole-genome sequencing (WGS) data from 303 LOAD patients and 1717 cognitively normal (CN) controls, we identified four-digit HLA class I alleles (A, B, and C) and class II alleles (DRB1, DQB1, and DPB1). We found a significant association between the HLA-DRB1*09:01-DQB1*03:03 haplotype and LOAD risk in <i>APOE</i> <span>({rm{varepsilon }})</span>4–negative samples (odds ratio = 1.81, 95% confidence interval = 1.38–2.38, <i>P</i> = 2.03<span>({times 10}^{-5})</span>). These alleles not only showed distinctive frequencies specific to East Asians but demonstrated a high degree of linkage disequilibrium in <i>APOE</i> <span>({rm{varepsilon }})</span>4–negative samples (<i>r</i>² = 0.88). Because HLA class II molecules interact with T-cell receptors (TCRs), we explored potential disparities in the diversities of TCR α chain (TRA) and β chain (TRB) repertoires between <i>APOE</i> <span>({rm{varepsilon }})</span>4–negative LOAD and CN samples. Lower diversity of TRA repertoires was associated with LOAD in <i>APOE</i> <span>({rm{varepsilon }})</span>4-negative samples, irrespective of the HLA DRB1*09:01-DQB1*03:03 haplotype. Our study enhances the understanding of the etiology of LOAD in the Japanese population and provides new insights into the underlying mechanisms of its pathogenesis.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139078363","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":"Absolute quantification of nicotinamide mononucleotide in biological samples by double isotope-mediated liquid chromatography-tandem mass spectrometry (dimeLC-MS/MS)","authors":"Junya Unno, Kathryn F. Mills, Tairo Ogura, Masayuki Nishimura, Shin-ichiro Imai","doi":"10.1038/s41514-023-00133-1","DOIUrl":"https://doi.org/10.1038/s41514-023-00133-1","url":null,"abstract":"<p>Nicotinamide adenine dinucleotide (NAD⁺) is an essential metabolite for fundamental biological phenomena, including aging. Nicotinamide mononucleotide (NMN) is a key NAD⁺ intermediate that has been extensively tested as an effective NAD⁺-boosting compound in mice and humans. However, the accurate measurement of NMN in biological samples has long been a challenge in the field. Here, we have established an accurate, quantitative methodology for measuring NMN by using liquid chromatography-triple quadrupole mass spectrometry (LC-MS/MS) with double isotopic NMN standards. In this new methodology, the matrix effects of biological samples were properly adjusted, and the fate of NMN could be traced during sample processing. We have demonstrated that this methodology can accurately quantitate NMN levels in mouse plasma and confirmed quick, direct NMN uptake into blood circulation and cells. This <u>d</u>ouble <u>i</u>sotope-<u>me</u>diated LC-MS/MS (dimeLC-MS/MS) can easily be expanded to other NAD⁺-related metabolites as a reliable standard methodology for NAD⁺ biology.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2024-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139084658","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":"Mendelian randomization study supports the causal effects of air pollution on longevity via multiple age-related diseases","authors":"Shizheng Qiu, Yang Hu, Guiyou Liu","doi":"10.1038/s41514-023-00126-0","DOIUrl":"https://doi.org/10.1038/s41514-023-00126-0","url":null,"abstract":"<p>Growing evidence suggests that exposure to fine particulate matter (PM_2.5) may reduce life expectancy; however, the causal pathways of PM_2.5 exposure affecting life expectancy remain unknown. Here, we assess the causal effects of genetically predicted PM_2.5 concentration on common chronic diseases and longevity using a Mendelian randomization (MR) statistical framework based on large-scale genome-wide association studies (GWAS) (&gt;400,000 participants). After adjusting for other types of air pollution and smoking, we find significant causal relationships between PM_2.5 concentration and angina pectoris, hypercholesterolaemia and hypothyroidism, but no causal relationship with longevity. Mediation analysis shows that although the association between PM_2.5 concentration and longevity is not significant, PM_2.5 exposure indirectly affects longevity via diastolic blood pressure (DBP), hypertension, angina pectoris, hypercholesterolaemia and Alzheimer’s disease, with a mediated proportion of 31.5, 70.9, 2.5, 100, and 24.7%, respectively. Our findings indicate that public health policies to control air pollution may help improve life expectancy.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2023-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138817759","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":"Author Correction: Age-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease.","authors":"Kristina Bečanović,&nbsp;Muhammad Asghar,&nbsp;Izabella Gadawska,&nbsp;Shiny Sachdeva,&nbsp;David Walker,&nbsp;Eduardo R Lazarowski,&nbsp;Sonia Franciosi,&nbsp;Kevin H J Park,&nbsp;Hélène C F Côté,&nbsp;Blair R Leavitt","doi":"10.1038/s41514-021-00080-9","DOIUrl":"https://doi.org/10.1038/s41514-021-00080-9","url":null,"abstract":"","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2021-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8651687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39578196","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-related mitochondrial alterations in brain and skeletal muscle of the YAC128 model of Huntington disease.","authors":"Kristina Bečanović,&nbsp;Muhammad Asghar,&nbsp;Izabella Gadawska,&nbsp;Shiny Sachdeva,&nbsp;David Walker,&nbsp;Eduardo R Lazarowski,&nbsp;Sonia Franciosi,&nbsp;Kevin H J Park,&nbsp;Hélène C F Côté,&nbsp;Blair R Leavitt","doi":"10.1038/s41514-021-00079-2","DOIUrl":"https://doi.org/10.1038/s41514-021-00079-2","url":null,"abstract":"<p><p>Mitochondrial dysfunction and bioenergetics failure are common pathological hallmarks in Huntington's disease (HD) and aging. In the present study, we used the YAC128 murine model of HD to examine the effects of mutant huntingtin on mitochondrial parameters related to aging in brain and skeletal muscle. We have conducted a cross-sectional natural history study of mitochondrial DNA changes in the YAC128 mouse. Here, we first show that the mitochondrial volume fraction appears to increase in the axons and dendrite regions adjacent to the striatal neuron cell bodies in old mice. Mitochondrial DNA copy number (mtDNAcn) was used as a proxy measure for mitochondrial biogenesis and function. We observed that the mtDNAcn changes significantly with age and genotype in a tissue-specific manner. We found a positive correlation between aging and the mtDNAcn in striatum and skeletal muscle but not in cortex. Notably, the YAC128 mice had lower mtDNAcn in cortex and skeletal muscle. We further show that mtDNA deletions are present in striatal and skeletal muscle tissue in both young and aged YAC128 and WT mice. Tracking gene expression levels cross-sectionally in mice allowed us to identify contributions of age and genotype to transcriptional variance in mitochondria-related genes. These findings provide insights into the role of mitochondrial dynamics in HD pathogenesis in both brain and skeletal muscle, and suggest that mtDNAcn in skeletal muscle tissue may be a potential biomarker that should be investigated further in human HD.</p>","PeriodicalId":19334,"journal":{"name":"NPJ Aging and Mechanisms of Disease","volume":null,"pages":null},"PeriodicalIF":5.0,"publicationDate":"2021-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9232322","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}