Pathobiology of aging & age related diseases最新文献

{"title":"A geroscience mouse model for Alzheimer's disease.","authors":"Martin Darvas, Dirk Keene, Warren Ladiges","doi":"10.1080/20010001.2019.1616994","DOIUrl":"https://doi.org/10.1080/20010001.2019.1616994","url":null,"abstract":"Geroscience is a multidisciplinary field that examines the relationship between biological aging and agerelated diseases [1]. Seven processes discussed by the trans-NIH Geroscience Interest Group Summit that contribute to biological aging included macromolecular damage, epigenetic changes, inflammation, adaptation to stress, impairments to proteostasis, stem cell regeneration, and metabolism [2]. These processes are highly integrated with one another such that targeting them as a group may be an effective approach to developing therapies to prevent or delay age-related disease. Alzheimer’s disease (AD) is an age-related disease and is expected to increase with the number of elderly individuals rapidly rising in both developed and developing countries. Efforts to find diseasemodifying treatments have met with limited success possibly because they have focused on identifying a specific pathogenic mechanism targeted by a specific drug. AD is a complex disease involving numerous mechanisms in line with processes of biological aging. Therefore, a geroscience approach to successfully treating AD is a logical concept that unfortunately has not yet been widely accepted by the neuroscience community. It is now time to explore preclinical studies in AD animal models to begin screening different drug combinations that target multiple aging-related processes for effect on AD dementia and neuropathology. A major challenge for preclinical drug testing is the selection of an AD animal model. A model is needed that shows amyloid (A) β and tau neuropathology, inflammation, oxidative stress, neuronal degeneration, and neurovascular deficits in an aging background. Currently available models are transgenic mice expressing amyloid precursor protein (APP) and presenilin mutations found in patients with early onset of AD. These mouse models are useful, but develop lesions at an early age, and none represent all the mechanisms representative of human AD. Ideally, the model should be easily manipulated so that dementia and neuropathology can be induced in an old-age animal as well as middle age, and young age to compare disease progression in different aging backgrounds. The animal of choice for large-scale drug testing is the mouse, but the rat could also be considered. There are advantages and disadvantages for both but our lab has extensive experience with aging mice so the aging mouse will be the prototype animal for this discussion. Aging in mice is in many ways similar to aging in people, so the geroscience concept is applicable, as depicted in Figure 1. The two hall-mark molecular pathologic changes of AD are accumulation of amyloid β 42 peptides (Aβ42) and paired helical filament (PHF)-tau (τ). Aβ42 pathology is not evenly distributed, but systematically localized to certain parts of the brain, following a prototypical sequence in which the regions are hierarchically involved: cortical Aβ42 deposits, followed by involvement of allocortical regions, involvement o","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"9 1","pages":"1616994"},"PeriodicalIF":0.0,"publicationDate":"2019-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/20010001.2019.1616994","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37290250","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":"Mice expressing an XRCC1 truncated protein are at increased risk for insulin resistance.","authors":"Kavita Sharma,&nbsp;Jinzi Wu,&nbsp;Shu Xian Lee,&nbsp;Warren C Ladiges,&nbsp;Jorming Goh","doi":"10.1080/20010001.2019.1603517","DOIUrl":"https://doi.org/10.1080/20010001.2019.1603517","url":null,"abstract":"<p><p>Insulin resistance is a metabolic disorder that is highly prevalent in older populations. Mice expressing a truncated X-ray repair cross-complementing protein 1 (XRCC1tp) have normal repair of single-stranded breaks (SSBs) but are sensitive to alkylating agents. XRCC1tp mice thus provide a model to study perturbations in physiological function, such as metabolism, in the presence of normal DNA repair but attenuated XRCC1 activity. XRCC1tp male mice at six months of age fed a diet high in fat (lard) and sugar (sucrose) (HFSD) for three months showed a significant delay in glucose clearance, indicative of insulin resistance. These mice also had a decrease in respiratory exchange ratio, suggesting a change in the way fats and carbohydrates are used as a fuel source. Mechanisms for these observations are of interest, since there is a suggestion that XRCC1 is involved in glucoregulatory pathways, and XRCC1tp mice would provide an excellent model to pursue these studies in an age-related manner.</p>","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"9 1","pages":"1603517"},"PeriodicalIF":0.0,"publicationDate":"2019-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/20010001.2019.1603517","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37996172","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":"Barshop Symposium on Aging 2018 Abstracts","authors":"W. Ladiges","doi":"10.1080/20010001.2019.1591258","DOIUrl":"https://doi.org/10.1080/20010001.2019.1591258","url":null,"abstract":"The theme of the 2018 Barshop Symposium on Aging at the Mayan Ranch in Bandera, Texas, USA was ‘Exercise regulation of biological aging’. Drs. Nicolas Musi and Darpan Patel were the conference orga...","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88285324","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":"Pathobiology of aging and age-related diseases is the official journal of the Geropathology Research Network.","authors":"Warren Ladiges","doi":"10.1080/20010001.2019.1593786","DOIUrl":"https://doi.org/10.1080/20010001.2019.1593786","url":null,"abstract":"We are pleased to announce that Pathobiology of Aging and Age-related Diseases is now the official journal of the Geropathology Research Network (GRN). In this capacity, the GRN will use the journal to publish workshop and conference proceedings, as well as technical articles related to pathological assessment of age-related lesions in rodents, other laboratory animals, pet dogs and cats, other domestic animals, nonhuman primates, and humans. The GRN has an active working committee, designated as the Geropathology Grading Committee, focusing on the establishment of guidelines for grading severity of lesions in tissues collected from mice in genetic or pharmacological aging intervention studies. In addition, Lesion of the Month and Geropathology in practice sections will be added to the journal. It is anticipated that these additions will be of interest, and help generate comments and feedback, as well as provide an increased awareness of the critical role geropathology plays in aging research, especially in preclinical studies, but in clinical studies as well. In addition to an active lesion grading committee, the GRN has an active molecular pathology working group focusing on identifying and characterizing secretory proteins associated with aging and age-related diseases, especially neurological. The group, designated as the Geropathology Secretome Committee, will be contributing technical as well as scientific articles for publication. Lastly, as the result of extensive tissue collection from rodents in aging studies in the last several years, the GRN has established a Geropathology Rodent Tissue Bank. This is just now getting started and will be ready for requests in the coming months from the scientific community. The journal will publish links for the tissue bank database, and periodic updates for issues of interest. We look forward to these relevant and interesting contributions. PATHOBIOLOGY OF AGING & AGE-RELATED DISEASES 2019, VOL. 9, 1593786 https://doi.org/10.1080/20010001.2019.1593786","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"9 1","pages":"1593786"},"PeriodicalIF":0.0,"publicationDate":"2019-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/20010001.2019.1593786","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"37090386","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":"Evaluation of the pharmacokinetics of metformin and acarbose in the common marmoset","authors":"Elizabeth Fernandez, C. Ross, Hanyu Liang, M. Javors, S. Tardif, A. Salmon","doi":"10.1080/20010001.2019.1657756","DOIUrl":"https://doi.org/10.1080/20010001.2019.1657756","url":null,"abstract":"ABSTRACT Metformin has beneficial effects on several age-related diseases (e.g., diabetes, obesity, cancer) and extends lifespan in nematodes and mice. Acarbose, an FDA-approved agent for treating type 2 diabetes, prevents breakdown of complex carbohydrates. Both compounds have been suggested as potential anti-aging interventions and acarbose has been shown to extend mouse longevity by the Intervention Testing Program (ITP). One potential next step is to assess the effect of these interventions on healthspan and lifespan in non-human primates. The common marmoset (Callithrix jacchus) is a small new world monkey with a relatively short life span and small size, both valuable for the translation potential of this nonhuman primate species for the study of aging and chronic disease. However, the dosing and assessment of potential side effects of either metformin or acarbose in this species have yet to be assessed. This study evaluated the pharmacokinetics of two dosage levels each of metformin or acarbose (given separately) in two small groups of young marmosets (n = 5/group) treated for 24 h to define the pharmacokinetics of each drug. The ability to rapidly and reliably dose socially housed marmosets with an oral form of acarbose or metformin that is well tolerated indicates that this species is a reliable model for testing acarbose and metformin in a safe and efficient way in a long-term intervention.","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"14 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77723453","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":"Wheel running predicts resilience to tumors in old mice","authors":"Lida Zhu, Juan Wang, C. Pettan-Brewer, W. Ladiges, Jorming Goh","doi":"10.1080/20010001.2019.1676104","DOIUrl":"https://doi.org/10.1080/20010001.2019.1676104","url":null,"abstract":"ABSTRACT Aging intervention studies are hampered by the lack of predictive measures for determination of individuals at risk of age-associated chronic disease. Assessment of physical resilience could be informative in this regard, especially for age-related diseases such as cancer. Voluntary wheel running is a mildly stressful physical activity that is easily quantifiable in the mouse but has not been studied as a predictor of resistance to tumor invasiveness with increasing age. Male C57BL/6 mice in cohorts of 4, 12, 20, and 28 months of age were allowed access to a slanted in-cage running wheel for 3 days. Three months later, mice were injected subcutaneously with B16 melanoma tumor cells and followed for two weeks before harvesting. No relation was observed between running distance and tumor burden in the 4-month age group. The 12-month age group showed a trend, and the 20- and 28-month age groups showed a negative correlation (P < 0.05) between running distance and tumor burden. Mice in the 20-month age group that ran longer distances had lower tumor invasive scores compared to mice in the same age group that ran shorter distances. In conclusion, short term exercise capability could be a marker for resilience to cancer, and possibly other age-related disease conditions, in mice.","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81922473","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":"A minimally invasive, low-stress method for serial blood collection in aging mice","authors":"Marianne Bjorner, Lida Zhu","doi":"10.1080/20010001.2019.1647400","DOIUrl":"https://doi.org/10.1080/20010001.2019.1647400","url":null,"abstract":"ABSTRACT Hematologic analysis is an efficient and valuable tool for real-time health monitoring and immune analysis in mouse aging studies. However, many frequently used blood sampling techniques in mice are incompatible with continuous monitoring with increasing age, as they may involve anesthesia, cause severe stress, or require a high volume of blood. This technical report describes a convenient relatively noninvasive procedure for counting white blood cells in C57Bl/6 mice by an optimized tail blood collection method followed by Wright-Giemsa and Türk staining. This technique can be performed on unanesthetized mice in less than 1 min with minimal stress using only a few microliters of blood. White blood cell analysis can include but is not limited to total and differential white blood cell count and cell morphology. The low blood volume collected is ideal for aging mice in longer-term experiments requiring regular and continuous monitoring.","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90922498","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":"Rapamycin increases breast tumor burden in young wheel-running mice","authors":"Juan Wang, Thomas Truong, W. Ladiges, Jorming Goh","doi":"10.1080/20010001.2019.1647746","DOIUrl":"https://doi.org/10.1080/20010001.2019.1647746","url":null,"abstract":"ABSTRACT Rapamycin is an immunosuppressive and anti-cancer drug recently shown to enhance healthy aging in animal models. Regular physical exercise is associated with healthy aging and reduced risk of age-related diseases, such as cancer. In order to test the combined effect of these approaches, mice with 4T1 breast cancer were fed rapamycin at 14 ppm and allowed access to voluntary running wheels. After 17 days of treatment, mice fed the rapamycin diet that ran showed a significant increase in tumor burden compared with mice that did not run (P = 0.017). Not only does this have implications for young breast cancer patients, but suggests that combining rapamycin and exercise as an anti-aging strategy at a young age might be contraindicated.","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86149375","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":"Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice.","authors":"Lisa C Flores,&nbsp;Madeline G Roman,&nbsp;Geneva M Cunningham,&nbsp;Christie Cheng,&nbsp;Sara Dube,&nbsp;Colton Allen,&nbsp;Holly Van Remmen,&nbsp;Gene B Hubbard,&nbsp;Thomas L Saunders,&nbsp;Yuji Ikeno","doi":"10.1080/20010001.2018.1533754","DOIUrl":"https://doi.org/10.1080/20010001.2018.1533754","url":null,"abstract":"<p><p>We examined the effects of continuous overexpression of thioredoxin (Trx) 1 on aging in Trx1 transgenic mice [Tg(<i>TXN</i>)^+/0]. This study was conducted to test whether increased thioredoxin expression over the lifespan in mice would alter aging and age-related pathology because our previous study demonstrated that Tg(act-<i>TXN</i>)^+/0 mice had no significant maximum life extension, possibly due to the use of actin as a promoter, which may have resulted in loss of Trx1 overexpression during aging. To test this hypothesis, we generated new Trx1 transgenic mice using a fragment of the human genome containing the <i>TXN</i> gene with an endogenous promoter to ensure continuous overexpression of Trx1 throughout the lifespan. Universal overexpression of Trx1 was observed, and Trx1 overexpression was maintained during aging (up to 22-24 months old) in the Tg(<i>TXN</i>)^+/0 mice. The levels of Trx1 are significantly higher (approximately 4 to 31 fold) in all of the tissues examined in the Tg(<i>TXN</i>)^+/0 mice compared to the wild-type (WT) littermates. The overexpression of Trx1 did not cause any changes in the levels of Trx2, glutaredoxin, glutathione, or other major antioxidant enzymes. The survival study demonstrated that male Tg(<i>TXN</i>)^+/0 mice slightly extended the earlier part of the lifespan compared to WT littermates, but no significant life extension was observed over the lifespan. The cross-sectional pathological analysis (22-25 months old) showed that Tg(<i>TXN</i>)^+/0 mice had a significantly higher severity of lymphoma and more tumor burden than WT mice, which was associated with the suppression of the apoptosis signal-regulating kinase 1 (ASK1) pathway. Our findings suggest that the increased levels of Trx1 over the lifespan in Tg(<i>TXN</i>)^+/0 mice showed some beneficial effects (slight extension of lifespan) in the earlier part of life but had no significant effects on median or maximum lifespans, and increased Trx1 levels enhanced tumor development in old mice.</p>","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"8 1","pages":"1533754"},"PeriodicalIF":0.0,"publicationDate":"2018-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/20010001.2018.1533754","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36625012","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":"Modeling Alzheimer's disease in progeria mice. An age-related concept.","authors":"Kavita Sharma,&nbsp;Martin Darvas,&nbsp;C Dirk Keene,&nbsp;Laura J Niedernhofer,&nbsp;Warren Ladiges","doi":"10.1080/20010001.2018.1524815","DOIUrl":"https://doi.org/10.1080/20010001.2018.1524815","url":null,"abstract":"<p><p>The prevalence of Alzheimer's disease (AD) is expected to dramatically increase in older people worldwide. Efforts to find disease-modifying treatments have been largely unsuccessful because of the focus on disease-specific pathogenesis, and lack of animal models to study AD in the context of aging and age-related co-morbidities. The geroscience approach to studying AD would suggest that modulation of aging <i>per se</i> would be a useful strategy, but a mammalian model system that combines both aging and AD is not available. One approach to study old age and AD is to utilize murine models of progeroid syndrome, which can provide a number of advantages not only for basic aging biology but also for preclinical drug testing. A progeria background, such as the <i>Ercc1</i> mutant mouse (<i>Ercc1^-/Δ</i> ), provides an aging component not seen in current murine models of AD that lack age-related co-morbidities typical of AD patients. <i>Ercc1^-/Δ</i> mice experience the same types of stochastic endogenous DNA damage as WT mice, but accumulate lesions faster due to impaired DNA repair, which accelerates the normal aging process by 6-fold. These mice do not show frank AD pathology but represent a predisposed or hypersensitive environment for AD pathology, where pathogenic elements of AD can be introduced, either by crossing with well-established AD transgenic mouse lines, or transcranial stereotaxic delivery directly into the brain. Since <i>Ercc1^-/Δ</i> mice age five to six times faster than WT mice, very rapid characterization and testing of therapeutic interventions is possible. Studies are urgently needed to capitalize on the highly informative potential of this novel AD mouse model.</p>","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"8 1","pages":"1524815"},"PeriodicalIF":0.0,"publicationDate":"2018-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1080/20010001.2018.1524815","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"36584842","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}