Pathobiology of aging & age related diseases最新文献

{"title":"Grip strength is potentially an early indicator of age-related decline in mice.","authors":"Xuan Ge,&nbsp;Anthony Cho,&nbsp;Marcia A Ciol,&nbsp;Christina Pettan-Brewer,&nbsp;Jessica Snyder,&nbsp;Peter Rabinovitch,&nbsp;Warren Ladiges","doi":"10.3402/pba.v6.32981","DOIUrl":"https://doi.org/10.3402/pba.v6.32981","url":null,"abstract":"<p><p>The hand grip test has been correlated with mobility and physical performance in older people and has been shown to be a long-term predictor of mortality. Implementation of new strategies for enhancing healthy aging and maintaining independent living are dependent on predictable preclinical studies. The mouse is used extensively as a model in these types of studies, and the paw grip strength test is similar to the hand grip test for people in that it assesses the ability to grip a device with the paw, is non-invasive and easy to perform, and provides reproducible information. However, little has been reported on how grip strength declines with increasing age in mice. This report shows that grip strength was decreased in C57BL/6 (B6) NIA and C57BL/6×BALB/c F1 (CB6F1) NIA male mice at 12 months of age compared to 8-month-old mice, and continued a robust decline to 20 months and then 28 months of age, when the study was terminated. The decline was not related to lean muscle mass, but extensive age-related carpal and digital exostosis could help explain the decreased grip strength times with increasing age. In conclusion, the grip strength test could be useful in mouse preclinical studies to help make translational predictions on treatment strategies to enhance healthy aging. </p>","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"6 ","pages":"32981"},"PeriodicalIF":0.0,"publicationDate":"2016-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3402/pba.v6.32981","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34734645","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":"Fatty old hearts: role of cardiac lipotoxicity in age-related cardiomyopathy.","authors":"Konstantinos Drosatos","doi":"10.3402/pba.v6.32221","DOIUrl":"https://doi.org/10.3402/pba.v6.32221","url":null,"abstract":"<p><p>Age-related cardiomyopathy accounts for a significant part of heart failure cases. Imbalance of the energetic equilibrium of the heart along with mitochondrial dysfunction and impaired β-adrenergic receptor signaling contributes in the aggravation of cardiac function in the elderly. In this review article, studies that correlate cardiac aging with lipotoxicity are summarized. The involvement of inhibition of peroxisome proliferator-activated receptor-α, β-adrenergic receptor desensitization, and mitochondrial dysfunction as underlying mechanisms for the lipid-driven age-related cardiomyopathy are presented with the aim to indicate potential therapeutic targets for cardiac aging. </p>","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"6 ","pages":"32221"},"PeriodicalIF":0.0,"publicationDate":"2016-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3402/pba.v6.32221","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34388327","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":"Moving toward 'common' use of the marmoset as a non-human primate aging model.","authors":"Adam B Salmon","doi":"10.3402/pba.v6.32758","DOIUrl":"10.3402/pba.v6.32758","url":null,"abstract":"","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"6 ","pages":"32758"},"PeriodicalIF":0.0,"publicationDate":"2016-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9e/29/PBA-6-32758.PMC4958916.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34698504","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":"Pharmaceutical inhibition of mTOR in the common marmoset: effect of rapamycin on regulators of proteostasis in a non-human primate.","authors":"Matthew Lelegren, Yuhong Liu, Corinna Ross, Suzette Tardif, Adam B Salmon","doi":"10.3402/pba.v6.31793","DOIUrl":"10.3402/pba.v6.31793","url":null,"abstract":"<p><strong>Background: </strong>Inhibition of mechanistic target of rapamycin (mTOR) has emerged as a viable means to lengthen lifespan and healthspan in mice, although it is still unclear whether these benefits will extend to other mammalian species. We previously reported results from a pilot experiment wherein common marmosets (Callithrix jacchus) were treated orally with rapamycin to reduce mTOR signaling in vivo in line with previous reports in mice and humans. Further, long-term treatment did not significantly alter body weight, daily activity, blood lipid concentrations, or glucose metabolism in this cohort.</p><p><strong>Methods: </strong>In this study, we report on the molecular consequences of rapamycin treatment in marmosets on mechanisms that regulate protein homeostasis (proteostasis) in vivo. There is growing appreciation for the role of proteostasis in longevity and for the role that mTOR plays in regulating this process. Tissue samples of liver and skeletal muscle from marmosets in our pilot cohort were assessed for expression and activity of components of the ubiquitin-proteasome system, macroautophagy, and protein chaperones.</p><p><strong>Results: </strong>Rapamycin treatment was associated with increased expression of PSMB5, a core subunit of the 20S proteasome, but not PSMB8 which is involved in the formation of the immunoproteasome, in the skeletal muscle and liver. Surprisingly, proteasome activity measured in these tissues was not affected by rapamycin. Rapamycin treatment was associated with an increased expression of mitochondria-targeted protein chaperones in skeletal muscle, but not liver. Finally, autophagy was increased in skeletal muscle and adipose, but not liver, from rapamycin-treated marmosets.</p><p><strong>Conclusions: </strong>Overall, these data show tissue-specific upregulation of some, but not all, components of the proteostasis network in common marmosets treated with a pharmaceutical inhibitor of mTOR.</p>","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"6 ","pages":"31793"},"PeriodicalIF":0.0,"publicationDate":"2016-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/1b/f3/PBA-6-31793.PMC4920937.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34607600","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":"Neuropathological assessment and validation of mouse models for Alzheimer's disease: applying NIA-AA guidelines.","authors":"C Dirk Keene,&nbsp;Martin Darvas,&nbsp;Brian Kraemer,&nbsp;Denny Liggitt,&nbsp;Christina Sigurdson,&nbsp;Warren Ladiges","doi":"10.3402/pba.v6.32397","DOIUrl":"https://doi.org/10.3402/pba.v6.32397","url":null,"abstract":"<p><p>Dozens of transgenic mouse models, generally based on mutations associated with familial Alzheimer's disease (AD), have been developed, in part, for preclinical testing of candidate AD therapies. However, none of these models has successfully predicted the clinical efficacy of drugs for treating AD patients. Therefore, development of more translationally relevant AD mouse models remains a critical unmet need in the field. A concept not previously implemented in AD preclinical drug testing is the use of mouse lines that have been validated for neuropathological features of human AD. Current thinking suggests that amyloid plaque and neurofibrillary tangle deposition is an essential component for accurate modeling of AD. Therefore, the AD translational paradigm would require pathologic Aβ and tau deposition, a disease-relevant distribution of plaques and tangles, and a pattern of disease progression of Aβ and tau isoforms similar to the neuropathological features found in the brains of AD patients. Additional parameters useful to evaluate parallels between AD and animal models would include 1) cerebrospinal fluid (CSF) AD biomarker changes with reduced Aβ and increased phospho-tau/tau; 2) structural and functional neuroimaging patterns including MRI hippocampal atrophy, fluorodeoxyglucose (FDG), and amyloid/tau PET alterations in activity and/or patterns of pathologic peptide deposition and distribution; and 3) cognitive impairment with emphasis on spatial learning and memory to distinguish presymptomatic and symptomatic mice at specific ages. A validated AD mouse model for drug testing would likely show tau-related neurofibrillary degeneration following Aβ deposition and demonstrate changes in pathology, CSF analysis, and neuroimaging that mirror human AD. Development of the ideal model would revolutionize the ability to establish the translational value of AD mouse models and serve as a platform for discussions about national phenotyping guidelines and standards for models of AD and other neurodegenerative disorders. </p>","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"6 ","pages":"32397"},"PeriodicalIF":0.0,"publicationDate":"2016-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3402/pba.v6.32397","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34588278","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":"Adaptations to chronic rapamycin in mice.","authors":"Sherry G Dodds, Carolina B Livi, Manish Parihar, Hang-Kai Hsu, Adriana D Benavides, Jay Morris, Martin Javors, Randy Strong, Barbara Christy, Paul Hasty, Zelton Dave Sharp","doi":"10.3402/pba.v6.31688","DOIUrl":"10.3402/pba.v6.31688","url":null,"abstract":"<p><p>Rapamycin inhibits mechanistic (or mammalian) target of rapamycin (mTOR) that promotes protein production in cells by facilitating ribosome biogenesis (RiBi) and eIF4E-mediated 5'cap mRNA translation. Chronic treatment with encapsulated rapamycin (eRapa) extended health and life span for wild-type and cancer-prone mice. Yet, the long-term consequences of chronic eRapa treatment are not known at the organ level. Here, we report our observations of chronic eRapa treatment on mTORC1 signaling and RiBi in mouse colon and visceral adipose. As expected, chronic eRapa treatment decreased detection of phosphorylated mTORC1/S6K substrate, ribosomal protein (rpS6) in colon and fat. However, in colon, contrary to expectations, there was an upregulation of 18S rRNA and some ribosomal protein genes (RPGs) suggesting increased RiBi. Among RPGs, eRapa increases rpl22l1 mRNA but not its paralog rpl22. Furthermore, there was an increase in the cap-binding protein, eIF4E relative to its repressor 4E-BP1 suggesting increased translation. By comparison, in fat, there was a decrease in the level of 18S rRNA (opposite to colon), while overall mRNAs encoding ribosomal protein genes appeared to increase, including rpl22, but not rpl22l1 (opposite to colon). In fat, there was a decrease in eIF4E relative to actin (opposite to colon) but also an increase in the eIF4E/4E-BP1 ratio likely due to reductions in 4E-BP1 at our lower eRapa dose (similar to colon). Thus, in contrast to predictions of decreased protein production seen in cell-based studies, we provide evidence that colon from chronically treated mice exhibited an adaptive 'pseudo-anabolic' state, which is only partially present in fat, which might relate to differing tissue levels of rapamycin, cell-type-specific responses, and/or strain differences. </p>","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"6 ","pages":"31688"},"PeriodicalIF":0.0,"publicationDate":"2016-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c5/53/PBA-6-31688.PMC4884683.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34592865","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":"Multiple morbidities in companion dogs: a novel model for investigating age-related disease","authors":"Kelly Jin, Jessica M. Hoffman, K. Creevy, D. O'Neill, D. Promislow","doi":"10.3402/pba.v6.33276","DOIUrl":"https://doi.org/10.3402/pba.v6.33276","url":null,"abstract":"The proportion of men and women surviving over 65 years has been steadily increasing over the last century. In their later years, many of these individuals are afflicted with multiple chronic conditions, placing increasing pressure on healthcare systems. The accumulation of multiple health problems with advanced age is well documented, yet the causes are poorly understood. Animal models have long been employed in attempts to elucidate these complex mechanisms with limited success. Recently, the domestic dog has been proposed as a promising model of human aging for several reasons. Mean lifespan shows twofold variation across dog breeds. In addition, dogs closely share the environments of their owners, and substantial veterinary resources are dedicated to comprehensive diagnosis of conditions in dogs. However, while dogs are therefore useful for studying multimorbidity, little is known about how aging influences the accumulation of multiple concurrent disease conditions across dog breeds. The current study examines how age, body weight, and breed contribute to variation in multimorbidity in over 2,000 companion dogs visiting private veterinary clinics in England. In common with humans, we find that the number of diagnoses increases significantly with age in dogs. However, we find no significant weight or breed effects on morbidity number. This surprising result reveals that while breeds may vary in their average longevity and causes of death, their age-related trajectories of morbidities differ little, suggesting that age of onset of disease may be the source of variation in lifespan across breeds. Future studies with increased sample sizes and longitudinal monitoring may help us discern more breed-specific patterns in morbidity. Overall, the large increase in multimorbidity seen with age in dogs mirrors that seen in humans and lends even more credence to the value of companion dogs as models for human morbidity and mortality.","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"11 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87706631","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":"Pathology assessment is necessary to validate translational endpoints in preclinical aging studies","authors":"W. Ladiges","doi":"10.3402/pba.v6.31478","DOIUrl":"https://doi.org/10.3402/pba.v6.31478","url":null,"abstract":"The Geropathology Research Network has established a plan to identify and use pathology-based surrogate endpoints for aging intervention in preclinical drug studies to provide a predictable and short-term anti-aging drug response in line with clinical trials. The plan involves pathological assessment of tissues and organs from strains of old mice, by independent pathology groups in a concurrent manner in order to characterize the changes in lesion incidence and severity in response to anti-aging drugs at specific time points. This approach allows for connection with translational endpoints of aging, such as serum factors and physiological parameters, between mice and humans. Preclinical drug testing is a critical component of the plan, designed to shorten testing times from lengthy lifespan studies by comparing lesion grades and composite scores in treated and placebo cohorts at cross-sectional time points. In conclusion, a geropathology-based preclinical testing program is a step toward assuring maximum utilization of translational resources and increasing predictability of efficacy of new or repurposed drugs for clinical aging intervention studies.","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82950626","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":"Cardiovascular KATP channels and advanced aging","authors":"Hua-Qian Yang, E. Subbotina, R. Ramasamy, W. Coetzee","doi":"10.3402/pba.v6.32517","DOIUrl":"https://doi.org/10.3402/pba.v6.32517","url":null,"abstract":"With advanced aging, there is a decline in innate cardiovascular function. This decline is not general in nature. Instead, specific changes occur that impact the basic cardiovascular function, which include alterations in biochemical pathways and ion channel function. This review focuses on a particular ion channel that couple the latter two processes, namely the KATP channel, which opening is promoted by alterations in intracellular energy metabolism. We show that the intrinsic properties of the KATP channel changes with advanced aging and argue that the channel can be further modulated by biochemical changes. The importance is widespread, given the ubiquitous nature of the KATP channel in the cardiovascular system where it can regulate processes as diverse as cardiac function, blood flow and protection mechanisms against superimposed stress, such as cardiac ischemia. We highlight questions that remain to be answered before the KATP channel can be considered as a viable target for therapeutic intervention.","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73628959","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":"Mitochondrial catalase suppresses naturally occurring lung cancer in old mice.","authors":"Xuang Ge,&nbsp;Christina Pettan-Brewer,&nbsp;John Morton,&nbsp;Katrina Carter,&nbsp;Sy Fatemi,&nbsp;Peter Rabinovitch,&nbsp;Warren C Ladiges","doi":"10.3402/pba.v5.28776","DOIUrl":"https://doi.org/10.3402/pba.v5.28776","url":null,"abstract":"<p><p>Lung cancer is generally difficult to detect until the late stages of disease, when it is much more difficult to treat because of the more aggressive and invasive behavior. Advanced lung cancer is much more common in older adults making it even more challenging to treat. Adenocarcinoma belongs to a category of non-small cell lung cancers, which comprise up to 40% of all lung cancers, and about half of these have an activating K-ras mutation. Because treatment relapses are common, more effective unconventional treatment and prevention methods are needed. In this regard, the antioxidant enzyme catalase targeted to mitochondria (mCAT) has been shown to delay aging and cancer in mice, and the progression of transgenic oncogene and syngeneic tumors was suppressed, helping support the notion that attenuation of mitochondria-generated hydrogen peroxide signaling is associated with an antitumor effect. In order to determine if mCAT has any effect on naturally occurring lung cancer of the adenocarcinoma type in old mice, the tumor incidence and progression were examined in the lungs of old mCAT transgenic and wild-type (WT) mice with a CB6F1 (Balb/c X C57BL/6) background. CB6F1 mice with a WT genotype were found to have a high incidence of adenomas at 24 months of age, which progressed to adenocarcinomas at 32 months of age. CB6F1 mice with the mCAT genotype had significantly reduced incidence and severity of lung tumors at both ages. Fibroblasts isolated from the lungs of old mCAT mice, but not WT mice, were shown to secrete soluble factors that inhibited lung tumor cell growth suggesting that stromal fibroblasts play a role in mediating the antitumor effects of mCAT. The aged CB6F1 mouse, with its high incidence of K-ras mutant lung cancer, is an excellent model to further study the anticancer potential of mitochondria-targeted therapy. </p>","PeriodicalId":89611,"journal":{"name":"Pathobiology of aging & age related diseases","volume":"5 ","pages":"28776"},"PeriodicalIF":0.0,"publicationDate":"2015-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.3402/pba.v5.28776","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34199262","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}