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Cover Illustration
2018, Vol.9  No.6
Figure 10. Embryonic development and organization structure of TE/SJ/ mesenchymal tissue system. Mesenchymal tissue system consists of mesodermal-derived all kinds of cells (Flk+Lin-/KLF4+GMNN+) from postembryonic subtotipotent stem cells to functional cells in different stages of the embryonic development. In mammals, the intraembryonic coelom is a fluid-filled cavity with the somatic and the visceral mesoderm layers, which then forms TE/SJ/mesenchymal tissue system. Meanwhile, TE/SJ/mesenchymal tissue system constitutes the source of major organs and is the connecting pathway between them. It is involved in the proliferation and differentiation of stem cells, tissue regeneration, and functional reconstruction. It also participates in human immune surveillance, cellular senescence and tissue metabolic.

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  • Table of Content
      04 December 2018, Volume 9 Issue 6 Previous Issue    Next Issue
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    Orginal Article
    Vitamin D Receptor in Muscle Atrophy of Elderly Patients: A Key Element of Osteoporosis-Sarcopenia Connection
    Manuel Scimeca, Federica Centofanti, Monica Celi, Elena Gasbarra, Giuseppe Novelli, Annalisa Botta, Umberto Tarantino
    Aging and disease. 2018, 9 (6): 952-964.   DOI: 10.14336/AD.2018.0215
    Abstract   HTML   PDF (1144KB) ( 701 )

    In this study, we investigated the relationship between sarcopenia (evaluated in term of fibers atrophy), vitamin d receptor protein expression and TaqI/Cdx2/FokI VDR genotypes in an Italian cohort of osteoporosis(n=44) and osteoarthritis (n=55) patients. Muscle biopsies were fixed and investigated by both immunohistochemistry (vitamin d receptor expression) and transmission electron microscopy (satellite stem cells niches). Vitamin d receptor polymorphisms were studied on DNA extracted from muscle paraffin sections. For the first time, we reported that aging differently affects the VDR activation in OA and OP patients. In particular, while in OP patients we observed a significant reduction of VDR positive myonuclei with age, no “age effect” was observed in OA patients. The frequent activation of VDR could explain the lower number of atrophic fiber that we observed in OA patients respect to OP. From genetic point of view, we showed a putative association among polymorphisms FokI and Cdx2 of VDR gene, vitamin d receptor activation and the occurrence of sarcopenia. Altogether these data open new prospective for the prevention and cure of age-related muscle disorders.

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    Prognostic Nomogram Associated with Longer Survival in Amyotrophic Lateral Sclerosis Patients
    Qian-Qian Wei, Yongping Chen, Xueping Chen, Bei Cao, RuWei Ou, Lingyu Zhang, Yanbing Hou, Huifang Shang
    Aging and disease. 2018, 9 (6): 965-975.   DOI: 10.14336/AD.2017.1016
    Abstract   HTML   PDF (915KB) ( 497 )

    Better understanding of survival factors in amyotrophic lateral sclerosis (ALS) could help physicians and patients schedule therapeutic interventions. We conducted a study to evaluate the predictive factors associated with longer survival and construct prognostic nomogram in ALS patients. A total of 553 ALS patients were enrolled and divided into 2 groups: a training set and a validation set. Risk factors for survival were identified using logistic regression analysis, and a nomogram created by R program was performed to predict the probability of longer survival in the training set; then receiver operating characteristic (ROC) analysis was applied to assess predictive value of the nomogram model. The median survival time was 3.2 years for all patients. Multivariate analyses revealed that age of onset, rate of disease progression, hemoglobin A1c (HbA1c) level, body mass index, creatinine, creatine kinase (CK), and non-invasive positive pressure ventilation (NIPPV) were independent predictors of longer survival. A nomogram based on the above seven predictive factors was developed to predict the possibility of longer survival. The ROC curve of the nomogram demonstrated good discrimination ability with an AUC of 0.92 (95% CI: 0.88-0.96) in the validation set. In ALS, serum CK, creatinine and HbA1c levels at baseline were independent biomarkers of longer survival. The prognostic nomogram model that integrated all significant independent factors for those who survived longer than 3 years provides an effective way to predict the probability of longer survival and can help doctors evaluate the disease progression and give personalized treatment recommendations.

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    Age-Related Changes in Femoral Head Trabecular Microarchitecture
    Charlene Greenwood, John Clement, Anthony Dicken, Paul Evans, Iain Lyburn, Richard M. Martin, Nick Stone, Peter Zioupos, Keith Rogers
    Aging and disease. 2018, 9 (6): 976-987.   DOI: 10.14336/AD.2018.0124
    Abstract   HTML   PDF (766KB) ( 616 )

    Osteoporosis is a prevalent bone condition, characterised by low bone mineral density and increased fracture risk. Currently, the gold standard for identifying osteoporosis and increased fracture risk is through quantification of bone mineral density using dual energy X-ray absorption. However, many studies have shown that bone strength, and consequently the probability of fracture, is a combination of both bone mass and bone ‘quality’ (architecture and material chemistry). Although the microarchitecture of both non-fracture and osteoporotic bone has been previously investigated, many of the osteoporotic studies are constrained by factors such as limited sample number, use of ovariectomised animal models, and lack of male and female discrimination. This study reports significant differences in bone quality with respect to the microarchitecture between fractured and non-fractured human femur specimens. Micro-computed tomography was utilised to investigate the microarchitecture of femoral head trabecular bone from a relatively large cohort of non-fracture and fracture human donors. Various microarchitectural parameters have been determined for both groups, providing an understanding of the differences between fracture and non -fracture material. The microarchitecture of non-fracture and fracture bone tissue is shown to be significantly different for many parameters. Differences between sexes also exist, suggesting differences in remodelling between males and females in the fracture group. The results from this study will, in the future, be applied to develop a fracture model which encompasses bone density, architecture and material chemical properties for both female and male tissues.

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    Muscle Fatigue Does Not Change the Effects on Lower Limbs Strength Caused by Aging and Parkinson’s Disease
    Vinicius Alota Ignacio Pereira, Fabio Augusto Barbieri, Alessandro Moura Zagatto, Paulo Cezar Rocha dos Santos, Lucas Simieli, Ricardo Augusto Barbieri, Felipe Pivetta Carpes, Lilian Teresa Bucken Gobbi
    Aging and disease. 2018, 9 (6): 988-998.   DOI: 10.14336/AD.2018.0203
    Abstract   HTML   PDF (642KB) ( 1293 )

    The aim of this study was to determine the impact of aging and Parkinson’s disease (PD) on lower limb muscle strength before and after muscle fatigue. One hundred thirty-five individuals were distributed over seven groups according to their age (20, 30, 40, 50, 60, 70 years old) and disease. Participants performed maximum voluntary isometric contractions (MVIC) in a leg press device followed by the muscle fatigue protocol (repeated sit-to-stand task). Immediately after muscle fatigue (less than 2 min), the MVIC were repeated. The peak force, peak rate of force development (first 50, 100, 200 ms), and root mean square and peak values of the vastus lateralis and vastus medialis muscle activity during MVIC were calculated before and after muscle fatigue. We found more pronounced reductions in lower limb muscle strength parameters (lower limb force, RFD-100 and RFD-200 - p<0.05) in individuals over 50 years of age and with PD. In addition, there was an inverse relation between aging and lower limb muscle strength parameters. The main findings were the lack of changes in peak force, RFDs and muscle activity of the vastus lateralis and vastus medialis after muscle fatigue according to aging and PD, and similar lower limb muscle strength parameters (before and after muscle fatigue) and effect of muscle fatigue in PD compared to the aged groups (60 and 70 years old groups).

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    Relationship between White Matter Hyperintensities and Hematoma Volume in Patients with Intracerebral Hematoma
    Xuemei Chen, Yuexinzi Jin, Jian Chen, Xin Chen, Xiang Cao, Linjie Yu, Yun Xu
    Aging and disease. 2018, 9 (6): 999-1009.   DOI: 10.14336/AD.2018.0108
    Abstract   HTML   PDF (664KB) ( 458 )

    The relationship of white-matter hyperintensity (WMH) to intracerebral hemorrhage (ICH) remains unclear. In this retrospective study, we investigated whether the severity and progression of WMH could be related to the hematoma volume and absorption in ICH. 2338 WMH patients with ICH aged≥40 years receiving brain computed tomography (CT) imaging within 12 hours of ICH symptom onset were screened, and 227 patients were included in the final study. The severity and progression of WMH were assessed using the software programs MRICRON and ITK-SNAP on brain magnetic resonance imaging (MRI) and the hematoma volumes and absorption with ITK-SNAP software on CT. We assessed the association of WMH severity with ICH volume in 227 patients at baseline. Totally 183 of 227 patients underwent repeated CT within 14 days of ICH onset. The relationship of WMH severity to ICH absorption was analyzed in 183 patients. Additionally, among all 227 patients, 37 subjected to another MRI before ICH onset were divided into two groups according to WMH progression: non-progression and progression groups. The link between WMH progression and hematoma volume was examined. The ICH volume was significantly larger in patients with the highest WMH scores than in those with the lowest WMH scores. Larger WMH volume was independently associated with larger ICH volume (odds ratio 1.00; 95% CI, 1.00 to 1.00; P = 0.049). There was a trend towards WMH progression being related to ICH volume (P =0.049). Contrastingly, the WMH volume was not linked with hematoma absorption (P = 0.79). In conclusion, we found that greater severity and progression of WMH were associated with larger ICH volume. Our findings suggest that WMH might provide important prognostic information about patients with ICH and may have implications for treatment stratification.

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    Stronger Association between Insomnia Symptoms and Shorter Telomere Length in Old HIV-Infected Patients Compared with Uninfected Individuals
    Yingying Ding, Haijiang Lin, Sujuan Zhou, Keran Wang, Lingling Li, Yucheng Zhang, Yuan Yao, Meiyang Gao, Xing Liu, Na He
    Aging and disease. 2018, 9 (6): 1010-1019.   DOI: 10.14336/AD.2018.0204
    Abstract   HTML   PDF (637KB) ( 659 )

    Growing evidence suggests that HIV infection may accelerate biological aging. Insomnia symptoms, particularly in later life, exacerbate cellular aging. We examined the association between insomnia symptoms and leukocyte telomere length (LTL), and further explored how this association was affected by HIV serostatus and age. Data were assessed from 244 HIV-infected individuals ≥40 years and 244 HIV-uninfected individuals who were frequency-matched by age, gender and education level. Insomnia symptoms were assessed by responses to four sleep-related questions covering the past month. We performed multivariable linear regression with logarithmically transformed LTL and reported exponentiated coefficients. HIV-infected individuals had shorter LTL compared to uninfected individuals (geometric mean 0.82 vs 0.89, P=0.052), and this association remained after adjustment for gender, education level, and smoking history (-7.4%, P=0.051) but markedly attenuated after additional adjustment for insomnia and depressive symptoms (-3.7%, P=0.367). Significant interactions between age group (55-82 vs 40-54 years) and insomnia symptoms on LTL were observed in the HIV-infected individuals (-28.4%, P=0.033) but not the uninfected (-17.9%, P=0.250). After stratifying by age group, LTL was independently associated with insomnia symptoms in those 55 years and older among the HIV-infected individuals (-24.5%, P=0.026) but not those 40-54 years old (-9.8%, P=0.428). Our findings suggest that elevated insomnia and depressive symptoms may partly explain the correlation between HIV serostatus and shorter LTL. Significant association between insomnia and shorter LTL observed in elderly HIV-infected but not in uninfected individuals suggest that such adverse effect may begin at an earlier age or is more pronounced in HIV-infected individuals but requires further investigation.

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    Relationship between Cortical Thickness and Neuropsychological Performance in Normal Older Adults and Those with Mild Cognitive Impairment
    Calvin Pak-Wing Cheng, Sheung-Tak Cheng, Cindy Woon-Chi Tam, Wai-Chi Chan, Winnie Chiu-Wing Chu, Linda Chiu-Wa Lam
    Aging and disease. 2018, 9 (6): 1020-1030.   DOI: 10.14336/AD.2018.0125
    Abstract   HTML   PDF (610KB) ( 512 )

    Mild cognitive impairment (MCI) has been extensively investigated in recent decades to identify groups with a high risk of dementia and to establish effective prevention methods during this period. Neuropsychological performance and cortical thickness are two important biomarkers used to predict progression from MCI to dementia. This study compares the cortical thickness and neuropsychological performance in people with MCI and cognitively healthy older adults. We further focus on the relationship between cortical thickness and neuropsychological performance in these two groups. Forty-nine participants with MCI and 40 cognitively healthy older adults were recruited. Cortical thickness was analysed with semiautomatic software, Freesurfer. The analysis reveals that the cortical thickness in the left caudal anterior cingulate (p=0.041), lateral occipital (p=0.009) and right superior temporal (p=0.047) areas were significantly thinner in the MCI group after adjustment for age and education. Almost all neuropsychological test results (with the exception of forward digit span) were significantly correlated to cortical thickness in the MCI group after adjustment for age, gender and education. In contrast, only the score on the Category Verbal Fluency Test and the forward digit span were found to have significant inverse correlations to cortical thickness in the control group of cognitively healthy older adults. The study results suggest that cortical thinning in the temporal region reflects the global change in cognition in subjects with MCI and may be useful to predict progression of MCI to Alzheimer’s disease. The different pattern in the correlation of cortical thickness to the neuropsychological performance of patients with MCI from the healthy control subjects may be explained by the hypothesis of MCI as a disconnection syndrome.

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    Omi/HtrA2 Participates in Age-Related Autophagic Deficiency in Rat Liver
    Jiahui Xu, Kun Jiao, Xin Liu, Qi Sun, Ke Wang, Haibo Xu, Shangyue Zhang, Ye Wu, Linguo Wu, Dan Liu, Wen Wang, Huirong Liu
    Aging and disease. 2018, 9 (6): 1031-1042.   DOI: 10.14336/AD.2018.0221
    Abstract   HTML   PDF (1815KB) ( 644 )

    Liver is a vital organ with many important functions, and the maintenance of normal hepatic function is necessary for health. As an essential mechanism for maintaining cellular homeostasis, autophagy plays an important role in ensuring normal organ function. Studies have indicated that the degeneration of hepatic function is associated with autophagic deficiency in aging liver. However, the underlying mechanisms still remain unclear. The serine protease Omi/HtrA2 belongs to the HtrA family and promotes apoptosis through either the caspase-dependent or caspase-independent pathway. Mice lacking Omi/HtrA2 exhibited progeria symptoms (premature aging), which were similar to the characteristics of autophagic insufficiency. In this study, we demonstrated that both the protein level of Omi/HtrA2 in liver and hepatic function were reduced as rats aged, and there was a positive correlation between them. Furthermore, several autophagy-related proteins (LC3II/I, Beclin-1 and LAMP2) in rat liver were decreased significantly with the increasing of age. Finally, inhibition of Omi/HtrA2 resulted in reduced autophagy and hepatic dysfunction. In conclusion, these results suggest that Omi/HtrA2 participates in age-related autophagic deficiency in rat liver. This study may offer a novel insight into the mechanism involved in liver aging.

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    A Transcriptome Study of Progeroid Neurocutaneous Syndrome Reveals POSTN As a New Element in Proline Metabolic Disorder
    Yu-Wen Huang, Ming-Fu Chiang, Che-Sheng Ho, Pi-Lien Hung, Mei-Hsin Hsu, Tsung-Han Lee, Lichieh Julie Chu, Hsuan Liu, Petrus Tang, Wailap Victor Ng, Dar-Shong Lin
    Aging and disease. 2018, 9 (6): 1043-1057.   DOI: 10.14336/AD.2018.0222
    Abstract   HTML   PDF (1236KB) ( 643 )

    Aging is a complex biological process. A study of pyrroline-5-carboxylate reductase 1 (PYCR1) deficiency, which causes a progeroid syndrome, may not only shed light on its genetic contribution to autosomal recessive cutis laxa (ARCL) but also help elucidate the functional mechanisms associated with aging. In this study, we used RNA-Seq technology to examine gene expression changes in primary skin fibroblasts from healthy controls and patients with PYCR1 mutations. Approximately 22 and 32 candidate genes were found to be up- and downregulated, respectively, in fibroblasts from patients. Among the downregulated candidates in fibroblasts with PYCR1 mutations, a strong reduction in the expression of 17 genes (53.1%) which protein products are localized in the extracellular space was detected. These proteins included several important ECM components, periostin (POSTN), elastin (ELN), and decorin (DCN); genetic mutations in these proteins are associated with different phenotypes of aging, such as cutis laxa and joint and dermal manifestations. The differential expression of ten selected extracellular space genes was further validated using quantitative RT-PCR. Ingenuity Pathway Analysis revealed that some of the affected genes may be associated with cardiovascular system development and function, dermatological diseases and conditions, and cardiovascular disease. POSTN, one of the most downregulated gene candidates in affected individuals, is a matricellular protein with pivotal functions in heart valvulogenesis, skin wound healing, and brain development. Perturbation of PYCR1 expression revealed that it is positively correlated with the POSTN levels. Taken together, POSTN might be one of the key molecules that deserves further investigation for its role in this progeroid neurocutaneous syndrome.

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    MiRNA-10b Reciprocally Stimulates Osteogenesis and Inhibits Adipogenesis Partly through the TGF-β/SMAD2 Signaling Pathway
    Hongling Li, Junfen Fan, Linyuan Fan, Tangping Li, Yanlei Yang, Haoying Xu, Luchan Deng, Jing Li, Tao Li, Xisheng Weng, Shihua Wang, Robert Chunhua Zhao
    Aging and disease. 2018, 9 (6): 1058-1073.   DOI: 10.14336/AD.2018.0214
    Abstract   HTML   PDF (1848KB) ( 1844 )

    As the population ages, the medical and socioeconomic impact of age-related bone disorders will further increase. An imbalance between osteogenesis and adipogenesis of mesenchymal stem cells (MSCs) can lead to various bone and metabolic diseases such as osteoporosis. Thus, understanding the molecular mechanisms underlying MSC osteogenic and adipogenic differentiation is important for the discovery of novel therapeutic paradigms for these diseases. miR-10b has been widely reported in tumorigenesis, cancer invasion and metastasis. However, the effects and potential mechanisms of miR-10b in the regulation of MSC adipogenic and osteogenic differentiation have not been explored. In this study, we found that the expression of miR-10b was positively correlated with bone formation marker genes ALP, RUNX2 and OPN, and negatively correlated with adipogenic markers CEBPα, PPARγ and AP2 in clinical osteoporosis samples. Overexpression of miR-10b enhanced osteogenic differentiation and inhibited adipogenic differentiation of human adipose-derived mesenchymal stem cells (hADSCs) in vitro, whereas downregulation of miR-10b reversed these effects. Furthermore, miR-10b promoted ectopic bone formation in vivo. Target prediction and dual luciferase reporter assays identified SMAD2 as a potential target of miR-10b. Silencing endogenous SMAD2 expression in hADSCs enhanced osteogenesis but repressed adipogenesis. Pathway analysis indicated that miR-10b promotes osteogenic differentiation and bone formation via the TGF-β signaling pathway, while suppressing adipogenic differentiation may be primarily mediated by other pathways. Taken together, our findings imply that miR-10b acts as a critical regulator for balancing osteogenic and adipogenic differentiation of hADSCs by repressing SMAD2 and partly through the TGF-β pathway. Our study suggests that miR-10b is a novel target for controlling bone and metabolic diseases.

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    Association between Leukoaraiosis and Symptomatic Intracranial Large Artery Stenoses and Occlusions: the Chinese Intracranial Atherosclerosis (CICAS) Study
    Wanying Duan, Yuehua Pu, Haiyan Liu, Jing Jing, Yuesong Pan, Xinying Zou, Yilong Wang, Xingquan Zhao, Chunxue Wang, Yongjun Wang, Ka Sing Lawrence Wong, Ling Wei, Liping Liu,
    Aging and disease. 2018, 9 (6): 1074-1083.   DOI: 10.14336/AD.2018.0118
    Abstract   HTML   PDF (533KB) ( 473 )

    Leukoaraiosis (LA) is frequently found in ischemic stroke patients, especially when those patients have intracranial atherosclerosis (ICAS). However, previous studies regarding an association of LA with cerebral large artery atherosclerosis showed conflicting results, and the relationship of LA with ICAS is uncertain. This study aimed to explore the association between LA and cerebral large artery atherosclerosis in Chinese patients with cerebral ischemia. Data were derived from the Chinese Intracranial Atherosclerosis (CICAS) study. Patients diagnosed with an ischemic stroke or transient ischemic attack (TIA) within 7 days of symptom onset were included. The analysis of magnetic resonance imaging (MRI) focused on severity of LA in periventricular and deep white matter; type of cerebral large artery stenosis; and the number, severity, and distribution of ICAS lesions. ICAS was defined as an occlusion or more than 50% stenosis of intracranial vessels on magnetic resonance angiography. Among 2420 patients included, distinct LA was observed in 898 (37.11%) patients, and the rate of LA increased significantly with an increased number of risk factors. Multivariate analysis revealed that LA was independently associated with ICAS (odds ratio [OR], 1.388; 95% confidence interval [CI], 1.132-1.702; P=0.0016). In the subgroup analysis of ICAS, LA was more frequently observed in multiple lesions (OR, 1.342; 95% CI, 1.060-1.699; P=0.0146), occlusive lesions (OR, 1.554; 95% CI, 1.214-1.998; P=0.0005), and lesions in the posterior circulation (OR, 1.360; 95% CI, 1.003-1.846; P=0.0481). In this nationwide prospective study, LA was associated with symptomatic ICAS, patients with multiple ICAS lesions, occlusive lesions, and atherosclerotic lesions in the posterior circulation were more likely to coexist with LA.

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    Olfactory Dysfunction and Its Relationship with Clinical Symptoms of Alzheimer Disease
    Qiujin Yu, Peng Guo, Danning Li, Lijun Zuo, Tenghong Lian, Shuyang Yu, Yang Hu, Li Liu, Zhao Jin, Ruidan Wang, Yingshan Piao, Lixia Li, Xiaomin Wang, Wei Zhang
    Aging and disease. 2018, 9 (6): 1084-1095.   DOI: 10.14336/AD.2018.0819
    Abstract   HTML   PDF (461KB) ( 557 )

    Our study aimed to analyse the olfactory dysfunction (OD) evaluations between self-report, the Hyposmia Rating Scale (HRS) and the Sniffin’ Sticks test, and the relationship between OD and clinical features of AD. Sixty patients with AD dementia, 37 patients with mild cognitive impairment (MCI) due to AD and 30 healthy controls were consecutively recruited. Olfactory function was evaluated by self-report, HRS and Sniffin’ Sticks test. Patients were divided into AD with OD (AD-OD) and AD with no OD (AD-NOD) groups based on the results of the Sniffin’ Sticks test. Cognitive symptoms and neuropsychiatric symptoms were assessed by corresponding scales, and activities of daily living (ADL) were assessed by the ADL scale. In the control, MCI due to AD and AD dementia groups, the frequency of OD was 10.0%, 13.5% and 18.3%, respectively, by self-report; 6.7%, 24.3% and 48.3%, respectively, by HRS; and 3.3%, 13.5% and 65.0%, respectively, by the Sniffin’ Sticks test. Compared to the results of the Sniffin’ Sticks test, the diagnostic coincidence rates of OD by HRS in patients with MCI due to AD and AD dementia were 89.2% and 66.7%, respectively. Compared to the AD-NOD group, the scores of global cognition and memory, visuospatial ability and attention were all decreased (P<0.05), the apathy score was increased (P<0.05), and the ADL score was elevated (P<0.01). The frequency and accuracy of OD by self-report is relatively low. HRS can be used for screening olfaction in patients with MCI due to AD. The Sniffin’ Sticks test can be used for validating OD in AD patients. AD-OD patients have severe impairments in global cognition and multiple cognitive domains of memory, visuospatial ability and attention, as well as neuropsychiatric symptoms of apathy, and thus have seriously compromised ADL.

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    Intracranial Atherosclerosis Burden and Stroke Recurrence for Symptomatic Intracranial Artery Stenosis (sICAS)
    Ping Sun, Liping Liu, Yuesong Pan, Xianwei Wang, Donghua Mi, Yuehua Pu, Xin Liu, Wanying Duan, Hongyi Yan, Chunxue Wang, Xingquan Zhao, Yilong Wang, Yongjun Wang,
    Aging and disease. 2018, 9 (6): 1096-1102.   DOI: 10.14336/AD.2018.0301
    Abstract   HTML   PDF (575KB) ( 471 )

    Intracranial atherosclerosis burden is an arising key index for the risk and prognosis for Intracranial Atherosclerosis Stenosis (ICAS). The present study estimated one-year prognosis for patients of symptomatic ICAS with different degrees of intracranial atherosclerosis burden (ICASB) and identified whether the category of multiple and single acute infarction was associated with atherosclerosis burden. A total of 2864 consecutive patients, from 22 hospitals across China, who experienced an acute cerebral ischemia <7 days after onset of symptoms were evaluated. All patients underwent magnetic resonance angiography, and the degree of intracranial stenosis with the ICASB was calculated. The patients were categorized into three groups according to ICASB grading: <4, 4-5 and >5scores. Multivariate Cox proportional hazards regression models were used to estimate the impact of the hazard ratios(HR) of the putative determinants of recurrent stroke in one year. In the groups with ICASB 4-5 and ICASB >5scores recurrent stroke were significantly higher than the other (P<0.0001). On multivariate logistic analysis, ICASB (4-5) indicated more stroke recurrence at 12 months (adjusted hazard ratio, 1.96; 95% confidence interval, 1.08-3.56; P=0.027), compared to the ICASB<4scores and >5 groups (P<0.001). Moreover, proportion of single and multiple infarction lesions differs with different ICASB. Multiple lesions were related with higher of ICASB(P<0.001). Intracranial atherosclerosis burden was associated with recurrent stroke at 12 months. Multiple infarction lesions were associated with higher ICASB score which indicate higher risk of recurrent.

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    MiR-1292 Targets FZD4 to Regulate Senescence and Osteogenic Differentiation of Stem Cells in TE/SJ/Mesenchymal Tissue System via the Wnt/β-catenin Pathway
    Junfen Fan, Xingyan An, Yanlei Yang, Haoying Xu, Linyuan Fan, Luchan Deng, Tao Li, Xisheng Weng, Jianmin Zhang, Robert Chunhua Zhao
    Aging and disease. 2018, 9 (6): 1103-1121.   DOI: 10.14336/AD.2018.1110
    Abstract   HTML   PDF (2316KB) ( 723 )

    With the expansion of the elderly population, age-related osteoporosis and the resulting bone loss have become a significant health and socioeconomic issue. In Triple Energizer (TE)/San Jiao (SJ)/mesenchymal tissue system, mesenchymal stem cell (MSC) senescence, and impaired osteogenesis are thought to contribute to age-related diseases such as osteoporosis. Therefore, comprehending the molecular mechanisms underlying MSC senescence and osteogenesis is essential to improve the treatment of bone metabolic diseases. With the increasing role of miRNAs in MSC aging and osteogenic differentiation, we need to understand further how miRNAs participate in relevant mechanisms. In this study, we observed that the expression of miR-1292 was augmented during cellular senescence and lessened with osteogenesis in human adipose-derived mesenchymal stem cells (hADSCs). miR-1292 expression was positively correlated with senescence markers and negatively associated with bone formation markers in clinical bone samples. Overexpression of miR-1292 notably accelerated hADSC senescence and restrained osteogenesis, whereas its knockdown decreased senescence and enhanced osteogenic differentiation. Furthermore, miR-1292 upregulation inhibited ectopic bone formation in vivo. Mechanistically, FZD4 was identified as a potential target of miR-1292. Downregulation of FZD4 phenocopied the effect of miR-1292 overexpression on hADSC senescence and osteogenic differentiation. Moreover, the impact of miR-1292 suppression on senescence and osteogenesis were reversed by the FZD4 knockdown. Pathway analysis revealed that miR-1292 regulates hADSC senescence and osteogenesis through the Wnt/β-catenin signaling pathway. Thus, TE/SJ/mesenchymal tissue system is the largest organ composed of various functional cells derived from mesoderm, responsible for maintaining homeostasis and regulating cell senescence. miR-1292 might serve as a novel therapeutic target for the prevention and treatment of osteoporosis or other diseases related to bone metabolism and aging.

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    Remote Ischemic Conditioning Protects Diabetic Retinopathy in Streptozotocin-induced Diabetic Rats via Anti-Inflammation and Antioxidation
    Changhong Ren, Hang Wu, Dongjie Li, Yong Yang, Yuan Gao, Yunneng Jizhang, Dachuan Liu, Xunming Ji, Xuxiang Zhang
    Aging and disease. 2018, 9 (6): 1122-1133.   DOI: 10.14336/AD.2018.0711
    Abstract   HTML   PDF (1126KB) ( 675 )

    Ischemic conditioning inhibits oxidative stress and inflammatory response in diabetes. However, whether limb remote ischemic conditioning (LRIC) has beneficial effects on diabetic retinopathy (DR) remains unknown. This study aims to investigate the protective effects of LRIC in retinal ganglion cell in streptozotocin (STZ) induced Type 1 diabetic rats. A total of 48 healthy male Sprague-Dawley (200-220g) rats were randomly assigned to the normal group, normal+LRIC group, diabetes mellitus (DM) group and DM+LRIC group. Streptozotocin (STZ, 60 mg/kg) was intraperitoneally injected into the rats to establish the diabetic model. LRIC was conducted by tightening a tourniquet around the upper thigh and releasing for three cycles daily (10 mins x 3 cycles). Retinas were harvested after 12 weeks of LRIC treatment for histopathologic, Western blot and ELISA analysis. Plasma were collected at the same time for ELISA analysis. LRIC alleviated diabetic retinopathy symptoms as evidenced by the increased number of retinal ganglion cells (P<0.01) and decreased glial fibrillary acidic protein (GFAP) expression level (P<0.01) in the rat retina. LRIC in DM rats exhibited anti-inflammatory and antioxidative effects as confirmed by the down-regulation of pro-inflammatory cytokine: interleukin-6 (IL-6), and the up-regulation of antioxidants: superoxide dismutase (SOD), and glutathione (GSH)/oxidized glutathione (GSSG). Furthermore, LRIC significantly downregulated VEGF protein expression in the retina (P<0.01). These results suggest that the antioxidative and anti-inflammatory activities of LRIC may be important mechanisms involved in the protective effect of LRIC in STZ-induced diabetic rats.

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    Review
    Molecular Bases of Alzheimer’s Disease and Neurodegeneration: The Role of Neuroglia
    Antonina Luca, Carmela Calandra, Maria Luca
    Aging and disease. 2018, 9 (6): 1134-1152.   DOI: 10.14336/AD.2018.0201
    Abstract   HTML   PDF (530KB) ( 720 )

    Neuroglia is an umbrella term indicating different cellular types that play a pivotal role in the brain, being involved in its development and functional homeostasis. Glial cells are becoming the focus of recent researches pertaining the pathogenesis of neurodegenerative disorders, Alzheimer’s Disease (AD) in particular. In fact, activated microglia is the main determinant of neuroinflammation, contributing to neurodegeneration. In addition, the oxidative insult occurring during pathological brain aging can activate glial cells that, in turn, can favor the production of free radicals. Moreover, the recent Glycogen Synthase Kinase 3 (GSK-3) hypothesis of AD suggests that GSK3, involved in the regulation of glial cells functioning, could exert a role in amyloid deposition and tau hyper-phosphorylation. In this review, we briefly describe the main physiological functions of the glial cells and discuss the link between neuroglia and the most studied molecular bases of AD. In addition, we dedicate a section to the glial changes occurring in AD, with particular attention to their role in terms of neurodegeneration. In the light of the literature data, neuroglia could play a fundamental role in AD pathogenesis and progression. Further studies are needed to shed light on this topic.

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    Therapeutic Potential and Effective Components of the Chinese Herb Gardeniae Fructus in the Treatment of Senile Disease
    Shichao Lv, Yang Ding, Haiping Zhao, Shihao Liu, Junping Zhang, Jun Wang
    Aging and disease. 2018, 9 (6): 1153-1164.   DOI: 10.14336/AD.2018.0112
    Abstract   HTML   PDF (502KB) ( 671 )

    Gardeniae fructus (GF), an evergreen Rubiaceae shrub, is one of the most commonly used Chinese herbs in traditional Chinese medicine (TCM) and has been used for over a thousand years. It is usually prescribed for the treatment of brain aging, vascular aging, bone and joint aging, and other age-related diseases. It has been demonstrated that several effective compounds of GF, such as geniposide, genipin and crocin, have neuroprotective or related activities which are involved in senile disease treatment. These bioactivities include the mitochondrion dysfunction, antioxidative activity, apoptosis regulation and an anti-inflammatory activity, which related to multiple signaling pathways such as the nuclear factor-κB pathway, AMP-activated protein kinase signaling pathway, and the mitogen-activated protein kinase pathway. To lay the ground for fully elucidating the potential mechanisms of GF in treating age-related pathologies, we summarized the available research conducted in the last fifteen years about GF and its effective components, which have been studied in vivo and in vitro

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    Emerging Anti-Aging Strategies - Scientific Basis and Efficacy
    Ashok K. Shetty, Maheedhar Kodali, Raghavendra Upadhya, Leelavathi N. Madhu
    Aging and disease. 2018, 9 (6): 1165-1184.   DOI: 10.14336/AD.2018.1026
    Abstract   HTML   PDF (481KB) ( 1765 )

    The prevalence of age-related diseases is in an upward trend due to increased life expectancy in humans. Age-related conditions are among the leading causes of morbidity and death worldwide currently. Therefore, there is an urgent need to find apt interventions that slow down aging and reduce or postpone the incidence of debilitating age-related diseases. This review discusses the efficacy of emerging anti-aging approaches for maintaining better health in old age. There are many anti-aging strategies in development, which include procedures such as augmentation of autophagy, elimination of senescent cells, transfusion of plasma from young blood, intermittent fasting, enhancement of adult neurogenesis, physical exercise, antioxidant intake, and stem cell therapy. Multiple pre-clinical studies suggest that administration of autophagy enhancers, senolytic drugs, plasma from young blood, drugs that enhance neurogenesis and BDNF are promising approaches to sustain normal health during aging and also to postpone age-related neurodegenerative diseases such as Alzheimer’s disease. Stem cell therapy has also shown promise for improving regeneration and function of the aged or Alzheimer’s disease brain. Several of these approaches are awaiting critical appraisal in clinical trials to determine their long-term efficacy and possible adverse effects. On the other hand, procedures such as intermittent fasting, physical exercise, intake of antioxidants such as resveratrol and curcumin have shown considerable promise for improving function in aging, some of which are ready for large-scale clinical trials, as they are non-invasive, and seem to have minimal side effects. In summary, several approaches are at the forefront of becoming mainstream therapies for combating aging and postponing age-related diseases in the coming years.

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  Editors-in-Chief  
Kunlin Jin, M.D., Ph.D., Professor
Ashok K. Shetty, Ph.D., Professor
David A. Greenberg, M.D., Ph.D., Professor
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