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Metformin and the Risk of Dementia in Type 2 Diabetes Patients
Tseng Chin-Hsiao
Aging and disease    2019, 10 (1): 37-48.   DOI: 10.14336/AD.2017.1202
Abstract2125)   HTML2)    PDF(pc) (607KB)(415)       Save

This retrospective cohort study investigated dementia risk associated with metformin use in type 2 diabetes patients by using the reimbursement database of the Taiwan’s National Health Insurance. The patients had new-onset diabetes during 1999-2005 and were followed up until December 31, 2011. An unmatched cohort of 147,729 ever users and 15,676 never users of metformin were identified, and a matched-pair cohort of 15,676 ever users and 15,676 never users was created by propensity score (PS). Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using PS. Results showed that in the unmatched cohort, 713 never users and 3943 ever users developed dementia with respective incidence of 1029.20 and 570.03 per 100,000 person-years. The overall hazard ratio was 0.550 (95% confidence interval: 0.508-0.596). The hazard ratio for the first (<27.0 months), second (27.0-58.1 months) and third (>58.1 months) tertile of cumulative duration of metformin therapy was 0.975 (0.893-1.066), 0.554 (0.506-0.607) and 0.286 (0.259-0.315), respectively. Analyses in the matched cohort showed an overall hazard ratio of 0.707 (0.632-0.791) and the hazard ratio for the respective tertile was 1.279 (1.100-1.488), 0.704 (0.598-0.829) and 0.387 (0.320-0.468). In conclusion, metformin use is associated with a reduced dementia risk.

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Transcultural Adaptation and Validation of the Spanish Bristol Foot Score (BFS-S)
Emmanuel Navarro-Flores, Marta Elena Losa-Iglesias, Ricardo Becerro-de-Bengoa-Vallejo, Daniel Lopez-Lopez, Juan Manuel Vilar-Fernandez, Patricia Palomo-Lopez, Cesar Calvo-Lobo
Aging and disease    2018, 9 (5): 861-868.   DOI: 10.14336/AD.2017.1215
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The Bristol Foot Score is considered an instrument for measuring the impact of foot problems and pain. It was developed and validated in United Kingdom. Therefore, this aim was to perform the transcultural adaptation and validation of the Spanish version. The recommended forward/backward translation protocol was applied for the procedure of translation, transcultural adaptation and validation to Spain. Considering each domain and question, internal consistency and reliability were analyzed through the Crombach alpha (α) and intraclass correlation coefficient (ICC) with a 95% confidence interval (95% CI). A very good internal consistency was shown for the 3 domains: concern and pain showed a Cronbach of 0.896, footwear and general foot health of 0.790, mobility 0.887. Each question had a very good test-retest reliability, ranged from 0.721 to 0.963 with no systematic differences (P>0.05) in each question of the Spanish Bristol Foot Score (BFS-S) questionnaire. The test-retest reliability was excellent (ICC 95%): concern and foot pain 0.950 (0.913-0971); footwear and general foot health 0.914 (0.851-0.950), mobility 0.973 (0.953-0.984) and there were no sistematic differences in any domain (P > 0.05). The BFS-S was shown to be a valid and reliable tool with an acceptable use in the Spanish population.

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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
Accepted: 21 November 2018

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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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Kidney Disease in Elderly: Importance of Collaboration between Geriatrics and Nephrology
Ahmed Faheemuddin Azher
Aging and disease    2018, 9 (4): 745-747.   DOI: 10.14336/AD.2018.0223
Abstract968)   HTML0)    PDF(pc) (259KB)(153)       Save

The population in the United States is aging and presents many challenges in the healthcare world. According to the report released by United States Census Bureau in June 2017, there are around 50 million residents aged 65 years and over as of 2016. Among the multiple healthcare challenges, kidney disease is a significant one because of its high burden, high cost and low awareness. Medicare spending on chronic kidney disease for 65 plus aged patients exceeded $ 50 billion in 2013. Different studies based on different calculations have estimated that at least one-third of chronic kidney disease patients are aged above 65 years. Most of the chronic kidney disease patients have multiple medical co-morbidities but geriatric syndromes are added factors that may be challenging for nephrologists. There is scarcity of well-trained geriatricians and in most instances, nephrologists take over the role of internist or geriatrician. This article outlines the need and importance of collaboration and coordination between geriatrics and nephrology for the best patient care and better healthcare outcomes.

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Relationship between Hypothyroidism and Endometrial Cancer
Yiqin Wang,Rong Zhou,Jianliu Wang
Aging and disease    2019, 10 (1): 190-196.   DOI: 10.14336/AD.2018.0224
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Thyroid dysfunction is involved in several types of carcinoma. Hypothyroidism is one of the most common medical morbidities among patients with endometrial cancer; however, the related mechanism is unclear. Among the risk factors related to endometrial cancer, hypothyroidism interacts with metabolic syndrome, polycystic ovarian syndrome and infertility or directly acts on the endometrium itself, which may influence the development and progression of endometrial cancer. We summarize recent studies on the relationship between hypothyroidism and endometrial cancer and its risk factors to provide references for basic research as well as for clinical treatment and prognostic evaluation.

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Quantitative Evaluation of Gait Disturbance on an Instrumented Timed Up-and-go Test
Shigeki Yamada,Yukihiko Aoyagi,Kazuo Yamamoto,Masatsune Ishikawa
Aging and disease    2019, 10 (1): 23-36.   DOI: 10.14336/AD.2018.0426
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Although the 3-m timed up-and-go test (TUG) is reliable for evaluating mobility, TUG time is insufficient to evaluate mild gait disturbance; we, therefore aimed to investigate other measurements with instrumented TUG (iTUG) using a free smartphone application. Our inclusion criterion in this study is only that participants can walk without any assistance. This study included three heterogeneous groups; patients who underwent a tap test or shunt surgery, 29 inpatients hospitalized for other reasons, and 87 day-care users. After the tap test, 28 were diagnosed with tap-positive idiopathic normal-pressure hydrocephalus (iNPH) and 8 were diagnosed with tap-negative. Additionally, 18 patients were assessed iTUG before and after shunt surgery. During iTUG, time and 3-dimensional (3D) acceleration were automatically recorded every 0.01 s. A volume of the 95% confidence ellipsoid (95%CE) of all plots for 3D acceleration was calculated. Additionally, an iTUG score was defined as (95%CE volume) 0.8 / 1.9 - 1.9 × (time) + 60. The measurement reliability was evaluated using intraclass correlations and Bland-Altman plots. The participants with mild gait disturbance who accomplished within 13.5 s on the iTUG time had the 95%CE volumes for 3D acceleration of ≥70 m3/s6 and iTUG scores of ≥50. The mean iTUG time was shortened and the mean 95%CE volumes and iTUG scores were increased after the tap test among 28 patients with tap-positive iNPH and after shunt surgery among 18 patients with definite iNPH. Conversely, the mean iTUG score among 8 patients with tap-negative was decreased after the tap test. The intraclass correlations for the time, 95%CE volume and iTUG score were 0.97, 0.80 and 0.90, respectively. Not only the iTUG time but also the 95%CE volume was important for evaluating mobility. Therefore, the novel iTUG score consisting both is useful for the quantitative assessment of mobility.

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Traditional Oriental Medicines and Alzheimer’s Disease
Jeon Seong Gak, Song Eun Ji, Lee Dongje, Park Junyong, Nam Yunkwon, Kim Jin-il, Moon Minho
Aging and disease    2019, 10 (2): 307-328.   DOI: 10.14336/AD.2018.0328
Accepted: 29 August 2018

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Alzheimer’s disease (AD), which is the most major cause of dementia, is a progressive neurodegenerative disease that affects cognitive functions. Even though the prevalence of AD is continuously increasing, few drugs including cholinesterase inhibitors and N-methyl D-aspartate-receptor antagonists were approved to treat AD. Because the clinical trials of AD drugs with single targets, such as β-amyloid and tau, have failed, the development of multi-target drugs that ameliorate many of the symptoms of AD is needed. Thus, recent studies have investigated the effects and underlying mechanisms of herbal formulae consisting of various herb combinations used to treat AD. This review discusses the results of clinical and nonclinical studies of the therapeutic efficacy in AD and underlying mechanisms of the herbal formulae of traditional Oriental medicines and bioactive compounds of medicinal plants.

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Neuroprotective Effect of Caffeic Acid Phenethyl Ester in A Mouse Model of Alzheimer’s Disease Involves Nrf2/HO-1 Pathway
Morroni Fabiana, Sita Giulia, Graziosi Agnese, Turrini Eleonora, Fimognari Carmela, Tarozzi Andrea, Hrelia Patrizia
Aging and disease    2018, 9 (4): 605-622.   DOI: 10.14336/AD.2017.0903
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Alzheimer’s disease (AD) is a progressive pathology, where dementia symptoms gradually worsen over a number of years. The hallmarks of AD, such as amyloid β-peptide (Aβ) in senile plaque and neurofibrillary tangles, are strongly intertwined with oxidative stress, which is considered one of the common effectors of the cascade of degenerative events. The endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) is the "master regulator" of the antioxidant response and it is known as an indicator and regulator of oxidative stress. The present study aimed to determine the potential neuroprotective activity of caffeic acid phenethyl ester (CAPE), a polyphenolic compound abundant in honeybee, against the neurotoxicity of Aβ1-42 oligomers (AβO) in mice. An intracerebroventricular (i.c.v.) injection of AβO into the mouse brain triggered increased reactive oxygen species levels, neurodegeneration, neuroinflammation, and memory impairment. In contrast, the intraperitoneal administration of CAPE (10 mg/kg) after i.c.v. AβO-injection counteracted oxidative stress accompanied by an induction of Nrf2 and heme oxygenase-1 via the modulation of glycogen synthase kinase 3β in the hippocampus of mice. Additionally, CAPE treatment decreased AβO-induced neuronal apoptosis and neuroinflammation, and improved learning and memory, protecting mice against the decline in spatial cognition. Our findings demonstrate that CAPE could potentially be considered as a promising neuroprotective agent against progressive neurodegenerative diseases such as AD.

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Hyperglycemia Alters Astrocyte Metabolism and Inhibits Astrocyte Proliferation
Li Wenjun, Roy Choudhury Gourav, Winters Ali, Prah Jude, Lin Wenping, Liu Ran, Yang Shao-Hua
Aging and disease    2018, 9 (4): 674-684.   DOI: 10.14336/AD.2017.1208
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Diabetes milieu is a complex metabolic disease that has been known to associate with high risk of various neurological disorders. Hyperglycemia in diabetes could dramatically increase neuronal glucose levels which leads to neuronal damage, a phenomenon referred to as glucose neurotoxicity. On the other hand, the impact of hyperglycemia on astrocytes has been less explored. Astrocytes play important roles in brain energy metabolism through neuron-astrocyte coupling. As the component of blood brain barrier, glucose might be primarily transported into astrocytes, hence, impose direct impact on astrocyte metabolism and function. In the present study, we determined the effect of high glucose on the energy metabolism and function of primary astrocytes. Hyperglycemia level glucose (25 mM) induced cell cycle arrest and inhibited proliferation and migration of primary astrocytes. Consistently, high glucose decreased cyclin D1 and D3 expression. High glucose enhanced glycolytic metabolism, increased ATP and glycogen content in primary astrocytes. In addition, high glucose activated AMP-activated protein kinase (AMPK) signaling pathway in astrocytes. In summary, our in vitro study indicated that hyperglycemia might impact astrocyte energy metabolism and function phenotype. Our study provides a potential mechanism which may underlie the diabetic cerebral neuropathy and warrant further in vivo study to determine the effect of hyperglycemia on astrocyte metabolism and function.

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Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept
Chung Hae Young, Kim Dae Hyun, Lee Eun Kyeong, Chung Ki Wung, Chung Sangwoon, Lee Bonggi, Seo Arnold Y., Chung Jae Heun, Jung Young Suk, Im Eunok, Lee Jaewon, Kim Nam Deuk, Choi Yeon Ja, Im Dong Soon, Yu Byung Pal
Aging and disease    2019, 10 (2): 367-382.   DOI: 10.14336/AD.2018.0324
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Age-associated chronic inflammation is characterized by unresolved and uncontrolled inflammation with multivariable low-grade, chronic and systemic responses that exacerbate the aging process and age-related chronic diseases. Currently, there are two major hypotheses related to the involvement of chronic inflammation in the aging process: molecular inflammation of aging and inflammaging. However, neither of these hypotheses satisfactorily addresses age-related chronic inflammation, considering the recent advances that have been made in inflammation research. A more comprehensive view of age-related inflammation, that has a scope beyond the conventional view, is therefore required. In this review, we discuss newly emerging data on multi-phase inflammatory networks and proinflammatory pathways as they relate to aging. We describe the age-related upregulation of nuclear factor (NF)-κB signaling, cytokines/chemokines, endoplasmic reticulum (ER) stress, inflammasome, and lipid accumulation. The later sections of this review present our expanded view of age-related senescent inflammation, a process we term “senoinflammation”, that we propose here as a novel concept. As described in the discussion, senoinflammation provides a schema highlighting the important and ever-increasing roles of proinflammatory senescence-associated secretome, inflammasome, ER stress, TLRs, and microRNAs, which support the senoinflammation concept. It is hoped that this new concept of senoinflammation opens wider and deeper avenues for basic inflammation research and provides new insights into the anti-inflammatory therapeutic strategies targeting the multiple proinflammatory pathways and mediators and mediators that underlie the pathophysiological aging process.

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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
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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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Fucoidan Protects Dopaminergic Neurons by Enhancing the Mitochondrial Function in a Rotenone-induced Rat Model of Parkinson’s Disease
Zhang Li, Hao Junwei, Zheng Yan, Su Ruijun, Liao Yajin, Gong Xiaoli, Liu Limin, Wang Xiaomin
Aging and disease    2018, 9 (4): 590-604.   DOI: 10.14336/AD.2017.0831
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The mitochondrion is susceptible to neurodegenerative disorders such as Parkinson’s disease (PD). Mitochondrial dysfunction has been considered to play an important role in the dopaminergic degeneration in PD. However, there are no effective drugs to protect mitochondria from dysfunction during the disease development. In the present study, fucoidan, a sulfated polysaccharide derived from Laminaria japonica, was investigated and characterized for its protective effect on the dopamine system and mitochondrial function of dopaminergic neurons in a rotenone-induced rat model of PD. We found that chronic treatment with fucoidan significantly reversed the loss of nigral dopaminergic neurons and striatal dopaminergic fibers and the reduction of striatal dopamine levels in PD rats. Fucoidan also alleviated rotenone-induced behavioral deficits. Moreover, the mitochondrial respiratory function as detected by the mitochondrial oxygen consumption and the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and nuclear transcription factor 2 (NRF2) were reduced in the substantia nigra of PD rats, which were markedly reversed by fucoidan. Oxidative products induced by rotenone were significantly reduced by fucoidan. Taken together, these results demonstrate that fucoidan possesses the ability to protect the dopamine system in PD rats. The neuroprotective effect of fucoidan may be mediated via reserving mitochondrial function involving the PGC-1α/NRF2 pathway. This study provides new evidence that fucoidan can be explored in PD therapy.

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Voxel-based Specific Regional Analysis System for Alzheimer’s Disease (VSRAD) on 3-tesla Normal Database: Diagnostic Accuracy in Two Independent Cohorts with Early Alzheimer’s Disease
Sone Daichi, Imabayashi Etsuko, Maikusa Norihide, Ogawa Masayo, Sato Noriko, Matsuda Hiroshi, Japanese-Alzheimer’s Disease Neuroimaging Initiative
Aging and disease    2018, 9 (4): 755-760.   DOI: 10.14336/AD.2017.0818
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Voxel-based specific regional analysis system for Alzheimer’s disease (VSRAD) software is widely used in clinical practice in Alzheimer’s disease (AD). The existing VSRAD is based on the normal database with 1.5-tesla MRI scans (VSRAD-1.5T), and its utility for patients have undergone 3-tesla MRI is still controversial. We recruited 19 patients with early AD and 28 healthy controls who had undergone 3-tesla MRI scans at our institute (Cohort 1). We also used the 3-tesla MRI data of 30 patients with early AD and 13 healthy controls from the Japanese Alzheimer’s Disease Neuroimaging Initiative (Cohort 2). We also created a new VSRAD based on 65 normal subjects’ 3-tesla MRI scans (VSRAD-3T), and compared the detectability of AD between VSRAD-1.5T and VSRAD-3T, using receiver operating characteristic curve and area under the curve (AUC) analyses. As a result, there were no significant differences in the detectability of AD between VSRAD-3T and VSRAD-1.5T, except for the whole white matter atrophy score, which showed significantly better AUC in VSRAD-3T than in VSRAD-1.5T in both Cohort 1 (p=0.04) and 2 (p<0.01). Generally, there were better diagnostic values in Cohort 2 than in Cohort 1. The optimal cutoff values varied but were generally lower than in the previously published data. In conclusion, for patients with 3-tesla MRI, the detectability of early AD by the existing VSRAD was not different from that by the new VSRAD based on 3-tesla database. We should exercise caution when using the existing VSRAD for 3-tesla white matter analyses or for setting cutoff values.

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The Role of Pulmonary and Systemic Immunosenescence in Acute Lung Injury
Brandenberger Christina, Kling Katharina Maria, Vital Marius, Christian Mühlfeld
Aging and disease    2018, 9 (4): 553-565.   DOI: 10.14336/AD.2017.0902
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Acute lung injury (ALI) is associated with increased morbidity and mortality in the elderly (> 65 years), but the knowledge about origin and effects of immunosenescence in ALI is limited. Here, we investigated the immune response at pulmonary, systemic and cellular level in young (2-3 months) and old (18-19 months) C57BL/6J mice to localize and characterize effects of immunosenescence in ALI. ALI was induced by intranasal lipopolysaccharide (LPS) application and the animals were sacrificed 24 or 72 h later. Pulmonary inflammation was investigated by analyzing histopathology, bronchoalveolar lavage fluid (BALF) cytometry and cytokine expression. Systemic serum cytokine expression, spleen lymphocyte populations and the gut microbiome were analyzed, as well as activation of alveolar and bone marrow derived macrophages (BMDM) in vitro. Pulmonary pathology of ALI was more severe in old compared with young mice. Old mice showed significantly more inflammatory cells and pro-inflammatory cyto- or chemokines (TNFα, IL-6, MCP-1, CXCL1, MIP-1α) in the BALF, but a delayed expression of cytokines associated with activation of adaptive immunity and microbial elimination (IL-12 and IFNγ). Alveolar macrophages, but not BMDM, of old mice showed greater activation after in vivo and in vitro stimulation with LPS. No systemic enhanced pro-inflammatory cytokine response was detected in old animals after LPS exposure, but a delayed expression of IL-12 and IFNγ. Furthermore, old mice had less CD8+ T-cells and NK cells and more regulatory T-cells in the spleen compared with young mice and a distinct gut microbiome structure. The results of our study show an increased alveolar macrophage activation and pro-inflammatory signaling in the lungs, but not systemically, suggesting a key role of senescent alveolar macrophages in ALI. A decrease in stimulators of adaptive immunity with advancing age might further promote the susceptibility to a worse prognosis in ALI in elderly.

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Mitochondria in Ischemic Stroke: New Insight and Implications
Fan Liu, Jianfei Lu, Anatol Manaenko, Junjia Tang, Qin Hu
Aging and disease    2018, 9 (5): 924-937.   DOI: 10.14336/AD.2017.1126
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Stroke is the leading cause of death and adult disability worldwide. Mitochondrial dysfunction has been regarded as one of the hallmarks of ischemia/reperfusion (I/R) induced neuronal death. Maintaining the function of mitochondria is crucial in promoting neuron survival and neurological improvement. In this article, we review current progress regarding the roles of mitochondria in the pathological process of cerebral I/R injury. In particular, we emphasize on the most critical mechanisms responsible for mitochondrial quality control, as well as the recent findings on mitochondrial transfer in acute stroke. We highlight the potential of mitochondria as therapeutic targets for stroke treatment and provide valuable insights for clinical strategies.

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The Prevalence of Mild Cognitive Impairment in China: A Systematic Review
Xue Jiang, Li Jiarui, Liang Jiaming, Chen Shulin
Aging and disease    2018, 9 (4): 706-715.   DOI: 10.14336/AD.2017.0928
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The aim of this study was to analyze the prevalence of mild cognitive impairment (MCI) among the aging population (60 years of age and above) in China. Epidemiological investigations on MCI in online Chinese journals were identified manually using the CQVIP, CNKI, and Wanfang databases. Articles from journals published in English were identified using PubMed and Web of Science. Original studies that included prevalence surveys of MCI were selected. Forty-eight relevant studies were included in the analysis, covering 22 provinces in China. Our results showed that the pooled prevalence of MCI in the older Chinese population was 14.71% (95% confidence interval [CI], 14.50-14.92%). The prevalence was 16.72% (95% CI, 15.68-17.71%) in clinical samples vs. 14.61% (95% CI, 14.40-14.83%) in nonclinical samples (χ2=16.60, P<0.01), and 15.20% (95% CI, 14.91-15.49%) in screened samples vs. 14.16% (95% CI, 13.85-14.46%) in diagnosed samples (χ2=22.11, P<0.01). People of older age, of female sex, or living in rural areas or western China were associated with a higher prevalence of MCI. The prevalence of MCI was high in Chinese older adults, and even higher in those who were older, female, or living in rural areas or western China. Future studies are recommended to address the prevalence of MCI in the other 12 provinces of China. Furthermore, diagnostic assessments should be included in the identification of MCI.

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Pkcδ Activation is Involved in ROS-Mediated Mitochondrial Dysfunction and Apoptosis in Cardiomyocytes Exposed to Advanced Glycation End Products (Ages)
Yang Yao-Chih, Tsai Cheng-Yen, Chen Chien-Lin, Kuo Chia-Hua, Hou Chien-Wen, Cheng Shi-Yann, Aneja Ritu, Huang Chih-Yang, Kuo Wei-Wen
Aging and disease    2018, 9 (4): 647-663.   DOI: 10.14336/AD.2017.0924
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Diabetic patients exhibit serum AGE accumulation, which is associated with reactive oxygen species (ROS) production and diabetic cardiomyopathy. ROS-induced PKCδ activation is linked to mitochondrial dysfunction in human cells. However, the role of PKCδ in cardiac and mitochondrial dysfunction caused by AGE in diabetes is still unclear. AGE-BSA-treated cardiac cells showed dose- and time-dependent cell apoptosis, ROS generation, and selective PKCδ activation, which were reversed by NAC and rotenone. Similar tendency was also observed in diabetic and obese animal hearts. Furthermore, enhanced apoptosis and reduced survival signaling by AGE-BSA or PKCδ-WT transfection were reversed by kinase-deficient (KD) of PKCδ transfection or PKCδ inhibitor, respectively, indicating that AGE-BSA-induced cardiomyocyte death is PKCδ-dependent. Increased levels of mitochondrial mass as well as mitochondrial fission by AGE-BSA or PKCδ activator were reduced by rottlerin, siPKCδ or KD transfection, indicating that the AGE-BSA-induced mitochondrial damage is PKCδ-dependent. Using super-resolution microscopy, we confirmed that PKCδ colocalized with mitochondria. Interestingly, the mitochondrial functional analysis by Seahorse XF-24 flux analyzer showed similar results. Our findings indicated that cardiac PKCδ activation mediates AGE-BSA-induced cardiomyocyte apoptosis via ROS production and may play a key role in the development of cardiac mitochondrial dysfunction in rats with diabetes and obesity.

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Gait Analyses in Mice: Effects of Age and Glutathione Deficiency
Mock J. Thomas, Knight Sherilynn G, Vann Philip H, Wong Jessica M, Davis Delaney L, Forster Michael J, Sumien Nathalie
Aging and disease    2018, 9 (4): 634-646.   DOI: 10.14336/AD.2017.0925
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Minor changes (~0.1 m/s) in human gait speed are predictive of various measures of decline and can be used to identify at-risk individuals prior to further decline. These associations are possible due to an abundance of human clinical research. However, age-related gait changes are not well defined in rodents, even though rodents are used as the primary pre-clinical model for many disease states as well as aging research. Our study investigated the usefulness of a novel automated system, the CatWalk™ XT, to measure age-related differences in gait. Furthermore, age-related functional declines have been associated with decreases in the reduced to oxidized glutathione ratio leading to a pro-oxidizing cellular shift. Therefore the secondary aim of this study was to determine whether chronic glutathione deficiency led to exacerbated age-associated impairments. Groups of male and female wild-type (gclm+/+) and knock-out (gclm-/-) mice aged 4, 10 and 17 months were tested on the CatWalk and gait measurements recorded. Similar age-related declines in all measures of gait were observed in both males and females, and chronic glutathione depletion was associated with some delays in age-related declines, which were further exacerbated. In conclusion, the CatWalk is a useful tool to assess gait changes with age, and further studies will be required to identify the potential compensating mechanisms underlying the effects observed with the chronic glutathione depletion.

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Superoxide Radical Dismutation as New Therapeutic Strategy in Parkinson’s Disease
De Lazzari Federica, Bubacco Luigi, Whitworth Alexander J, Bisaglia Marco
Aging and disease    2018, 9 (4): 716-728.   DOI: 10.14336/AD.2017.1018
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Aging is the biggest risk factor for developing many neurodegenerative disorders, including idiopathic Parkinson’s disease (PD). PD is still an incurable disorder and the available medications are mainly directed to the treatment of symptoms in order to improve the quality of life. Oxidative injury has been identified as one of the principal factors involved in the progression of PD and several indications are now reported in the literature highlighting the prominent role of the superoxide radical in inducing neuronal toxicity. It follows that superoxide anions represent potential cellular targets for new drugs offering a novel therapeutic approach to cope with the progression of the disease. In this review we first present a comprehensive overview of the most common cellular reactive oxygen and nitrogen species, describing their cellular sources, their potential physiological roles in cell signalling pathways and the mechanisms through which they could contribute to the oxidative damage. We then analyse the potential therapeutic use of SOD-mimetic molecules, which can selectively remove superoxide radicals in a catalytic way, focusing on the classes of molecules that have therapeutically exploitable properties.

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N-acetylcysteine Treatment Reduces Age-related Hearing Loss and Memory Impairment in the Senescence-Accelerated Prone 8 (SAMP8) Mouse Model
Marie Aurore, Meunier Johann, Brun Emilie, Malmstrom Susanna, Baudoux Veronique, Flaszka Elodie, Naert Gaëlle, Roman François, Cosnier-Pucheu Sylvie, Gonzalez-Gonzalez Sergio
Aging and disease    2018, 9 (4): 664-673.   DOI: 10.14336/AD.2017.0930
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Age-related hearing loss (ARHL) is the most common sensory disorder in the elderly population. SAMP8 mouse model presents accelerated senescence and has been identified as a model of gerontological research. SAMP8 displays a progressive age-related decline in brain function associated with a progressive hearing loss mimicking human aging memory deficits and ARHL. The molecular mechanisms associated with SAMP8 senescence process involve oxidative stress leading to chronic inflammation and apoptosis. Here, we studied the effect of N-acetylcysteine (NAC), an antioxidant, on SAMP8 hearing loss and memory to determine the potential interest of this model in the study of new antioxidant therapies. We observed a strong decrease of auditory brainstem response thresholds from 45 to 75 days of age and an increase of distortion product amplitudes from 60 to 75 days in NAC treated group compared to vehicle. Moreover, NAC treated group presented also an increase of memory performance at 60 and 105 days of age. These results confirm that NAC delays the senescence process by slowing the age-related hearing loss, protecting the cochlear hair cells and improving memory, suggesting that antioxidants could be a pharmacological target for age-related hearing and memory loss.

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Is Dementia More Fatal Than Previously Estimated? A Population-based Prospective Cohort Study
Jong Bin Bae,Ji Won Han,Kyung Phil Kwak,Bong Jo Kim,Shin Gyeom Kim,Jeong Lan Kim,Tae Hui Kim,Seung-Ho Ryu,Seok Woo Moon,Joon Hyuk Park,Jong Chul Youn,Dong Young Lee,Dong Woo Lee,Seok Bum Lee,Jung Jae Lee,Jin Hyeong Jhoo,Ki Woong Kim
Aging and disease    2019, 10 (1): 1-11.   DOI: 10.14336/AD.2018.0123
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Dementia increases the risk of mortality (ROM) in the elderly and estimates of hazard ratio (HR) of dementia for mortality have ranged from 1.7 to 6.3. However, previous studies may have underestimated ROM of dementia due to length bias, which occurs when failing to include the persons with rapidly progressive diseases, who died before they could be included in the study. This population-based prospective cohort study conducted on 6,752 randomly sampled Koreans, aged 60 years or older (the Korean Longitudinal Study on Cognitive Aging and Dementia). Cognitive disorders were evaluated at baseline and 2-year follow-up using the Korean version of the Consortium to Establish a Registry for Alzheimer’s Disease Assessment Packet (CERAD-K), and prevalent and incident cases of dementia were identified. The participants’ deaths were confirmed through the National Mortality Database of Statistics Korea. We compared the ROM between prevalent and incident dementia, and estimated HR of dementia for mortality using Cox proportional hazards model. Of the 5,097 responders to the 2-year follow-up assessment, 150 participants had dementia from the baseline (prevalent dementia), and 95 participants developed dementia during the 2-year follow-up period (incident dementia). The ROM of participants with incident dementia was about 3 times higher than the ROM of those with prevalent dementia (HR = 3.04, 95% confidence interval [CI] = 1.34-6.91). Compared to cognitively normal participants at both the baseline and 2-year follow-up assessments, the ROM of those with incident dementia approximately 8 times higher (HR = 8.37, 95 % CI = 4.23-16.54). In conclusion, the ROM of dementia using prevalent cases was underestimated due to length bias, and dementia may be much more fatal than previously estimated. In clinical settings, the ROM of dementia warrants the attention of physicians, particularly in recently incident dementia cases.

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Epigenetic Regulation of Bone Marrow Stem Cell Aging: Revealing Epigenetic Signatures associated with Hematopoietic and Mesenchymal Stem Cell Aging
Dimitrios Cakouros,Stan Gronthos
Aging and disease    2019, 10 (1): 174-189.   DOI: 10.14336/AD.2017.1213
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In this review we explore the importance of epigenetics as a contributing factor for aging adult stem cells. We summarize the latest findings of epigenetic factors deregulated as adult stem cells age and the consequence on stem cell self-renewal and differentiation, with a focus on adult stem cells in the bone marrow. With the latest whole genome bisulphite sequencing and chromatin immunoprecipitations we are able to decipher an emerging pattern common for adult stem cells in the bone marrow niche and how this might correlate to epigenetic enzymes deregulated during aging. We begin by briefly discussing the initial observations in yeast, drosophila and Caenorhabditis elegans (C. elegans) that led to the breakthrough research that identified the role of epigenetic changes associated with lifespan and aging. We then focus on adult stem cells, specifically in the bone marrow, which lends strong support for the deregulation of DNA methyltransferases, histone deacetylases, acetylates, methyltransferases and demethylases in aging stem cells, and how their corresponding epigenetic modifications influence gene expression and the aging phenotype. Given the reversible nature of epigenetic modifications we envisage “epi” targeted therapy as a means to reprogram aged stem cells into their younger counterparts.

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The Effect of Aquaporin-4 Knockout on Interstitial Fluid Flow and the Structure of the Extracellular Space in the Deep Brain
Ze Teng, Aibo Wang, Peng Wang, Rui Wang, Wei Wang, Hongbin Han
Aging and disease    2018, 9 (5): 808-816.   DOI: 10.14336/AD.2017.1115
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It has been reported that aquaporin-4 (AQP4) deficiency impairs transportation between the cerebrospinal fluid and interstitial fluid (ISF) as well as the clearance of interstitial solutes in the superficial brain. However, the effect of AQP4 on ISF flow in the deep brain remains unclear. This study compared the brain ISF flow in the caudate nucleus and thalamus of normal rats (NO) and AQP4 knockout rats (KO) using tracer-based magnetic resonance imaging. The rate of brain ISF flow slowed to different degrees in the two regions of KO rats’ brains. Compared with NO rats, the half-life of ISF in the thalamus of KO rats was significantly prolonged, with a corresponding decrease in the clearance coefficient. The tortuosity of the brain extracellular space (ECS) was unchanged in the thalamus of KO rats. In the caudate nucleus of KO rats, the volume fraction of the ECS and the diffusion coefficient were increased, with significantly decreased tortuosity; no significant changes in brain ISF flow were demonstrated. Combined with a change in the expression of glial fibrillary acidic protein and AQP4 in two brain regions, we found that the effect of AQP4 knockout on ISF flow and ECS structure in these two regions differed. This difference may be related to the distribution of astrocytes and the extent of AQP4 decline. This study provides evidence for the involvement of AQP4 in ISF transportation in the deep brain and provides a basis for the establishment of a pharmacokinetic model of the brain’s interstitial pathway.

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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
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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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Effect of Aging and Glucagon-like Peptide 2 on Intestinal Microbiota in SD Rats
Wu Jiayu, Ren Weiying, Li Li, Luo Man, Xu Kan, Shen Jiping, Wang Jia, Chang Guilin, Lu Yi, Qi Yiming, Xu Binger, He Yuting, Hu Yu
Aging and disease    2018, 9 (4): 566-577.   DOI: 10.14336/AD.2017.1001
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Recent research suggests that intestinal microbiota affect the aging process. Glucagon-like peptide 2 (GLP-2), a growth factor found in the intestinal mucosal epithelium, reduces intestinal permeability and affects intestinal microbiota. The relationship between aging, GLP-2, and intestinal microbiota are still not well understood. The current study examined the influence of aging and GLP-2 on the intestinal microbiota of rats. Twelve 3-month old male SD rats were randomly divided into two groups: a young control group (group C) and a young GLP-2 treatment group (group G). Twelve 26-month old male SD rats were randomly divided into two groups: an aged control group (group L) and an aged GLP-2 treatment group (group T). GLP-2 was intraperitoneally injected into rats from group G and group T for 14 days. Plasma GLP-2 concentration was evaluated by ELISA tests. Fresh intestinal stool samples were collected from each group and total fecal bacterial genomic DNA was extracted from the associated rats. The bacterial composition of fecal samples was analyzed by Miseq high-throughput sequencing and comparison with SRA databases. Overall, the diversity of intestinal microbiota significantly decreases with age in SD rats, while GLP-2 has no significant effect on the diversity of intestinal microbiota. Upon aging, there is a reduction in probiotic bacteria and a concomitant increase in pathogenic bacteria in rats. Treatment with GLP-2 results in a significant reduction in the prevalence of pathogenic bacterial genera and an increase in some potential benefit bacteria in aged rats. In addition, treatment with GLP-2 results in an increase in several probiotics and a reduction in the prevalence of pathogenic bacterial genera in young rats.

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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
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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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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
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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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The Synergy of Aging and LPS Exposure in a Mouse Model of Parkinson’s Disease
Yong-Fei Zhao, Qiong Zhang, Jian-Feng Zhang, Zhi-Yin Lou, Hen-Bing Zu, Zi-Gao Wang, Wei-Cheng Zeng, Kai Yao, Bao-Guo Xiao
Aging and disease    2018, 9 (5): 785-797.   DOI: 10.14336/AD.2017.1028
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Aging is an inevitable physiological challenge occurring in organisms over time, and is also the most important risk factor of neurodegenerative diseases. In this study, we observed cellular and molecular changes of different age mice and LPS-induced Parkinson disease (PD) model. The results showed that behavioral performance and dopaminergic (DA) neurons were declined, accompanied by increased expression of pro-inflammatory factors (TLR2, p-NF-kB-p65, IL-1β and TNF-α), as well as pro-oxidative stress factor gp91phox in aged mice compared with young mice. Aging exaggerated inflammatory M1 microglia, and destroyed the balance between oxidation and anti-oxidation. The intranasal LPS instillation induced PD model in both young and aged mice. The poor behavioral performance and the loss of DA neurons as well as TLR2, p-NF-kB-p65, IL-1β, TNF-α, iNOS and gp91phox were further aggravated in LPS-aged mice. Interestingly, the expression of Nrf2 and HO-1 was up-regulated by LPS only in young LPS-PD mice, but not in aged mice. The results indicate that the synergy of aging process and LPS exposure may prominently aggravate the DA neurons loss caused by more serious neuroinflammation and oxidative stress in the brain.

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Involvement of Kif4a in Spindle Formation and Chromosome Segregation in Mouse Oocytes
Tang Feng, Pan Meng-Hao, Lu Yujie, Wan Xiang, Zhang Yu, Sun Shao-Chen
Aging and disease    2018, 9 (4): 623-633.   DOI: 10.14336/AD.2017.0901
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Kif4a, a member of the kinesin superfamily, has been reported to participate in a series of cellular processes such as chromosome condensation and cytokinesis during mitosis. However, the roles of KIF4a in meiosis are still unknown. In present study we found that the Kif4a protein expression decreased in maternal aged mouse oocytes. We then explored the roles of Kif4a in mouse oocyte meiosis by knockdown analysis. Kif4a was enriched at the spindle during mouse oocyte maturation. By specific knock down of the Kif4a using morpholino microinjection, we found that the disruption of Kif4a caused the failure of polar body extrusion. Further analysis indicated that Kif4a might affect the spindle morphology and chromosome alignment in the mouse oocytes, and this might be due to the regulation of tubulin acetylation. Moreover, our results showed that an increased proportion of aneuploidy in the Kif4a knock down oocytes, and this might be due to the loss of kinetochore-microtubule attachment. Taken together, these results suggested that Kif4a possibly regulated mouse oocyte meiosis through its effects on the spindle organization and accurate chromosome segregation, and the loss of Kif4a might be related with aneuploidy of aging oocytes.

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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
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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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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
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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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Glibenclamide Enhances the Therapeutic Benefits of Early Hypothermia after Severe Stroke in Rats
Zhu Shuzhen, Gao Xiaoya, Huang Kaibin, Gu Yong, Hu Yafang, Wu Yongming, Ji Zhong, Wang Qing, Pan Suyue
Aging and disease    2018, 9 (4): 685-695.   DOI: 10.14336/AD.2017.0927
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Glibenclamide (GBC) is an antidiabetic drug that is in a class of medications known as sulfonylureas, which play critical roles in attenuating brain edema and reducing mortality in ischemic stroke patients. Therapeutic hypothermia (TH) is another robust neuroprotectant that prevents brain swelling and improves the neurological outcomes of stroke patients. However, whether the combination of GBC and TH can be used as a reliable neuroprotectant in ischemic stroke remains largely unknown. We used the middle cerebral artery occlusion (MCAO) rat model as well as oxygen and glucose deprivation-reoxygenation (OGD/R) endothelial cells as ischemic stroke models to investigate the efficacy and mechanisms of treating ischemic stroke with the combination of GBC and TH. The serum glucose, mortality rate, neurobehavioral functions, tight junctions, endothelial cells and inflammatory cytokines were evaluated in the stroke models after treatment with GBC, TH or the combination of them. After 5-hour occlusion and subsequent reperfusion, rats exhibited a large volume of hemispheric swelling and a high mortality rate. Stroke rats treated with the combined therapy did not exhibit hypoglycemia. The combination of GBC and TH exhibited synergistic neuroprotective effects in stroke rats that were associated with greater reductions in edema volume, better improvement in neurobehavioral functions, prevention of tight junction loss, and reduction of expression of the inflammatory cytokines COX-2 and iNOS. In OGD/R endothelia cells, the combination reduced endothelial cell death. This study demonstrated that both GBC and TH are neuroprotective after the severe stroke; however, combined therapy with GBC and TH enhanced the efficiency and efficacy of the effects of TH and GBC in the treatment of ischemia. This combined therapy may facilitate the clinical translation of TH management for severe stroke. The combination of GBC and TH seems to be a feasible and promising clinical strategy to alleviate cerebral injury following severe stroke.

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Mitochondrial Pharmacology of Dimebon (Latrepirdine) Calls for a New Look at its Possible Therapeutic Potential in Alzheimer’s Disease
Eckert Schamim H, Gaca Janett, Kolesova Nathalie, Friedland Kristina, Eckert Gunter P, Muller Walter E
Aging and disease    2018, 9 (4): 729-744.   DOI: 10.14336/AD.2017.1014
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Dimebon (latrepirdine), an old antihistaminic drug, showed divergent results in two large clinical trials in Alzheimer disease (AD), which according to our review might be related to the specific pharmacological properties of the drug and the different patient populations included in both studies. Out of the many pharmacological effects of Dimebon, improvement of impaired mitochondrial function seeems to be most relevant for the substantial effects on cognition and behaviour reported in one of the studies, as these effects are already present at the low concentrations of dimebon measured in plasma and tissues of patients and experimental animals. Since impaired mitochondrial function seems to be the major driving force for the progression of the clinical symptoms and since most of the clinical benefits of dimebon originate from an effect on the symptomatic deterioration, mitochondrial improvement can also explain the lack of efficacy of this drug in another clinical trial where symptoms of the patiets remained stable for the time of the study. Accordingly, it seems worthwhile to reevaluate the clinical data to proof that clinical response is correlated with high levels of Neuropsychiatric Symptoms as these show a good relationship to the individual speed of symptomatic decline in AD patients related to mitochondrial dysfunction.

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Processing of Mutant β-Amyloid Precursor Protein and the Clinicopathological Features of Familial Alzheimer’s Disease
Bi Christopher, Bi Stephanie, Li Bin
Aging and disease    2019, 10 (2): 383-403.   DOI: 10.14336/AD.2018.0425
Accepted: 12 November 2018

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Alzheimer’s disease (AD) is a complex, multifactorial disease involving many pathological mechanisms. Nonetheless, single pathogenic mutations in amyloid precursor protein (APP) or presenilin 1 or 2 can cause AD with almost all of the clinical and neuropathological features, and therefore, we believe an important mechanism of pathogenesis in AD could be revealed from examining pathogenic APP missense mutations. A comprehensive review of the literature, including clinical, neuropathological, cellular and animal model data, was conducted through PubMed and the databases of Alzforum mutations, HGMD, UniProt, and AD&FTDMDB. Pearson correlation analysis combining the clinical and neuropathological data and aspects of mutant APP processing in cellular models was performed. We find that an increase in Aβ42 has a significant positive correlation with the appearance of neurofibrillary tangles (NFTs) and tends to cause an earlier age of AD onset, while an increase in Aβ40 significantly increases the age at death. The increase in the α-carboxyl terminal fragment (CTF) has a significantly negative correlation with the age of AD onset, and β-CTF has a similar effect without statistical significance. Animal models show that intracellular Aβ is critical for memory defects. Based on these results and the fact that amyloid plaque burden correlates much less well with cognitive impairment than do NFT counts, we propose a “snowball hypothesis”: the accumulation of intraneuronal NFTs caused by extracellular Aβ42 and the increase in intraneuronal APP proteolytic products (CTFs and Aβs) could cause cellular organelle stress that leads to neurodegeneration in AD, which then resembles the formation of abnormal protein “snowballs” both inside and outside of neurons.

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The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases
Tu Wenjun, Wang Hong, Li Song, Liu Qiang, Sha Hong
Aging and disease    2019, 10 (3): 637-651.   DOI: 10.14336/AD.2018.0513
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Oxidative stress is defined as an imbalance between production of free radicals and reactive metabolites or [reactive oxygen species (ROS)] and their elimination by through protective mechanisms, including (antioxidants). This Such imbalance leads to damage of cells and important biomolecules and cells, with hence posing a potential adverse impact on the whole organism. At the center of the day-to-day biological response to oxidative stress is the Kelch-like ECH-associated protein 1 (Keap1) - nuclear factor erythroid 2-related factor 2 (Nrf2)- antioxidant response elements (ARE) pathway, which regulates the transcription of many several antioxidant genes that preserve cellular homeostasis and detoxification genes that process and eliminate carcinogens and toxins before they can cause damage. The redox-sensitive signaling system Keap1/Nrf2/ARE plays a key role in the maintenance of cellular homeostasis under stress, inflammatory, carcinogenic, and pro-apoptotic conditions, which allows us to consider it as a pharmacological target. Herein, we review and discuss the recent advancements in the regulation of the Keap1/Nrf2/ARE system, and its role under physiological and pathophysiological conditions, e.g. such as in exercise, diabetes, cardiovascular diseases, cancer, neurodegenerative disorders, stroke, liver and kidney system, etc. and such.

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Hyperphosphatemia Promotes Senescence of Myoblasts by Impairing Autophagy Through Ilk Overexpression, A Possible Mechanism Involved in Sarcopenia
Patricia Sosa, Elena Alcalde-Estevez, Patricia Plaza, Nuria Troyano, Cristina Alonso, Laura Martinez-Arias, Andresa Evelem de Melo Aroeira, Diego Rodriguez-Puyol, Gemma Olmos, Susana Lopez-Ongil, Maria P. Ruiz-Torres
Aging and disease    2018, 9 (5): 769-784.   DOI: 10.14336/AD.2017.1214
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In mammalians, advancing age is associated with sarcopenia, the progressive and involuntary loss of muscle mass and strength. Hyperphosphatemia is an aging-related condition involved in several pathologies. The aim of this work was to assess whether hyperphosphatemia plays a role in the age-related loss of mass muscle and strength by inducing cellular senescence in murine myoblasts and to explore the intracellular mechanism involved in this effect. Cultured mouse C2C12 cells were treated with 10 mM beta-glycerophosphate (BGP] at different periods of time to induce hyperphosphatemia. BGP promoted cellular senescence after 24 h of treatment, assessed by the increased expression of p53, acetylated-p53 and p21 and senescence associated β-galactosidase activity. In parallel, BGP increased ILK expression and activity, followed by mTOR activation and autophagy reduction. Knocking-down ILK expression increased autophagy and protected cells from senescence induced by hyperphosphatemia. BGP also reduced the proliferative capacity of cultured myoblasts. Old mice (24-months-old] presented higher serum phosphate concentration, lower forelimb strength, higher expression of p53 and ILK and less autophagy in vastus muscle than young mice (5-months-old]. In conclusion, we propose that hyperphosphatemia induces senescence in cultured myoblasts through ILK overexpression, reducing their proliferative capacity, which could be a mechanism involved in the development of sarcopenia, since old mice showed loss of muscular strength correlated with high serum phosphate concentration and increased levels of ILK and p53.

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Overweight in the Elderly Induces a Switch in Energy Metabolism that Undermines Muscle Integrity
Potes Yaiza, Pérez-Martinez Zulema, Bermejo-Millo Juan C., Rubio-Gonzalez Adrian, Fernandez-Fernández María, Bermudez Manuel, Arche Jose M., Solano Juan J., Boga Jose A., Oliván Mamen, Caballero Beatriz, Vega-Naredo Ignacio, Coto-Montes Ana
Aging and disease    2019, 10 (2): 217-230.   DOI: 10.14336/AD.2018.0430
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Aging is characterized by a progressive loss of skeletal muscle mass and function (sarcopenia). Obesity exacerbates age-related decline and lead to frailty. Skeletal muscle fat infiltration increases with aging and seems to be crucial for the progression of sarcopenia. Additionally, skeletal muscle plasticity modulates metabolic adaptation to different pathophysiological situations. Thus, cellular bioenergetics and mitochondrial profile were studied in the skeletal muscle of overweight aged people without reaching obesity to prevent this extreme situation. Overweight aged muscle lacked ATP production, as indicated by defects in the phosphagen system, glycolysis and especially mostly by oxidative phosphorylation metabolic pathway. Overweight subjects exhibited an inhibition of mitophagy that was linked to an increase in mitochondrial biogenesis that underlies the accumulation of dysfunctional mitochondria and encourages the onset of sarcopenia. As a strategy to maintain cellular homeostasis, overweight subjects experienced a metabolic switch from oxidative to lactic acid fermentation metabolism, which allows continued ATP production under mitochondrial dysfunction, but without reaching physiological aged basal levels. This ATP depletion induced early signs of impaired contractile function and a decline in skeletal muscle structural integrity, evidenced by lower levels of filamin C. Our findings reveal the main effector pathways at an early stage of obesity and highlight the importance of mitochondrial metabolism in overweight and obese individuals. Exploiting mitochondrial profiles for therapeutic purposes in humans is an ambitious strategy for treating muscle impairment diseases.

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Elevated Inflammatory Status and Increased Risk of Chronic Disease in Chronological Aging: Inflamm-aging or Inflamm-inactivity?
Michael G. Flynn,Melissa M. Markofski,Andres E. Carrillo
Aging and disease    2019, 10 (1): 147-156.   DOI: 10.14336/AD.2018.0326
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Age-associated hyper-inflammation or “inflamm-aging” has been linked to the development of chronic diseases and characterized as an unavoidable aspect of aging. However, the inflamm-aging model does not adequately address the potential anti-inflammatory effects of exercise training and the potential for exercise to ameliorate several age-related diseases. In this brief review, we introduce a new paradigm—inflamm-inactivity—that describes a potent counter-measure to age-associated inflammatory illness.

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Prospective Views for Whey Protein and/or Resistance Training Against Age-related Sarcopenia
Yuxiao Liao,Zhao Peng,Liangkai Chen,Yan Zhang,Qian Cheng,Andreas K. Nüssler,Wei Bao,Liegang Liu,Wei Yang
Aging and disease    2019, 10 (1): 157-173.   DOI: 10.14336/AD.2018.0325
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Skeletal muscle aging is characterized by decline in skeletal muscle mass and function along with growing age, which consequently leads to age-related sarcopenia, if without any preventive timely treatment. Moreover, age-related sarcopenia in elder people would contribute to falls and fractures, disability, poor quality of life, increased use of hospital services and even mortality. Whey protein (WP) and/or resistance training (RT) has shown promise in preventing and treating age-related sarcopenia. It seems that sex hormones could be potential contributors for gender differences in skeletal muscle and age-related sarcopenia. In addition, skeletal muscle and the development of sarcopenia are influenced by gut microbiota, which in turn is affected by WP or RT. Gut microbiota may be a key factor for WP and/or RT against age-related sarcopenia. Therefore, focusing on sex hormones and gut microbiota may do great help for preventing, treating and better understanding age-related sarcopenia.

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Removal of Chylomicron Remnants from the Bloodstream is Delayed in Aged Subjects
Vinagre Carmen G, Freitas Fatima R, de Mesquita Carlos H, Vinagre Juliana C, Mariani Ana Carolina, Kalil-Filho Roberto, Maranhão Raul C
Aging and disease    2018, 9 (4): 748-754.   DOI: 10.14336/AD.2017.1003
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Dietary fats absorbed in the intestine are transported in the circulation as chylomicrons and remnants that have atherogenic potential. Although postprandial lipidemia is increased in older subjects, the specific chylomicron metabolism has not been explored in older subjects nor compared to young subjects, which is the focus of this study. After a 12 h fast, artificially-made emulsions similar to lymph chylomicrons and doubly labeled with radioactive cholesteryl esters and triglycerides were intravenously injected in 23 older (66±4 years) and 20 young (24±3 years) subjects. Sequential blood samples were collected to determine fractional clearance rates (FCR, in min-1) by compartmental analysis. Older subjects had higher LDL-cholesterol (p<0.001) and triglycerides (p<0.0001) than young subjects; HDL-cholesterol presented no difference. The emulsion cholesteryl-ester FCR was lower in older subjects compared to the young (p=0.0001). The emulsion triglyceride FCR did not differ in the two groups. Tested in vitro, however, the lipolysis of the emulsion triglycerides was less intense in the older than in the young subjects. As delayed removal of remnants, indicated by the pronouncedly smaller cholesteryl ester FCR, is related to the presence of cardiovascular diseases, this can be a risk factor which could accelerate atherogenic complications occurring in aged subjects

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