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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
Abstract2309)   HTML3)    PDF(pc) (607KB)(730)       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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CLARITY for High-resolution Imaging and Quantification of Vasculature in the Whole Mouse Brain
Zhang Lin-Yuan, Lin Pan, Pan Jiaji, Ma Yuanyuan, Wei Zhenyu, Jiang Lu, Wang Liping, Song Yaying, Wang Yongting, Zhang Zhijun, Jin Kunlin, Wang Qian, Yang Guo-Yuan
Aging and disease    2018, 9 (2): 262-272.   DOI: 10.14336/AD.2017.0613
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Elucidating the normal structure and distribution of cerebral vascular system is fundamental for understanding its function. However, studies on visualization and whole-brain quantification of vasculature with cellular resolution are limited. Here, we explored the structure of vasculature at the whole-brain level using the newly developed CLARITY technique. Adult male C57BL/6J mice undergoing transient middle cerebral artery occlusion and Tie2-RFP transgenic mice were used. Whole mouse brains were extracted for CLARITY processing. Immunostaining was performed to label vessels. Customized MATLAB code was used for image processing and quantification. Three-dimensional images were visualized using the Vaa3D software. Our results showed that whole mouse brain became transparent using the CLARITY method. Three-dimensional imaging and visualization of vasculature were achieved at the whole-brain level with a 1-μm voxel resolution. The quantitative results showed that the fractional vascular volume was 0.018 ± 0.004 mm3 per mm3, the normalized vascular length was 0.44 ± 0.04 m per mm3, and the mean diameter of the microvessels was 4.25 ± 0.08 μm. Furthermore, a decrease in the fractional vascular volume and a decrease in the normalized vascular length were found in the penumbra of ischemic mice compared to controls (p < 0.05). In conclusion, CLARITY provides a novel approach for mapping vasculature in the whole mouse brain at cellular resolution. CLARITY-optimized algorithms facilitate the assessment of structural change in vasculature after brain injury.

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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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Serum Zonulin and Endotoxin Levels in Exceptional Longevity versus Precocious Myocardial Infarction
Carrera-Bastos Pedro, Picazo Óscar, Fontes-Villalba Maelán, Pareja-Galeano Helios, Lindeberg Staffan, Martínez-Selles Manuel, Lucia Alejandro, Emanuele Enzo
Aging and disease    2018, 9 (2): 317-321.   DOI: 10.14336/AD.2017.0630
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Endotoxemia-induced inflammation has been associated with insulin resistance and atherosclerosis, ultimately increasing the risk of coronary heart disease. Increased intestinal permeability is an important event leading to endotoxemia. This study aims to elucidate the possible association between endotoxin (lipopolysaccharide) and zonulin (a biomarker of intestinal permeability) levels and the risk of coronary heart disease, and thus healthy aging. Serum levels of zonulin, lipopolysaccharide and soluble CD14 (a protein that binds lipopolysaccharide) were measured in disease-free centenarians, young healthy controls and patients with precocious acute myocardial infarction. Disease-free centenarians had significantly lower levels of serum zonulin (P<0.01) and lipopolysaccharide (P<0.001) than young patients with acute myocardial infarction, and had significantly lower concentrations of serum lipopolysaccharide than young healthy controls (P<0.05). No significant differences were found for soluble CD14 between groups. Our findings may stimulate further research into the role played by intestinal permeability and endotoxemia not only in coronary heart disease but also in lifespan modulation.

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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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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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SIRT3 Protects Rotenone-induced Injury in SH-SY5Y Cells by Promoting Autophagy through the LKB1-AMPK-mTOR Pathway
Zhang Meng, Deng Yong-Ning, Zhang Jing-Yi, Liu Jie, Li Yan-Bo, Su Hua, Qu Qiu-Min
Aging and disease    2018, 9 (2): 273-286.   DOI: 10.14336/AD.2017.0517
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SIRT3 is a class III histone deacetylase that modulates energy metabolism, genomic stability and stress resistance. It has been implicated as a potential therapeutic target in a variety of neurodegenerative diseases, including Parkinson’s disease (PD). Our previous study demonstrates that SIRT3 had a neuroprotective effect on a rotenone-induced PD cell model, however, the exact mechanism is unknown. In this study, we investigated the underlying mechanism. We established a SIRT3 stable overexpression cell line using lentivirus infection in SH-SY5Y cells. Then, a PD cell model was established using rotenone. Our data demonstrate that overexpression of SIRT3 increased the level of the autophagy markers LC3 II and Beclin 1. After addition of the autophagy inhibitor 3-MA, the protective effect of SIRT3 diminished: the cell viability decreased, while the apoptosis rate increased; α-synuclein accumulation enhanced; ROS production increased; antioxidants levels, including SOD and GSH, decreased; and MMP collapsed. These results reveal that SIRT3 has neuroprotective effects on a PD cell model by up-regulating autophagy. Furthermore, SIRT3 overexpression also promoted LKB1 phosphorylation, followed by activation of AMPK and decreased phosphorylation of mTOR. These results suggest that the LKB1-AMPK-mTOR pathway has a role in induction of autophagy. Together, our findings indicate a novel mechanism by which SIRT3 protects a rotenone-induced PD cell model through the regulation of autophagy, which, in part, is mediated by activation of the LKB1-AMPK-mTOR pathway.

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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
Abstract1177)   HTML0)    PDF(pc) (259KB)(423)       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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Anserine/Carnosine Supplementation Preserves Blood Flow in the Prefrontal Brain of Elderly People Carrying APOE e4
Ding Qiong, Tanigawa Kitora, Kaneko Jun, Totsuka Mamoru, Katakura Yoshinori, Imabayashi Etsuko, Matsuda Hiroshi, Hisatsune Tatsuhiro
Aging and disease    2018, 9 (3): 334-345.   DOI: 10.14336/AD.2017.0809
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In a previously reported double-blind, randomized controlled trial (RCT), we demonstrated that daily supplementation with anserine (750 mg) and carnosine (250 mg) improves brain blood flow and memory function in elderly people. Here, we conducted a sub-analysis of MRI data and test scores from the same RCT to determine whether anserine/carnosine supplementation specifically benefits elderly people carrying the APOE e4 allele, which is a risk gene for accelerated brain aging and for the onset of Alzheimer’s Disease. We collected data from 68 participants aged 65 years or older who received anserine/carnosine supplementation (ACS) or placebo for 12 months. Subjects were assessed at the start and end of the trial using several neuropsychological tests, including the Wechsler Memory Scale-Logical Memory (WMS-LM). We also collected two types of MRI data, arterial spin labeling (ASL) and diffusion tensor imaging (DTI) at the start and end of the trial. We found that ACS significantly preserved verbal memory (WMS-LM, F[1,65] = 4.2003, p = 0.0445) and blood flow at frontal areas of the brain (FWEcluster level, p < 0.001). Sub-analysis based on the APOE4 genotype showed a significant preservation of blood flow (p = 0.002, by ASL analysis) and white-matter microstructure (p = 0.003, by DTI analysis) at prefrontal areas in APOE4+ subjects in the active group, while there was no significant difference between APOE4- subjects in the active and placebo groups. The effect of ACS in preserving brain structure and function in elderly people carrying APOE4 should be verified by further studies.

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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
Seong Gak Jeon, Eun Ji Song, Dongje Lee, Junyong Park, Yunkwon Nam, Jin-il Kim, Minho Moon
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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Effects of Elastic Therapeutic Taping on Knee Osteoarthritis: A Systematic Review and Meta-analysis
Li Xin, Zhou Xuan, Liu Howe, Chen Nan, Liang Juping, Yang Xiaoyan, Zhao Guoyun, Song Yanping, Du Qing
Aging and disease    2018, 9 (2): 296-308.   DOI: 10.14336/AD.2017.0309
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Elastic therapeutic taping (ET) has been widely used for a series of musculoskeletal diseases in recent years. However, there remains clinical uncertainty over its efficiency for knee osteoarthritis (knee OA) management. To assess the effects of ET on patients with knee OA, we investigated outcomes including self-reported pain, knee flexibility, knee-related health status, adverse events, muscle strength, and proprioceptive sensibility. Ten databases including PubMed, EMBASE, Cochrane Library, CINAHL, Web of Science, PEDro, Research Gate, CNKI, CBM, and Wanfang were systematically searched. Eleven randomized controlled trials (RCTs) with 168 participants with knee OA provided data for the meta-analysis. Statistical significance was reported in four from five outcomes, such as self-related pain (during activity, MD -0.85, 95% CI, -1.55 to -0.14; P =0.02), knee flexibility (MD 7.59, 95% CI, 0.61 to 14.57; P =0.03), knee-related health status (WOMAC scale, MD -4.10, 95% CI, -7.75 to -0.45; P =0.03), and proprioceptive sensibility (MD -4.69, 95% CI, -7.75 to -1.63; P =0.003), while no significant enhancement was reported regarding knee muscle strength (MD 1.25, 95% CI, -0.03 to 2.53; P =0.06). Adverse events were not reported in any of the included trials. The overall quality of evidence was from moderate to very low. In conclusion, there is underpowered evidence to suggest that ET is effective in the treatment of knee OA. Large, well-designed RCTs with better designs are needed.

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Frailty in Older Adults with Cardiovascular Disease: Cause, Effect or Both?
Kleipool Emma EF., Hoogendijk Emiel O., Trappenburg Marijke C., Handoko M. Louis, Huisman Martijn, Peters Mike JL., Muller Majon
Aging and disease    2018, 9 (3): 489-497.   DOI: 10.14336/AD.2017.1125
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Cardiovascular disease (CVD) has been associated with an increased risk of frailty, but the direction of the association remains unclear. This study set out to examine the bidirectional longitudinal association between CVD and frailty over an extended period of time. Data are from 1432 older adults (aged 65-88yrs) of the Longitudinal Aging Study Amsterdam (LASA), who were followed for 17 years. At baseline and follow-up, CVD was assessed through self-report, medication use and medical records, and classified as angina pectoris, myocardial infarction, heart failure (HF), stroke, and peripheral artery disease. Throughout the study, frailty was assessed using Fried’s frailty criteria. Cox regression models showed that patients with HF had an increased frailty risk (HR 2.7; 95%CI: 1.5-5.1) after a median follow-up of 8.4 yrs. This finding was independent of potential confounders (age, sex, several comorbidities). Examinations of the reverse association revealed that frail older adults were not at risk of incident CVD. Of all older adults with CVD, those with HF have an increased risk of frailty and frail older adults do not have an increased risk of CVD. Our findings emphasize the need for cardiac rehabilitation programs evaluating the effect of physical exercise programs in order to prevent frailty and therewith improve quality of life and independence of care in CVD patients.

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Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept
Hae Young Chung, Dae Hyun Kim, Eun Kyeong Lee, Ki Wung Chung, Sangwoon Chung, Bonggi Lee, Arnold Y. Seo, Jae Heun Chung, Young Suk Jung, Eunok Im, Jaewon Lee, Nam Deuk Kim, Yeon Ja Choi, Dong Soon Im, Byung Pal Yu
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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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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Metformin Alters Locomotor and Cognitive Function and Brain Metabolism in Normoglycemic Mice
Wenjun Li, Kiran Chaudhari, Ritu Shetty, Ali Winters, Xiaofei Gao, Zeping Hu, Woo-Ping Ge, Nathalie Sumien, Michael Forster, Ran Liu, Shao-Hua Yang
Aging and disease    2019, 10 (5): 949-963.   DOI: 10.14336/AD.2019.0120
Accepted: 25 January 2019

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Metformin is currently the most effective treatment for type-2 diabetes. The beneficial actions of metformin have been found even beyond diabetes management and it has been considered as one of the most promising drugs that could potentially slow down aging. Surprisingly, the effect of metformin on brain function and metabolism has been less explored given that brain almost exclusively uses glucose as substrate for energy metabolism. We determined the effect of metformin on locomotor and cognitive function in normoglycemic mice. Metformin enhanced locomotor and balance performance, while induced anxiolytic effect and impaired cognitive function upon chronic treatment. We conducted in vitro assays and metabolomics analysis in mice to evaluate metformin’s action on the brain metabolism. Metformin decreased ATP level and activated AMPK pathway in mouse hippocampus. Metformin inhibited oxidative phosphorylation and elevated glycolysis by inhibiting mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) in vitro at therapeutic doses. In summary, our study demonstrated that chronic metformin treatment affects brain bioenergetics with compound effects on locomotor and cognitive brain function in non-diabetic mice.

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Aging Health and R&D for Healthy Longevity Must Be Included into the WHO Work Program
Stambler Ilia, Jin Kunlin, Lederman Stephanie, Barzilai Nir, Olshansky S. Jay, Omokaro Emem, Barratt Jane, Anisimov Vladimir N., Rattan Suresh, Yang Shaohua, Forster Michael, Byles Julie
Aging and disease    2018, 9 (2): 331-333.   DOI: 10.14336/AD.2017.1120
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Aged Mice are More Resistant to Influenza Virus Infection due to Reduced Inflammation and Lung Pathology
Lu Jiao, Duan Xuefeng, Zhao Wenming, Wang Jing, Wang Haoyu, Zhou Kai, Fang Min
Aging and disease    2018, 9 (3): 358-373.   DOI: 10.14336/AD.2017.0701
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Immune responses are a double-edged sword. Effective and appropriate immune responses capable of controlling viral infection while also largely preserving tissue integrity, are critical for host survival. Too strong immune responses might result in immune pathology, while too weak immune responses might cause viral persistence. Physiologic ageing is accompanied with a decline in the normal functioning of the immune system, which is termed as "immunosenescence". We show that aged mice (16-19 months old) are more resistant to influenza A virus (IAV) infection than the young mice. Strong immune responses in the young mice after IAV infection result in faster clearance of virus, but also cause severe lung injury and higher mortality rate. While in the aged mice, the delayed and milder immune responses contribute to reduced pulmonary damage, and are still capable to clear the infection even with a slower kinetics, displaying a more resistant phenotype during IAV infection. Hence, our work demonstrates that moderate immune responses as a decline with ageing in the aged mice balance the immune pathology and viral clearance, might be beneficial for the host during certain circumstances. Our results provide important insight to our basic knowledge of immunosenescence and immune defenses to invading pathogens. Further, our results indicate that age factors should be considered when investigating the vaccination and therapeutic strategies for severe IAV infection.

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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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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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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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The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases
Wenjun Tu, Hong Wang, Song Li, Qiang Liu, Hong Sha
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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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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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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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 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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Enhancement of Mesenchymal Stem Cell-Driven Bone Regeneration by Resveratrol-Mediated SOX2 Regulation
Yoorim Choi, Dong Suk Yoon, Kyoung-Mi Lee, Seong Mi Choi, Myon-Hee Lee, Kwang Hwan Park, Seung Hwan Han, Jin Woo Lee
Aging and disease    2019, 10 (4): 818-833.   DOI: 10.14336/AD.2018.0802
Accepted: 18 September 2018

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Mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine. However, MSCs age rapidly during long-term ex vivo culture and lose their therapeutic potential before they reach effective cell doses (ECD) for cell therapy. Thus, a prerequisite for effective MSC therapy is the development of cell culture methods to preserve the therapeutic potential during long-term ex vivo cultivation. Resveratrol (RSV) has been highlighted as a therapeutic candidate for bone disease. Although RSV treatment has beneficial effects on bone-forming cells, in vivo studies are lacking. The current study showed that long-term (6 weeks from primary culture date)-cultured MSCs with RSV induction retained their proliferative and differentiation potential despite reaching ECD. The mechanism of RSV action depends entirely on the SIRT1-SOX2 axis in MSC culture. In a rat calvarial defect model, RSV induction significantly improved bone regeneration after MSC transplantation. This study demonstrated an example of efficient MSC therapy for treating bone defects by providing a new strategy using the plant polyphenol RSV.

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BDNF Polymorphism: A Review of Its Diagnostic and Clinical Relevance in Neurodegenerative Disorders
Shen Ting, You Yuyi, Joseph Chitra, Mirzaei Mehdi, Klistorner Alexander, Graham Stuart L., Gupta Vivek
Aging and disease    2018, 9 (3): 523-536.   DOI: 10.14336/AD.2017.0717
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Brain-derived neurotrophic factor (BDNF) has a unique role in the neuronal development, differentiation, and survival in the developing and adult nervous system. A common single-nucleotide polymorphism in the pro-region of the human BDNF gene, resulting in a valine to methionine substitution (Val66Met), has been associated with the susceptibility, incidence, and clinical features of several neurodegenerative disorders. Much research has been dedicated to evaluating the effects of polymorphism in the past decade, and functional effects of this genetic variation. A better understanding of how this naturally occurring polymorphism associates with or influences physiology, anatomy, and cognition in both healthy and diseased adults in neurodegenerative conditions will help understand neurochemical mechanisms and definable clinical outcomes in humans. Here we review the role and relevance of the BDNF Val66Met polymorphism in neurodegenerative diseases, with particular emphasis on glaucoma, multiple sclerosis (MS), Alzheimer’s disease (AD) and Parkinson’s disease (PD). Several controversies and unresolved issues, including small effect sizes, possible ethnicity, gender, and age effects of the BDNF Val66Met are also discussed with respect to future research.

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Age-Dependent Decrease in Adropin is Associated with Reduced Levels of Endothelial Nitric Oxide Synthase and Increased Oxidative Stress in the Rat Brain
Yang Changjun, DeMars Kelly M., Candelario-Jalil Eduardo
Aging and disease    2018, 9 (2): 322-330.   DOI: 10.14336/AD.2017.0523
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Adropin is a peptide highly expressed in the brain. Emerging evidence indicates that low plasma levels of adropin are closely associated with aging and endothelial dysfunction. We hypothesized that aging reduces adropin levels in the brain, which correlates with reduced endothelial nitric oxide synthase (eNOS) and increased oxidative stress associated with age-related endothelial dysfunction. Cortical brain tissue and plasma were collected from young (10-12 weeks old) and aged (18-20 months old) male Sprague-Dawley naïve rats. Using RT-qPCR, we quantified the mRNA levels of the energy homeostasis associated (Enho) gene encoding for adropin. Western blotting was utilized to measure adropin and markers of endothelial dysfunction and oxidative stress in the brain tissue. Levels of adropin in plasma were measured using an ELISA kit. Compared to young rats, both Enho mRNA and protein levels were dramatically reduced in the aged rat brain, which was accompanied by a significant reduction in plasma adropin levels in aged compared to young rats. Additionally, total and phosphorylated levels of endothelial nitric oxide synthase (eNOS) were significantly decreased in aged rat brains and were associated with dramatically increased gp91phox-containing NADPH oxidase (a major source of free radicals) and 4-hydroxynonenal (4-HNE), a lipid peroxidation marker. Brain levels of Akt and caveolin-1 were significantly reduced in aged rats compared with young animals. Collectively, these findings indicate that adropin levels negatively correlate with markers of endothelial dysfunction and oxidative injury, which raises the possibility that loss of brain adropin might play a role in the pathogenesis and development of aging-associated cerebrovascular dysfunction.

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The Prevalence of Frailty and its Associated Factors in Japanese Hemodialysis Patients
Takeuchi Hidemi, Uchida Haruhito A., Kakio Yuki, Okuyama Yuka, Okuyama Michihiro, Umebayashi Ryoko, Wada Kentaro, Sugiyama Hitoshi, Sugimoto Ken, Rakugi Hiromi, Wada Jun
Aging and disease    2018, 9 (2): 192-207.   DOI: 10.14336/AD.2017.0429
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The population undergoing dialysis is aging worldwide, particularly in Japan. The clinical condition of frailty is the most problematic expression in the elderly population. Potential pathophysiological factors of frailty present in patients with CKD and are accentuated in patients with ESRD. The aim of this study was to identify the prevalence and predictors of frailty in Japanese HD patients. This study was a multicenter, cross-sectional and observational investigation conducted at 6 institutions. To evaluate frailty, the modified Fried’s frailty phenotype adjusted for Japanese as the self-reported questionnaire was used. Of the 542 patients visiting each institution, 388 were enrolled in this study. In total, 26.0% of participants were categorized as not-frailty, 52.6% as pre-frailty and 21.4% as frailty. The prevalence of frailty increased steadily with age and was more prevalent in females than in males and the subjects with frailty received polypharmacy. A multivariate logistic regression analysis revealed that the factors independently associated with frailty were the following: female gender (odds ratio [OR] = 3.661, 95% confidence interval [CI] 1.398-9.588), age (OR = 1.065, 95% CI 1.014-1.119), age ≥ 75 years old (OR = 4.892, 95% CI 1.715-13.955), body mass index (BMI) < 18.5 (OR = 0.110, 95% CI 0.0293-0.416), number of medications being taken (OR = 1.351, 95% CI 1.163-1.570), diabetes mellitus (DM) (OR = 2.765, 95% CI 1.081-7.071) and MNA-SF ≤ 11 (OR = 7.405, 95% CI 2.732-20.072). Frailty was associated with the accumulation of risk factors. The prevalence of frailty in Japanese patients with HD was relatively lower than that previously reported in Western developed countries; however, it was extremely high compared to the general population regardless of age. Our findings suggest that frailty might be associated with an increase in the prevalence of adverse health outcomes in patients with HD.

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Temporal Gene Expression Profiles after Focal Cerebral Ischemia in Mice
Zhang Chengjie, Zhu Yanbing, Wang Song, Zachory Wei Zheng, Jiang Michael Qize, Zhang Yongbo, Pan Yuhualei, Tao Shaoxin, Li Jimei, Wei Ling
Aging and disease    2018, 9 (2): 249-261.   DOI: 10.14336/AD.2017.0424
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A cascade of pathological processes is triggered in the lesion area after ischemic stroke. Unfortunately, our understanding of these complicated molecular events is incomplete. In this investigation, we sought to better understand the detailed molecular and inflammatory events occurring after ischemic stroke. RNA-seq technology was used to identify whole gene expression profiles at days (D1, D3, D7, D14, D21) after focal cerebral ischemia in mice. Enrichment analyses based on Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms for the differentially expressed genes (DEGs) were then analyzed. Inflammation-related genes that were significantly expressed after stroke were selected for analysis and the temporal expression patterns of pro-inflammatory and anti-inflammatory genes were reported. These data illustrated that the number of DEGs increased accumulatively after cerebral ischemia. In summary, there were 1967 DEGs at D1, 2280 DEGs at D3, 2631 DEGs at D7, 5516 DEGs at D14 and 7093 DEGs at D21. The significantly enriched GO terms also increased. 58 GO terms and 18 KEGG pathways were significantly enriched at all inspected time points. We identified 87 DEGs which were functionally related to inflammatory responses. The expression levels of pro-inflammation related genes CD16, CD32, CD86, CD11b, Tumour necrosis factor α (TNF-α), Interleukin 1β (IL-1β) increased over time and peaked at D14. Anti-inflammation related genes Arginase 1 (Arg1) and Chitinase-like 3 (Ym1) peaked at D1 while IL-10, Transforming growth factor β (TGF-β) and CD206, which were induced at 1 day after cerebral ischemia, peaked by 7 to 14 days. These gene profile changes were potentially linked to microglia/macrophage phenotype changes and could play a role in astroglial activation. This study supplies new insights and detailed information on the molecular events and pathological mechanisms that occur after experimental ischemic stroke.

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TOPK Promotes Microglia/Macrophage Polarization towards M2 Phenotype via Inhibition of HDAC1 and HDAC2 Activity after Transient Cerebral Ischemia
Han Ziping, Zhao Haiping, Tao Zhen, Wang Rongliang, Fan Zhibin, Luo Yumin, Luo Yinghao, Ji Xunming
Aging and disease    2018, 9 (2): 235-248.   DOI: 10.14336/AD.2017.0328
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T-LAK-cell-originated protein kinase (TOPK) is a newly identified member of the mitogen-activated protein kinase family. Our previous study has showed that TOPK has neuroprotective effects against cerebral ischemia-reperfusion injury. Here, we investigated the involvement of TOPK in microglia/ macrophage M1/M2 polarization and the underlying epigenetic mechanism. The expression profiles, co-localization and in vivo interaction of TOPK, M1/M2 surface markers, and HDAC1/HDAC2 were detected after middle cerebral artery occlusion models (MCAO). We demonstrated that TOPK, the M2 surface markers CD206 and Arg1, p-HDAC1, and p-HDAC2 showed a similar pattern of in vivo expression over time after MCAO. TOPK co-localized with CD206, p-HDAC1, and p-HDAC2 positive cells, and was shown to bind to HDAC1 and HDAC2. In vitro study showed that TOPK overexpression in BV2 cells up-regulated CD206 and Arg1, and promoted the phosphorylation of HDAC1 and HDAC2. In addition, TOPK overexpression also prevented LPS plus IFN-γ-induced M1 transformation through reducing release of inflammatory factor of M1 phenotype TNF-α, IL-6 and IL-1β, and increasing TGF-β release and the mRNA levels of TGF-β and SOCS3, cytokine of M2 phenotype and its regulator. Moreover, the increased TNF-α induced by TOPK siRNA could be reversed by HDAC1/HDAC2 inhibitor, FK228. TOPK overexpression increased M2 marker expression in vivo concomitant with the amelioration of cerebral injury, neurological functions deficits, whereas TOPK silencing had the opposite effects, which were completely reversed by the FK228 and partially by the SAHA. These findings suggest that TOPK positively regulates microglia/macrophage M2 polarization by inhibiting HDAC1/HDAC2 activity, which may contribute to its neuroprotective effects against cerebral ischemia-reperfusion injury.

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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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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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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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Health and Aging: Unifying Concepts, Scores, Biomarkers and Pathways
Georg Fuellen, Ludger Jansen, Alan A Cohen, Walter Luyten, Manfred Gogol, Andreas Simm, Nadine Saul, Francesca Cirulli, Alessandra Berry, Peter Antal, Rüdiger Köhling, Brecht Wouters, Steffen Möller
Aging and disease    2019, 10 (4): 883-900.   DOI: 10.14336/AD.2018.1030
Accepted: 19 November 2018

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Despite increasing research efforts, there is a lack of consensus on defining aging or health. To understand the underlying processes, and to foster the development of targeted interventions towards increasing one’s health, there is an urgent need to find a broadly acceptable and useful definition of health, based on a list of (molecular) features; to operationalize features of health so that it can be measured; to identify predictive biomarkers and (molecular) pathways of health; and to suggest interventions, such as nutrition and exercise, targeted at putative causal pathways and processes. Based on a survey of the literature, we propose to define health as a state of an individual characterized by the core features of physiological, cognitive, physical and reproductive function, and a lack of disease. We further define aging as the aggregate of all processes in an individual that reduce its wellbeing, that is, its health or survival or both. We define biomarkers of health by their attribute of predicting future health better than chronological age. We define healthspan pathways as molecular features of health that relate to each other by belonging to the same molecular pathway. Our conceptual framework may integrate diverse operationalizations of health and guide precision prevention efforts.

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Prehospital Notification Procedure Improves Stroke Outcome by Shortening Onset to Needle Time in Chinese Urban Area
Zhang Sheng, Zhang Jungen, Zhang Meixia, Zhong Genlong, Chen Zhicai, Lin Longting, Lou Min
Aging and disease    2018, 9 (3): 426-434.   DOI: 10.14336/AD.2017.0601
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Intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) can improve clinical outcome in eligible patients with acute ischemic stroke (AIS). However, its efficacy is strongly time-dependent. This study was aimed to examine whether prehospital notification by emergency medical service (EMS) providers could reduce onset to needle time (ONT) and improve neurological outcome in AIS patients who received IVT. We prospectively collected the consecutive clinical and time data of AIS patients who received IVT during one year after the initiation of prehospital notification procedure (PNP). Patients were divided into three groups, including patients that transferred by EMS with and without PNP and other means of transportation (non-EMS). We then compared the effect of EMS with PNP and EMS use only on ONT, and the subsequent neurological outcome. Good outcome was defined as modified Rankin Scale score of 0-2 at 3-months. In 182 patients included in this study, 77 (42.3%) patients were transferred by EMS, of whom 41 (53.2%) patients entered PNP. Compared with non-EMS group, EMS without PNP group greatly shortened the onset to door time (ODT), but EMS with PNP group showed both a significantly shorter DNT (41.3 ± 10.7 min vs 51.9±23.8 min, t=2.583, p=0.012) and ODT (133.2 ± 90.2 min vs 174.8 ± 105.1 min, t=2.228, p=0.027) than non-EMS group. Multivariate analysis showed that the use of EMS with PNP (OR=2.613, p=0.036), but not EMS (OR=1.865, p=0.103), was independently associated with good outcome after adjusting for age and baseline NIHSS score. When adding ONT into the regression model, ONT (OR=0.994, p=0.001), but not EMS with PNP (OR=1.785, p=0.236), was independently associated with good outcome. EMS with PNP, rather than EMS only, improved stroke outcome by shortening ONT. PNP could be a feasible strategy for better stroke care in Chinese urban area.

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Adipose-derived Stem Cells Attenuates Diabetic Osteoarthritis via Inhibition of Glycation-mediated Inflammatory Cascade
Navneet Kumar Dubey, Hong-Jian Wei, Sung-Hsun Yu, David F. Williams, Joseph R. Wang, Yue-Hua Deng, Feng-Chou Tsai, Peter D. Wang, Win-Ping Deng
Aging and disease    2019, 10 (3): 483-496.   DOI: 10.14336/AD.2018.0616
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Diabetes mellitus (DM) is well-known to exert complications such as retinopathy, cardiomyopathy and neuropathy. However, in recent years, an elevated osteoarthritis (OA) complaints among diabetics have been observed, portending the risk of diabetic OA. Since formation of advanced glycation end products (AGE) is believed to be the etiology of various diseases under hyperglycemic conditions, we firstly established that streptozotocin-induced DM could potentiate the development of OA in C57BL/6J mouse model, and further explored the intra-articularly administered adipose-derived stem cell (ADSC) therapy focusing on underlying AGE-associated mechanism. Our results demonstrated that hyperglycemic mice exhibited OA-like structural impairments including a proteoglycan loss and articular cartilage fibrillations in knee joint. Highly expressed levels of carboxymethyl lysine (CML), an AGE and their receptors (RAGE), which are hallmarks of hyperglycemic microenvironment were manifested. The elevated oxidative stress in diabetic OA knee-joint was revealed through increased levels of malondialdehyde (MDA). Further, oxidative stress-activated nuclear factor kappa B (NF-κB), the marker of proinflammatory signalling pathway was also accrued; and levels of matrix metalloproteinase-1 and 13 were upregulated. However, ADSC treatment attenuated all OA-like changes by 4 weeks, and dampened levels of CML, RAGE, MDA, NF-κB, MMP-1 and 13. These results suggest that during repair and regeneration, ADSCs inhibited glycation-mediated inflammatory cascade and rejuvenated cartilaginous tissue, thereby promoting knee-joint integrity in diabetic milieu.

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Brain Interstitial Fluid Drainage Alterations in Glioma-Bearing Rats
Guan Xiangping, Wang Wei, Wang Aibo, Teng Ze, Han Hongbin
Aging and disease    2018, 9 (2): 228-234.   DOI: 10.14336/AD.2017.0415
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Real time imaging and measurement of the drug distribution in the brain interstitial space (ISS) are able to determine the effeicency of local brain drug delivery to treatment gliomas. In the present study, we used a tracer-based magnetic resonance imaging (MRI) method to quantitatively analyze the effects of glioma growth on ISF drainage. Sprague-Dawley rats were randomly divided into six groups (n = 6). C6 glioma cells were implanted into either the caudate nucleus or thalamus of rats and then were examined 10 or 20 days after implantation. The two control groups were treated with vehicle. A tracer was injected into the caudate nucleus of control rats and rats with gliomas growing in the thalamus for 10 or 20 days. The tracer was similarly injected into the thalamus of control rats and rats implanted with gliomas in the caudate nucleus. The diffusion and clearance parameters of the tracer were calculated using tracer-based MRI techniques. We found that glioma implanted in the caudate nucleus significantly decreased the speed of the ISF flow in thalamus. With the growth of the glioma in thalamus, the drainage route of the brain ISF flow was altered in the caudate nucleus, but the speed of the flow was not significantly changed. These findings indicate that tracer-based MRI is a promising technique for optimizing the interstitial administration of therapeutics aimed at treating brain gliomas.

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