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ISSN 2152-5250
Since 2010
2016 impact factor: 4.648
5 year impact factor: 4.1
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Predictors of Memory in Healthy Aging: Polyunsaturated Fatty Acid Balance and Fornix White Matter Integrity
Marta K. Zamroziewicz,Erick J. Paul,Chris E. Zwilling,Aron K. Barbey
Aging and Disease    2017, 8 (4): 372-383.   DOI: 10.14336/AD.2017.0501
Abstract   HTML   PDF (1195KB)

Recent evidence demonstrates that age and disease-related decline in cognition depends not only upon degeneration in brain structure and function, but also on dietary intake and nutritional status. Memory, a potential preclinical marker of Alzheimer’s disease, is supported by white matter integrity in the brain and dietary patterns high in omega-3 and omega-6 polyunsaturated fatty acids. However, the extent to which memory is supported by specific omega-3 and omega-6 polyunsaturated fatty acids, and the degree to which this relationship is reliant upon microstructure of particular white matter regions is not known. This study therefore examined the cross-sectional relationship between empirically-derived patterns of omega-3 and omega-6 polyunsaturated fatty acids (represented by nutrient biomarker patterns), memory, and regional white matter microstructure in healthy, older adults. We measured thirteen plasma phospholipid omega-3 and omega-6 polyunsaturated fatty acids, memory, and regional white matter microstructure in 94 cognitively intact older adults (65 to 75 years old). A three-step mediation analysis was implemented using multivariate linear regressions, adjusted for age, gender, education, income, depression status, and body mass index. The mediation analysis revealed that a mixture of plasma phospholipid omega-3 and omega-6 polyunsaturated fatty acids is linked to memory and that white matter microstructure of the fornix fully mediates the relationship between this pattern of plasma phospholipid polyunsaturated fatty acids and memory. These results suggest that memory may be optimally supported by a balance of plasma phospholipid omega-3 and omega-6 polyunsaturated fatty acids through the preservation of fornix white matter microstructure in cognitively intact older adults. This report provides novel evidence for the benefits of plasma phospholipid omega-3 and omega-6 polyunsaturated fatty acid balance on memory and underlying white matter microstructure.

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Bioactive Flavonoids and Catechols as Hif1 and Nrf2 Protein Stabilizers - Implications for Parkinson’s Disease
Natalya A. Smirnova,Navneet Ammal Kaidery,Dmitry M. Hushpulian,Ilay I. Rakhman,Andrey A. Poloznikov,Vladimir I. Tishkov,Saravanan S. Karuppagounder,Irina N. Gaisina,Anton Pekcec,Klaus Van Leyen,Sergey V. Kazakov,Lichuan Yang,Bobby Thomas,Rajiv R. Ratan,Irina G. Gazaryan
Aging and Disease    2016, 7 (6): 745-762.   DOI: 10.14336/AD.2016.0505
Abstract   HTML   PDF (2250KB)

Flavonoids are known to trigger the intrinsic genetic adaptive programs to hypoxic or oxidative stress via estrogen receptor engagement or upstream kinase activation. To reveal specific structural requirements for direct stabilization of the transcription factors responsible for triggering the antihypoxic and antioxidant programs, we studied flavones, isoflavones and catechols including dihydroxybenzoate, didox, levodopa, and nordihydroguaiaretic acid (NDGA), using novel luciferase-based reporters specific for the first step in HIF1 or Nrf2 protein stabilization. Distinct structural requirements for either transcription factor stabilization have been found: as expected, these requirements for activation of HIF ODD-luc reporter correlate with in silico binding to HIF prolyl hydroxylase. By contrast, stabilization of Nrf2 requires the presence of 3,4-dihydroxy- (catechol) groups. Thus, only some but not all flavonoids are direct activators of the hypoxic and antioxidant genetic programs. NDGA from the Creosote bush resembles the best flavonoids in their ability to directly stabilize HIF1 and Nrf2 and is superior with respect to LOX inhibition thus favoring this compound over others. Given much higher bioavailability and stability of NDGA than any flavonoid, NDGA has been tested in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-animal model of Parkinson’s Disease and demonstrated neuroprotective effects.

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Effects of Different Concurrent Resistance and Aerobic Training Frequencies on Muscle Power and Muscle Quality in Trained Elderly Men: A Randomized Clinical Trial
Rodrigo Ferrari,Sandra C. Fuchs,Luiz Fernando Martins Kruel,Eduardo Lusa Cadore,Cristine Lima Alberton,Ronei Silveira Pinto,Régis Radaelli,Maira Schoenell,Mikel Izquierdo,Hirofumi Tanaka,Daniel Umpierre
Aging and Disease    2016, 7 (6): 697-704.   DOI: 10.14336/AD.2016.0504
Abstract   HTML   PDF (790KB)

Muscle power is a strong predictor of functional status in the elderly population and is required to perform different daily activities. To compare the effects of different weekly training frequencies on muscle power and muscle quality induced by concurrent training (resistance + aerobic) in previously trained elderly men. Twenty-four trained elderly men (65 ± 4 years), previously engaged in a regular concurrent training program, three times per week, for the previous five months, were randomly allocated to concurrent training programs in which training was performed either twice a week (2·week-1, n = 12) or three times per week (3·week-1, n = 12). The groups trained with an identical exercise intensity and volume per session for 10 weeks. Before and after the exercise training, we examined muscle power, as estimated by countermovement jump height; knee extensor isokinetic peak torque at 60 and 180o.s-1; and muscle quality, a quotient between the one-repetition maximum of the knee extensors and the sum of quadriceps femoris muscle thickness determined by ultrasonography. Additionally, as secondary outcomes, blood pressure and reactive hyperemia were evaluated. Two-way ANOVA with repeated measures were used and statistical significance was set at α = 0.05. Muscular power (2·week-1: 7%, and 3·week-1: 10%) and muscle quality (2·week-1: 15%, and 3·week-1: 8%) improved with the concurrent exercise training (p < 0.001) but with no differences between groups. The isokinetic peak torque at 60 (2·week-1: 4%, and 3·week-1: 2%) and 180o.s-1 (2·week-1: 7%, and 3·week-1: 1%) increased in both groups (p = 0.036 and p=0.014, respectively). There were no changes in blood pressure or reactive hyperemia with the concurrent training. Concurrent training performed twice a week promotes similar adaptations in muscular power and muscle quality when compared with the same program performed three times per week in previously trained elderly men.

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Association between Serum Magnesium Levels and Depression in Stroke Patients
Yingying Gu,Kai Zhao,Xiaoqian Luan,Zhihua Liu,Yan Cai,Qiongzhang Wang,Beilei Zhu,Jincai He
Aging and Disease    2016, 7 (6): 687-690.   DOI: 10.14336/AD.2016.0402
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Post-stroke depression (PSD) is a common psychiatric complication of stroke that is associated with a poor outcome in stroke patients. Our aim was to assess the association between the serum magnesium levels and the presence of PSD in Chinese patients. Two hundred nine stroke patients were included in the study. Depressive symptoms were measured by the 17-Hamilton Rating Scale for Depression at 3 months after stroke. Based on the depressive symptoms, diagnoses of depression were made in line with the DSM-IV criteria for PSD. Serum magnesium levels were evaluated using the dimethyl aniline blue colorimetric method at admission. Multivariate analyses were conducted using logistic regression models. Further, 120 normal subjects were recruited, and their serum magnesium levels were also measured as control. At 3 months, fifty-nine patients (28.2%) were diagnosed as PSD. The serum magnesium levels were significantly lower in both PSD patients and non-PSD patients than in normal subjects (p < 0.001). Indeed, patients with PSD showed lower serum magnesium levels (p < 0.001) than did non-PSD patients at admission. In the multivariate analyses, after adjusting for potential variables, we found that an increased risk of PSD was associated with serum magnesium levels ≤ 0.84mmol/L (OR 2.614, 95% CI 1.178-5.798, p=0.018). Low serum magnesium levels at admission were found to be associated with the presence of PSD at 3 months after stroke.

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Long Non-coding RNA H19 Induces Cerebral Ischemia Reperfusion Injury via Activation of Autophagy
Jue Wang,Bin Cao,Dong Han,Miao Sun,Juan Feng
Aging and Disease    2017, 8 (1): 71-84.   DOI: 10.14336/AD.2016.0530
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Long non-coding RNA H19 (lncRNA H19) was found to be upregulated by hypoxia, its expression and function have never been tested in cerebral ischemia and reperfusion (I/R) injury. This study intended to investigate the role of lncRNA H19 and H19 gene variation in cerebral I/R injury with focusing on its relationship with autophagy activation. Cerebral I/R was induced in rats by middle cerebral artery occlusion followed by reperfusion. SH-SY5Y cells were subjected to oxygen and glucose deprivation and reperfusion (OGD/R) to simulate I/R injury. Real-time PCR, flow cytometry, immunofluorescence and Western blot were used to evaluate the level of lncRNA H19, apoptosis, autophagy and some related proteins. The modified multiple ligase reaction was used to analyze the gene polymorphism of six SNPs in H19, rs217727, rs2067051, rs2251375, rs492994, rs2839698 and rs10732516 in ischemic stroke patients. We found that the expression of lncRNA H19 was upregulated by cerebral I/R in rats, as well as by OGD/R in vitro in the cells. Inhibition of lncRNA H19 and autophagy protected cells from OGD/R-induced death, respectively. Autophagy activation induced by OGD/R was prevented by H19 siRNA. Autophagy inducer, rapamycin, abolished lncRNA H19 effect. Furthermore, we found that lncRNA H19 inhibited autophagy through DUSP5-ERK1/2 axis. The result from blood samples of ischemic patients revealed that the variation of H19 gene increased the risk of ischemic stroke. Taken together, the results of present study suggest that LncRNA H19 could be a new therapeutic target of ischemic stroke.

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Low Normal TSH levels are Associated with Impaired BMD and Hip Geometry in the Elderly
Su Jin Lee,Kyoung Min Kim,Eun Young Lee,Mi Kyung Song,Dae Ryong Kang,Hyeon Chang Kim,Yoosik Youm,Young Mi Yun,Hyun-Young Park,Chang Oh Kim,Yumie Rhee
Aging and Disease    2016, 7 (6): 734-743.   DOI: 10.14336/AD.2016.0325
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Subclinical hyperthyroidism is known to be associated with the risk of fractures in elderly people. However, there are few studies assessing whether low normal thyroid-stimulating hormone (TSH) levels affect bone density and geometry. Here, we aimed to assess the influence of the TSH level on bone mineral density (BMD) and geometry in elderly euthyroid subjects. This was a cross-sectional cohort study. A total of 343 men and 674 women with euthyroidism were included and analyzed separately. The subjects were divided into tertiles based on the serum TSH level. The BMD and geometry were measured using dual-energy X-ray absorptiometry and a hip structural analysis program. Multiple regression analysis was used to compute the odds ratios of osteoporosis in the lower TSH tertile group and the association between geometry parameters and the TSH level. We found that the femoral neck and total hip BMDs were lower in the lower TSH tertile group. In women, the cross-sectional area and cortical thickness of the femur were negatively associated with the TSH level in all three regions (the narrow neck, intertrochanter, and femoral shaft); however, in men, these geometry parameters were significantly associated with the TSH level only in the intertrochanter region. The buckling ratio, a bone geometry parameter representing cortical instability, was significantly higher in the lower TSH tertile group in all three regions in women, but not in men. Our results indicated that lower TSH levels in the euthyroid range are related to lower BMD and weaker femoral structure in elderly women.

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Geroprotectors: A Unified Concept and Screening Approaches
Alexey Moskalev,Elizaveta Chernyagina,Anna Kudryavtseva,Mikhail Shaposhnikov
Aging and Disease    2017, 8 (3): 354-363.   DOI: 10.14336/AD.2016.1022
Abstract   HTML   PDF (691KB)

Although the geroprotectors discovery is a new biomedicine trend and more than 200 compounds can slow aging and increase the lifespan of the model organism, there are still no geroprotectors on the market. The reasons may be partly related to the lack of a unified concept of geroprotector, accepted by the scientific community. Such concept as a system of criteria for geroprotector identification and classification can form a basis for an analytical model of anti-aging drugs, help to consolidate the efforts of various research initiatives in this area and compare their results. Here, we review the existing classification and characteristics of geroprotectors based on their effect on the survival of a group of individuals or pharmaceutics classes, according to the proposed mechanism of their geroprotective action or theories of aging. After discussing advantages and disadvantages of these approaches, we offer a new concept based on the maintenance of homeostatic capacity because aging can be considered as exponential shrinkage of homeostatic capacity leading to the onset of age-related diseases and death. Besides, we review the most promising current screening approaches to finding new geroprotectors. Establishing the classification of existing geroprotectors based on physiology and current understanding of the nature of aging is essential for putting the existing knowledge into a single system. This system could be useful to formulate standards for finding and creating new geroprotectors. Standardization, in turn, would allow easier comparison and combination of experimental data obtained by different research groups.

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Pretreatment with Ginseng Fruit Saponins Affects Serotonin Expression in an Experimental Comorbidity Model of Myocardial Infarction and Depression
Mei-Yan Liu,Yan-Ping Ren,Li-Jun Zhang,Jamie Y. Ding
Aging and Disease    2016, 7 (6): 680-686.   DOI: 10.14336/AD.2016.0729
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We previously demonstrated that serotonin (5-HT) and 5-HT2A receptor (5-HT2AR) levels in platelets were up- or down-regulated after myocardial infarction (MI) associated with depression. In this study, we further evaluated the effects of pretreatment with ginseng fruit saponins (GFS) on the expression of 5-HT and 5-HT2AR in MI with or without depression. Eighty Sprague-Dawley (SD) rats were treated with saline and GFS (n=40 per group). The animals were then randomly divided into four subgroups: sham, MI, depression, and MI + depression (n=10 per subgroup). Protein levels of 5-HT and 5-HT2AR in the serum, platelets and brain tissues were determined with ELISA. The results demonstrated that serum 5-HT levels was significantly increased by GFS pretreatment in all subgroups (except the sham subgroup) when compared with saline-treated counterparts (p<0.01). In platelets, GFS pretreatment significantly increased 5-HT levels in all subgroups when compared with their respective saline-treated counterparts (p<0.01). Brain 5-HT levels also declined with GFS pretreatment in the MI-only and depression-only subgroups (p<0.05 vs. saline pretreatment). With respect to 5-HT2AR levels, platelet 5-HT2AR was decreased in GFS pretreated MI, depression and MI + depression subgroups (p<0.01 vs. saline pretreatment). Similarly, brain 5-HT2AR levels decreased in all four subgroups pretreated with GFS (p<0.01 vs. saline pretreatment). We conclude that GFS plays a clear role in modulating 5-HT and 5-HT2AR expressions after MI and depression. Although the effects of GFS on brain 5-HT remain to be elucidated, its therapeutic potential for comorbidities of acute cardiovascular events and depression appears to hold much promise.

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MicroRNA-181c Exacerbates Brain Injury in Acute Ischemic Stroke
Qingfeng Ma,Haiping Zhao,Zhen Tao,Rongliang Wang,Ping Liu,Ziping Han,Shubei Ma,Yumin Luo,Jianping Jia
Aging and Disease    2016, 7 (6): 705-714.   DOI: 10.14336/AD.2016.0320
Abstract   HTML   PDF (1933KB)

MicroRNA-181 (miR-181) is highly expressed in the brain, and downregulated in miRNA expression profiles of acute ischemic stroke patients. However, the roles of miR-181c in stroke are not known. The clinical relevance of miR-181c in acute stroke patients was evaluated by real-time PCR and correlation analyses. Proliferation and apoptosis of BV2 microglial cells and Neuro-2a cells cultured separately or together under oxidative stress or inflammation were assessed with the Cell Counting Kit-8 and by flow cytometry, respectively. Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) in C57/BL6 mice, and cerebral infarct volume, microglia activation, and expression of pro-apoptotic factors were evaluated by 2,3,5-triphenyl-2H-tetrazolium chloride staining, immunocytochemistry, and western blotting, respectively. Plasma levels of miR-181c were decreased in stroke patients relative to healthy individuals, and were positively correlated with neutrophil number and blood platelet count and negatively correlated with lymphocyte number. Lipopolysaccharide (LPS)/hydrogen peroxide (H2O2) treatment inhibited BV2 microglia proliferation without inducing apoptosis, while miR-181c reduced proliferation but increased the apoptosis of these cells with or without LPS/H2O2 treatment. LPS/H2O2 induced apoptosis in Neuro-2a cells co-cultured with BV2 cells, an effect that was potentiated by miR-181c. In the MCAO model, miR-181c agomir modestly increased infarct volume, markedly decreased microglia activation and B cell lymphoma-2 expression, and increased the levels of pro-apoptotic proteins in the ischemic brain. Our data indicate that miR-181c contributes to brain injury in acute ischemic stroke by promoting apoptosis of microglia and neurons via modulation of pro- and anti-apoptotic proteins.

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Shining the Light on Senescence Associated LncRNAs
A.R. Ghanam,Qianlan Xu,Shengwei Ke,Muhammad Azhar,Qingyu Cheng,Xiaoyuan Song
Aging and Disease    2017, 8 (2): 149-161.   DOI: 10.14336/AD.2016.0810
Abstract   HTML   PDF (1144KB)

Cellular senescence can be described as a complex stress response that leads to irreversible cell cycle arrest. This process was originally described as an event that primary cells go through after many passages of cells during cell culture. More recently, cellular senescence is viewed as a programmed process by which the cell displays a senescence phenotype when exposed to a variety of stresses. Cellular senescence has been implicated in tumor suppression and aging such that senescence may contribute to both tumor progression and normal tissue repair. Here, we review different forms of cellular senescence, as well as current biomarkers used to identify senescent cells in vitro and in vivo. Additionally, we highlight the role of senescence-associated long noncoding RNAs (lncRNAs).

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Evaluation of the Mann Assessment of Swallowing Ability in Elderly Patients with Pneumonia
Yasuo Chojin,Tatsuji Kato,Mariko Rikihisa,Masami Omori,Shingo Noguchi,Kentaro Akata,Takaaki Ogoshi,Kazuhiro Yatera,Hiroshi Mukae
Aging and Disease    2017, 8 (4): 420-433.   DOI: 10.14336/AD.2017.0102
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Elderly pneumonia patients have various underlying diseases and social backgrounds, and it is difficult to predict their mortality using the current severity assessment tools. However, aspiration is a risk factor for mortality in pneumonia patients. In the evaluation of aspiration, endoscopic and video fluoroscopic methods are reliable but cannot be performed in all pneumonia patients. We evaluated the significance of the Mann Assessment of Swallowing Ability (MASA) in these patients. This study was prospectively performed between December 2014 and June 2015, and all adult hospitalized patients with pneumonia were consecutively enrolled. The MASA score was evaluated soon after admission. The outcome measures were in-hospital mortality, a recurrence of pneumonia within 30 days, 6-month mortality, and the detection of antibiotic-resistant bacteria. A total of 153 patients were ultimately included. The proportion of in-hospital mortality was greater among the severe MASA score patients than normal score patients (p < 0.01), as was the proportion of recurrence of pneumonia (p < 0.01) and 6-month mortality (p < 0.01). In addition, patients with a moderate MASA score more often experienced recurrence of pneumonia than normal score patients (p < 0.05). Furthermore, patients with a mild MASA score more often experienced recurrence of pneumonia (p < 0.01) and 6-month mortality (p < 0.05) than normal score patients. The areas under the curve were 0.74 (95% confidence interval [CI], 0.67-0.82) for in-hospital mortality, 0.75 (95% CI, 0.68-0.82) for recurrence of pneumonia, 0.72 (95% Cl, 0.64-0.81) for 6-month mortality, and 0.60 (95% CI, 0.46-0.73) for detection of antibiotic-resistant bacteria. A multivariate analysis showed an abnormal MASA score to be an independent risk factor for the recurrence of pneumonia (p = 0.001) and 6-month mortality (p = 0.005). The MASA is useful for predicting the mortality and recurrence of pneumonia in elderly patients.

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Potential Biochemical Mechanisms of Lung Injury in Diabetes
Hong Zheng,Jinzi Wu,Zhen Jin,Liang-Jun Yan
Aging and Disease    2017, 8 (1): 7-16.   DOI: 10.14336/AD.2016.0627
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Accumulating evidence has shown that the lung is one of the target organs for microangiopathy in patients with either type 1 or type 2 diabetes mellitus (DM). Diabetes is associated with physiological and structural abnormalities in the diabetic lung concurrent with attenuated lung function. Despite intensive investigations in recent years, the pathogenic mechanisms of diabetic lung injury remain largely elusive. In this review, we summarize currently postulated mechanisms of diabetic lung injury. We mainly focus on the pathogenesis of diabetic lung injury that implicates key pathways, including oxidative stress, non-enzymatic protein glycosylation, polyol pathway, NF-κB pathway, and protein kinase c pathway. We also highlight that while numerous studies have mainly focused on tissue or cell damage in the lung, studies focusing on mitochondrial dysfunction in the diabetic lung have remained sketchy. Hence, further understanding of mitochondrial mechanisms of diabetic lung injury should provide invaluable insights into future therapeutic approaches for diabetic lung injury.

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Bulbocavernosus Reflex Test for Diagnosis of Pudendal Nerve Injury in Female Patients with Diabetic Neurogenic Bladder
Xiaoting Niu,Xun Wang,Huanjie Huang,Peiqi Ni,Yuanshao Lin,Bei Shao
Aging and Disease    2016, 7 (6): 715-720.   DOI: 10.14336/AD.2016.0309
Abstract   HTML   PDF (868KB)

The study was designed to investigate the clinical application and significance of the bulbocavernosus reflex (BCR) test for diagnosing diabetic neurogenic bladder (DNB) in female subjects. In this study, 68 female patients with DNB and 40 female normal controls were subjected to a nerve conduction study (NCS) of all four limbs and the BCR test. The data were analyzed and compared, and the corresponding diagnostic sensitivities were discussed. Mean BCR latency for female DNB patients was significantly prolonged, compared to that of the control group, suggesting pudendal nerve injuries in female DNB patients. Moreover, DNB patients were categorized according to the diabetes course. Compared to that of Group A (diabetes course < 5 y), the mean BCR latency was significantly prolonged in Group B (diabetes course between 5 and 10 y) and then further prolonged in Group C (diabetes course > 10 y), which were all longer than the control group. Furthermore, compared with that of the controls, the mean BCR latency was prolonged in DNB patients with or without NCS abnormalities in limbs. Nevertheless, no significant difference was observed in BCR latency between DNB patients with and without NCS abnormalities. Significantly increasing trends were also observed in the NCS and BCR abnormality rates along with increased diabetes course. Most importantly, compared with the NCS of limbs, the BCR test was more sensitive in diagnosing DNB in the female subjects. Overall, our findings suggest that the BCR test would help to assess the pudendal nerve injury in female DNB patients, which might be a potential diagnostic tool in the clinic.

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Sensorineural Organs Dysfunction and Cognitive Decline: A Review Article
Supakanya Wongrakpanich,Aisawan Petchlorlian,Andrew Rosenzweig
Aging and Disease    2016, 7 (6): 763-769.   DOI: 10.14336/AD.2016.0515
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Vision, hearing, olfaction, and cognitive function are essential components of healthy and successful aging. Multiple studies demonstrate relationship between these conditions with cognitive function. The present article focuses on hearing loss, visual impairment, olfactory loss, and dual sensory impairments in relation to cognitive declination and neurodegenerative disorders. Sensorineural organ impairment is a predictive factor for mild cognitive impairment and neurodegenerative disorders in the elderly. We recommend early detection of sensorineural dysfunction by history, physical examination, and screening tests. Assisted device and early cognitive rehabilitation may be beneficial. Future research is warranted in order to explore advanced treatment options and method to slow progression for cognitive declination and sensorineural organ impairment.

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Is Technology Present in Frailty? Technology a Back-up Tool for Dealing with Frailty in the Elderly: A Systematic Review
Iranzu Mugueta-Aguinaga, Begonya Garcia-Zapirain
Aging and Disease    2017, 8 (2): 176-195.   DOI: 10.14336/AD.2016.0901
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This study analyzes the technologies used in dealing with frailty within the following areas: prevention, care, diagnosis and treatment. The aim of this paper is, on the one hand, to analyze the extent to which technology is present in terms of its relationship with frailty and what technological resources are used to treat it. Its other purpose is to define new challenges and contributions made by physiotherapy using technology. Eighty documents related to research, validation and/or the ascertaining of different types of hardware, software or both were reviewed in prominent areas. The authors used the following scales: in the area of diagnosis, Fried’s phenotype model of frailty and a model based on trials for the design of devices. The technologies developed that are based on these models accounted for 55% and 45% of cases respectively. In the area of prevention, the results proved similar regarding the use of wireless sensors with cameras (35.71%), and Kinect™ sensors (28.57%) to analyze movements and postures that indicate a risk of falling. In the area of care, results were found referring to the use of different motion, physiological and environmental wireless sensors (46,15%), i.e. so-called smart homes. In the area of treatment, the results show with a percentage of 37.5% that the Nintendo® Wii™ console is the most used tool for treating frailty in elderly persons. Further work needs to be carried out to reduce the gap existing between technology, frail elderly persons, healthcare professionals and carers to bring together the different views about technology. This need raises the challenge of developing and implementing technology in physiotherapy via serious games that may via play and connectivity help to improve the functional capacity, general health and quality of life of frail individuals.

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Serum Hepcidin Levels, Iron Dyshomeostasis and Cognitive Loss in Alzheimer’s Disease
Zohara Sternberg,Zihua Hu,Daniel Sternberg,Shayan Waseh,Joseph F. Quinn,Katharine Wild,Kaye Jeffrey,Lin Zhao,Michael Garrick
Aging and Disease    2017, 8 (2): 215-227.   DOI: 10.14336/AD.2016.0811
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This pilot study examined the status of the master iron regulatory peptide, hepcidin, and peripheral related iron parameters in Alzheimer’s disease (AD) and mild cognitive impairment patients, and evaluated the relationship between iron dyshomeostasis and amyloid-beta (Aβ), cognitive assessment tests, neuroimaging and clinical data. Frozen serum samples from the Oregon Tissue Bank were used to measure serum levels of hepcidin, ferritin, Aβ40, Aβ42 using enzyme-linked immunosorbent assay. Serum transferrin levels were determined indirectly as total iron binding capacity, serum iron was measured and the percent saturation of transferrin calculated. The study variables were correlated with the patients’ existing cognitive assessment tests, neuroimaging, and clinical data. Hepcidin, and iron-related proteins tended to be higher in AD patients than controls, reaching statistical significance for ferritin, whereas Aβ40, Aβ42 serum levels tended to be lower. Patients with pure AD had three times higher serum hepcidin levels than controls; gender differences in hepcidin and iron-related proteins were observed. Patient stratification based on clinical dementia rating-sum of boxes revealed significantly higher levels of iron and iron-related proteins in AD patients in the upper 50% as compared to controls, suggesting that iron dyshomeostasis worsens as cognitive impairment increases. Unlike Aβ peptides, iron and iron-related proteins showed significant association with cognitive assessment tests, neuroimaging, and clinical data. Hepcidin and iron-related proteins comprise a group of serum biomarkers that relate to AD diagnosis and AD disease progression. Future studies should determine whether strategies targeted to diminishing hepcidin synthesis/secretion and improving iron homeostasis could have a beneficial impact on AD progression.

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Metformin Impairs Spatial Memory and Visual Acuity in Old Male Mice
Nopporn Thangthaeng,Margaret Rutledge,Jessica M. Wong,Philip H. Vann,Michael J. Forster,Nathalie Sumien
Aging and Disease    2017, 8 (1): 17-30.   DOI: 10.14336/AD.2016.1010
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Metformin is an oral anti-diabetic used as first-line therapy for type 2 diabetes. Because benefits of metformin extend beyond diabetes to other age-related pathology, and because its effect on gene expression profiles resembles that of caloric restriction, metformin has a potential as an anti-aging intervention and may soon be assessed as an intervention to extend healthspan. However, beneficial actions of metformin in the central nervous system have not been clearly established. The current study examined the effect of chronic oral metformin treatment on motor and cognitive function when initiated in young, middle-aged, or old male mice. C57BL/6 mice aged 4, 11, or 22 months were randomly assigned to either a metformin group (2 mg/ml in drinking water) or a control group. The mice were monitored weekly for body weight, as well as food and water intake and a battery of behavioral tests for motor, cognitive and visual function was initiated after the first month of treatment. Liver, hippocampus and cortex were collected at the end of the study to assess redox homeostasis. Overall, metformin supplementation in male mice failed to affect blood glucose, body weights and redox homeostasis at any age. It also had no beneficial effect on age-related declines in psychomotor, cognitive or sensory functions. However, metformin treatment had a deleterious effect on spatial memory and visual acuity, and reduced SOD activity in brain regions. These data confirm that metformin treatment may be associated with deleterious effect resulting from the action of metformin on the central nervous system.

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Allergy and Aging: An Old/New Emerging Health Issue
Massimo De Martinis,Maria Maddalena Sirufo,Lia Ginaldi
Aging and Disease    2017, 8 (2): 162-175.   DOI: 10.14336/AD.2016.0831
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Allergy reactions are the most common immunological diseases and represent one of the most widespread and fast growing chronic human health problems among people over 15 years of age in developed countries. As populations get older worldwide, allergy manifestations in aged persons will occur more often in the future. To date, there has been much more studies on allergies in children than in adults. As the population ages, clinicians must be prepared to meet all the elderly's health care needs, including these new and emerging health issue. Allergic diseases represent an old/new emerging health issue. Because many common illnesses masquerade as atopic disease, the differential diagnosis of suspected allergic diseases becomes more expanded in an aging population. Research in the field needs to focus on both human and animal model systems to investigate the impact of the aging process on the immunologic pathways underpinning allergy and its different facets.

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Associations among Metabolism, Circadian Rhythm and Age-Associated Diseases
Yiwei Cao,Rui-Hong Wang
Aging and Disease    2017, 8 (3): 314-333.   DOI: 10.14336/AD.2016.1101
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Accumulating epidemiological studies have implicated a strong link between age associated metabolic diseases and cancer, though direct and irrefutable evidence is missing. In this review, we discuss the connection between Warburg effects and tumorigenesis, as well as adaptive responses to environment such as circadian rhythms on molecular pathways involved in metabolism. We also review the central role of the sirtuin family of proteins in physiological modulation of cellular processes and age-associated metabolic diseases. We also provide a macroscopic view of how the circadian rhythm affects metabolism and may be involved in cell metabolism reprogramming and cancer pathogenesis. The aberrations in metabolism and the circadian system may lead to age-associated diseases directly or through intermediates. These intermediates may be either mutated or reprogrammed, thus becoming responsible for chromatin modification and oncogene transcription. Integration of circadian rhythm and metabolic reprogramming in the holistic understanding of metabolic diseases and cancer may provide additional insights into human diseases.

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Intercellular Adhesion Molecular-5 as Marker in HIV Associated Neurocognitive Disorder
Lin Yuan,Feili Wei,Xin Zhang,Xianghua Guo,Xiaofan Lu,Bin Su,Tong Zhang,Hao Wu,Dexi Chen
Aging and Disease    2017, 8 (3): 250-256.   DOI: 10.14336/AD.2016.0918
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Despite the use of antiretroviral drugs HIV associated neurocognitive disorders (HAND) are still common in HIV-seropositive patients. Identification of HIV patients with cognitive impairment in early-stage might benefit a great deal from disease progression monitoring and treatment adjustment. Intercellular adhesion molecule-5 (ICAM5), characteristically expressed on neuron, may suppress immune functions by inhibition of T cell activation in central nervous system. Previous studies have shown that ICAM5 could be detected in patients with brain injury. To investigate the relationship between cognitive impairment and ICAM5 in HIV patients, we compared soluble ICAM5 levels in paired CSF and plasma specimens from HIV-infected individuals with or without neurocognitive impairment. sICAM5 concentrations were measured by ICAM5 ELISA kit. A total of 41 Patients were classified into HIV infected with normal cognition (HIV-NC) and impaired cognition groups (HIV-CI) based on Memorial Sloan-Kettering Scale. CSF and plasma levels of sICAM5 in HIV-CI patients were significantly higher than HIV-NC group (p<0.0001, p=0.0054 respectively). sICAM5 concentrations in plasma strongly correlated with sICAM5 in CSF (r=0.7250, p<0.0001) and S100B in CSF (r=0.3812, p<0.0139). Among 6 follow-up patients we found that sICAM5 levels in CSF and plasma might change consistently with HAND progression. In summary, we have shown that the expressions of sICAM5 in CSF and plasma may correlate with neurocognitive impairment in HIV infected patients. The elevation of sICAM5 in plasma were correspond with that in CSF as a consequence of blood-brain barrier permeability changes. ICAM5 can serve as a potential and readily accessible biomarker to predict HIV associated neurocognitive disorder.

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Spanning from the West to East: An Updated Review on Endovascular Treatment of Intracranial Atherosclerotic Disease
Mohammed Hussain,Neil Datta,Zhe Cheng,David Dornbos,Asif Bashir,Ibrahim Sultan,Tapan Mehta,Faris Shweikeh,Paul Mazaris,Nora Lee,Amre Nouh,Xiaokun Geng,Yuchuan Ding
Aging and Disease    2017, 8 (2): 196-202.   DOI: 10.14336/AD.2016.0807
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Ischemic stroke is a major cause of morbidity and mortality, incurring significant cost. Intracranial atherosclerotic disease (ICAD) accounts for 10-15% of ischemic stroke in Western societies, but is an underlying pathology in up to 54% of ischemic strokes in Asian populations. ICAD has largely been treated with medical management, although a few studies have examined outcomes following endovascular treatment. Our objective was to summarize the major trials that have been performed thus far in regard to the endovascular treatment of ICAD and to provide direction for future management of this disease process. Systematic review of the literature from 1966 to 2015, was conducted in regard to intracranial angioplasty and stenting. Studies were analyzed from PubMed, American Heart Association and Society of Neurointerventional Surgery databases. SAMMPRIS and VISSIT are the only randomized controlled trials from which Western guidelines of intracranial stenting have been derived, which have displayed the superiority of medical management. However, pooled reviews of smaller studies and other nonrandomized trials have shown better outcomes with endovascular therapy in select patient subsets, such as intracranial vertebrobasilar stenosis or in the presence of robust collaterals. Suboptimal cases, including longer lesions, bifurcations and significant tortuosity tend to fair better with medical management. Medical management has been shown to be more efficacious with less adverse outcomes than endovascular therapy. However, the majority of studies on endovascular management included a diverse patient population without ideal selection criteria, resulting in higher adverse outcomes. Population analyses and selective utilization of endovascular therapy have shown that the treatment may be superior to other management in select patients.

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Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Focus on Mitochondrial DNA and Alzheimer’s Disease
Annamaria Zaia,Pierluigi Maponi,Giuseppina Di Stefano,Tiziana Casoli
Aging and Disease    2017, 8 (1): 44-56.   DOI: 10.14336/AD.2016.0629
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Alzheimer’s disease (AD) represents one major health concern for our growing elderly population. It accounts for increasing impairment of cognitive capacity followed by loss of executive function in late stage. AD pathogenesis is multifaceted and difficult to pinpoint, and understanding AD etiology will be critical to effectively diagnose and treat the disease. An interesting hypothesis concerning AD development postulates a cause-effect relationship between accumulation of mitochondrial DNA (mtDNA) mutations and neurodegenerative changes associated with this pathology. Here we propose a computerized method for an easy and fast mtDNA mutations-based characterization of AD. The method has been built taking into account the complexity of living being and fractal properties of many anatomic and physiologic structures, including mtDNA. Dealing with mtDNA mutations as gaps in the nucleotide sequence, fractal lacunarity appears a suitable tool to differentiate between aging and AD. Therefore, Chaos Game Representation method has been used to display DNA fractal properties after adapting the algorithm to visualize also heteroplasmic mutations. Parameter β from our fractal lacunarity method, based on hyperbola model function, has been measured to quantitatively characterize AD on the basis of mtDNA mutations. Results from this pilot study to develop the method show that fractal lacunarity parameter β of mtDNA is statistically different in AD patients when compared to age-matched controls. Fractal lacunarity analysis represents a useful tool to analyze mtDNA mutations. Lacunarity parameter β is able to characterize individual mutation profile of mitochondrial genome and appears a promising index to discriminate between AD and aging.

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Cerebral Microvascular Accumulation of Tau Oligomers in Alzheimer’s Disease and Related Tauopathies
Diana L Castillo-Carranza,Ashley N Nilson,Candice E Van Skike,Jordan B Jahrling,Kishan Patel,Prajesh Garach,Julia E Gerson,Urmi Sengupta,Jose Abisambra,Peter Nelson,Juan Troncoso,Zoltan Ungvari,Veronica Galvan,Rakez Kayed
Aging and Disease    2017, 8 (3): 257-266.   DOI: 10.14336/AD.2017.0112
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The importance of vascular contributions to cognitive impairment and dementia (VCID) associated with Alzheimer’s disease (AD) and related neurodegenerative diseases is increasingly recognized, however, the underlying mechanisms remain obscure. There is growing evidence that in addition to Aβ deposition, accumulation of hyperphosphorylated oligomeric tau contributes significantly to AD etiology. Tau oligomers are toxic and it has been suggested that they propagate in a “prion-like” fashion, inducing endogenous tau misfolding in cells. Their role in VCID, however, is not yet understood. The present study was designed to determine the severity of vascular deposition of oligomeric tau in the brain in patients with AD and related tauopathies, including dementia with Lewy bodies (DLB) and progressive supranuclear palsy (PSP). Further, we examined a potential link between vascular deposition of fibrillar Aβ and that of tau oligomers in the Tg2576 mouse model. We found that tau oligomers accumulate in cerebral microvasculature of human patients with AD and PSP, in association with vascular endothelial and smooth muscle cells. Cerebrovascular deposition of tau oligomers was also found in DLB patients. We also show that tau oligomers accumulate in cerebral microvasculature of Tg2576 mice, partially in association with cerebrovascular Aβ deposits. Thus, our findings add to the growing evidence for multifaceted microvascular involvement in the pathogenesis of AD and other neurodegenerative diseases. Accumulation of tau oligomers may represent a potential novel mechanism by which functional and structural integrity of the cerebral microvessels is compromised.

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Lens Endogenous Peptide αA66-80 Generates Hydrogen Peroxide and Induces Cell Apoptosis
Murugesan Raju,Puttur Santhoshkumar,K. Krishna Sharma
Aging and Disease    2017, 8 (1): 57-70.   DOI: 10.14336/AD.2016.0805
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In previous studies, we reported the presence of a large number of low-molecular-weight (LMW) peptides in aged and cataract human lens tissues. Among the LMW peptides, a peptide derived from αA-crystallin, αA66-80, was found in higher concentration in aged and cataract lenses. Additional characterization of the αA66-80 peptide showed beta sheet signature, and it formed well-defined unbranched fibrils. Further experimental data showed that αA66-80 peptide binds α-crystallin, impairs its chaperone function, and attracts additional crystallin proteins to the peptide α-crystallin complex, leading to the formation of larger light scattering aggregates. It is well established that Aβ peptide exhibits cell toxicity by the generation of hydrogen peroxide. The αA66-80 peptide shares the principal properties of Aβ peptide. Therefore, the present study was undertaken to determine whether the fibril-forming peptide αA66-80 has the ability to generate hydrogen peroxide. The results show that the αA66-80 peptide generates hydrogen peroxide, in the amount of 1.2 nM H2O2 per µg of αA66-80 peptide by incubation at 37°C for 4h. We also observed cytotoxicity and apoptotic cell death in αA66-80 peptide-transduced Cos7 cells. As evident, we found more TUNEL-positive cells in αA66-80 peptide transduced Cos7 cells than in control cells, suggesting peptide-mediated cell apoptosis. Additional immunohistochemistry analysis showed the active form of caspase-3, suggesting activation of the caspase-dependent pathway during peptide-induced cell apoptosis. These results confirm that the αA66-80 peptide generates hydrogen peroxide and promotes hydrogen peroxide-mediated cell apoptosis.

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Relationship of Circulating CXCR4+ EPC with Prognosis of Mild Traumatic Brain Injury Patients
Yunpeng Lin,Lan Lan Luo,Jian Sun,Weiwei Gao,Ye Tian,Eugene Park,Andrew Baker,Jieli Chen,Rongcai Jiang,Jianning Zhang
Aging and Disease    2017, 8 (1): 115-127.   DOI: 10.14336/AD.2016.0610
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To investigate the changes of circulating endothelial progenitor cells (EPCs) and stromal cell-derived factor-1α (SDF-1α)/CXCR4 expression in patients with mild traumatic brain injury (TBI) and the correlation between EPC level and the prognosis of mild TBI. 72 TBI patients (57 mild TBI, 15 moderate TBI patients) and 25 healthy subjects (control) were included. The number of circulating EPCs, CD34+, and CD133+ cells and the percentage of CXCR4+ cells in each cell population at 1,4,7,14,21 days after TBI were counted by flow cytometer. SDF-1α levels in serum were detected by ELISA assay. The patients were divided into poor and good prognosis groups based on Extended Glasgow Outcome Scale and Activity of Daily Living Scale at 3 months after TBI. Correlation analysis between each detected index and prognosis of mild TBI was performed. Moderate TBI patients have higher levels of SDF-1α and CXCR4 expression than mild TBI patients (P < 0.05). The percentage of CXCR4+ EPCs at day 7 post-TBI was significantly higher in mild TBI patients with poor prognosis than the ones with good prognosis (P < 0.05). HAMA and HAMD scores in mild TBI patients were significantly lower than moderate TBI patients (P < 0.05) in early term. The percentage of CXCR4+ EPCs at day 7 after TBI was significantly correlated with the prognosis outcome at 3 months. The mobilization of circulating EPCs can be induced in mild TBI. The expression of CXCR4+ in EPCs at 7 days after TBI reflects the short-term prognosis of brain injury, and could be a potential biological marker for prognosis prediction of mild TBI.

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LW-AFC Effects on N-glycan Profile in Senescence-Accelerated Mouse Prone 8 Strain, a Mouse Model of Alzheimer’s Disease
Jianhui Wang,Xiaorui Cheng,Ju Zeng,Jiangbei Yuan,Zhongfu Wang,Wenxia Zhou,Yongxiang Zhang
Aging and Disease    2017, 8 (1): 101-114.   DOI: 10.14336/AD.2016.0522
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Glycosylation is one of the most common eukaryotic post-translational modifications, and aberrant glycosylation has been linked to many diseases. However, glycosylation and glycome analysis is a significantly challenging task. Although several lines of evidence have indicated that protein glycosylation is defective in Alzheimer’s disease (AD), only a few studies have focused on AD glycomics. The etiology of AD is unclear and there are no effective disease-modifying treatments for AD. In this study, we found that the object recognition memory, passive avoidance, and spatial learning and memory of senescence-accelerated mouse prone 8 (SAMP8) strain, an AD animal model, were deficient, and LW-AFC, which was prepared from the traditional Chinese medicine prescription Liuwei Dihuang decoction, showed beneficial effects on the deterioration of cognitive capability in SAMP8 mice. Forty-three and 56 N-glycan were identified in the cerebral cortex and serum of SAMP8 mice, respectively. The N-glycan profile in SAMP8 mice was significantly different from that of senescence accelerated mouse resistant 1 (SAMR1) strains, the control of SAMP8 mice. Treatment with LW-AFC modulated the abundance of 21 and 6 N-glycan in the cerebral cortex and serum of SAMP8 mice, respectively. The abundance of (Hex)3(HexNAc)5(Fuc)1(Neu5Ac)1 and (Hex)2(HexNAc)4 decreased in the cerebral cortex and serum of SAMP8 mice compared with SAMR1 mice, decreases that were significantly correlated with learning and memory measures. The administration of LW-AFC could reverse or increase these levels in SAMP8 mice. These results indicated that the effects of LW-AFC on cognitive impairments in SAMP8 mice might be through modulation of N-glycan patterns, and LW-AFC may be a potential anti-AD agent.

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Imaging and Quantitative Analysis of the Interstitial Space in the Caudate Nucleus in a Rotenone-Induced Rat Model of Parkinson’s Disease Using Tracer-based MRI
Deyong Lv,Jingbo Li,Hongfu Li,Yu Fu,Wei Wang
Aging and Disease    2017, 8 (1): 1-6.   DOI: 10.14336/AD.2016.0625
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Parkinson’s disease (PD) is characterized by pathological changes within several deep structures of the brain, including the substantia nigra and caudate nucleus. However, changes in interstitial fluid (ISF) flow and the microstructure of the interstitial space (ISS) in the caudate nucleus in PD have not been reported. In this study, we used tracer-based magnetic resonance imaging (MRI) to quantitatively investigate the alterations in ISS and visualize ISF flow in the caudate nucleus in a rotenone-induced rat model of PD treated with and without madopar. In the rotenone-induced rat model, the ISF flow was slowed and the tortuosity of the ISS was significantly decreased. Administration of madopar partially prevented these changes of ISS and ISF. Therefore, our data suggest that tracer-based MRI can be used to monitor the parameters related to ISF flow and ISS microstructure. It is a promising technique to investigate the microstructure and functional changes in the deep brain regions of PD.

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Galanin Protects from Caspase-8/12-initiated Neuronal Apoptosis in the Ischemic Mouse Brain via GalR1
Yun Li,Zhu Mei,Shuiqiao Liu,Tong Wang,Hui Li,Xiao-Xiao Li,Song Han,Yutao Yang,Junfa Li,Zhi-Qing David Xu
Aging and Disease    2017, 8 (1): 85-100.   DOI: 10.14336/AD.2016.0806
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Galanin (GAL) plays key role in many pathophysiological processes, but its role in ischemic stroke remains unclear. Here, the models of 1 h middle cerebral artery occlusion (MCAO)/1-7 d reperfusion (R)-induced ischemic stroke and in vitro cell ischemia of 1 h oxygen-glucose deprivation (OGD)/24 h reoxygenation in primary cultured cortical neurons were used to explore GAL’s effects and its underlying mechanisms. The results showed significant increases of GAL protein levels in the peri-infarct region (P) and infarct core (I) within 48 h R of MCAO mice (p<0.001). The RT-qPCR results also demonstrated significant increases of GAL mRNA during 24-48 h R (p<0.001), and GAL receptors GalR1-2 (but not 3) mRNA levels in the P region at 24 h R of MCAO mice (p<0.001). Furthermore, the significant decrease of infarct volume (p<0.05) and improved neurological outcome (p<0.001-0.05) were observed in MCAO mice following 1 h pre- or 6 h post-treatment of GAL during 1-7 d reperfusion. GalR1 was confirmed as the receptor responsible for GAL-induced neuroprotection by using GalR2/3 agonist AR-M1896 and Lentivirus-based RNAi knockdown of GalR1. GAL treatment inhibited Caspase-3 activation through the upstream initiators Capsases-8/-12 (not Caspase-9) in both P region and OGD-treated cortical neurons. Meanwhile, GAL’s neuroprotective effect was not observed in cortical neurons from conventional protein kinase C (cPKC) γ knockout mice. These results suggested that exogenous GAL protects the brain from ischemic injury by inhibiting Capsase-8/12-initiated apoptosis, possibly mediated by GalR1 via the cPKCγ signaling pathway.

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Global Metabolic Profiling of Plasma Shows that Three-Year Mild-Caloric Restriction Lessens an Age-Related Increase in Sphingomyelin and Reduces L-leucine and L-phenylalanine in Overweight and Obese Subjects
Minjoo Kim,Sang-Hyun Lee,Jong Ho Lee
Aging and Disease    2016, 7 (6): 721-733.   DOI: 10.14336/AD.2016.0330
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The effect of weight loss from long-term, mild-calorie diets (MCD) on plasma metabolites is unknown. This study was to examine whether MCD-induced weight reduction caused changes in the extended plasma metabolites. Overweight and obese subjects aged 40-59 years consumed a MCD (approximately 100 kcal/day deficit, n=47) or a weight-maintenance diet (control, n=47) in a randomized, controlled design with a three-year clinical intervention period and plasma samples were analyzed by using UPLC-LTQ-Orbitrap mass spectrometry. The three-year MCD intervention resulted in weight loss (-8.87%) and significant decreases in HOMA-IR and TG. The three-year follow-up of the MCD group showed reductions in the following 13 metabolites: L-leucine; L-phenylalanine; 9 lysoPCs; PC (18:0/20:4); and SM (d18:0/16:1). The three-year MCD group follow-up identified increases in palmitic amide, oleamide, and PC (18:2/18:2). Considering the age-related alterations in the identified metabolites, the MCD group showed a greater decrease in L-leucine, L-phenylalanine, and SM (d18:0/16:1) compared with those of the control group. Overall, the change (Δ) in BMI positively correlated with the ΔTG, ΔHOMA-IR, ΔL-leucine, and ΔSM (d18:0/16:1). The ΔHOMA-IR positively correlated with ΔTG, ΔL-leucine, ΔL-phenylalanine, and ΔSM (d18:0/16:1). The weight loss resulting from three-year mild-caloric restriction lessens the age-related increase in SM and reduces L-leucine and L-phenylalanine in overweight and obese subjects. These changes were coupled with improved insulin resistance (ClinicalTrials.gov: NCT02081898).

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Serum Leptin Concentration is Associated with Incident Frailty in Older Adults
Alberto Lana,Ana Valdés-Bécares,Antonio Buño,Fernando Rodríguez-Artalejo,Esther Lopez-Garcia
Aging and Disease    2017, 8 (2): 240-249.   DOI: 10.14336/AD.2016.0819
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Obesity has been associated with higher risk of frailty in older adults, but the pathophysiological mechanisms are unclear. No previous study has examined the association between leptin, an adipokine, and the risk of frailty in older adults, and whether this association could be explained by insulin resistance or chronic inflammation. Data were taken from 1,573 individuals without diabetes mellitus, aged ≥60 years, from the Seniors-ENRICA cohort. In 2008-2010, leptin, the homeostasis model assessment of insulin resistance (HOMA-IR) and C-reactive protein (CRP) were measured. Study participants were followed-up through 2012 to assess incident frailty, defined as at least two of the following Fried criteria: exhaustion, weakness, low physical activity, and slow walking speed. Analyses were performed with logistic regression and adjusted for the main confounders. Over a median follow-up of 3.5 years, 280 cases of incident frailty were identified. Compared to individuals in the lowest tertile of serum leptin, those in the highest tertile showed an increased risk of frailty (odds ratio [OR]: 2.12; 95% confidence interval [CI]: 1.47-3.06; p-trend <0.001). Further adjustment for the percentage of body fat led to an OR of 1.69 (95% CI: 1.11-2.61; p-trend=0.01). After additional adjustment for HOMA-IR and CRP, the OR for frailty was 1.59 (95% CI: 1.01-2.52; p-trend=0.04). Results did not vary according to sex, abdominal obesity or the percentage of body fat. Being in the highest versus lowest tertile of leptin was associated with increased risk of exhaustion (OR: 2.16; 95% CI: 1.32-3.55; p-trend=0.001) and muscle weakness (OR: 1.77; 95% CI: 1.25-2.51; p-trend=0.001), in the analyses adjusted for potential confounders and body fat. Higher leptin concentration was associated with greater risk of frailty in older adults. This association was only modestly explained by insulin resistance and chronic inflammation, as measured by CRP.

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