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A Comprehensive Review of Non-Steroidal Anti-Inflammatory Drug Use in The Elderly
Wongrakpanich Supakanya, Wongrakpanich Amaraporn, Melhado Katie, Rangaswami Janani
Aging and disease    2018, 9 (1): 143-150.   DOI: 10.14336/AD.2017.0306
Abstract2885)   HTML21)    PDF(pc) (874KB)(1867)       Save

NSAIDs, non-steroidal anti-inflammatory drugs, are one of the most commonly prescribed pain medications. It is a highly effective drug class for pain and inflammation; however, NSAIDs are known for multiple adverse effects, including gastrointestinal bleeding, cardiovascular side effects, and NSAID induced nephrotoxicity. As our society ages, it is crucial to have comprehensive knowledge of this class of medication in the elderly population. Therefore, we reviewed the pharmacodynamics and pharmacokinetics, current guidelines for NSAIDs use, adverse effect profile, and drug interaction of NSAIDs and commonly used medications in the elderly.

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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)(731)       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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Predictors of Memory in Healthy Aging: Polyunsaturated Fatty Acid Balance and Fornix White Matter Integrity
Zamroziewicz Marta K., Paul Erick J., Zwilling Chris E., Barbey Aron K.
Aging and disease    2017, 8 (4): 372-383.   DOI: 10.14336/AD.2017.0501
Abstract2013)   HTML10)    PDF(pc) (1195KB)(846)       Save

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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Evaluation of the Mann Assessment of Swallowing Ability in Elderly Patients with Pneumonia
Chojin Yasuo, Kato Tatsuji, Rikihisa Mariko, Omori Masami, Noguchi Shingo, Akata Kentaro, Ogoshi Takaaki, Yatera Kazuhiro, Mukae Hiroshi
Aging and disease    2017, 8 (4): 420-433.   DOI: 10.14336/AD.2017.0102
Abstract1995)   HTML6)    PDF(pc) (1178KB)(566)       Save

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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Role of Dietary Protein and Muscular Fitness on Longevity and Aging
Strasser Barbara, Volaklis Konstantinos, Fuchs Dietmar, Burtscher Martin
Aging and disease    2018, 9 (1): 119-132.   DOI: 10.14336/AD.2017.0202
Abstract1911)   HTML12)    PDF(pc) (936KB)(1204)       Save

Muscle atrophy is an unfortunate effect of aging and many diseases and can compromise physical function and impair vital metabolic processes. Low levels of muscular fitness together with insufficient dietary intake are major risk factors for illness and mortality from all causes. Ultimately, muscle wasting contributes significantly to weakness, disability, increased hospitalization, immobility, and loss of independence. However, the extent of muscle wasting differs greatly between individuals due to differences in the aging process per se as well as physical activity levels. Interventions for sarcopenia include exercise and nutrition because both have a positive impact on protein anabolism but also enhance other aspects that contribute to well-being in sarcopenic older adults, such as physical function, quality of life, and anti-inflammatory state. The process of aging is accompanied by chronic immune activation, and sarcopenia may represent a consequence of a counter-regulatory strategy of the immune system. Thereby, the kynurenine pathway is induced, and elevation in the ratio of kynurenine to tryptophan concentrations, which estimates the tryptophan breakdown rate, is often linked with inflammatory conditions and neuropsychiatric symptoms. A combined exercise program consisting of both resistance-type and endurance-type exercise may best help to ameliorate the loss of skeletal muscle mass and function, to prevent muscle aging comorbidities, and to improve physical performance and quality of life. In addition, the use of dietary protein supplementation can further augment protein anabolism but can also contribute to a more active lifestyle, thereby supporting well-being and active aging in the older population.

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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
Abstract1789)   HTML3)    PDF(pc) (1299KB)(1114)       Save

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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Recognizing Degenerative Aging as a Treatable Medical Condition: Methodology and Policy
Stambler Ilia
Aging and disease    2017, 8 (5): 583-589.   DOI: 10.14336/AD.2017.0130
Abstract1640)   HTML3)    PDF(pc) (789KB)(689)       Save

It is becoming increasingly clear that in order to accomplish healthy longevity for the population, there is an urgent need for the research and development of effective therapies against degenerative aging processes underlying major aging-related diseases, including heart disease, neurodegenerative diseases, type 2 diabetes, cancer, pulmonary obstructive diseases, as well as aging-related complications and susceptibilities of infectious communicable diseases. Yet, an important incentive for the research and development of such therapies appears to be the development of clinically applicable and scientifically grounded definitions and criteria for the multifactorial degenerative aging process (or “senility” using the existing ICD category), underlying those diseases, as well as for the safety and effectiveness of interventions against it. Such generally agreed definitions and criteria are currently absent. The devising of such criteria is important not only for the sake of their scientific value and their utility for the development of therapeutic solutions for the aging population, but also to comply with and implement major existing national and international programmatic and regulatory requirements. Some methodological suggestions and potential pitfalls for the development of such criteria are examined.

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The Study of Rhabdomyolysis in the Elderly: An Epidemiological Study and Single Center Experience
Wongrakpanich Supakanya, Kallis Christos, Prasad Prithiv, Rangaswami Janani, Rosenzweig Andrew
Aging and disease    2018, 9 (1): 1-7.   DOI: 10.14336/AD.2017.0304
Abstract1608)   HTML15)    PDF(pc) (650KB)(824)       Save

Rhabdomyolysis is a syndrome caused by injury to skeletal muscle. There is limited data of rhabdomyolysis in the elderly. The objective of this study is to investigate demographic data, etiologies, laboratory values, prognostic factors, and mortality of rhabdomyolysis in the geriatric population. A 4-years retrospective chart review study was conducted. Our inclusion criteria were age above 65 years and creatinine kinase level excess five times of normal upper limit. Among 167 patients, 47.3% were male. The median age at diagnosis was 80.11 (66-101) years. The duration of follow up in the study ranged from 0 to 48 months. Fall (with or without immobilization) was the most frequent cause of rhabdomyolysis in 56.9%. The mean baseline glomerular filtration rate (GFR), GFR at diagnosis, and peak decline in GFR was 76.94, 48.96, and 54.41 cc/min respectively. The mean CK at diagnosis and peak CK was 5097.22 and 6320.07. There were 45 deaths (21%) over the span of 4 years. Multivariate analysis demonstrated that number of medications pre-admission (Meds No.), peak decline in GFR, and acute kidney injury (AKI) are independent predictors for overall survival for rhabdomyolysis in the elderly. To our knowledge, this is the first epidemiological study of rhabdomyolysis in the elderly. Falls (with and without immobilization) were the most common etiology. Meds No. (>8), peak decline in GFR (<30 cc/min), and evidence of AKI are associated with shorter overall survival and can serve as potential independent prognostic markers for rhabdomyolysis in elderly patients.

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The Biology of Aging and Cancer: A Brief Overview of Shared and Divergent Molecular Hallmarks
Aunan Jan R., Cho William C, Søreide Kjetil
Aging and disease    2017, 8 (5): 628-642.   DOI: 10.14336/AD.2017.0103
Abstract1594)   HTML6)    PDF(pc) (1005KB)(1071)       Save

Aging is the inevitable time-dependent decline in physiological organ function and is a major risk factor for cancer development. Due to advances in health care, hygiene control and food availability, life expectancy is increasing and the population in most developed countries is shifting to an increasing proportion of people at a cancer susceptible age. Mechanisms of aging are also found to occur in carcinogenesis, albeit with shared or divergent end-results. It is now clear that aging and cancer development either share or diverge in several disease mechanisms. Such mechanisms include the role of genomic instability, telomere attrition, epigenetic changes, loss of proteostasis, decreased nutrient sensing and altered metabolism, but also cellular senescence and stem cell function. Cancer cells and aged cells are also fundamentally opposite, as cancer cells can be thought of as hyperactive cells with advantageous mutations, rapid cell division and increased energy consumption, while aged cells are hypoactive with accumulated disadvantageous mutations, cell division inability and a decreased ability for energy production and consumption. Nonetheless, aging and cancer are tightly interconnected and many of the same strategies and drugs may be used to target both, while in other cases antagonistic pleiotrophy come into effect and inhibition of one can be the activation of the other. Cancer can be considered an aging disease, though the shared mechanisms underpinning the two processes remain unclear. Better understanding of the shared and divergent pathways of aging and cancer is needed.

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Acute Sarcopenia Secondary to Hospitalisation - An Emerging Condition Affecting Older Adults
Welch Carly, K. Hassan-Smith Zaki, A. Greig Carolyn, M. Lord Janet, A. Jackson Thomas
Aging and disease    2018, 9 (1): 151-164.   DOI: 10.14336/AD.2017.0315
Abstract1558)   HTML6)    PDF(pc) (837KB)(870)       Save

There has been increasing interest and research into sarcopenia in community-dwelling older adults since the European Working Group on Sarcopenia in Older People (EWGSOP) agreed a consensus definition in 2010. Sarcopenia has been defined as loss of muscle mass with loss of muscle function (strength or physical performance), with measurements two Standard Deviations (SDs) below the mean of a young reference population. This definition does not necessitate longitudinal measurements, or the absence of acute illness and diagnosis can be made from single measurements. We hypothesise that hospitalisation, due to a combination of acute inflammatory burden and muscle disuse, leads to an acute decline in muscle mass and function and may lead to some individuals meeting criteria for sarcopenia, acutely, based on the EWGSOP definition. This may be partially recoverable or may lead to increased risk of developing sarcopenia long-term. We have denoted the term “acute sarcopenia” to refer to acute loss of muscle mass and function associated with hospitalisation. This review discusses some of the current available research in this context and also identifies some of the knowledge gaps and potential areas for future research.

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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
Abstract1550)   HTML2)    PDF(pc) (317KB)(1179)       Save

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
Abstract1457)   HTML4)    PDF(pc) (325KB)(609)       Save

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

Abstract1440)   HTML1)    PDF(pc) (481KB)(1547)       Save

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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Anti-Aging Implications of Astragalus Membranaceus (Huangqi): A Well-Known Chinese Tonic
Liu Ping, Zhao Haiping, Luo Yumin
Aging and disease    2017, 8 (6): 868-886.   DOI: 10.14336/AD.2017.0816
Abstract1428)   HTML3)    PDF(pc) (1198KB)(1281)       Save

Owing to a dramatic increase in average life expectancy and the Family Planning program of the 1970s - 1990s, China is rapidly becoming an aging society. Therefore, the investigation of healthspan-extending drugs becomes more urgent. Astragalus membranaceus (Huangqi) is a major medicinal herb that has been commonly used in many herbal formulations in the practice of traditional Chinese medicine (TCM) to treat a wide variety of diseases and body disorders, or marketed as life-prolonging extracts for human use in China, for more than 2000 years. The major components of Astragalus membranaceus are polysaccharides, flavonoids, and saponins. Pharmacological research indicates that the extract component of Astragalus membranaceus can increase telomerase activity, and has antioxidant, anti-inflammatory, immunoregulatory, anticancer, hypolipidemic, antihyperglycemic, hepatoprotective, expectorant, and diuretic effects. A proprietary extract of the dried root of Astragalus membranaceus, called TA-65, was associated with a significant age-reversal effect in the immune system. Our review focuses on the function and the underlying mechanisms of Astragalus membranaceus in lifespan extension, anti-vascular aging, anti-brain aging, and anti-cancer effects, based on experimental and clinical studies.

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Is Technology Present in Frailty? Technology a Back-up Tool for Dealing with Frailty in the Elderly: A Systematic Review
Mugueta-Aguinaga Iranzu, Garcia-Zapirain Begonya
Aging and disease    2017, 8 (2): 2005-2015.   DOI: 10.14336/AD.2016.0901
Abstract1407)   HTML9)    PDF(pc) (1256KB)(949)       Save

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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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
Abstract1363)   HTML2)    PDF(pc) (428KB)(651)       Save

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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Vitamin D and Chronic Diseases
Wang Hanmin, Chen Weiwen, Li Dongqing, Yin Xiaoe, Zhang Xiaode, Olsen Nancy, Zheng Song Guo
Aging and disease    2017, 8 (3): 346-353.   DOI: 10.14336/AD.2016.1021
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Vitamin D is one of the essential nutrients to sustain the human health. As a member of the steroid hormone family, it has a classic role in regulating metabolism of calcium and a non-classic role in affecting cell proliferation and differentiation. Epidemiological studies have shown that 25OHD deficiency is closely associated with common chronic diseases such as bone metabolic disorders, tumors, cardiovascular diseases, and diabetes. 25OHD deficiency is also a risk factor for neuropsychiatric disorders and autoimmune diseases. 25OHD deficiency is highly prevalent in the world. It is therefore necessary to know the adverse health effects of 25OHD deficiency, and to design interventions and early treatments for those who are likely to have low levels of 25OHD.

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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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Causes of Death in Chinese Patients with Multiple System Atrophy
Zhang LingYu, Cao Bei, Zou Yutong, Wei Qian-Qian, Ou RuWei, Liu Wanglin, Zhao Bi, Yang Jing, Wu Ying, Shang HuiFang
Aging and disease    2018, 9 (1): 102-108.   DOI: 10.14336/AD.2017.0711
Abstract1193)   HTML3)    PDF(pc) (711KB)(403)       Save

The objective of this study was to explore the causes of death in Chinese patients with multiple system atrophy (MSA) as well as differences in the cause of death according to sex, subtype, disease onset, and whether the disease was accompanied by nocturnal stridor. A total of 131 MSA patients were enrolled and followed up once every year until their deaths. Clinical information was collected by neurologists, and the cause of death of the MSA patients was obtained from the patients’ relatives or caregivers. The current study included 62 MSA with predominant parkinsonism (MSA-P) and 69 MSA with predominant cerebellar ataxia (MSA-C) patients. Median survival time from disease onset to death of the MSA patients was 5.59 years. The most common cause of death was respiratory infection (65.6%). The second most common cause of death was sudden death (14.5%). Other causes included nutritional disorder due to dysphagia (9.2%), urinary tract infection (3.1%), suicide (2.3%), choking (1.5%), cerebrovascular accident (1.5%), myocardial infarction (1.5%), and lymphoma (0.8%). We found that sudden death was more likely to occur in patients with nocturnal stridor than in those without (P<0.001). There were no significant differences in the cause of death according to subtype, sex, or onset symptoms (autonomic failure or motor symptoms). Sudden death is a relatively common cause of death in MSA patients, second only to respiratory infection, especially in patients with nocturnal stridor. The information provided by our study may help to provide better medical care to MSA patients.

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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
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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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Allergy and Aging: An Old/New Emerging Health Issue
De Martinis Massimo, Sirufo Maria Maddalena, Ginaldi Lia
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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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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Effect of Rhythmic Auditory Cueing on Aging Gait: A Systematic Review and Meta-Analysis
Shashank Ghai, Ishan Ghai, Alfred O. Effenberg
Aging and disease    0, (): 131-200.   DOI: 10.14336/AD.2017.1031
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Rhythmic auditory cueing has been widely used in gait rehabilitation over the past decade. The entrainment effect has been suggested to introduce neurophysiological changes, alleviate auditory-motor coupling and reduce cognitive-motor interferences. However, a consensus as to its influence over aging gait is still warranted. A systematic review and meta-analysis was carried out to analyze the effects of rhythmic auditory cueing on spatiotemporal gait parameters among healthy young and elderly participants. This systematic identification of published literature was performed according to PRISMA guidelines, from inception until May 2017, on online databases: Web of science, PEDro, EBSCO, MEDLINE, Cochrane, EMBASE, and PROQUEST. Studies were critically appraised using PEDro scale. Of 2789 records, 34 studies, involving 854 (499 young/ 355 elderly) participants met our inclusion criteria. The meta-analysis revealed enhancements in spatiotemporal parameters of gait i.e. gait velocity (Hedge’s g: 0.85), stride length (0.61), and cadence (1.1), amongst both age groups. This review, for the first time, evaluates the effects of auditory entrainment on aging gait and discusses its implications under higher and lower information processing constraints. Clinical implications are discussed with respect to applications of auditory entrainment in rehabilitation settings.

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Geroprotectors: A Unified Concept and Screening Approaches
Moskalev Alexey, Chernyagina Elizaveta, Kudryavtseva Anna, Shaposhnikov Mikhail
Aging and disease    2017, 8 (3): 354-363.   DOI: 10.14336/AD.2016.1022
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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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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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Shining the Light on Senescence Associated LncRNAs
Ghanam A.R., Xu Qianlan, Ke Shengwei, Azhar Muhammad, Cheng Qingyu, Song Xiaoyuan
Aging and disease    2017, 8 (2): 149-161.   DOI: 10.14336/AD.2016.0810
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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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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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Associations among Metabolism, Circadian Rhythm and Age-Associated Diseases
Cao Yiwei, Wang Rui-Hong
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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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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Herba Cistanches: Anti-aging
Wang Ningqun, Ji Shaozhen, Zhang Hao, Mei Shanshan, Qiao Lumin, Jin Xianglan
Aging and disease    2017, 8 (6): 740-759.   DOI: 10.14336/AD.2017.0720
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The Cistanche species (“Rou Cong Rong” in Chinese) is an endangered wild species growing in arid or semi-arid areas. The dried fleshy stem of Cistanches has been used as a tonic in China for many years. Modern pharmacological studies have since demonstrated that Herba Cistanches possesses broad medicinal functions, especially for use in anti-senescence, anti-oxidation, neuroprotection, anti-inflammation, hepatoprotection, immunomodulation, anti-neoplastic, anti-osteoporosis and the promotion of bone formation. This review summarizes the up-to-date and comprehensive information on Herba Cistanches covering the aspects of the botany, traditional uses, phytochemistry and pharmacology, to lay ground for fully elucidating the potential mechanisms of Herba Cistanches’ anti-aging effect and promote its clinical application as an anti-aging herbal medicine.

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Cerebral Microvascular Accumulation of Tau Oligomers in Alzheimer’s Disease and Related Tauopathies
Castillo-Carranza Diana L, Nilson Ashley N, Van Skike Candice E, Jahrling Jordan B, Patel Kishan, Garach Prajesh, Gerson Julia E, Sengupta Urmi, Abisambra Jose, Nelson Peter, Troncoso Juan, Ungvari Zoltan, Galvan Veronica, Kayed Rakez
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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Rhizoma Coptidis and Berberine as a Natural Drug to Combat Aging and Aging-Related Diseases via Anti-Oxidation and AMPK Activation
Xu Zhifang, Feng Wei, Shen Qian, Yu Nannan, Yu Kun, Wang Shenjun, Chen Zhigang, Shioda Seiji, Guo Yi
Aging and disease    2017, 8 (6): 760-777.   DOI: 10.14336/AD.2016.0620
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Aging is the greatest risk factor for human diseases, as it results in cellular growth arrest, impaired tissue function and metabolism, ultimately impacting life span. Two different mechanisms are thought to be primary causes of aging. One is cumulative DNA damage induced by a perpetuating cycle of oxidative stress; the other is nutrient-sensing adenosine monophosphate-activated protein kinase (AMPK) and rapamycin (mTOR)/ ribosomal protein S6 (rpS6) pathways. As the main bioactive component of natural Chinese medicine rhizoma coptidis (RC), berberine has recently been reported to expand life span in Drosophila melanogaster, and attenuate premature cellular senescence. Most components of RC including berberine, coptisine, palmatine, and jatrorrhizine have been found to have beneficial effects on hyperlipidemia, hyperglycemia and hypertension aging-related diseases. The mechanism of these effects involves multiple cellular kinase and signaling pathways, including anti-oxidation, activation of AMPK signaling and its downstream targets, including mTOR/rpS6, Sirtuin1/ forkhead box transcription factor O3 (FOXO3), nuclear factor erythroid-2 related factor-2 (Nrf2), nicotinamide adenine dinucleotide (NAD+) and nuclear factor-κB (NF-κB) pathways. Most of these mechanisms converge on AMPK regulation on mitochondrial oxidative stress. Therefore, such evidence supports the possibility that rhizoma coptidis, in particular berberine, is a promising anti-aging natural product, and has pharmaceutical potential in combating aging-related diseases via anti-oxidation and AMPK cellular kinase activation.

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Cancer and Aging - the Inflammatory Connection
Zinger Adar, Cho William C, Ben-Yehuda Arie
Aging and disease    2017, 8 (5): 611-627.   DOI: 10.14336/AD.2016.1230
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Aging and cancer are highly correlated biological phenomena. Various cellular processes such as DNA damage responses and cellular senescence that serve as tumor suppressing mechanisms throughout life result in degenerative changes and contribute to the aging phenotype. In turn, aging is considered a pro-tumorigenic state, and constitutes the single most important risk factor for cancer development. However, the causative relations between aging and cancer is not straight forward, as these processes carry contradictory hallmarks; While aging is characterized by tissue degeneration and organ loss of function, cancer is a state of sustained cellular proliferation and gain of new functions. Here, we review the molecular and cellular pathways that stand in the base of aging related cancer. Specifically, we deal with the inflammatory perspective that link these two processes, and suggest possible molecular targets that may be exploited to modify their courses.

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Age-Related Gray and White Matter Changes in Normal Adult Brains
Farokhian Farnaz, Yang Chunlan, Beheshti Iman, Matsuda Hiroshi, Wu Shuicai
Aging and disease    2017, 8 (6): 899-909.   DOI: 10.14336/AD.2017.0502
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Normal aging is associated with both structural changes in many brain regions and functional declines in several cognitive domains with advancing age. Advanced neuroimaging techniques enable explorative analyses of structural alterations that can be used as assessments of such age-related changes. Here we used voxel-based morphometry (VBM) to investigate regional and global brain volume differences among four groups of healthy adults from the IXI Dataset: older females (OF, mean age 68.35 yrs; n=69), older males (OM, 68.43 yrs; n=66), young females (YF, 27.09 yrs; n=71), and young males (YM, 27.91 yrs; n=71), using 3D T1-weighted MRI data. At the global level, we investigated the influence of age and gender on brain volumes using a two-way analysis of variance. With respect to gender, we used the Pearson correlation to investigate global brain volume alterations due to age in the older and young groups. At the regional level, we used a flexible factorial statistical test to compare the means of gray matter (GM) and white matter (WM) volume alterations among the four groups. We observed different patterns in both the global and regional GM and WM alterations in the young and older groups with respect to gender. At the global level, we observed significant influences of age and gender on global brain volumes. At the regional level, the older subjects showed a widespread reduction in GM volume in regions of the frontal, insular, and cingulate cortices compared to the young subjects in both genders. Compared to the young subjects, the older subjects showed a widespread WM decline prominently in the thalamic radiations, in addition to increased WM in pericentral and occipital areas. Knowledge of these observed brain volume differences and changes may contribute to the elucidation of mechanisms underlying aging as well as age-related brain atrophy and disease.

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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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The Effect of Traditional Chinese Medicine on Neural Stem Cell Proliferation and Differentiation
Qin Wei, Chen Shiya, Yang Shasha, Xu Qian, Xu Chuanshan, Cai Jing
Aging and disease    2017, 8 (6): 792-811.   DOI: 10.14336/AD.2017.0428
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Neural stem cells (NSCs) are special types of cells with the potential for self-renewal and multi-directional differentiation. NSCs are regulated by multiple pathways and pathway related transcription factors during the process of proliferation and differentiation. Numerous studies have shown that the compound medicinal preparations, single herbs, and herb extracts in traditional Chinese medicine (TCM) have specific roles in regulating the proliferation and differentiation of NSCs. In this study, we investigate the markers of NSCs in various stages of differentiation, the related pathways regulating the proliferation and differentiation, and the corresponding transcription factors in the pathways. We also review the influence of TCM on NSC proliferation and differentiation, to facilitate the development of TCM in neural regeneration and neurodegenerative diseases.

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Lycium Barbarum: A Traditional Chinese Herb and A Promising Anti-Aging Agent
Gao Yanjie, Wei Yifo, Wang Yuqing, Gao Fang, Chen Zhigang
Aging and disease    2017, 8 (6): 778-791.   DOI: 10.14336/AD.2017.0725
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Lycium barbarum has been used in China for more than 2,000 years as a traditional medicinal herb and food supplement. Lycium barbarum contains abundant Lycium barbarum polysaccharides (LBPs), betaine, phenolics, carotenoids (zeaxanthin and β-carotene), cerebroside, 2-O-β-d-glucopyranosyl-l-ascorbic acid (AA-2βG), β-sitosterol, flavonoids and vitamins (in particular, riboflavin, thiamine, and ascorbic acid). LBPs are the primary active components of Lycium barbarum. In this review, we discuss the pharmacological activities of LBPs and other major components. They have been reported to mediate significant anti-aging effects, through antioxidant, immunoregulative, anti-apoptotic activities and reducing DNA damage. Thus, the basic scientific evidence for anti-aging effects of LBPs is already available. However, additional studies are needed to understand mechanisms by which LBPs mediate anti-aging properties. Novel findings from such studies would likely pave the way for the clinical application of traditional chinese medicine Lycium barbarum in modern evidence-based medicine.

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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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