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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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Recognizing Degenerative Aging as a Treatable Medical Condition: Methodology and Policy
Ilia Stambler
Aging and Disease    2017, 8 (5): 583-589.   DOI: 10.14336/AD.2017.0130
Abstract   HTML   PDF (789KB)

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

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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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
Abstract   HTML   PDF (1178KB)

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

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

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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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
Abstract   HTML   PDF (1256KB)

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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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
Abstract   HTML   PDF (1447KB)

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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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
Abstract   HTML   PDF (810KB)

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

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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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
Abstract   HTML   PDF (1212KB)

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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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
Abstract   HTML   PDF (957KB)

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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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
Abstract   HTML   PDF (511KB)

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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Vitamin D and Chronic Diseases
Hanmin Wang,Weiwen Chen,Dongqing Li,Xiaoe Yin,Xiaode Zhang,Nancy Olsen,Song Guo Zheng
Aging and Disease    2017, 8 (3): 346-353.   DOI: 10.14336/AD.2016.1021
Abstract   HTML   PDF (752KB)

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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Role of Pro-Inflammatory Cytokines and Vitamin D in Probable Alzheimer's Disease with Depression
Anindita Banerjee,Vineet Kumar Khemka,Debashree Roy,Aparajita Dhar,Tapan Kumar Sinha Roy,Atanu Biswas,Barun Mukhopadhyay,Sasanka Chakrabarti
Aging and Disease    2017, 8 (3): 267-276.   DOI: 10.14336/AD.2016.1017
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Symptoms of depression are present in a significant proportion of Alzheimer's disease (AD) patients. While epidemiological studies have shown a strong association between depression and AD, it has not been established whether depression is a risk factor or merely a co-morbidity of AD. It is also uncertain if depression affects the pathogenesis of AD. In this paper, we address these questions by measuring the serum levels of two common metabolic risk factors of AD and depression, inflammatory cytokines (IL 6 and TNF alpha) and serum 25-hydroxyvitamin D, in a case-control study. We measured the serum levels of IL 6, TNF α and 25-hydroxyvitamin D in age-matched healthy controls (n= 60) and in AD patients without depression (n=26) or AD patients with depression (n=34), and statistically analyzed the changes in these parameters among different groups under this study. Our results show that in AD there is a significant increase in IL 6 and TNF α and a marked decrease in 25-hydroxyvitamin D in the peripheral circulation compared to age-matched healthy controls. Furthermore, AD patients with depression have even significantly higher levels of IL 6 or TNF α and a lower level of 25-hydroxyvitamin D in circulation than in AD patients without depression. We also found a strong statistical correlation between the disease severity and the serum levels of IL 6, TNF α and 25-hydroxyvitamin D in AD patients with depression. These results suggest that altered circulating levels of common metabolic risk factors lead to the co-existence of depression with AD in many patients, and when they co-exist, the depression presumably affects the severity of AD presentations through more aggravated changes in these risk factors.

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New Developments in the Pathophysiology, Workup, and Diagnosis of Dural Venous Sinus Thrombosis (DVST) and a Systematic Review of Endovascular Treatments
Sanjay Konakondla,Clemens M. Schirmer,Fengwu Li,Xiaogun Geng,Yuchuan Ding
Aging and Disease    2017, 8 (2): 136-148.   DOI: 10.14336/AD.2016.0915
Abstract   HTML   PDF (1026KB)

Dural venous sinus thrombosis (DVST) is a rare cause of stroke, which typically affects young women. The importance of identifying pre-disposing factors that lead to venous stasis lies in the foundation of understanding the etiology, pathophysiology and clinical presentation. The precise therapeutic role of interventional therapies is not fully understood though the current data do suggest potential applications. The aim of the study was to perform a systematic review and meta-analysis to evaluate the utility of and short-term 30-day survival after endovascular therapy for patients with DVST. Standard PRISMA guidelines were followed. Data sources included PubMed keywords and phrases, which were also incorporated into a MeSH search to yield articles indexed in Medline over a 5-year period. All RCTs, observational cohort studies, and administrative registries comparing or reporting DVST were included. Sixty-six studies met inclusion criteria. 35 articles investigating treatment in a summation of 10,285 patients were eligible for data extraction and included in the review of treatment modalities. A total of 312 patients were included for statistical analysis. All patients included received endovascular intervention with direct thrombolysis, mechanical thrombectomy or both. 133 (42.6%) patients were documented to have a neurologic decline, which prompted endovascular intervention. All patients who had endovascular interventions were those who were started on and failed systemic anticoagulation. 44 patients were reported to have intracranial hemorrhages after intervention. Regardless of systemic anticoagulation, patients were still reported to have complications of VTE and PE. Primary outcome at 3-6 month follow up revealed mRS<1 in 224 patients. DVST presents with many diagnostic and therapeutic challenges. The utility of invasive interventions such as local thrombolysis and mechanical thrombectomy is not fully understood. It is exceedingly difficult to conduct large randomized trials for this low incidence disease process with large pathophysiological heterogeneity.

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Motor Imagery-Based Rehabilitation: Potential Neural Correlates and Clinical Application for Functional Recovery of Motor Deficits after Stroke
Yanna Tong,John T. Pendy,William A. Li,Huishan Du,Tong Zhang,Xiaokun Geng,Yuchuan Ding
Aging and Disease    2017, 8 (3): 364-371.   DOI: 10.14336/AD.2016.1012
Abstract   HTML   PDF (949KB)

Motor imagery (MI), defined as the mental implementation of an action in the absence of movement or muscle activation, is a rehabilitation technique that offers a means to replace or restore lost motor function in stroke patients when used in conjunction with conventional physiotherapy procedures. This article briefly reviews the concepts and neural correlates of MI in order to promote improved understanding, as well as to enhance the clinical utility of MI-based rehabilitation regimens. We specifically highlight the role of the cerebellum and basal ganglia, premotor, supplementary motor, and prefrontal areas, primary motor cortex, and parietal cortex. Additionally, we examine the recent literature related to MI and its potential as a therapeutic technique in both upper and lower limb stroke rehabilitation.

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A Fine-Tune Role of Mir-125a-5p on Foxn1 During Age-Associated Changes in the Thymus
Minwen Xu,Olga Sizova,Liefeng Wang,Dong-Ming Su
Aging and Disease    2017, 8 (3): 277-286.   DOI: 10.14336/AD.2016.1109
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Decline of transcription factor FoxN1, which predominantly regulates thymic epithelial cell (TEC) differentiation and homeostasis lifelong, is demonstrated to be casually related to age-related thymic involution. Whereas, a global role of microRNAs (miRNAs) has also been demonstrated to control and maintain TEC-constituting thymic microenvironment and to be changed in expression profile in the aged thymus. Therefore, it is urgently necessary to build knowledge regarding whether and which miRNAs regulate FoxN1 gene in the aged thymus. We primarily compared changes in miRNA expression profile between young and aged murine TECs with Mus musculus miRBase-V20 arrays (containing 1892 unique probes), and clearly identified and validated that at least one miRNA, miR-125a-5p, was increased in aged thymus. Applying miR-125a-5p mimics was able to inhibit FoxN1 3′UTR luciferase activity in a 293T cell line and to suppress FoxN1 expression in murine TEC Z210 cells. Since a single miRNA can play a fine-tuning role to regulate expression of multiple genes and a single gene can be regulated by multiple miRNAs, our result adds a single miRNA, miR-125a-5p, into the panel of FoxN1-regulating miRNAs associated with thymic aging.

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Cancer and Aging - the Inflammatory Connection
Adar Zinger,William C Cho,Arie Ben-Yehuda
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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Mitochondrial Ferritin Protects Hydrogen Peroxide-Induced Neuronal Cell Damage
Guofen Gao, Nan Zhang, Yue-Qi Wang, Qiong Wu, Peng Yu, Zhen-Hua Shi, Xiang-Lin Duan, Bao-Lu Zhao, Wen-Shuang Wu, Yan-Zhong Chang
Aging and Disease    2017, 8 (4): 458-470.   DOI: 10.14336/AD.2016.1108
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Oxidative stress and iron accumulation are tightly associated with neurodegenerative diseases. Mitochondrial ferritin (FtMt) is identified as an iron-storage protein located in the mitochondria, and its role in regulation of iron hemeostasis in neurodegenerative diseases has been reported. However, the role of FtMt in hydrogen peroxide (H2O2)-induced oxidative stress and iron accumulation in neuronal cells has not been studied. Here, we overexpressed FtMt in neuroblastoma SH-SY5Y cells and induced oxidative stress by treating with extracellular H2O2. We found that overexpression of FtMt significantly prevented cell death induced by H2O2, particularly the apoptosis-dependent cell death. The protective effects involved inhibiting the generation of cellular reactive oxygen species, sustaining mitochondrial membrane potential, maintaining the level of anti-apoptotic protein Bcl-2, and inhibiting the activation of pro-apoptotic protein caspase 3. We further explored the mechanism of these protective effects and found that FtMt expression markedly altered iron homeostasis of the H2O2 treated cells as compared to that of controls. The FtMt overexpression significantly reduced cellular labile iron pool (LIP) and protected H2O2-induced elevation on LIP. While in H2O2 treated SH-SY5Y cells, the increased iron uptake and reduced iron release, in correlation with levels of DMT1(-IRE) and ferroportin 1, resulted in heavy iron accumulation, the FtMt overexpressing cells didn’t show any significant changes in levels of iron transport proteins and in the level of LIP. These results implicate a neuroprotective role of FtMt on H2O2-induced oxidative stress, which may provide insights into the treatment of iron accumulation associated neurodegenerative diseases.

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Combining Injectable Plasma Scaffold with Mesenchymal Stem/Stromal Cells for Repairing Infarct Cavity after Ischemic Stroke
Hongxia Zhang,Fen Sun,Jixian Wang,Luokun Xie,Chenqi Yang,Mengxiong Pan,Bei Shao,Guo-Yuan Yang,Shao-Hua Yang,Qichuan ZhuGe,Kunlin Jin
Aging and Disease    2017, 8 (2): 203-214.   DOI: 10.14336/AD.2017.0305
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Stroke survivors are typically left with structural brain damage and associated functional impairment in the chronic phase of injury, for which few therapeutic options exist. We reported previously that transplantation of human embryonic stem cell (hESC)-derived neural stem cells together with Matrigel scaffolding into the brains of rats after focal ischemia reduced infarct volume and improved neurobehavioral performance. Matrigel is a gelatinous protein mixture extracted from mouse sarcoma cells, thus would not be approved for use as a scaffold clinically. In this study, we generated a gel-like scaffold from plasma that was controlled by changing the concentration of CaCl2. In vitro study confirmed that 10-20 mM CaCl2 and 10-40% plasma did not affect the viability and proliferation of human and rat bone marrow mesenchymal stem/stromal cells (BMSCs) and neural stem cells (NSCs). We transplanted plasma scaffold in combination of BMSCs into the cystic cavity after focal cerebral ischemia, and found that the atrophy volume was dramatically reduced and motor function was significantly improved in the group transplanted with scaffold/BMSCs compared with the groups treated with vehicle, scaffold or BMSCs only. Our data suggest that plasma-derived scaffold in combination of BMSCs is feasible for tissue engineering approach for the stroke treatment.

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The Study of Rhabdomyolysis in the Elderly: An Epidemiological Study and Single Center Experience
Supakanya Wongrakpanich,Christos Kallis,Prithiv Prasad,Janani Rangaswami,Andrew Rosenzweig
Aging and Disease    2018, 9 (1): 1-7.   DOI: 10.14336/AD.2017.0304
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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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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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Association between Coagulation Function and Cerebral Microbleeds in Ischemic Stroke Patients with Atrial Fibrillation and/or Rheumatic Heart Disease
Junfeng Liu,Deren Wang,Yao Xiong,Bian Liu,Jing Lin,Shihong Zhang,Bo Wu,Chenchen Wei,Ming Liu
Aging and Disease    2017, 8 (2): 131-135.   DOI: 10.14336/AD.2016.0715
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Cerebral microbleeds (CMBs), which indicate hemorrhage-prone disease, may associate with hemostatic abnormalities, but the association between CMBs and coagulation function is uncertain. We aimed to examine this possible association. The following coagulation function indicators were evaluated in 85 consecutive ischemic stroke patients diagnosed with atrial fibrillation and/or rheumatic heart disease: prothrombintime (PT), activated partial thromboplastin time (APTT), and levels of D-dimer and fibrinogen. Indicators were assessed within 24 h after admission. CMBs were identified based on published criteria by two experienced stroke neurologists working independently. PT, APPT, and levels of D-dimer and fibrinogen were compared between patients with and without CMBs using univariate and multivariate analysis. CMBs were detected in 48 patients (56.5%), and fibrinogen levels in these patients were independently and significantly higher than in patients without CMBs after adjustment (OR 2.16, 95% CI 1.20-3.90, P=0.01), whereas the two types of patients did not differ significantly in PT, APPT, or D-dimer levels. The presence of CMBs in ischemic stroke patients with atrial fibrillation and/or rheumatic heart disease is associated with elevated levels of fibrinogen. Larger prospective studies are needed to verify this association and explore the mechanisms involved.

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On the Relationship between Energy Metabolism, Proteostasis, Aging and Parkinson’s Disease: Possible Causative Role of Methylglyoxal and Alleviative Potential of Carnosine
Alan R. Hipkiss
Aging and Disease    2017, 8 (3): 334-345.   DOI: 10.14336/AD.2016.1030
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Recent research shows that energy metabolism can strongly influence proteostasis and thereby affect onset of aging and related disease such as Parkinson’s disease (PD). Changes in glycolytic and proteolytic activities (influenced by diet and development) are suggested to synergistically create a self-reinforcing deleterious cycle via enhanced formation of triose phosphates (dihydroxyacetone-phosphate and glyceraldehyde-3-phosphate) and their decomposition product methylglyoxal (MG). It is proposed that triose phosphates and/or MG contribute to the development of PD and its attendant pathophysiological symptoms. MG can induce many of the macromolecular modifications (e.g. protein glycation) which characterise the aged-phenotype. MG can also react with dopamine to generate a salsolinol-like product, 1-acetyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinaline (ADTIQ), which accumulates in the Parkinson’s disease (PD) brain and whose effects on mitochondria, analogous to MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), closely resemble changes associated with PD. MG can directly damage the intracellular proteolytic apparatus and modify proteins into non-degradable (cross-linked) forms. It is suggested that increased endogenous MG formation may result from either, or both, enhanced glycolytic activity and decreased proteolytic activity and contribute to the macromolecular changes associated with PD. Carnosine, a naturally-occurring dipeptide, may ameliorate MG-induced effects due, in part, to its carbonyl-scavenging activity. The possibility that ingestion of highly glycated proteins could also contribute to age-related brain dysfunction is briefly discussed.

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Cardiovascular Risk Factors Are Correlated with Low Cognitive Function among Older Adults Across Europe Based on The SHARE Database
Joana Lourenco,Antonio Serrano,Alice Santos-Silva,Marcos Gomes,Claudia Afonso,Paula Freitas,Constanca Paul,Elisio Costa
Aging and Disease    2018, 9 (1): 90-101.   DOI: 10.14336/AD.2017.0128
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Increased life expectancy is associated with a high prevalence of chronic, non-communicable diseases including cognitive decline and dementia. The purpose of this study was to evaluate the prevalence of cognitive impairment using three cognitive abilities (verbal fluency, numeracy and perceived memory) and their association with cardiovascular risk factors in seniors across Europe. Data from participants in wave 4 of the SHARE (Survey of Health, Ageing, and Retirement in Europe) database was used. Cognitive performance in perceived memory, verbal fluency and numeracy was evaluated using simple tests and a memory complaints questionnaire. Clinical and sociodemographic variables were also studied for potential associations. Standardised prevalence rates of cognitive impairment based on age and gender were calculated by country. The prevalence of cognitive impairment was 28.02% for perceived memory, 27.89% for verbal fluency and 20.75% for numeracy throughout the 16 evaluated countries. Years of education, being a current or former smoker, number of chronic diseases, diabetes or hyperglycemia, heart attack and stroke were all independent variables associated with impairment in the three studied cognitive abilities. We also found independent associations between physical inactivity and verbal fluency and numeracy impairment, as well as hypertension and perceived memory impairment. Lower performance in the evaluated cognitive abilities and higher memory complaints are highly prevalent, have a heterogeneous distribution across Europe, and are associated with multiple factors, most of which are potentially preventable or treatable, especially cardiovascular risk factors.

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