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NF-κB in Aging and Disease
Jeremy S. Tilstra,Cheryl L. Clauson,Laura J. Niedernhofer,Paul D. Robbins
Aging and Disease    2011, 2 (6): 449-465.  
Abstract5645)   HTML8)    PDF(pc) (1175KB)(2171)       Save

Stochastic damage to cellular macromolecules and organelles is thought to be a driving force behind aging and associated degenerative changes. However, stress response pathways activated by this damage may also contribute to aging. The IKK/NF-κB signaling pathway has been proposed to be one of the key mediators of aging. It is activated by genotoxic, oxidative, and inflammatory stresses and regulates expression of cytokines, growth factors, and genes that regulate apoptosis, cell cycle progression, cell senescence, and inflammation. Transcriptional activity of NF-κB is increased in a variety of tissues with aging and is associated with numerous age-related degenerative diseases including Alzheimer’s, diabetes and osteoporosis. In mouse models, inhibition of NF-κB leads to delayed onset of age-related symptoms and pathologies. In addition, NF-κB activation is linked with many of the known lifespan regulators including insulin/IGF-1, FOXO, SIRT, mTOR, and DNA damage. Thus NF-κB represents a possible therapeutic target for extending mammalian healthspan.

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Modern Biological Theories of Aging
Kunlin Jin
Aging and Disease    2010, 1 (2): 72-74.  
Abstract4545)   HTML21)    PDF(pc) (291KB)(1387)       Save

Despite recent advances in molecular biology and genetics, the mysteries that control human lifespan are yet to be unraveled. Many theories, which fall into two main categories: programmed and error theories, have been proposed to explain the process of aging, but neither of them appears to be fully satisfactory. These theories may interact with each other in a complex way. By understanding and testing the existing and new aging theories, it may be possible to promote successful aging.

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Aging and Cardiac Fibrosis
Anna Biernacka,Nikolaos G Frangogiannis
Aging and Disease    2011, 2 (2): 158-173.  
Abstract3679)   HTML15)    PDF(pc) (830KB)(2091)       Save

The aging heart is characterized by morphological and structural changes that lead to its functional decline and are associated with diminished ability to meet increased demand. Extensive evidence, derived from both clinical and experimental studies suggests that the aging heart undergoes fibrotic remodeling. Age-dependent accumulation of collagen in the heart leads to progressive increase in ventricular stiffness and impaired diastolic function. Increased mechanical load, due to reduced arterial compliance, and direct senescence-associated fibrogenic actions appear to be implicated in the pathogenesis of cardiac fibrosis in the elderly. Evolving evidence suggests that activation of several distinct molecular pathways may contribute to age-related fibrotic cardiac remodeling. Reactive oxygen species, chemokine-mediated recruitment of mononuclear cells and fibroblast progenitors, transforming growth factor (TGF)-β activation, endothelin-1 and angiotensin II signaling mediate interstitial and perivascular fibrosis in the senescent heart. Reduced collagen degradation may be more important than increased de novo synthesis in the pathogenesis of aging-associated fibrosis. In contrast to the baseline activation of fibrogenic pathways in the senescent heart, aging is associated with an impaired reparative response to cardiac injury and defective activation of reparative fibroblasts in response to growth factors. Because these reparative defects result in defective scar formation, senescent hearts are prone to adverse dilative remodeling following myocardial infarction. Understanding the pathogenesis of interstitial fibrosis in the aging heart and dissecting the mechanisms responsible for age-associated healing defects following cardiac injury are critical in order to design new strategies for prevention of adverse remodeling and heart failure in elderly patients.

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Insulin, IGF-1 and longevity
Diana van Heemst
Aging and Disease    2010, 1 (2): 147-157.  
Abstract3532)   HTML18)    PDF(pc) (637KB)(1781)       Save

It has been demonstrated in invertebrate species that the evolutionarily conserved insulin and insulin-like growth factor (IGF) signaling (IIS) pathway plays a major role in the control of longevity. In the roundworm Caenorhabditis elegans, single mutations that diminish insulin/IGF-1 signaling can increase lifespan more than twofold and cause the animal to remain active and youthful much longer than normal. Likewise, substantial increases in lifespan are associated with mutations that reduce insulin/IGF-1 signaling in the fruit fly Drosophila melanogaster. In invertebrates, multiple insulin-like ligands exist that bind to a common single insulin/IGF-1 like receptor. In contrast, in mammals, different receptors exist that bind insulin, IGF-1 and IGF-2 with different affinities. In several mouse models, mutations that are associated with decreased GH/IGF-1 signaling or decreased insulin signaling have been associated with enhanced lifespan. However, the increased complexity of the mammalian insulin/IGF-1 system has made it difficult to separate the roles of insulin, GH and IGF-1 in mammalian longevity. Likewise, the relevance of reduced insulin and IGF-1 signaling in human longevity remains controversial. However, studies on the genetic and metabolic characteristics that are associated with healthy longevity and old age survival suggest that the conserved ancient IIS pathway may also play a role in human longevity.

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The Critical Need to Promote Research of Aging and Aging-related Diseases to Improve Health and Longevity of the Elderly Population
Jin Kunlin, Simpkins James W., Ji Xunming, Leis Miriam, Stambler Ilia
Aging and disease    2015, 6 (1): 1-5.   DOI: 10.14336/AD.2014.1210
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Due to the aging of the global population and the derivative increase in aging-related non-communicable diseases and their economic burden, there is an urgent need to promote research on aging and aging-related diseases as a way to improve healthy and productive longevity for the elderly population. To accomplish this goal, we advocate the following policies: 1) Increasing funding for research and development specifically directed to ameliorate degenerative aging processes and to extend healthy and productive lifespan for the population; 2) Providing a set of incentives for commercial, academic, public and governmental organizations to foster engagement in such research and development; and 3) Establishing and expanding coordination and consultation structures, programs and institutions involved in aging-related research, development and education in academia, industry, public policy agencies and at governmental and supra-governmental levels.

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Dizziness and Imbalance in the Elderly: Age-related Decline in the Vestibular System
Iwasaki Shinichi, Yamasoba Tatsuya
Aging and disease    2015, 6 (1): 38-47.   DOI: 10.14336/AD.2014.0128
Abstract3454)   HTML30)    PDF(pc) (457KB)(2186)       Save

Dizziness and imbalance are amongst the most common complaints in older people, and are a growing public health concern since they put older people at a significantly higher risk of falling. Although the causes of dizziness in older people are multifactorial, peripheral vestibular dysfunction is one of the most frequent causes. Benign paroxysmal positional vertigo is the most frequent form of vestibular dysfunction in the elderly, followed by Meniere#cod#x02019;s disease. Every factor associated with the maintenance of postural stability deteriorates during aging. Age-related deterioration of peripheral vestibular function has been demonstrated through quantitative measurements of the vestibulo-ocular reflex with rotational testing and of the vestibulo-collic reflex with testing of vestibular evoked myogenic potentials. Age-related decline of vestibular function has been shown to correlate with the age-related decrease in the number of vestibular hair cells and neurons. The mechanism of age-related cellular loss in the vestibular endorgan is unclear, but it is thought that genetic predisposition and cumulative effect of oxidative stress may both play an important role. Since the causes of dizziness in older people are multi-factorial, management of this disease should be customized according to the etiologies of each individual. Vestibular rehabilitation is found to be effective in treating both unilateral and bilateral vestibular dysfunction. Various prosthetic devices have also been developed to improve postural balance in older people. Although there have been no medical treatments improving age-related vestibular dysfunction, new medical treatments such as mitochondrial antioxidants or caloric restriction, which have been effective in preventing age-related hearing loss, should be ienvestigated in the future.

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Metabolic Syndrome, Aging and Involvement of Oxidative Stress
Bonomini Francesca, Rodella Luigi Fabrizio, Rezzani Rita
Aging and disease    2015, 6 (2): 109-120.   DOI: 10.14336/AD.2014.0305
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The prevalence of the metabolic syndrome, a cluster of cardiovascular risk factors associated with obesity and insulin resistance, is dramatically increasing in Western and developing countries. This disorder consists of a cluster of metabolic conditions, such as hypertriglyceridemia, hyper-low-density lipoproteins, hypo-high-density lipoproteins, insulin resistance, abnormal glucose tolerance and hypertension, that-in combination with genetic susceptibility and abdominal obesity-are risk factors for type 2 diabetes, vascular inflammation, atherosclerosis, and renal, liver and heart diseases. One of the defects in metabolic syndrome and its associated diseases is excess of reactive oxygen species. Reactive oxygen species generated by mitochondria, or from other sites within or outside the cell, cause damage to mitochondrial components and initiate degradative processes. Such toxic reactions contribute significantly to the aging process. In this article we review current understandings of oxidative stress in metabolic syndrome related disease and its possible contribution to accelerated senescence.

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Depression in the Elderly: Clinical Features and Risk Factors
Gülfizar Sözeri-Varma
Aging and Disease    2012, 3 (6): 465-471.  
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Depression in elderlies is not known quite well and thus cannot be treated adequately. The fact that elderliness is accepted as a property of depressive symptoms both by the relatives of the patients and doctors is one of the factors which make it difficult to recognize depression. Existence of multiple physical diseases in elderlies, use of multiple medicines, occurrence of pharmacokinetic and pharmacodynamics changes depending on the age necessitate to take several factors into account while diagnosing and using medicines. In this study, clinical properties and risk factors of depression in old age period was reviewed and the properties of such depressions were summarized.

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Strength and Endurance Training Prescription in Healthy and Frail Elderly
Eduardo Lusa Cadore,Ronei Silveira Pinto,Martim Bottaro,Mikel Izquierdo
Aging and Disease    2014, 5 (3): 183-195.   DOI: 10.14336/AD.2014.0500183
Abstract3160)   HTML19)          Save

Aging is associated with declines in the neuromuscular and cardiovascular systems, resulting in an impaired capacity to perform daily activities. Frailty is an age-associated biological syndrome characterized by decreases in the biological functional reserve and resistance to stressors due to changes in several physiological systems, which puts older individuals at special risk of disability. To counteract the neuromuscular and cardiovascular declines associated with aging, as well as to prevent and treat the frailty syndrome, the strength and endurance training seems to be an effective strategy to improve muscle hypertrophy, strength and power output, as well as endurance performance. The first purpose of this review was discuss the neuromuscular adaptations to strength training, as well as the cardiovascular adaptations to endurance training in healthy and frail elderly subjects. In addition, the second purpose of this study was investigate the concurrent training adaptations in the elderly. Based on the results found, the combination of strength and endurance training (i.e., concurrent training) performed at moderate volume and moderate to high intensity in elderly populations is the most effective way to improve both neuromuscular and cardiorespiratory functions. Moreover, exercise interventions that include muscle power training should be prescribed to frail elderly in order to improve the overall physical status of this population and prevent disability.

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Dopamine Receptors and Neurodegeneration
Claudia Rangel-Barajas, Israel Coronel, Benjamín Florán
Aging and disease    2015, 6 (5): 349-368.   DOI: 10.14336/AD.2015.0330
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Dopamine (DA) is one of the major neurotransmitters and participates in a number of functions such as motor coordination, emotions, memory, reward mechanism, neuroendocrine regulation etc. DA exerts its effects through five DA receptors that are subdivided in 2 families: D1-like DA receptors (D1 and D5) and the D2-like (D2, D3 and D4). All DA receptors are widely expressed in the central nervous system (CNS) and play an important role in not only in physiological conditions but also pathological scenarios. Abnormalities in the DAergic system and its receptors in the basal ganglia structures are the basis Parkinson’s disease (PD), however DA also participates in other neurodegenerative disorders such as Huntington disease (HD) and multiple sclerosis (MS). Under pathological conditions reorganization of DAergic system has been observed and most of the times, those changes occur as a mechanism of compensation, but in some cases contributes to worsening the alterations. Here we review the changes that occur on DA transmission and DA receptors (DARs) at both levels expression and signals transduction pathways as a result of neurotoxicity, inflammation and in neurodegenerative processes. The better understanding of the role of DA receptors in neuropathological conditions is crucial for development of novel therapeutic approaches to treat alterations related to neurodegenerative diseases.

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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
Abstract2881)   HTML21)    PDF(pc) (874KB)(1862)       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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Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity
Luo Xiaoting, Wu Jinzi, Jing Siqun, Yan Liang-Jun
Aging and disease    2016, 7 (1): 90-110.   DOI: 10.14336/AD.2015.0702
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Diabetes and its complications are caused by chronic glucotoxicity driven by persistent hyperglycemia. In this article, we review the mechanisms of diabetic glucotoxicity by focusing mainly on hyperglycemic stress and carbon stress. Mechanisms of hyperglycemic stress include reductive stress or pseudohypoxic stress caused by redox imbalance between NADH and NAD+ driven by activation of both the polyol pathway and poly ADP ribose polymerase; the hexosamine pathway; the advanced glycation end products pathway; the protein kinase C activation pathway; and the enediol formation pathway. Mechanisms of carbon stress include excess production of acetyl-CoA that can over-acetylate a proteome and excess production of fumarate that can over-succinate a proteome; both of which can increase glucotoxicity in diabetes. For hyperglycemia stress, we also discuss the possible role of mitochondrial complex I in diabetes as this complex, in charge of NAD+ regeneration, can make more reactive oxygen species (ROS) in the presence of excess NADH. For carbon stress, we also discuss the role of sirtuins in diabetes as they are deacetylases that can reverse protein acetylation thereby attenuating diabetic glucotoxicity and improving glucose metabolism. It is our belief that targeting some of the stress pathways discussed in this article may provide new therapeutic strategies for treatment of diabetes and its complications.

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The Role of the Tripartite Glutamatergic Synapse in the Pathophysiology of Alzheimer’s Disease
Rudy Carolyn C., Hunsberger Holly C., Weitzner Daniel S., Reed Miranda N.
Aging and disease    2015, 6 (2): 131-148.   DOI: 10.14336/AD.2014.0423
Abstract2386)   HTML10)    PDF(pc) (915KB)(1240)       Save

Alzheimer’s disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (Aβ) and tau. Both Aβ and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse, comprised of a presynaptic terminal, a postsynaptic spine, and an astrocytic process, may underlie the pathogenic mechanisms of AD. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in learning and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This review discusses the ways in which both beta-amyloid (Aβ) and tau act alone and in concert to perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of N-methyl-D-aspartate (NMDA) as a possible convergence point for Aβ and tau toxicity.

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Phenylketonuria Pathophysiology: on the Role of Metabolic Alterations
Patrícia Fernanda Schuck, Fernanda Malgarin, José Henrique Cararo, Fabiola Cardoso, Emilio Luiz Streck, Gustavo Costa Ferreira
Aging and disease    2015, 6 (5): 390-399.   DOI: 10.14336/AD.2015.0827
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Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism caused by the deficiency of phenylalanine hydroxylase. This deficiency leads to the accumulation of Phe and its metabolites in tissues and body fluids of PKU patients. The main signs and symptoms are found in the brain but the pathophysiology of this disease is not well understood. In this context, metabolic alterations such as oxidative stress, mitochondrial dysfunction, and impaired protein and neurotransmitters synthesis have been described both in animal models and patients. This review aims to discuss the main metabolic disturbances reported in PKU and relate them with the pathophysiology of this disease. The elucidation of the pathophysiology of brain damage found in PKU patients will help to develop better therapeutic strategies to improve quality of life of patients affected by this condition.

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Stop Aging Disease! ICAD 2014
Ilia Stambler
Aging and disease    2015, 6 (2): 76-94.   DOI: 10.14336/AD.2015.0115
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On November 1–2, 2014, there took place in Beijing, China, the first International Conference on Aging and Disease (ICAD 2014) of the International Society on Aging and Disease (ISOAD). The conference participants presented a wide and exciting front of work dedicated to amelioration of aging-related conditions, ranging from regenerative medicine through developing geroprotective substances, elucidating a wide range of mechanisms of aging and aging-related diseases, from energy metabolism through genetics and immunomodulation to systems biology. The conference further emphasized the need to intensify and support research on aging and aging-related diseases to provide solutions for the urgent health challenges of the aging society.

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Metformin and the Risk of Dementia in Type 2 Diabetes Patients
Tseng Chin-Hsiao
Aging and disease    2019, 10 (1): 37-48.   DOI: 10.14336/AD.2017.1202
Abstract2309)   HTML3)    PDF(pc) (607KB)(730)       Save

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

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Amyotrophic Lateral Sclerosis: An update for 2013 Clinical Features, Pathophysiology, Management and Therapeutic Trials
Paul H. Gordon
Aging and Disease    2013, 4 (5): 295-310.   DOI: 10.14336/AD.2013.0400295
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Amyotrophic lateral sclerosis (ALS), first described by Jean-Martin Charcot in the 1870s, is an age-related disorder that leads to degeneration of motor neurons. The disease begins focally in the central nervous system and then spreads relentlessly. The clinical diagnosis, defined by progressive signs and symptoms of upper and lower motor neuron dysfunction, is confirmed by electromyography. Additional testing excludes other conditions. The disease is heterogeneous, but most patients die of respiratory muscle weakness less than 3 years from symptom-onset. Like other age-related neurodegenerative diseases, ALS has genetic and environmental triggers. Of the five to 10% of cases that are inherited, mutations have been discovered for a high proportion. In addition to genetic factors, age, tobacco use, and athleticism may contribute to sporadic ALS, but important etiologies are unidentified for most patients. Complex pathophysiological processes, including mitochondrial dysfunction, aggregation of misfolded protein, oxidative stress, excitotoxicity, inflammation and apoptosis, involve both motor neurons and surrounding glial cells. There is clinical and pathological overlap with other neurodegenerative diseases, particularly frontotemporal dementia. The mechanisms leading to disease propagation in the brain are a current focus of research. To date, one medication, riluzole, licensed in 1996, has been proved to prolong survival in ALS. Numerous clinical trials have so far been unable to identify another neuroprotective agent. Researchers now aim to slow disease progression by targeting known pathophysiological pathways or genetic defects. Current approaches are directed at muscle proteins such as Nogo, energetic balance, cell replacement, and abnormal gene products resulting from mutations. Until better understanding of the causes and mechanisms underlying progression lead to more robust neuroprotective agents, symptomatic therapies can extend life and improve quality of life. Palliative care programs such as hospice give emotional and physical support to patients and families throughout much of the disease course.

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Improving the Treatment of Parkinson’s Disease: A Novel Approach by Modulating 5-HT1A Receptors
Saki Shimizu,Yukihiro Ohno
Aging and Disease    2013, 4 (1): 1-13.  
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Parkinson’s disease, the most common neurological disorder in the elderly, is characterized by progressive extrapyramidal motor dysfunction including resting tremors, muscle rigidity, hypolocomotion (bradykinesia and akinesia) and postural instability. Various non-motor features are also seen such as cognitive impairments (deficits in learning and memory) and mood disorders (depression and anxiety). While the 5-HT1A receptor has long been implicated in the pathogenesis and treatment of anxiety and depression, recent research has revealed new therapeutic roles for 5-HT1A receptors in the treatment of Parkinson’s disease. These include the modulation of parkinsonian motor symptoms, L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia, cognitive impairments and emesis. Thus, 5-HT1A agonists improve the various motor disorders associated with dopaminergic deficits, dyskinesia induced by chronic L-DOPA treatment, mood disturbances (anxiety and depression) and dopamine agonist-induced emesis. In addition, partial 5-HT1A agonists are expected to improve cognitive impairment in Parkinson’s patients. These findings encourage research into new 5-HT1A receptor ligands, which will improve efficacy and/or ameliorate adverse reactions in the treatment of Parkinson’s disease.

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Eating Disorders in Late-life
Luca Antonina, Luca Maria, Calandra2 Carmela
Aging and disease    2015, 6 (1): 48-55.   DOI: 10.14336/AD.2014.0124
Abstract2233)   HTML38)    PDF(pc) (492KB)(1626)       Save

Eating disorders are a heterogeneous group of complex psychiatric disorders characterized by abnormal eating behaviours that lead to a high rate of morbidity, or even death, if underestimated and untreated. The main disorders enlisted in the chapter of the Diagnostic and Statistic Manual of Mental Disorders-5 dedicated to #cod#x0201C;Feeding and Eating Disorders#cod#x0201D; are: anorexia nervosa, bulimia nervosa and binge eating disorder. Even though these abnormal behaviours are mostly diagnosed during childhood, interesting cases of late-life eating disorders have been reported in literature. In this review, these eating disorders are discussed, with particular attention to the diagnosis and management of those cases occurring in late-life.

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The involvement of BDNF, NGF and GDNF in aging and Alzheimer's disease
Josiane Budni, Tatiani Bellettini-Santos, Francielle Mina, Michelle Lima Garcez, Alexandra Ioppi Zugno
Aging and disease    2015, 6 (5): 331-341.   DOI: 10.14336/AD.2015.0825
Abstract2226)   HTML11)    PDF(pc) (849KB)(1646)       Save

Aging is a normal physiological process accompanied by cognitive decline. This aging process has been the primary risk factor for development of aging-related diseases such as Alzheimer's disease (AD). Cognitive deficit is related to alterations of neurotrophic factors level such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF) and glial cell-derived neurotrophic factor (GDNF). These strong relationship between aging and AD is important to investigate the time which they overlap, as well as, the pathophysiological mechanism in each event. Considering that aging and AD are related to cognitive impairment, here we discuss the involving these neurotrophic factors in the aging process and AD.

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Exercise, Inflammation and Aging
Jeffrey A. Woods,Kenneth R. Wilund,Stephen A. Martin,Brandon M. Kistler
Aging and Disease    2012, 3 (1): 130-140.  
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Aging results in chronic low grade inflammation that is associated with increased risk for disease, poor physical functioning and mortality. Strategies that reduce age-related inflammation may improve the quality of life in older adults. Regular exercise is recommended for older people for a variety of reasons including increasing muscle mass and reducing risk for chronic diseases of the heart and metabolic systems. Only recently has exercise been examined in the context of inflammation. This review will highlight key randomized clinical trial evidence regarding the influence of exercise training on inflammatory biomarkers in the elderly. Potential mechanisms will be presented that might explain why exercise may exert an anti-inflammatory effect.

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mTOR Signaling from Cellular Senescence to Organismal Aging
Shaohua Xu,Ying Cai,Yuehua Wei
Aging and Disease    2014, 5 (4): 263-273.   DOI: 10.14336/AD.2014.0500263
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The TOR (target of rapamycin) pathway has been convincingly shown to promote aging in various model organisms. In mice, inhibiting mTOR (mammalian TOR) by rapamycin treatment later in life can significantly extend lifespan and mitigate multiple age-related diseases. However, the underlying mechanisms are poorly understood. Cellular senescence is strongly correlated to organismal aging therefore providing an attractive model to examine the mechanisms by which mTOR inhibition contributes to longevity and delaying the onset of related diseases. In this review, we examine the connections between mTOR and cellular senescence and discuss how understanding cellular senescence on the aspect of mTOR signaling may help to fully appreciate its role in the organismal aging. We also highlight the opposing roles of senescence in various human diseases and discuss the caveats in interpreting the emerging experimental data.

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The Role of Nutrition in Enhancing Immunity in Aging
Munkyong Pae,Simin Nikbin Meydani,Dayong Wu
Aging and Disease    2012, 3 (1): 91-129.  
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Aging is associated with declined immune function, particularly T cell-mediated activity, which contributes to increased morbidity and mortality from infectious disease and cancer in the elderly. Studies have shown that nutritional intervention may be a promising approach to reversing impaired immune function and diminished resistance to infection with aging. However, controversy exists concerning every nutritional regimen tested to date. In this article, we will review the progress of research in this field with a focus on nutrition factor information that is relatively abundant in the literature. While vitamin E deficiency is rare, intake above recommended levels can enhance T cell function in aged animals and humans. This effect is believed to contribute toward increased resistance to influenza infection in animals and reduced incidence of upper respiratory infection in the elderly. Zinc deficiency, common in the elderly, is linked to impaired immune function and increased risk for acquiring infection, which can be rectified by zinc supplementation. However, higher than recommended upper limits of zinc may adversely affect immune function. Probiotics are increasingly being recognized as an effective, immune-modulating nutritional factor. However, to be effective, they require an adequate supplementation period; additionally, their effects are strain-specific and among certain strains, a synergistic effect is observed. Increased intake of fish or n-3 PUFA may be beneficial to inflammatory and autoimmune disorders as well as to several age-related diseases. Conversely, the immunosuppressive effect of fish oils on T cell-mediated function has raised concerns regarding their impact on resistance to infection. Caloric restriction (CR) is shown to delay immunosenescence in animals, but this effect needs to be verified in humans. Timing for CR initiation may be important to determine whether CR is effective or even beneficial at all. Recent studies have suggested that CR, which is effective at improving the immune response of unchallenged animals, might compromise the host’s defense against pathogenic infection and result in higher morbidity and mortality. The studies published thus far describe a critical role for nutrition in maintaining the immune response of the aged, but they also indicate the need for a more in-depth, wholestic approach to determining the optimal nutritional strategies that would maintain a healthy immune system in the elderly and promote their resistance to infection and other immune-related diseases

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Mitochondrial Dysfunction in Alzheimer’s Disease and the Rationale for Bioenergetics Based Therapies
Onyango Isaac G., Dennis Jameel, Khan Shaharyah M.
Aging and disease    2016, 7 (2): 201-214.   DOI: 10.14336/AD.2015.1007
Abstract2037)   HTML21)    PDF(pc) (901KB)(1862)       Save

Alzheimer’s disease (AD) is a debilitating neurodegenerative disorder characterized by the progressive loss of cholinergic neurons, leading to the onset of severe behavioral, motor and cognitive impairments. It is a pressing public health problem with no effective treatment. Existing therapies only provide symptomatic relief without being able to prevent, stop or reverse the pathologic process. While the molecular basis underlying this multifactorial neurodegenerative disorder remains a significant challenge, mitochondrial dysfunction appears to be a critical factor in the pathogenesis of this disease. It is therefore important to target mitochondrial dysfunction in the prodromal phase of AD to slow or prevent the neurodegenerative process and restore neuronal function. In this review, we discuss mechanisms of action and translational potential of current mitochondrial and bioenergetic therapeutics for AD including: mitochondrial enhancers to potentiate energy production; antioxidants to scavenge reactive oxygen species and reduce oxidative damage; glucose metabolism and substrate supply; and candidates that target apoptotic and mitophagy pathways to remove damaged mitochondria. While mitochondrial therapeutic strategies have shown promise at the preclinical stage, there has been little progress in clinical trials thus far.

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

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Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment
Chakrabarti Sasanka, Kumar Khemka Vineet, Banerjee Anindita, Chatterjee Gargi, Ganguly Anirban, Biswas Atanu
Aging and disease    2015, 6 (4): 282-299.   DOI: 10.14336/AD.2014.002
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Alzheimer's disease (AD), the major cause of dementia among the elderly world-wide, manifests in familial and sporadic forms, and the latter variety accounts for the majority of the patients affected by this disease. The etiopathogenesis of sporadic AD is complex and uncertain. The autopsy studies of AD brain have provided limited understanding of the antemortem pathogenesis of the disease. Experimental AD research with transgenic animal or various cell based models has so far failed to explain the complex and varied spectrum of AD dementia. The review, therefore, emphasizes the importance of AD related risk factors, especially those with metabolic implications, identified from various epidemiological studies, in providing clues to the pathogenesis of this complex disorder. Several metabolic risk factors of AD like hypercholesterolemia, hyperhomocysteinemia and type 2 diabetes have been studied extensively both in epidemiology and experimental research, while much less is known about the role of adipokines, pro-inflammatory cytokines and vitamin D in this context. Moreover, the results from many of these studies have shown a degree of variability which has hindered our understanding of the role of AD related risk factors in the disease progression. The review also encompasses the recent recommendations regarding clinical and neuropathological diagnosis of AD and brings out the inherent uncertainty and ambiguity in this area which may have a distinct impact on the outcome of various population-based studies on AD-related risk factors.

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Neuroimaging of Cerebrovascular Disease in the Aging Brain
Ajay Gupta,Sreejit Nair,Andrew D. Schweitzer,Sirish Kishore,Carl E. Johnson,Joseph P. Comunale,Apostolos J. Tsiouris,Pina C. Sanelli
Aging and Disease    2012, 3 (5): 414-425.  
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Cerebrovascular disease remains a significant public health burden with its greatest impact on the elderly population. Advances in neuroimaging techniques allow detailed and sophisticated evaluation of many manifestations of cerebrovascular disease in the brain parenchyma as well as in the intracranial and extracranial vasculature. These tools continue to contribute to our understanding of the multifactorial processes that occur in the age-dependent development of cerebrovascular disease. Structural abnormalities related to vascular disease in the brain and vessels have been well characterized with CT and MRI based techniques. We review some of the pathophysiologic mechanisms in the aging brain and cerebral vasculature and the related structural abnormalities detectable on neuroimaging, including evaluation of age-related white matter changes, atherosclerosis of the cerebral vasculature, and cerebral infarction. In addition, newer neuroimaging techniques, such as diffusion tensor imaging, perfusion techniques, and assessment of cerebrovascular reserve, are also reviewed, as these techniques can detect physiologic alterations which complement the morphologic changes that cause cerebrovascular disease in the aging brain.Further investigation of these advanced imaging techniques has potential application to the understanding and diagnosis of cerebrovascular disease in the elderly.

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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
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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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Myocardial Infarction in the Elderly
Amelia Carro,Juan Carlos Kaski
Aging and Disease    2011, 2 (2): 116-137.  
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Advances in pharmacological treatment and effective early myocardial revascularization have –in recent years- led to improved clinical outcomes in patients with acute myocardial infarction (AMI). However, it has been suggested that compared to younger subjects, elderly AMI patients are less likely to receive evidence-based treatment, including myocardial revascularization therapy. Several reasons have been postulated to explain this trend, including uncertainty regarding the true benefits of the interventions commonly used in this setting as well as increased risk mainly associated with comorbidities. The diagnosis, management, and post-hospitalization care of elderly patients presenting with an acute coronary syndrome pose many difficulties at present. A complex interplay of variables such as comorbidities, functional and socioeconomic status, side effects associated with multiple drug administration, and individual biologic variability, all contribute to creating a complex clinical scenario. In this complex setting, clinicians are often required to extrapolate evidence-based results obtained in cardiovascular trials from which older patients are often, implicitly or explicitly, excluded. This article reviews current recommendations regarding management of AMI in the elderly.

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Hypoglycemia in Older People - A Less Well Recognized Risk Factor for Frailty
Abdelhafiz Ahmed H, Rodríguez-Mañas Leocadio, Morley John E., Sinclair Alan J
Aging and disease    2015, 6 (2): 156-167.   DOI: 10.14336/AD.2014.0330
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Recurrent hypoglycemia is common in older people with diabetes and is likely to be less recognized and under reported by patients and health care professionals. Hypoglycemia in this age group is associated with significant morbidities leading to both physical and cognitive dysfunction. Repeated hospital admissions due to frequent hypoglycemia are also associated with further deterioration in patients’ general health. This negative impact of hypoglycemia is likely to eventually lead to frailty, disability and poor outcomes. It appears that the relationship between hypoglycemia and frailty is bidirectional and mediated through a series of influences including under nutrition. Therefore, attention should be paid to the management of under nutrition in the general elderly population by improving energy intake and maintaining muscle mass. Increasing physical activity and having a more conservative approach to glycemic targets in frail older people with diabetes may be worthwhile.

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Increasing Proliferation of Intrinsic Tubular Cells after Renal Ischemia-reperfusion Injury in Adult Rat
Feng Jian, Hu Weiming, Feng Chunyue, Mao XiaoOu, Jin Kunlin, Ye Youxin
Aging and disease    2015, 6 (4): 228-235.   DOI: 10.14336/AD.2014.0917
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The kidney is capable of regeneration following injury. However, whether renal stem/progenitor cells contribute to the repair process after injury, as well as the origin of the cells that repair and replace damaged renal tubule cells remains debated. Therefore, better understanding of the repair process will be critical to developing new strategies for the treatment of acute renal failure. Using an ischemia-reperfusion injury mode and an immunocytochemistry method, we counted the number of BrdU-positive cells in damged regions at different durations of reperfusion. We found that BrdU, a cell proliferative marker, was mainly incorporated in the tubular cells of both medulla and cortex 1 day after reperfusion. The number of BrdU-positive cells reached a peak at 3 days and lasted for two months after injury. BrdU-positive cells were barely found in the renal glomerulus and the parietal layer of Bowman’s capsule after injury, and only a few were found in the intersititium. PAX2, an embryonic renal marker, was also increased in renal tubule cells. Confocal images show that BrdU-positive cells co-expressed PAX2, but not the activated form of caspase-3, a cell death marker. Our data suggest that renal stem-like cells or dedifferentiation of surviving renal tubular cells in both the medulla and cortex may predominantly contribute to the repair process after renal ischemia-reperfusion injury in rat.

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

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The Intricate Interplay between Mechanisms Underlying Aging and Cancer
Piano Amanda, Titorenko Vladimir I.
Aging and disease    2015, 6 (1): 56-75.   DOI: 10.14336/AD.2014.0209
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Age is the major risk factor in the incidence of cancer, a hyperplastic disease associated with aging. Here, we discuss the complex interplay between mechanisms underlying aging and cancer as a reciprocal relationship. This relationship progresses with organismal age, follows the history of cell proliferation and senescence, is driven by common or antagonistic causes underlying aging and cancer in an age-dependent fashion, and is maintained via age-related convergent and divergent mechanisms. We summarize our knowledge of these mechanisms, outline the most important unanswered questions and suggest directions for future research.

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Link between PI3K/AKT/PTEN Pathway and NOX Proteinin Diseases
Atsuko Nakanishi,Yoko Wada,Yasuko Kitagishi,Satoru Matsuda
Aging and Disease    2014, 5 (3): 203-211.   DOI: 10.14336/AD.2014.0500203
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Accumulating evidence has revealed that thePI3K/AKT/PTENpathway acts as a pivotal determinant of cell fate regarding senescence and apoptosis, which is mediated by intracellular reactive oxygen species (ROS) generation. NADPH oxidase (NOX) family of enzymes generates the ROS. The regulation of NOX enzymes is complex, with many members of this family exhibiting complexity in terms of subunit composition, cellular location, and tissue-specific expression. Cells are continuously exposed to the ROS, which represent mutagens and are thought to be a major contributor to several diseases including cancer and aging process. Therefore, cellular ROS sensing and metabolism are firmly regulated by a variety of proteins involved in the redox mechanism. In this review, the roles of oxidative stress in PI3K/AKT/PTEN signaling are summarized with a focus on the links between the pathways and NOX protein in several diseases including cancer and aging.

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Aging Is Not a Disease: Implications for Intervention
Suresh I. S. Rattan
Aging and Disease    2014, 5 (3): 196-202.   DOI: 10.14336/AD.2014.0500196
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Aging of biological systems occurs in spite of numerous complex pathways of maintenance, repair and defense. There are no gerontogenes which have the specific evolutionary function to cause aging. Although aging is the common cause of all age-related diseases, aging in itself cannot be considered a disease. This understanding of aging as a process should transform our approach towards interventions from developing illusory anti-aging treatments to developing realistic and practical methods for maintaining health throughout the lifespan. The concept of homeodynamic space can be a useful one in order to identify a set of measurable, evidence-based and demonstratable parameters of health, robustness and resilience. Age-induced health problems, for which there are no other clear-cut causative agents, may be better tackled by focusing on health mechanisms and their maintenance, rather than only disease management and treatment. Continuing the disease-oriented research and treatment approaches, as opposed to health-oriented and preventive strategies, are economically, socially and psychologically unsustainable.

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Voxel-based Morphometry of Brain MRI in Normal Aging and Alzheimer’s Disease
Hiroshi Matsuda
Aging and Disease    2013, 4 (1): 29-37.  
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Voxel-based morphometry (VBM) using structural brain MRI has been widely used for assessment of normal aging and Alzheimer’s disease (AD). VBM of MRI data comprises segmentation into gray matter, white matter, and cerebrospinal fluid partitions, anatomical standardization of all the images to the same stereotactic space using linear affine transformation and further non-linear warping, smoothing, and finally performing a statistical analysis. Two techniques for VBM are commonly used, optimized VBM using statistical parametric mapping (SPM) 2 or SPM5 with non-linear warping based on discrete cosine transforms and SPM8 plus non-linear warping based on diffeomorphic anatomical registration using exponentiated Lie algebra (DARTEL). In normal aging, most cortical regions prominently in frontal and insular areas have been reported to show age-related gray matter atrophy. In contrast, specific structures such as amygdala, hippocampus, and thalamus have been reported to be preserved in normal aging. On the other hand, VBM studies have demonstrated progression of atrophy mapping upstream to Braak’s stages of neurofibrillary tangle deposition in AD. The earliest atrophy takes place in medial temporal structures. Stand-alone VBM software using SPM8 plus DARTEL running on Windows has been newly developed as an adjunct to the clinical assessment of AD. This software provides a Z-score map as a consequence of comparison of a patient’s MRI with a normal database.

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Does Upper Extremity Training Influence Body Composition after Spinal Cord Injury?
A. Fisher Justin, A. McNelis Meredith, S. Gorgey Ashraf, R. Dolbow David, L. Goetz Lance
Aging and disease    2015, 6 (4): 271-281.   DOI: 10.14336/AD.2014.0912
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Spinal cord injury (SCI) leads to serious body composition adaptations characterized by increasing whole body fat mass and decreased soft tissue lean mass (LM). These adaptations in body composition may lead to several cardio-metabolic disorders that reduce the quality of life, increase patients’ and caregivers’ burden and eventually leads to mortality. Exercise, an appropriate dietary regimen, and an active lifestyle may alleviate several of the negative effects on body composition after a SCI. Today however, there is no established consensus on the recommended dose, frequency or type of exercise to ameliorate several of the body composition sequelae after an acute SCI. Resistance training has been previously recommended as an effective strategy to restore soft tissue LM and decrease fat mass (FM). The strategy can be simply implemented as a routine home-based training program using free weights or resistance bands after a SCI. Additionally, upper extremity (UE) circuit resistance training has been previously used to improve cardiovascular and metabolic parameters after a SCI; however compared to the vast knowledge regarding the able-bodied (AB) population, the effects of UE circuit resistance training on body composition after a SCI is not well established. In summary, the available evidence does not support the rationale that UE circuit resistance training can lead to positive adaptations in body composition after a SCI. Further studies are suggested to examine the effects of UE circuit resistance training on body composition.

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The p38 MAP Kinase Family as Regulators of Proinflammatory Cytokine Production in Degenerative Diseases of the CNS
Adam D. Bachstetter,Linda J. Van Eldik
Aging and Disease    2010, 1 (3): 199-211.  
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Inflammation in the central nervous system (CNS) is a common feature of age-related neurodegenerative diseases. Proinflammatory cytokines, such as IL-1β and TNFα, are produced primarily by cells of the innate immune system, namely microglia in the CNS, and are believed to contribute to the neuronal damage seen in the disease. The p38 mitogen-activated protein kinase (MAPK) is one of the kinase pathways that regulate the production of IL-1β and TNFα. Importantly, small molecule inhibitors of the p38 MAPK family have been developed and show efficacy in blocking the production of IL-1β and TNFα. The p38 family consists of at least four isoforms (p38α, β, γ, δ) encoded by separate genes. Recent studies have begun to demonstrate unique functions of the different isoforms, with p38α being implicated as the key isoform involved in CNS inflammation. Interestingly, there is also emerging evidence that two downstream substrates of p38 may have opposing roles, with MK2 being pro-inflammatory and MSK1/2 being antiinflammatory. This review discusses the properties, function and regulation of the p38 MAPK family as it relates to cytokine production in the CNS.

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Regulation and Role of TGFβ Signaling Pathway in Aging and Osteoarthritis Joints
Baugé Catherine,Girard Nicolas,Lhuissier Eva,Bazille Celine,Boumediene Karim
Aging and Disease    2014, 5 (6): 394-405.   DOI: 10.14336/AD.2014.0500394
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Transforming growth factor beta (TGFβ) is a major signalling pathway in joints. This superfamilly is involved in numerous cellular processes in cartilage. Usually, they are considered to favor chondrocyte differentiation and cartilage repair. However, other studies show also deleterious effects of TGFβ which may induce hypertrophy. This may be explained at least in part by alteration of TGFβ signaling pathways in aging chondrocytes. This review focuses on the functions of TGFβ in joints and the regulation of its signaling mediators (receptors, Smads) during aging and osteoarthritis.

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