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Transplantation of ACE2- Mesenchymal Stem Cells Improves the Outcome of Patients with COVID-19 Pneumonia
Zikuan Leng, Rongjia Zhu, Wei Hou, Yingmei Feng, Yanlei Yang, Qin Han, Guangliang Shan, Fanyan Meng, Dongshu Du, Shihua Wang, Junfen Fan, Wenjing Wang, Luchan Deng, Hongbo Shi, Hongjun Li, Zhongjie Hu, Fengchun Zhang, Jinming Gao, Hongjian Liu, Xiaoxia Li, Yangyang Zhao, Kan Yin, Xijing He, Zhengchao Gao, Yibin Wang, Bo Yang, Ronghua Jin, Ilia Stambler, Lee Wei Lim, Huanxing Su, Alexey Moskalev, Antonio Cano, Sasanka Chakrabarti, Kyung-Jin Min, Georgina Ellison-Hughes, Calogero Caruso, Kunlin Jin, Robert Chunhua Zhao
Aging and disease    2020, 11 (2): 216-228.   DOI: 10.14336/AD.2020.0228
Accepted: 29 February 2020

Abstract40433)   HTML9)    PDF(pc) (1473KB)(16605)       Save

A coronavirus (HCoV-19) has caused the novel coronavirus disease (COVID-19) outbreak in Wuhan, China. Preventing and reversing the cytokine storm may be the key to save the patients with severe COVID-19 pneumonia. Mesenchymal stem cells (MSCs) have been shown to possess a comprehensive powerful immunomodulatory function. This study aims to investigate whether MSC transplantation improves the outcome of 7 enrolled patients with COVID-19 pneumonia in Beijing YouAn Hospital, China, from Jan 23, 2020 to Feb 16, 2020. The clinical outcomes, as well as changes of inflammatory and immune function levels and adverse effects of 7 enrolled patients were assessed for 14 days after MSC injection. MSCs could cure or significantly improve the functional outcomes of seven patients without observed adverse effects. The pulmonary function and symptoms of these seven patients were significantly improved in 2 days after MSC transplantation. Among them, two common and one severe patient were recovered and discharged in 10 days after treatment. After treatment, the peripheral lymphocytes were increased, the C-reactive protein decreased, and the overactivated cytokine-secreting immune cells CXCR3+CD4+ T cells, CXCR3+CD8+ T cells, and CXCR3+ NK cells disappeared in 3-6 days. In addition, a group of CD14+CD11c+CD11bmid regulatory DC cell population dramatically increased. Meanwhile, the level of TNF-α was significantly decreased, while IL-10 increased in MSC treatment group compared to the placebo control group. Furthermore, the gene expression profile showed MSCs were ACE2- and TMPRSS2- which indicated MSCs are free from COVID-19 infection. Thus, the intravenous transplantation of MSCs was safe and effective for treatment in patients with COVID-19 pneumonia, especially for the patients in critically severe condition.

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Mesenchymal Stem Cell Infusion Shows Promise for Combating Coronavirus (COVID-19)- Induced Pneumonia
Ashok K Shetty
Aging and disease    2020, 11 (2): 462-464.   DOI: 10.14336/AD.2020.0301
Accepted: 01 March 2020

Abstract3654)   HTML1)    PDF(pc) (212KB)(3188)       Save

A new study published by the journal Aging & Disease reported that intravenous administration of clinical-grade human mesenchymal stem cells (MSCs) into patients with coronavirus disease 2019 (COVID-19) resulted in improved functional outcomes (Leng et al., Aging Dis, 11:216-228, 2020). This study demonstrated that intravenous infusion of MSCs is a safe and effective approach for treating patients with COVID-19 pneumonia, including elderly patients displaying severe pneumonia. COVID-19 is a severe acute respiratory illness caused by a new coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Currently, treating COVID-19 patients, particularly those afflicted with severe pneumonia, is challenging as no specific drugs or vaccines against SARS-CoV-2 are available. Therefore, MSC therapy inhibiting the overactivation of the immune system and promoting endogenous repair by improving the lung microenvironment after the SARS-CoV-2 infection found in this study is striking. Additional studies in a larger cohort of patients are needed to validate this therapeutic intervention further, however.

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Alzheimer’s Disease: Fatty Acids We Eat may be Linked to a Specific Protection via Low-dose Aspirin
Massimo F. L. Pomponi,Giovanni Gambassi,Massimiliano Pomponi,Carlo Masullo
Aging and Disease    2010, 1 (1): 37-59.  
Abstract1420)   HTML13)    PDF(pc) (1008KB)(3144)       Save

It has been suggested that cognitive decline in aging is the consequence of a growing vulnerability to an asymptomatic state of neuroinflammation. Moreover, it is becoming more evident that inflammation occurs in the brain of Alzheimer’s disease (AD) patients and that the classical mediators of inflammation, eicosanoids and cytokines, may contribute to the neurodegeneration. In agreement with this observation, aspirin (ASA) - a non-steroidal anti-inflammatory drug - may protect against AD and/or vascular dementia. However, both the time of prescription and the dose of ASA may be critical. A major indication for low-dose ASA is in combination with docosahexaenoic acid (DHA). DHA plays an essential role in neural function and its anti-inflammatory properties are associated with the well-known ability of this fatty acid to inhibit the production of various pro-inflammatory mediators, including eicosanoids and cytokines. Higher DHA intake is inversely correlated with relative risk of AD and DHA+ASA supplement may further decrease cognitive decline in healthy elderly adults. Although low-dose ASA may be insufficient for any anti-inflammatory action the concomitant presence of DHA favours a neuroprotective role for ASA. This depends on the allosteric effects of ASA on cyclooxygenase-2 and following production - from DHA - of specific lipid mediators (resolvins, protectins, and electrophilic oxo-derivatives). ASA and DHA might protect against AD, although controlled trials are warranted.

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mHealth For Aging China: Opportunities and Challenges
Sun Jing, Guo Yutao, Wang Xiaoning, Zeng Qiang
Aging and disease    2016, 7 (1): 53-67.   DOI: 10.14336/AD.2015.1011
Abstract1284)   HTML17)    PDF(pc) (874KB)(2667)       Save

The aging population with chronic and age-related diseases has become a global issue and exerted heavy burdens on the healthcare system and society. Neurological diseases are the leading chronic diseases in the geriatric population, and stroke is the leading cause of death in China. However, the uneven distribution of caregivers and critical healthcare workforce shortages are major obstacles to improving disease outcome. With the advancement of wearable health devices, cloud computing, mobile technologies and Internet of Things, mobile health (mHealth) is rapidly developing and shows a promising future in the management of chronic diseases. Its advantages include its ability to improve the quality of care, reduce the costs of care, and improve treatment outcomes by transferring in-hospital treatment to patient-centered medical treatment at home. mHealth could also enhance the international cooperation of medical providers in different time zones and the sharing of high-quality medical service resources between developed and developing countries. In this review, we focus on trends in mHealth and its clinical applications for the prevention and treatment of diseases, especially aging-related neurological diseases, and on the opportunities and challenges of mHealth in China. Operating models of mHealth in disease management are proposed; these models may benefit those who work within the mHealth system in developing countries and developed countries.

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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
Abstract3531)   HTML14)    PDF(pc) (571KB)(2665)       Save

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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Evaluation of Cardiac Autonomic Functions in Older Parkinson’s Disease Patients: a Cross-Sectional Study
Yalcin Ahmet, Atmis Volkan, Karaarslan Cengiz Ozlem, Cinar Esat, Aras Sevgi, Varli Murat, Atli Teslime
Aging and disease    2016, 7 (1): 28-35.   DOI: 10.14336/AD.2015.0819
Abstract850)   HTML18)          Save

In Parkinson’s disease (PD), non-motor symptoms may occur such as autonomic dysfunction. We aimed to evaluate both parasympathetic and sympathetic cardiovascular autonomic dysfunction in older PD cases. 84 PD cases and 58 controls, for a total of 142, participated in the study. Parasympathetic tests were performed using electrocardiography. Sympathetic tests were assessed by blood pressure measurement and 24-hour ambulatory blood pressure measurement. The prevalence of orthostatic hypotension in PD patients was 40.5% in PD patients and 24.1% in the control group (p> 0.05). The prevalence of postprandial hypotension was 47.9% in the PD group and 27.5% in the controls (p <0.05). The prevalence of impairment in heart rate response to deep breathing was 26.2% in the PD group and 6.9% in the control group (p <0.05). The prevalence of postprandial hypotension in PD with orthostatic hypotension was 94% and 16% in PD patients without orthostatic hypotension (p <0.05). The prevalence of impairment in heart rate response to deep breathing was 52.9% in PD patients with orthostatic hypotension and 8% in PD cases without orthostatic hypotension (p<0.05). The prevalence of impairment in heart rate response to postural change was 41% in PD cases with orthostatic hypotension and 12% in PD cases without orthostatic hypotension (p <0.05).Although there are tests for assessing cardiovascular autonomic function that are more reliable, they are more complicated, and evaluation of orthostatic hypotension by blood pressure measurement and cardiac autonomic tests by electrocardiography are recommended since these tests are cheap and easy.

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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
Abstract3688)   HTML30)    PDF(pc) (457KB)(2579)       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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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
Abstract3569)   HTML21)    PDF(pc) (874KB)(2564)       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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Emerging Anti-Aging Strategies - Scientific Basis and Efficacy
Ashok K. Shetty, Maheedhar Kodali, Raghavendra Upadhya, Leelavathi N. Madhu
Aging and disease    2018, 9 (6): 1165-1184.   DOI: 10.14336/AD.2018.1026
Accepted: 21 November 2018

Abstract1662)   HTML1)    PDF(pc) (481KB)(2510)       Save

The prevalence of age-related diseases is in an upward trend due to increased life expectancy in humans. Age-related conditions are among the leading causes of morbidity and death worldwide currently. Therefore, there is an urgent need to find apt interventions that slow down aging and reduce or postpone the incidence of debilitating age-related diseases. This review discusses the efficacy of emerging anti-aging approaches for maintaining better health in old age. There are many anti-aging strategies in development, which include procedures such as augmentation of autophagy, elimination of senescent cells, transfusion of plasma from young blood, intermittent fasting, enhancement of adult neurogenesis, physical exercise, antioxidant intake, and stem cell therapy. Multiple pre-clinical studies suggest that administration of autophagy enhancers, senolytic drugs, plasma from young blood, drugs that enhance neurogenesis and BDNF are promising approaches to sustain normal health during aging and also to postpone age-related neurodegenerative diseases such as Alzheimer’s disease. Stem cell therapy has also shown promise for improving regeneration and function of the aged or Alzheimer’s disease brain. Several of these approaches are awaiting critical appraisal in clinical trials to determine their long-term efficacy and possible adverse effects. On the other hand, procedures such as intermittent fasting, physical exercise, intake of antioxidants such as resveratrol and curcumin have shown considerable promise for improving function in aging, some of which are ready for large-scale clinical trials, as they are non-invasive, and seem to have minimal side effects. In summary, several approaches are at the forefront of becoming mainstream therapies for combating aging and postponing age-related diseases in the coming years.

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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
Abstract3626)   HTML41)    PDF(pc) (734KB)(2417)       Save

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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Effect of a Leucine-rich Repeat Kinase 2 Variant on Motor and Non-motor Symptoms in Chinese Parkinson’s Disease Patients
Sun Qian, Wang Tian, Jiang Tian-Fang, Huang Pei, Li Dun-Hui, Wang Ying, Xiao Qin, Liu Jun, Chen Sheng-Di
Aging and disease    2016, 7 (3): 230-236.   DOI: 10.14336/AD.2015.1026
Abstract667)   HTML11)    PDF(pc) (845KB)(2339)       Save

The G2385R variant of the leucine-rich repeat kinase 2 (LRRK2) is strongly associated with Parkinson’s disease (PD) in Asian populations. However, it is still unclear whether the clinical phenotype of PD patients with the G2385R variant can be distinguished from that of patients with idiopathic PD. In this study, we investigated motor and non-motor symptoms of LRRK2 G2385R variant carriers in a Chinese population. We genotyped 1031 Chinese PD patients for the G2385R variant of the LRRK2 gene, and examined the demographic and clinical characteristics of LRRK2 G2385R variant carrier and non-carrier PD patients. LRRK2 G2385R variant carriers were more likely to present the postural instability and gait difficulty dominant (PIGD) phenotype. This variant was also significantly associated with motor fluctuations and the levodopa equivalent dose (LED). G2385R variant carriers had higher REM sleep behavior disorder (RBD) screening questionnaire (RBDSQ) score and more RBD symptoms compared with non-carriers. We concluded that the G2385R variant could be a risk factor for the PIGD phenotype, motor fluctuations, LED values and RBD symptoms.

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MiRNA-10b Reciprocally Stimulates Osteogenesis and Inhibits Adipogenesis Partly through the TGF-β/SMAD2 Signaling Pathway
Hongling Li, Junfen Fan, Linyuan Fan, Tangping Li, Yanlei Yang, Haoying Xu, Luchan Deng, Jing Li, Tao Li, Xisheng Weng, Shihua Wang, Robert Chunhua Zhao
Aging and disease    2018, 9 (6): 1058-1073.   DOI: 10.14336/AD.2018.0214
Abstract691)   HTML5)    PDF(pc) (1848KB)(2272)       Save

As the population ages, the medical and socioeconomic impact of age-related bone disorders will further increase. An imbalance between osteogenesis and adipogenesis of mesenchymal stem cells (MSCs) can lead to various bone and metabolic diseases such as osteoporosis. Thus, understanding the molecular mechanisms underlying MSC osteogenic and adipogenic differentiation is important for the discovery of novel therapeutic paradigms for these diseases. miR-10b has been widely reported in tumorigenesis, cancer invasion and metastasis. However, the effects and potential mechanisms of miR-10b in the regulation of MSC adipogenic and osteogenic differentiation have not been explored. In this study, we found that the expression of miR-10b was positively correlated with bone formation marker genes ALP, RUNX2 and OPN, and negatively correlated with adipogenic markers CEBPα, PPARγ and AP2 in clinical osteoporosis samples. Overexpression of miR-10b enhanced osteogenic differentiation and inhibited adipogenic differentiation of human adipose-derived mesenchymal stem cells (hADSCs) in vitro, whereas downregulation of miR-10b reversed these effects. Furthermore, miR-10b promoted ectopic bone formation in vivo. Target prediction and dual luciferase reporter assays identified SMAD2 as a potential target of miR-10b. Silencing endogenous SMAD2 expression in hADSCs enhanced osteogenesis but repressed adipogenesis. Pathway analysis indicated that miR-10b promotes osteogenic differentiation and bone formation via the TGF-β signaling pathway, while suppressing adipogenic differentiation may be primarily mediated by other pathways. Taken together, our findings imply that miR-10b acts as a critical regulator for balancing osteogenic and adipogenic differentiation of hADSCs by repressing SMAD2 and partly through the TGF-β pathway. Our study suggests that miR-10b is a novel target for controlling bone and metabolic diseases.

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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.  
Abstract5814)   HTML8)    PDF(pc) (1175KB)(2269)       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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Healthcare-associated Pneumonia and Aspiration Pneumonia
Komiya Kosaku, Ishii Hiroshi, Kadota Jun-ichi
Aging and disease    2015, 6 (1): 27-37.   DOI: 10.14336/AD.2014.0127
Abstract1622)   HTML26)    PDF(pc) (689KB)(2250)       Save

Healthcare-associated pneumonia (HCAP) is a new concept of pneumonia proposed by the American Thoracic Society/Infectious Diseases Society of America in 2005. This category is located between community-acquired pneumonia and hospital-acquired pneumonia with respect to the characteristics of the causative pathogens and mortality, and primarily targets elderly patients in healthcare facilities. Aspiration among such patients is recognized to be a primary mechanism for the development of pneumonia, particularly since the HCAP guidelines were published. However, it is difficult to manage patients with aspiration pneumonia because the definition of the condition is unclear, and the treatment is associated with ethical aspects. This review focused on the definition, prevalence and role of aspiration pneumonia as a prognostic factor in published studies of HCAP and attempted to identify problems associated with the concept of aspiration pneumonia.

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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
Abstract2818)   HTML18)    PDF(pc) (1213KB)(2234)       Save

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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Aging, Metabolism, and Cancer Development: from Peto’s Paradox to the Warburg Effect
Tidwell Tia R., Søreide Kjetil, Hagland Hanne R.
Aging and disease    2017, 8 (5): 662-676.   DOI: 10.14336/AD.2017.0713
Abstract881)   HTML5)    PDF(pc) (1084KB)(2228)       Save

Medical advances made over the last century have increased our lifespan, but age-related diseases are a fundamental health burden worldwide. Aging is therefore a major risk factor for cardiovascular disease, cancer, diabetes, obesity, and neurodegenerative diseases, all increasing in prevalence. However, huge inter-individual variations in aging and disease risk exist, which cannot be explained by chronological age, but rather physiological age decline initiated even at young age due to lifestyle. At the heart of this lies the metabolic system and how this is regulated in each individual. Metabolic turnover of food to energy leads to accumulation of co-factors, byproducts, and certain proteins, which all influence gene expression through epigenetic regulation. How these epigenetic markers accumulate over time is now being investigated as the possible link between aging and many diseases, such as cancer. The relationship between metabolism and cancer was described as early as the late 1950s by Dr. Otto Warburg, before the identification of DNA and much earlier than our knowledge of epigenetics. However, when the stepwise gene mutation theory of cancer was presented, Warburg’s theories garnered little attention. Only in the last decade, with epigenetic discoveries, have Warburg’s data on the metabolic shift in cancers been brought back to life. The stepwise gene mutation theory fails to explain why large animals with more cells, do not have a greater cancer incidence than humans, known as Peto’s paradox. The resurgence of research into the Warburg effect has given us insight to what may explain Peto’s paradox. In this review, we discuss these connections and how age-related changes in metabolism are tightly linked to cancer development, which is further affected by lifestyle choices modulating the risk of aging and cancer through epigenetic control.

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Aging and Cardiac Fibrosis
Anna Biernacka,Nikolaos G Frangogiannis
Aging and Disease    2011, 2 (2): 158-173.  
Abstract3788)   HTML15)    PDF(pc) (830KB)(2165)       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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Imaging and Quantitative Analysis of the Interstitial Space in the Caudate Nucleus in a Rotenone-Induced Rat Model of Parkinson’s Disease Using Tracer-based MRI
Lv Deyong, Li Jingbo, Li Hongfu, Fu Yu, Wang Wei
Aging and disease    2017, 8 (1): 1-6.   DOI: 10.14336/AD.2016.0625
Abstract761)   HTML19)    PDF(pc) (1155KB)(2148)       Save

Parkinson’s disease (PD) is characterized by pathological changes within several deep structures of the brain, including the substantia nigra and caudate nucleus. However, changes in interstitial fluid (ISF) flow and the microstructure of the interstitial space (ISS) in the caudate nucleus in PD have not been reported. In this study, we used tracer-based magnetic resonance imaging (MRI) to quantitatively investigate the alterations in ISS and visualize ISF flow in the caudate nucleus in a rotenone-induced rat model of PD treated with and without madopar. In the rotenone-induced rat model, the ISF flow was slowed and the tortuosity of the ISS was significantly decreased. Administration of madopar partially prevented these changes of ISS and ISF. Therefore, our data suggest that tracer-based MRI can be used to monitor the parameters related to ISF flow and ISS microstructure. It is a promising technique to investigate the microstructure and functional changes in the deep brain regions of PD.

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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
Abstract2152)   HTML21)    PDF(pc) (901KB)(2110)       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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Biocomplexity and Fractality in the Search of Biomarkers of Aging and Pathology: Focus on Mitochondrial DNA and Alzheimer’s Disease
Zaia Annamaria, Maponi Pierluigi, Di Stefano Giuseppina, Casoli Tiziana
Aging and disease    2017, 8 (1): 44-56.   DOI: 10.14336/AD.2016.0629
Abstract816)   HTML7)    PDF(pc) (1185KB)(2092)       Save

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

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Neuroprotective Effect of Caffeic Acid Phenethyl Ester in A Mouse Model of Alzheimer’s Disease Involves Nrf2/HO-1 Pathway
Morroni Fabiana, Sita Giulia, Graziosi Agnese, Turrini Eleonora, Fimognari Carmela, Tarozzi Andrea, Hrelia Patrizia
Aging and disease    2018, 9 (4): 605-622.   DOI: 10.14336/AD.2017.0903
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Alzheimer’s disease (AD) is a progressive pathology, where dementia symptoms gradually worsen over a number of years. The hallmarks of AD, such as amyloid β-peptide (Aβ) in senile plaque and neurofibrillary tangles, are strongly intertwined with oxidative stress, which is considered one of the common effectors of the cascade of degenerative events. The endogenous nuclear factor erythroid 2-related factor 2 (Nrf2) is the "master regulator" of the antioxidant response and it is known as an indicator and regulator of oxidative stress. The present study aimed to determine the potential neuroprotective activity of caffeic acid phenethyl ester (CAPE), a polyphenolic compound abundant in honeybee, against the neurotoxicity of Aβ1-42 oligomers (AβO) in mice. An intracerebroventricular (i.c.v.) injection of AβO into the mouse brain triggered increased reactive oxygen species levels, neurodegeneration, neuroinflammation, and memory impairment. In contrast, the intraperitoneal administration of CAPE (10 mg/kg) after i.c.v. AβO-injection counteracted oxidative stress accompanied by an induction of Nrf2 and heme oxygenase-1 via the modulation of glycogen synthase kinase 3β in the hippocampus of mice. Additionally, CAPE treatment decreased AβO-induced neuronal apoptosis and neuroinflammation, and improved learning and memory, protecting mice against the decline in spatial cognition. Our findings demonstrate that CAPE could potentially be considered as a promising neuroprotective agent against progressive neurodegenerative diseases such as AD.

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Potential Therapeutical Contributions of the Endocannabinoid System towards Aging and Alzheimer’s Disease
Amandine E. Bonnet, Yannick Marchalant
Aging and disease    2015, 6 (5): 400-405.   DOI: 10.14336/AD.2015.0617
Abstract927)   HTML8)    PDF(pc) (636KB)(2028)       Save

Aging can lead to decline in cognition, notably due to neurodegenerative processes overwhelming the brain over time. As people live longer, numerous concerns are rightfully raised toward long-term slowly incapacitating diseases with no cure, such as Alzheimer’s disease. Since the early 2000’s, the role of neuroinflammation has been scrutinized for its potential role in the development of diverse neurodegenerative diseases notably because of its slow onset and chronic nature in aging. Despite the lack of success yet, treatment of chronic neuroinflammation could help alleviate process implicated in neurodegenerative disease. A growing number of studies including our own have aimed at the endocannabinoid system and unfolded unique effects of this system on neuroinflammation, neurogenesis and hallmarks of Alzheimer’s disease and made it a reasonable target in the context of normal and pathological brain aging.

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Higher Plasma LDL-Cholesterol is Associated with Preserved Executive and Fine Motor Functions in Parkinson’s Disease
Sterling Nicholas W., Lichtenstein Maya, Lee Eun-Young, Lewis Mechelle M., Evans Alicia, Eslinger Paul J., Du Guangwei, Gao Xiang, Chen Honglei, Kong Lan, Huang Xuemei
Aging and disease    2016, 7 (3): 237-245.   DOI: 10.14336/AD.2015.1030
Abstract714)   HTML6)    PDF(pc) (817KB)(2015)       Save

Plasma low density lipoprotein (LDL) cholesterol has been associated both with risk of Parkinson’s disease (PD) and with age-related changes in cognitive function. This prospective study examined the relationship between baseline plasma LDL-cholesterol and cognitive changes in PD and matched Controls. Fasting plasma LDL-cholesterol levels were obtained at baseline from 64 non-demented PD subjects (62.7 ± 7.9 y) and 64 Controls (61.3 ± 6.8 y). Subjects underwent comprehensive neuropsychological testing at baseline, 18-, and 36-months. Linear mixed-effects modeling was used to assess the relationships between baseline LDL-cholesterol levels and longitudinal cognitive changes. At baseline, PD patients had lower scores of fine motor (p<0.0001), executive set shifting (p=0.018), and mental processing speed (p=0.049) compared to Controls. Longitudinally, Controls demonstrated improved fine motor and memory test scores (p=0.044, and p=0.003), whereas PD patients demonstrated significantly accelerated loss in fine motor skill (p=0.002) compared to Controls. Within the PD group, however, higher LDL-cholesterol levels were associated with improved executive set shifting (β=0.003, p<0.001) and fine motor scores (β=0.002, p=0.030) over time. These associations were absent in Controls (p>0.7). The cholesterol - executive set shifting association differed significantly between PDs and Controls (interaction p=0.005), whereas the cholesterol - fine motor association difference did not reach significance (interaction, p=0.104). In summary, higher plasma LDL-cholesterol levels were associated with better executive function and fine motor performance over time in PD, both of which may reflect an effect on nigrostriatal mediation. Confirmation of these results and elucidation of involved mechanisms are warranted, and might lead to feasible therapeutic strategies.

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Anti-Aging Implications of Astragalus Membranaceus (Huangqi): A Well-Known Chinese Tonic
Liu Ping, Zhao Haiping, Luo Yumin
Aging and disease    2017, 8 (6): 868-886.   DOI: 10.14336/AD.2017.0816
Abstract1834)   HTML3)    PDF(pc) (1198KB)(2002)       Save

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

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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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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
Abstract3448)   HTML11)    PDF(pc) (1415KB)(1969)       Save

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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The Anti-Inflammatory and Anti-Oxidant Mechanisms of the Keap1/Nrf2/ARE Signaling Pathway in Chronic Diseases
Wenjun Tu, Hong Wang, Song Li, Qiang Liu, Hong Sha
Aging and disease    2019, 10 (3): 637-651.   DOI: 10.14336/AD.2018.0513
Abstract1055)   HTML1)    PDF(pc) (478KB)(1964)       Save

Oxidative stress is defined as an imbalance between production of free radicals and reactive metabolites or [reactive oxygen species (ROS)] and their elimination by through protective mechanisms, including (antioxidants). This Such imbalance leads to damage of cells and important biomolecules and cells, with hence posing a potential adverse impact on the whole organism. At the center of the day-to-day biological response to oxidative stress is the Kelch-like ECH-associated protein 1 (Keap1) - nuclear factor erythroid 2-related factor 2 (Nrf2)- antioxidant response elements (ARE) pathway, which regulates the transcription of many several antioxidant genes that preserve cellular homeostasis and detoxification genes that process and eliminate carcinogens and toxins before they can cause damage. The redox-sensitive signaling system Keap1/Nrf2/ARE plays a key role in the maintenance of cellular homeostasis under stress, inflammatory, carcinogenic, and pro-apoptotic conditions, which allows us to consider it as a pharmacological target. Herein, we review and discuss the recent advancements in the regulation of the Keap1/Nrf2/ARE system, and its role under physiological and pathophysiological conditions, e.g. such as in exercise, diabetes, cardiovascular diseases, cancer, neurodegenerative disorders, stroke, liver and kidney system, etc. and such.

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Lens Endogenous Peptide αA66-80 Generates Hydrogen Peroxide and Induces Cell Apoptosis
Raju Murugesan, Santhoshkumar Puttur, Sharma K. Krishna
Aging and disease    2017, 8 (1): 57-70.   DOI: 10.14336/AD.2016.0805
Abstract770)   HTML7)    PDF(pc) (1587KB)(1959)       Save

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

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Hypoxia-Inducible Histone Lysine Demethylases: Impact on the Aging Process and Age-Related Diseases
Antero Salminen, Kai Kaarniranta, Anu Kauppinen
Aging and disease    2016, 7 (2): 180-200.   DOI: 10.14336/AD.2015.0929
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Hypoxia is an environmental stress at high altitude and underground conditions but it is also present in many chronic age-related diseases, where blood flow into tissues is impaired. The oxygen-sensing system stimulates gene expression protecting tissues against hypoxic insults. Hypoxia stabilizes the expression of hypoxia-inducible transcription factor-1α (HIF-1α), which controls the expression of hundreds of survival genes related to e.g. enhanced energy metabolism and autophagy. Moreover, many stress-related signaling mechanisms, such as oxidative stress and energy metabolic disturbances, as well as the signaling cascades via ceramide, mTOR, NF-κB, and TGF-β pathways, can also induce the expression of HIF-1α protein to facilitate cell survival in normoxia. Hypoxia is linked to prominent epigenetic changes in chromatin landscape. Screening studies have indicated that the stabilization of HIF-1α increases the expression of distinct histone lysine demethylases (KDM). HIF-1α stimulates the expression of KDM3A, KDM4B, KDM4C, and KDM6B, which enhance gene transcription by demethylating H3K9 and H3K27 sites (repressive epigenetic marks). In addition, HIF-1α induces the expression of KDM2B and KDM5B, which repress transcription by demethylating H3K4me2,3 sites (activating marks). Hypoxia-inducible KDMs support locally the gene transcription induced by HIF-1α, although they can also control genome-wide chromatin landscape, especially KDMs which demethylate H3K9 and H3K27 sites. These epigenetic marks have important role in the control of heterochromatin segments and 3D folding of chromosomes, as well as the genetic loci regulating cell type commitment, proliferation, and cellular senescence, e.g. the INK4 box. A chronic stimulation of HIF-1α can provoke tissue fibrosis and cellular senescence, which both are increasingly present with aging and age-related diseases. We will review the regulation of HIF-1α-dependent induction of KDMs and clarify their role in pathological processes emphasizing that long-term stress-related insults can impair the maintenance of chromatin landscape and provoke cellular senescence and tissue fibrosis associated with aging and age-related diseases.

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Plasma Epidermal Growth Factor Decreased in the Early Stage of Parkinson’s Disease
Jiang Qian-Wen, Wang Cheng, Zhou Yi, Hou Miao-Miao, Wang Xi, Tang Hui-Dong, Wu Yi-Wen, Ma Jian-Fang, Chen Sheng-Di
Aging and disease    2015, 6 (3): 168-173.   DOI: 10.14336/AD.2014.0925
Abstract1056)   HTML20)    PDF(pc) (340KB)(1933)       Save

Epidermal growth factor (EGF) is a neurotrophic factor that plays an important role in Parkinson’s disease (PD). We measured plasma EGF level in PD, essential tremor (ET) and normal controls toinvestigate whether it changes in PD and whether it is associated with motor and non-motor symptoms of PD. 100 patients with PD, 40 patients with ET as disease control and 76 healthy persons were enrolled in the present study. Motor and non-motor symptoms were assessed by different scales. Plasma EGF levels of three groups were measured by enzyme-linked immunosorbent assay kit. Spearman test and linear logistics regression model were used to test the correlation of EGF with motor and non-motor symptoms of PD. Plasma EGF level was significantly decreased in early PD patients compared with normal control, butnot in advanced PD patients. Interestingly, plasma EGF level was significantly increased in advanced PD and total PD patients compared with ET patients, but not in early PD patients. In addition, plasma EGF level was correlated with UPDRS-III scores in PD. Also plasma EGF level was correlated with UPDRS-III scores and NMS scores in early PD.Our results suggested that plasma EGF decreased in the early stage of PD and increased later on in the PD disease course. Also, plasma EGF level was increased significantly in PD compared with ET patients and correlated with motor and non-motor symptoms in early PD.

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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
Abstract2372)   HTML11)    PDF(pc) (849KB)(1933)       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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On the Relationship between Energy Metabolism, Proteostasis, Aging and Parkinson’s Disease: Possible Causative Role of Methylglyoxal and Alleviative Potential of Carnosine
Hipkiss Alan R.
Aging and disease    2017, 8 (3): 334-345.   DOI: 10.14336/AD.2016.1030
Abstract823)   HTML5)    PDF(pc) (816KB)(1921)       Save

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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Possible Benefit of Dietary Carnosine towards Depressive Disorders
Alan R. Hipkiss*
Aging and disease    2015, 6 (5): 300-303.   DOI: 10.14336/AD.2014.1211
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Many stress-related and depressive disorders have been shown to be associated with one or more of the following; shortened telomeres, raised cortisol levels and increased susceptibility to age-related dysfunction. It is suggested here that insufficient availability of the neurological peptide, carnosine, may provide a biochemical link between stress- and depression-associated phenomena: there is evidence that carnosine can enhance cortisol metabolism, suppress telomere shortening and exert anti-aging activity in model systems. Dietary supplementation with carnosine has been shown to suppress stress in animals, and improve behaviour, cognition and well-being in human subjects. It is therefore proposed that the therapeutic potential of carnosine dietary supplementation towards stress-related and depressive disorders should be examined.

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Early-life Exposure to Endocrine Disrupting Chemicals and Later-life Health Outcomes: An Epigenetic Bridge?
Vaiserman* Alexander
Aging and Disease    2014, 5 (6): 419-429.   DOI: 10.14336/AD.2014.0500419
Abstract1070)   HTML22)          Save

A growing body of evidence demonstrates that adverse events early in development, and particularly during intrauterine life, may program risks for diseases in adult life. Increasing evidence has been accumulated indicating the important role of epigenetic regulation including DNA methylation, histone modifications and miRNAs in developmental programming. Among the environmental factors which play an important role in programming of chronic pathologies, the endocrine-disrupting chemicals (EDCs) that have estrogenic, anti-estrogenic, and anti-androgenic activity are of specific concern because the developing organism is extremely sensitive to perturbation by substances with hormone-like activity. Among EDCs, there are many substances that are constantly present in the modern human environment or are in widespread use, including dioxin and dioxin-like compounds, phthalates, agricultural pesticides, polychlorinated biphenyls, industrial solvents, pharmaceuticals, and heavy metals. Apart from their common endocrine active properties, several EDCs have been shown to disrupt developmental epigenomic programming. The purpose of this review is to provide a summary of recent research findings which indicate that exposure to EDCs during in-utero and/or neonatal development can cause long-term health outcomes via mechanisms of epigenetic memory.

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Impact of Resistance Circuit Training on Neuromuscular, Cardiorespiratory and Body Composition Adaptations in the Elderly
Salvador Romero-Arenas,Miryam Martínez-Pascual,Pedro E. Alcaraz
Aging and Disease    2013, 4 (5): 256-263.   DOI: 10.14336/AD.2013.0400256
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Declines in maximal aerobic power and skeletal muscle force production with advancing age are examples of functional declines with aging, which can severely limit physical performance and independence, and are negatively correlated with all cause mortality. It is well known that both endurance exercise and resistance training can substantially improve physical fitness and health-related factors in older individuals. Circuit-based resistance training, where loads are lifted with minimal rest, may be a very effective strategy for increasing oxygen consumption, pulmonary ventilation, strength, and functional capacity while improving body composition. In addition, circuit training is a time-efficient exercise modality that can elicit demonstrable improvements in health and physical fitness. Hence, it seems reasonable to identify the most effective combination of intensity, volume, work to rest ratio, weekly frequency and exercise sequence to promote neuromuscular, cardiorespiratory and body composition adaptations in the elderly. Thus, the purpose of this review was to summarize and update knowledge about the effects of circuit weight training in older adults and elderly population, as a starting point for developing future interventions that maintain a higher quality of life in people throughout their lifetime.

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Age-Related Disruption of Steady-State Thymic Medulla Provokes Autoimmune Phenotype via Perturbing Negative Selection
Jiangyan Xia,Hongjun Wang,Jianfei Guo,Zhijie Zhang,Brandon Coder,Dong-Ming Su
Aging and Disease    2012, 3 (3): 248-259.  
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The hymic medulla plays an essential role in the generation of central tolerance by eliminating self-reactive T-cell clones through thymic negative selection and developing natural regulatory T cells. Age-related FoxN1 decline induces disruption of medullary thymic epithelial cells (mTECs). However, it is unknown whether this perturbs central tolerance to increase autoimmune predisposition in the elderly. Using a loxP-floxed-FoxN1 (FoxN1flox) mouse model, which exhibits a spontaneous ubiquitous deletion of FoxN1 with age to accelerate thymic aging, we investigated whether disruption of steady-state thymic medulla results in an increase of autoimmune-prone associated with age. We demonstrated age-associated ubiquitous loss of FoxN1flox-formed two-dimensional thymic epithelial cysts were primarily located in the medulla. This resulted in disruption of thymic medullary steady state, with evidence of perturbed negative selection, including reduced expression of the autoimmune regulator (Aire) gene and disrupted accumulation of thymic dendritic cells in the medulla, which are required for negative selection. These provoke autoimmune phenotypes, including increased inflammatory cell infiltration in multiple organs in these mice. This finding in an animal model provides a mechanistic explanation of increased susceptibility to autoimmunity in aged humans, although they may not show clinic manifestations without induction.

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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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Insulin, IGF-1 and longevity
Diana van Heemst
Aging and Disease    2010, 1 (2): 147-157.  
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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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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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Education and Genetic Risk Modulate Hippocampal Structure in Alzheimer’s Disease
Baumgaertel Johanna, Haussmann Robert, Gruschwitz Antonia, Werner Annett, Osterrath Antje, Lange Jan, Donix Katharina L., Linn Jennifer, Donix Markus
Aging and disease    2016, 7 (5): 553-560.   DOI: 10.14336/AD.2016.0305
Abstract896)   HTML9)    PDF(pc) (869KB)(1845)       Save

Genetic and environmental protective factors and risks modulate brain structure and function in neurodegenerative diseases and their preclinical stages. We wanted to investigate whether the years of formal education, a proxy measure for cognitive reserve, would influence hippocampal structure in Alzheimer’s disease patients, and whether apolipoprotein Eε4 (APOE4) carrier status and a first-degree family history of the disease would change a possible association. Fifty-eight Alzheimer’s disease patients underwent 3T magnetic resonance imaging. We applied a cortical unfolding approach to investigate individual subregions of the medial temporal lobe. Among patients homozygous for the APOE4 genotype or carrying both APOE4 and family history risks, lower education was associated with a thinner cortex in multiple medial temporal regions, including the hippocampus. Our data suggest that the years of formal education and genetic risks interact in their influence on hippocampal structure in Alzheimer’s disease patients.

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