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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

Abstract41486)   HTML9)    PDF(pc) (1473KB)(17985)       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

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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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COVID-19 Virulence in Aged Patients Might Be Impacted by the Host Cellular MicroRNAs Abundance/Profile
Sadanand Fulzele, Bikash Sahay, Ibrahim Yusufu, Tae Jin Lee, Ashok Sharma, Ravindra Kolhe, Carlos M Isales
Aging and disease    2020, 11 (3): 509-522.   DOI: 10.14336/AD.2020.0428
Accepted: 29 April 2020

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The World health organization (WHO) declared Coronavirus disease 2019 (COVID-19) a global pandemic and a severe public health crisis. Drastic measures to combat COVID-19 are warranted due to its contagiousness and higher mortality rates, specifically in the aged patient population. At the current stage, due to the lack of effective treatment strategies for COVID-19 innovative approaches need to be considered. It is well known that host cellular miRNAs can directly target both viral 3'UTR and coding region of the viral genome to induce the antiviral effect. In this study, we did in silico analysis of human miRNAs targeting SARS (4 isolates) and COVID-19 (29 recent isolates from different regions) genome and correlated our findings with aging and underlying conditions. We found 848 common miRNAs targeting the SARS genome and 873 common microRNAs targeting the COVID-19 genome. Out of a total of 848 miRNAs from SARS, only 558 commonly present in all COVID-19 isolates. Interestingly, 315 miRNAs are unique for COVID-19 isolates and 290 miRNAs unique to SARS. We also noted that out of 29 COVID-19 isolates, 19 isolates have identical miRNA targets. The COVID-19 isolates, Netherland (EPI_ISL_422601), Australia (EPI_ISL_413214), and Wuhan (EPI_ISL_403931) showed six, four, and four unique miRNAs targets, respectively. Furthermore, GO, and KEGG pathway analysis showed that COVID-19 targeting human miRNAs involved in various age-related signaling and diseases. Recent studies also suggested that some of the human miRNAs targeting COVID-19 decreased with aging and underlying conditions. GO and KEGG identified impaired signaling pathway may be due to low abundance miRNA which might be one of the contributing factors for the increasing severity and mortality in aged individuals and with other underlying conditions. Further, in vitro and in vivo studies are needed to validate some of these targets and identify potential therapeutic targets.

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Novel Insights on Systemic and Brain Aging, Stroke, Amyotrophic Lateral Sclerosis, and Alzheimer’s Disease
Ashok K. Shetty, Raghavendra Upadhya, Leelavathi N. Madhu, Maheedhar Kodali
Aging and disease    2019, 10 (2): 470-482.   DOI: 10.14336/AD.2019.0330
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The mechanisms that underlie the pathophysiology of aging, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD) and stroke are not fully understood and have been the focus of intense and constant investigation worldwide. Studies that provide insights on aging and age-related disease mechanisms are critical for advancing novel therapies that promote successful aging and prevent or cure multiple age-related diseases. The April 2019 issue of the journal, "Aging & Disease" published a series of articles that confer fresh insights on numerous age-related conditions and diseases. The age-related topics include the detrimental effect of overweight on energy metabolism and muscle integrity, senoinflammation as the cause of neuroinflammation, the link between systemic C-reactive protein and brain white matter loss, the role of miR-34a in promoting healthy heart and brain, the potential of sirtuin 3 for reducing cardiac and pulmonary fibrosis, and the promise of statin therapy for ameliorating asymptomatic intracranial atherosclerotic stenosis. Additional aging-related articles highlighted the involvement of miR-181b-5p and high mobility group box-1 in hypertension, Yes-associated protein in cataract formation, multiple miRs and long noncoding RNAs in coronary artery disease development, the role of higher meat consumption on sleep problems, and the link between glycated hemoglobin and depression. The topics related to ALS suggested that individuals with higher education and living in a rural environment have a higher risk for developing ALS, and collagen XIX alpha 1 is a prognostic biomarker of ALS. The topics discussed on AD implied that extracellular amyloid β42 is likely the cause of intraneuronal neurofibrillary tangle accumulation in familial AD and traditional oriental concoctions may be useful for slowing down the progression of AD. The article on stroke suggested that inhibition of the complement system is likely helpful in promoting brain repair after ischemic stroke. The significance of the above findings for understanding the pathogenesis in aging, ALS, AD, and stroke, slowing down the progression of aging, ALS and AD, and promoting brain repair after stroke are discussed.

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The Potential Markers of Circulating microRNAs and long non-coding RNAs in Alzheimer's Disease
Yanfang Zhao, Yuan Zhang, Lei Zhang, Yanhan Dong, Hongfang Ji, Liang Shen
Aging and disease    2019, 10 (6): 1293-1301.   DOI: 10.14336/AD.2018.1105
Accepted: 13 November 2018

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Alzheimer’s disease (AD) is a neurodegenerative disorder and one of the leading causes of disability and mortality in the late life with no curative treatment currently. Thus, it is urgently to establish sensitive and non-invasive biomarkers for AD diagnosis, particularly in the early stage. Recently, emerging number of microRNAs (miRNAs) and long-noncoding RNAs (lncRNAs) are considered as effective biomarkers in various diseases as they possess characteristics of stable, resistant to RNAase digestion and many extreme conditions in circulatory fluid. This review highlights recent advances in the identification of the aberrantly expressed miRNAs and lncRNAs in circulatory network for detection of AD. We summarized the abnormal expressed miRNAs in blood and cerebrospinal fluid (CSF), and detailed discussed the functions and molecular mechanism of serum or plasma miRNAs-miR-195, miR-155, miR-34a, miR-9, miR-206, miR-125b and miR-29 in the regulation of AD progression. In addition, we also elaborated the role of circulating lncRNA major including beta-site APP cleaving enzyme 1 (BACE1) and its antisense lncRNA BACE1-AS in AD pathological advancement. In brief, confirming the aberrantly expressed circulating miRNAs and lncRNAs will provide an effective testing tools for treatment of AD in the future.

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Pyroptosis in Liver Disease: New Insights into Disease Mechanisms
Jiali Wu, Su Lin, Bo Wan, Bharat Velani, Yueyong Zhu
Aging and disease    2019, 10 (5): 1094-1108.   DOI: 10.14336/AD.2019.0116
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There has been increasing interest in pyroptosis as a novel form of pro-inflammatory programmed cell death. The mechanism of pyroptosis is significantly different from other forms of cell death in its morphological and biochemical features. Pyroptosis is characterized by the activation of two different types of caspase enzymes—caspase-1 and caspase-4/5/11, and by the occurrence of a proinflammatory cytokine cascade and an immune response. Pyroptosis participates in the immune defense mechanisms against intracellular bacterial infections. On the other hand, excessive inflammasome activation can induce sterile inflammation and eventually cause some diseases, such as acute or chronic hepatitis and liver fibrosis. The mechanism and biological significance of this novel form of cell death in different liver diseases will be evaluated in this review. Specifically, we will focus on the role of pyroptosis in alcoholic and non-alcoholic fatty liver disease, as well as in liver failure. Finally, the therapeutic implications of pyroptosis in liver diseases will be discussed.

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Parkinson Disease and Orthostatic Hypotension in the Elderly: Recognition and Management of Risk Factors for Falls
Peter A LeWitt, Steve Kymes, Robert A Hauser
Aging and disease    2020, 11 (3): 679-691.   DOI: 10.14336/AD.2019.0805
Accepted: 03 October 2019

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Parkinson disease (PD) is often associated with postural instability and gait dysfunction that can increase the risk for falls and associated consequences, including injuries, increased burden on healthcare resources, and reduced quality of life. Patients with PD have nearly twice the risk for falls and associated bone fractures compared with their general population counterparts of similar age. Although the cause of falls in patients with PD may be multifactorial, an often under-recognized factor is neurogenic orthostatic hypotension (nOH). nOH is a sustained decrease in blood pressure upon standing whose symptomology can include dizziness/lightheadedness, weakness, fatigue, and syncope. nOH is due to dysfunction of the autonomic nervous system compensatory response to standing and is a consequence of the neurodegenerative processes of PD. The symptoms associated with orthostatic hypotension (OH)/nOH can increase the risk of falls, and healthcare professionals may not be aware of the real-world clinical effect of nOH, the need for routine screening, or the value of early diagnosis of nOH when treating elderly patients with PD. nOH is easily missed and, importantly, healthcare providers may not realize that there are effective treatments for nOH symptoms that could help lessen the fall risk resulting from the condition. This review discusses the burden of, and key risk factors for, falls among patients with PD, with a focus on practical approaches for the recognition, assessment, and successful management of OH/nOH. In addition, insights are provided as to how fall patterns can suggest fall etiology, thereby influencing the choice of intervention.

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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

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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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Comorbid Chronic Diseases are Strongly Correlated with Disease Severity among COVID-19 Patients: A Systematic Review and Meta-Analysis
Hong Liu, Shiyan Chen, Min Liu, Hao Nie, Hongyun Lu
Aging and disease    2020, 11 (3): 668-678.   DOI: 10.14336/AD.2020.0502
Accepted: 07 May 2020

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Coronavirus disease 2019 (COVID-19) has resulted in considerable morbidity and mortality worldwide since December 2019. In order to explore the effects of comorbid chronic diseases on clinical outcomes of COVID-19, a search was conducted in PubMed, Ovid MEDLINE, EMBASE, CDC, and NIH databases to April 25, 2020. A total of 24 peer-reviewed articles, including 10948 COVID-19 cases were selected. We found diabetes was present in 10.0%, coronary artery disease/cardiovascular disease (CAD/CVD) was in 8.0%, and hypertension was in 20.0%, which were much higher than that of chronic pulmonary disease (3.0%). Specifically, preexisting chronic conditions are strongly correlated with disease severity [Odds ratio (OR) 3.50, 95% CI 1.78 to 6.90], and being admitted to intensive care unit (ICU) (OR 3.36, 95% CI 1.67 to 6.76); in addition, compared to COVID-19 patients with no preexisting chronic diseases, COVID-19 patients who present with either diabetes, hypertension, CAD/CVD, or chronic pulmonary disease have a higher risk of developing severe disease, with an OR of 2.61 (95% CI 1.93 to 3.52), 2.84 (95% CI 2.22 to 3.63), 4.18 (95% CI 2.87 to 6.09) and 3.83 (95% CI 2.15 to 6.80), respectively. Surprisingly, we found no correlation between chronic conditions and increased risk of mortality (OR 2.09, 95% CI 0.26 to16.67). Taken together, cardio-metabolic diseases, such as diabetes, hypertension and CAD/CVD were more common than chronic pulmonary disease in COVID-19 patients, however, each comorbid disease was correlated with increased disease severity. After active treatment, increased risk of mortality in patients with preexisting chronic diseases may reduce.

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REST rs3796529 Genotype and Rate of Functional Deterioration in Alzheimer’s Disease
Poyin Huang,Cheng-Sheng Chen,Yuan-Han Yang,Mei-Chuan Chou,Ya-Hsuan Chang,Chiou-Lian Lai,Hsuan-Yu Chen,Ching-Kuan Liu
Aging and disease    2019, 10 (1): 94-101.   DOI: 10.14336/AD.2018.0116
Abstract431)   HTML1)    PDF(pc) (537KB)(2520)       Save

Recently, REST (RE1-silencing transcription factor) gene has been shown to be lost in Alzheimer’s disease (AD), and a missense minor REST allele rs3796529-T has been shown to reduce the rate of hippocampal volume loss. However, whether the REST rs3796529 genotype is associated with the rate of functional deterioration in AD is unknown. A total of 584 blood samples from Taiwanese patients with AD were collected from January 2002 to December 2013. The diagnosis of AD was based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria. The allele frequency of rs3796529-T was compared between the AD cohort and 993 individuals from the general population in Taiwan. Kaplan-Meier analysis, the log rank test and a multivariate Cox model were then used to evaluate the association between rs3796529-T and functional deterioration in the AD cohort. The allele frequency of rs3796529-T was significantly lower in the AD cohort compared to the general population cohort (36.82% vs. 40.73%, p=0.029). Kaplan-Meier analysis and the log rank test showed that the AD patients carrying the rs3796529 T/T genotype had a longer progression-free survival than those with the C/C genotype (p=0.012). In multivariate analysis, the rs3796529 T/T genotype (adjusted HR=0.593, 95% CI: 0.401-0.877, p=0.009) was an independent protective factor for functional deterioration. The rs3796529 T/T genotype was associated with slower functional deterioration in patients with AD. This finding may lead to a to better understanding of the molecular pathways involved, and prompt further development of novel biomarkers to monitor AD.

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Population Aging in the European Information Societies: Towards a Comprehensive Research Agenda in eHealth Innovations for Elderly
Vancea Mihaela, Solé-Casals Jordi
Aging and disease    2016, 7 (4): 526-539.   DOI: 10.14336/AD.2015.1214
Abstract781)   HTML16)    PDF(pc) (776KB)(1344)       Save

Population ageing is one of the major social and economic challenges of our contemporary societies. With the advent of the information society, new research and technological developments have been promoted in the field of assistive technologies and information and communication technologies of benefit to elderly people. This article examines the potentialities of new informatics developments in generating solutions to better address elderly people’s daily-life, especially those with chronic illness and/or low autonomy. The authours attempt to propose a research agenda, by exposing various strengts and weaknesses of eHealth innovations for elderly, mainly grounded in secondary sources analysis.

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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
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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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Multi-organ Dysfunction in Patients with COVID-19: A Systematic Review and Meta-analysis
Ting Wu,Zhihong Zuo,Shuntong Kang,Liping Jiang,Xuan Luo,Zanxian Xia,Jing Liu,Xiaojuan Xiao,Mao Ye,Meichun Deng
Aging and disease    2020, 11 (4): 874-894.   DOI: 10.14336/AD.2020.0520
Accepted: 30 May 2020

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This study aimed to provide systematic evidence for the association between multiorgan dysfunction and COVID-19 development. Several online databases were searched for articles published until May 13, 2020. Two investigators independently selected trials, extracted data, and evaluated the quality of individual trials. Single-arm meta-analysis was performed to summarize the clinical features of confirmed COVID-19 patients. Fixed effects meta-analysis was performed for clinically relevant parameters that were closely related to the patients’ various organ functions. A total of 73 studies, including 171,108 patients, were included in this analysis. The overall incidence of severe COVID-19 and mortality were 24% (95% confidence interval [CI], 20%-28%) and 2% (95% CI, 1%-3%), respectively. Patients with hypertension (odds ratio [OR] = 2.40; 95% CI, 2.08-2.78), cardiovascular disease (CVD) (OR = 3.54; 95% CI, 2.68-4.68), chronic obstructive pulmonary disease (COPD) (OR=3.70; 95% CI, 2.93-4.68), chronic liver disease (CLD) (OR=1.48; 95% CI, 1.09-2.01), chronic kidney disease (CKD) (OR = 1.84; 95% CI, 1.47-2.30), chronic cerebrovascular diseases (OR = 2.53; 95% CI, 1.84-3.49) and chronic gastrointestinal (GI) disease (OR = 2.13; 95% CI, 1.12-4.05) were more likely to develop severe COVID-19. Increased levels of lactate dehydrogenase (LDH), creatine kinase (CK), high-sensitivity cardiac troponin I (hs-cTnI), myoglobin, creatinine, urea, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin were highly associated with severe COVID-19. The incidence of acute organ injuries, including acute cardiac injury (ACI); (OR = 11.87; 95% CI, 7.64-18.46), acute kidney injury (AKI); (OR=10.25; 95% CI, 7.60-13.84), acute respiratory distress syndrome (ARDS); (OR=27.66; 95% CI, 18.58-41.18), and acute cerebrovascular diseases (OR=9.22; 95% CI, 1.61-52.72) was more common in patients with severe COVID-19 than in patients with non-severe COVID-19. Patients with a history of organ dysfunction are more susceptible to severe conditions. COVID-19 can aggravate an acute multiorgan injury.

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A Review of Exercise as Medicine in Cardiovascular Disease: Pathology and Mechanism
Piotr Gronek, Dariusz Wielinski, Piotr Cyganski, Andrzej Rynkiewicz, Adam Zając, Adam Maszczyk, Joanna Gronek, Robert Podstawski, Wojciech Czarny, Stefan Balko, Cain CT. Clark, Roman Celka
Aging and disease    2020, 11 (2): 327-340.   DOI: 10.14336/AD.2019.0516
Accepted: 02 July 2019

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Background

Physical inactivity and resultant lower energy expenditure contribute unequivocally to cardiovascular diseases, such as coronary artery disease and stroke, which are considered major causes of disability and mortality worldwide.

Aim

The aim of the study was to investigate the influence of physical activity (PA) and exercise on different aspects of health - genetics, endothelium function, blood pressure, lipid concentrations, glucose intolerance, thrombosis, and self - satisfaction. Materials and

Methods

In this article, we conducted a narrative review of the influence PA and exercise have on the cardiovascular system, risk factors of cardiovascular diseases, searching the online databases; Web of Science, PubMed and Google Scholar, and, subsequently, discuss possible mechanisms of this action.

Results and Discussion

Based on our narrative review of literature, discussed the effects of PA on telomere length, nitric oxide synthesis, thrombosis risk, blood pressure, serum glucose, cholesterol and triglycerides levels, and indicated possible mechanisms by which physical training may lead to improvement in chronic cardiovascular diseases.

Conclusion

PA is effective for the improvement of exercise tolerance, lipid concentrations, blood pressure, it may also reduce the serum glucose level and risk of thrombosis, thus should be advocated concomitant to, or in some cases instead of, traditional drug-therapy.

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Handgrip Strength and Pulmonary Disease in the Elderly: What is the Link?
Tatiana Rafaela Lemos Lima, Vívian Pinto Almeida, Arthur Sá Ferreira, Fernando Silva Guimarães, Agnaldo José Lopes
Aging and disease    2019, 10 (5): 1109-1129.   DOI: 10.14336/AD.2018.1226
Accepted: 31 December 2018

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Societies in developed countries are aging at an unprecedented rate. Considering that aging is the most significant risk factor for many chronic lung diseases (CLDs), understanding this process may facilitate the development of new interventionist approaches. Skeletal muscle dysfunction is a serious problem in older adults with CLDs, reducing their quality of life and survival. In this study, we reviewed the possible links between handgrip strength (HGS)—a simple, noninvasive, low-cost measure of muscle function—and CLDs in the elderly. Different mechanisms appear to be involved in this association, including systemic inflammation, chronic hypoxemia, physical inactivity, malnutrition, and corticosteroid use. Respiratory and peripheral myopathy, associated with muscle atrophy and a shift in muscle fiber type, also seem to be major etiological contributors to CLDs. Moreover, sarcopenic obesity, which occurs in older adults with CLDs, impairs common inflammatory pathways that can potentiate each other and further accelerate the functional decline of HGS. Our findings support the concept that the systemic effects of CLDs may be determined by HGS, and HGS is a relevant measurement that should be considered in the clinical assessment of the elderly with CLDs. These reasons make HGS a useful practical tool for indirectly evaluating functional status in the elderly. At present, early muscle reconditioning and optimal nutrition appear to be the most effective approaches to reduce the impact of CLDs and low muscle strength on the quality of life of these individuals. Nonetheless, larger in-depth studies are needed to evaluate the link between HGS and CLDs.

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Alteration in the Function and Expression of SLC and ABC Transporters in the Neurovascular Unit in Alzheimer’s Disease and the Clinical Significance
Yongming Jia, Na Wang, Yingbo Zhang, Di Xue, Haoming Lou, Xuewei Liu
Aging and disease    2020, 11 (2): 390-404.   DOI: 10.14336/AD.2019.0519
Accepted: 05 June 2019

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The neurovascular unit (NVU) plays an important role in maintaining the function of the central nervous system (CNS). Emerging evidence has indicated that the NVU changes function and molecules at the early stage of Alzheimer’s disease (AD), which initiates multiple pathways of neurodegeneration. Cell types in the NVU have become attractive targets in the interventional treatment of AD. The NVU transportation system contains a variety of proteins involved in compound transport and neurotransmission. Brain transporters can be classified as members of the solute carrier (SLC) and ATP-binding cassette (ABC) families in the NVU. Moreover, the transporters can regulate both endogenous toxins, including amyloid-beta (Aβ) and xenobiotic homeostasis, in the brains of AD patients. Genome-wide association studies (GWAS) have identified some transporter gene variants as susceptibility loci for late-onset AD. Therefore, the present study summarizes changes in blood-brain barrier (BBB) permeability in AD, identifies the location of SLC and ABC transporters in the brain and focuses on major SLC and ABC transporters that contribute to AD pathology.

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Interplay between Exosomes and Autophagy in Cardiovascular Diseases: Novel Promising Target for Diagnostic and Therapeutic Application
Jinfan Tian, Sharif Popal Mohammad, Yingke Zhao, Yanfei Liu, Keji Chen, Yue Liu
Aging and disease    2019, 10 (6): 1302-1310.   DOI: 10.14336/AD.2018.1020
Accepted: 20 November 2018

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Exosome, is identified as a nature nanocarrier and intercellular messenger that regulates cell to cell communication. Autophagy is critical in maintenance of protein homeostasis by degradation of damaged proteins and organelles. Autophagy and exosomes take pivotal roles in cellular homeostasis and cardiovascular disease. Currently, the coordinated mechanisms for exosomes and autophagy in the maintenance of cellular fitness are now garnering much attention. In the present review, we discussed the interplay of exosomes and autophagy in the context of physiology and pathology of the heart, which might provide novel insights for diagnostic and therapeutic application of cardiovascular diseases.

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Gut Microbiome and Osteoporosis
Kai Ding, Fei Hua, Wenge Ding
Aging and disease    2020, 11 (2): 438-447.   DOI: 10.14336/AD.2019.0523
Accepted: 14 June 2019

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Gut microbiome refers to the microbes that live in human digestive tract and are symbiotic with the human body. They participate in the regulation of various physiological and pathological processes of the human body and are associated with various diseases. The pathological process of osteoporosis is affected by gut microbes. The molecular mechanisms of osteoporosis mainly include: 1) Intestinal barrier and nutrient absorption (involving SCFAs). 2) Immunoregulation (Th-17 and T-reg cells balance). 3) Regulation of intestinal-brain axis (involving 5-HT). Gut microbes can increase bone mass and improve osteoporosis by inhibiting osteoclast proliferation and differentiation, inducing apoptosis, reducing bone resorption, or promoting osteoblast proliferation and maturation. However, the therapeutic effect of gut microbes on osteoporosis remains to be further proven. At present, some of the findings on the impact of gut microbes on osteoporosis has been applied in clinical, including early diagnosis and intervention of osteoporosis and adjuvant therapy. In this article, we reviewed the molecular mechanisms underlying the regulatory effect of gut microbes on osteoporosis and the clinical practice of using gut microbes to improve bone health.

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TGF-β Signaling: A Therapeutic Target to Reinstate Regenerative Plasticity in Vascular Dementia?
Mahesh Kandasamy,Muthuswamy Anusuyadevi,Kiera M Aigner,Michael S Unger,Kathrin M Kniewallner,Diana M Bessa de Sousa,Barbara Altendorfer,Heike Mrowetz,Ulrich Bogdahn,Ludwig Aigner
Aging and disease    2020, 11 (4): 828-850.   DOI: 10.14336/AD.2020.0222
Accepted: 18 March 2020

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Vascular dementia (VaD) is the second leading form of memory loss after Alzheimer's disease (AD). Currently, there is no cure available. The etiology, pathophysiology and clinical manifestations of VaD are extremely heterogeneous, but the impaired cerebral blood flow (CBF) represents a common denominator of VaD. The latter might be the result of atherosclerosis, amyloid angiopathy, microbleeding and micro-strokes, together causing blood-brain barrier (BBB) dysfunction and vessel leakage, collectively originating from the consequence of hypertension, one of the main risk factors for VaD. At the histopathological level, VaD displays abnormal vascular remodeling, endothelial cell death, string vessel formation, pericyte responses, fibrosis, astrogliosis, sclerosis, microglia activation, neuroinflammation, demyelination, white matter lesions, deprivation of synapses and neuronal loss. The transforming growth factor (TGF) β has been identified as one of the key molecular factors involved in the aforementioned various pathological aspects. Thus, targeting TGF-β signaling in the brain might be a promising therapeutic strategy to mitigate vascular pathology and improve cognitive functions in patients with VaD. This review revisits the recent understanding of the role of TGF-β in VaD and associated pathological hallmarks. It further explores the potential to modulate certain aspects of VaD pathology by targeting TGF-β signaling.

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Redefining Chronic Inflammation in Aging and Age-Related Diseases: Proposal of the Senoinflammation Concept
Hae Young Chung, Dae Hyun Kim, Eun Kyeong Lee, Ki Wung Chung, Sangwoon Chung, Bonggi Lee, Arnold Y. Seo, Jae Heun Chung, Young Suk Jung, Eunok Im, Jaewon Lee, Nam Deuk Kim, Yeon Ja Choi, Dong Soon Im, Byung Pal Yu
Aging and disease    2019, 10 (2): 367-382.   DOI: 10.14336/AD.2018.0324
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Age-associated chronic inflammation is characterized by unresolved and uncontrolled inflammation with multivariable low-grade, chronic and systemic responses that exacerbate the aging process and age-related chronic diseases. Currently, there are two major hypotheses related to the involvement of chronic inflammation in the aging process: molecular inflammation of aging and inflammaging. However, neither of these hypotheses satisfactorily addresses age-related chronic inflammation, considering the recent advances that have been made in inflammation research. A more comprehensive view of age-related inflammation, that has a scope beyond the conventional view, is therefore required. In this review, we discuss newly emerging data on multi-phase inflammatory networks and proinflammatory pathways as they relate to aging. We describe the age-related upregulation of nuclear factor (NF)-κB signaling, cytokines/chemokines, endoplasmic reticulum (ER) stress, inflammasome, and lipid accumulation. The later sections of this review present our expanded view of age-related senescent inflammation, a process we term “senoinflammation”, that we propose here as a novel concept. As described in the discussion, senoinflammation provides a schema highlighting the important and ever-increasing roles of proinflammatory senescence-associated secretome, inflammasome, ER stress, TLRs, and microRNAs, which support the senoinflammation concept. It is hoped that this new concept of senoinflammation opens wider and deeper avenues for basic inflammation research and provides new insights into the anti-inflammatory therapeutic strategies targeting the multiple proinflammatory pathways and mediators and mediators that underlie the pathophysiological aging process.

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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
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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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COVID-19 in India: Are Biological and Environmental Factors Helping to Stem the Incidence and Severity?
Sankha Shubhra Chakrabarti, Upinder Kaur, Anindita Banerjee, Upasana Ganguly, Tuhina Banerjee, Sarama Saha, Gaurav Parashar, Suvarna Prasad, Suddhachitta Chakrabarti, Amit Mittal, Bimal Kumar Agrawal, Ravindra Kumar Rawal, Robert Chunhua Zhao, Indrajeet Singh Gambhir, Rahul Khanna, Ashok K Shetty, Kunlin Jin, Sasanka Chakrabarti
Aging and disease    2020, 11 (3): 480-488.   DOI: 10.14336/AD.2020.0402
Accepted: 03 April 2020

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The ongoing Corona virus (COVID-19) pandemic has witnessed global political responses of unimaginable proportions. Many nations have implemented lockdowns that involve mandating citizens not to leave their residences for non-essential work. The Indian government has taken appropriate and commendable steps to curtail the community spread of COVID-19. While this may be extremely beneficial, this perspective discusses the other reasons why COVID-19 may have a lesser impact on India. We analyze the current pattern of SARS-CoV-2 transmission, testing, and mortality in India with an emphasis on the importance of mortality as a marker of the clinical relevance of COVID-19 disease. We also analyze the environmental and biological factors which may lessen the impact of COVID-19 in India. The importance of cross-immunity, innate immune responses, ACE polymorphism, and viral genetic mutations are discussed.

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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
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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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The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-related Pathogenesis
Seong Gak Jeon, Anji Yoo, Dong Wook Chun, Sang Bum Hong, Hyunju Chung, Jin-il Kim, Minho Moon
Aging and disease    2020, 11 (3): 705-724.   DOI: 10.14336/AD.2019.0718
Accepted: 01 August 2019
Online available: 02 August 2019

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Several studies have revealed that the transcription factor nuclear receptor related 1 (Nurr1) plays several roles not only in the regulation of gene expression related to dopamine synthesis, but also in alternative splicing, and miRNA targeting. Moreover, it regulates cognitive functions and protects against inflammation-induced neuronal death. In particular, the role of Nurr1 in the pathogenesis of Parkinson’s disease (PD) has been well investigated; for example, it has been shown that it restores behavioral and histological impairments in PD models. Although many studies have evaluated the connection between Nurr1 and PD pathogenesis, the role of Nurr1 in Alzheimer’s disease (AD) remain to be studied. There have been several studies describing Nurr1 protein expression in the AD brain. However, only a few studies have examined the role of Nurr1 in the context of AD. Therefore, in this review, we highlight the overall effects of Nurr1 under the neuropathologic conditions related to AD. Furthermore, we suggest the possibility of using Nurr1 as a therapeutic target for AD or other neurodegenerative disorders.

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Physical Activity and Alzheimer’s Disease: A Narrative Review
Piotr Gronek, Stefan Balko, Joanna Gronek, Adam Zajac, Adam Maszczyk, Roman Celka, Agnieszka Doberska, Wojciech Czarny, Robert Podstawski, Cain C. T Clark, Fang Yu
Aging and disease    2019, 10 (6): 1282-1292.   DOI: 10.14336/AD.2019.0226
Accepted: 12 March 2019

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Although age is a dominant risk factor for Alzheimer’s disease (AD), epidemiological studies have shown that physical activity may significantly decrease age-related risks for AD, and indeed mitigate the impact in existing diagnosis. The aim of this study was to perform a narrative review on the preventative, and mitigating, effects of physical activity on AD onset, including genetic factors, mechanism of action and physical activity typology. In this article, we conducted a narrative review of the influence physical activity and exercise have on AD, utilising key terms related to AD, physical activity, mechanism and prevention, searching the online databases; Web of Science, PubMed and Google Scholar, and, subsequently, discuss possible mechanisms of this action. On the basis of this review, it is evident that physical activity and exercise may be incorporated in AD, notwithstanding, a greater number of high-quality randomised controlled trials are needed, moreover, physical activity typology must be acutely considered, primarily due to a dearth of research on the efficacy of physical activity types other than aerobic.

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Rapid Eye Movement Sleep Behavior Disorder and Neurodegenerative Diseases: An Update
Feng Zhang, Long Niu, Xinyao Liu, Yufei Liu, Song Li, Huan Yu, Weidong Le
Aging and disease    2020, 11 (2): 315-326.   DOI: 10.14336/AD.2019.0324
Accepted: 29 August 2019

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Rapid eye movement sleep behavior disorder (RBD) is a sleep behavior disorder characterized by abnormal behaviors and loss of muscle atonia during rapid eye movement (REM) sleep. RBD is generally considered to be associated with synucleinopathies, such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), and usually precedes years before the first symptom of these diseases. It is believed that RBD predicts the neurodegeneration in synucleinopathy. However, increasing evidences have shown that RBD is also found in non-synucleinopathy neurodegenerative diseases, including Alzheimer’s disease (AD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), etc. Sleep disturbance such as RBD may be an early sign of neurodegeneration in these diseases, and also serve as an assessment of cognitive impairments. In this review, we updated the clinical characteristics, diagnosis, and possible mechanisms of RBD in neurogenerative diseases. A better understanding of RBD in these neurogenerative diseases will provide biomarkers and novel therapeutics for the early diagnosis and treatment of the diseases.

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Short Telomere Length is Associated with Aging, Central Obesity, Poor Sleep and Hypertension in Lebanese Individuals
Zgheib Nathalie K, Sleiman Fatima, Nasreddine Lara, Nasrallah Mona, Nakhoul Nancy, Isma’eel Hussain, Tamim Hani
Aging and disease    2018, 9 (1): 77-89.   DOI: 10.14336/AD.2017.0310
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In Lebanon, data stemming from national cross-sectional surveys indicated significant increasing trends in the prevalence of cardiovascular diseases and associated behavioral and age-related risk factors. To our knowledge, no data are available on relative telomere length (RTL) as a potential biomarker for age-related diseases in a Lebanese population. The aim of this study was to evaluate whether there is an association between RTL and demographic characteristics, lifestyle habits and diseases in the Lebanese. This was a cross-sectional study of 497 Lebanese subjects. Peripheral blood RTL was measured by amplifying telomere and single copy gene using real-time PCR. Mean ± SD RTL was 1.42 ± 0.83, and it was categorized into 3 tertiles. Older age (P=0.002) and wider waist circumference (WC) (P=0.001) were statistically significantly associated with shorter RTL. Multinomial logistic regression showed that subjects who had some level of sleeping difficulty had a statistically significantly shorter RTL when compared to those with no sleeping difficulties at all [OR (95% CI): 2.01 (1.11-3.62) in the first RTL tertile]. Importantly, statistically significantly shorter RTL was found with every additional 10 cm of WC [OR (95% CI): 1.30 (1.11-1.52) for first RTL tertile]. In addition, and after performing the multivariate logistic regression and adjusting for “predictors” of RTL, the odds of having hypertension or being treated for hypertension were higher in patients who had shorter RTL: OR (95% CI): 2.45 (1.36-4.44) and 2.28 (1.22-4.26) in the first RTL tertiles respectively with a similar trend, though not statistically significant, in the second RTL tertiles. This is the first study in Lebanon to show an association between age, central obesity, poor sleep and hypertension and RTL. It is hoped that telomere length measurement be potentially used as a biomarker for biological age and age-related diseases and progression in the Lebanese.

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Entorhinal Cortex Atrophy in Early, Drug-naive Parkinson’s Disease with Mild Cognitive Impairment
Xiuqin Jia, Zhijiang Wang, Tao Yang, Ying Li, Shuai Gao, Guorong Wu, Tao Jiang, Peipeng Liang
Aging and disease    2019, 10 (6): 1221-1232.   DOI: 10.14336/AD.2018.1116
Accepted: 18 November 2018
Online available: 18 November 2018

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Patients with Parkinson’s disease (PD) generally have a higher proportion of suffering from mild cognitive impairment (MCI) than normal aged adults. This study aimed to identify the specific neuroanatomical alterations in early, drug-naive PD with MCI (PD-MCI) by comparing to those PD with normal cognition (PD-NC) and healthy controls (HCs), which could help to elucidate the underlying neuropathology and facilitate the development of early therapeutic strategies for treating this disease. Structural MRI data of 237 early, drug-naive non-demented PD patients (classified as 61 PD-MCI and 176 PD-NC) and 69 HCs were included from Parkinson's Progression Markers Initiative (PPMI) database after data quality control. Within these data, a subset of 61 HCs and a subset of 61 PD-NC who were matched to the 61 PD-MCI group for age, gender, and education-level were selected to further eliminate the sample size effect. The gray matter (GM) volume changes between groups were analyzed using voxel-based morphometry (VBM). Furthermore, correlations between GM volume alterations and neuropsychological performances and non-cognitive assessments (including olfactory performance) were further examined. Compared to HC, patients with PD-NC and PD-MCI commonly exhibited atrophies in the bilateral amygdala (AM) and the left primary motor cortex (M1). Patients with PD-MCI exclusively exhibited atrophy in the right entorhinal cortex (ENT) compared to PD-NC. Significantly negative correlations were found between GM loss in the bilateral AM and olfactory performance in all PD patients, and between ENT loss and memory performance in PD-MCI. The findings suggest that the right ENT atrophy may subserve as a biomarker in early, drug-naive PD-MCI, which shed light on the neural underpinnings of the disease and provide new evidence on differentiating the neuroanatomical states between PD-MCI and PD-NC.

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Brain Atrophy, Anti-Smooth Muscle Antibody and Cognitive Impairment: An Association Study
Giulia Paroni, Michele Lauriola, Andrea Fontana, Grazia D’Onofrio, Filomena Ciccone, Francesco Paris, Leandro Cascavilla, Maria Urbano, Carolina Gravina, Massimiliano Copetti, Antonio Greco
Aging and disease    2016, 7 (4): 318-325.   DOI: 10.14336/AD.2015.1124
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Cortical atrophy, neuronal loss, beta-amyloid deposition, neuritic plaques, and neurofibrillary tangles are neuropathological key features in the Alzheimer’s disease (AD). Antibodies against beta-amyloid, neurotransmitters, microvascular endothelium components and microglial cells have been detected in AD serum suggesting that AD could be another autoimmune disease and provides a link between vascular pathology, endothelium dysfunction and neuronal cells death. Aim of the present study was to evaluate the association between autoantibody profile and cognitive impairment in geriatric patients, accounting for ApoE genotype as a potential confounding factor. Three hundred and forty-four geriatric patients, attending the clinic for the cognitive decline, underwent a biochemical and immunological profile, chest X-ray, cerebral computed tomography scan and complete cognitive evaluation. All patients were also screened for the ApoE genotype. A significantly higher prevalence of Anti-Smooth Muscle Antibody (ASMA) positivity was found in 89/204 (43.63%) patients with diagnosed neuroradiological signs of cerebral atrophy compared with 15/140 (10.71%) patients without the condition (p<0.001). Multivariable logistic model evidenced that such association was independent of patient’s age, gender and Mini-Mental State Examination (OR=8.25, 95%CI: 4.26-15.99) and achieved a good discriminatory power (c-statistic=0.783). Results were also independent of ApoE genotype, which resulted not associated both with the presence of brain atrophy and with the presence of ASMA positivity. Our results shows a strong association between brain atrophy and ASMA positivity and are consistent with several studies that focused attention on the mechanisms of endothelial immune response in the development of dementia.

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Preclinical Evidence and Possible Mechanisms of Extracts or Compounds from Cistanches for Alzheimer’s Disease
Xiao-Li Zhou, Meng-Bei Xu, Ting-Yu Jin, Pei-Qing Rong, Guo-Qing Zheng, Yan Lin
Aging and disease    2019, 10 (5): 1075-1093.   DOI: 10.14336/AD.2018.0815-1
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Currently, disease-modified strategies to prevent, halt or reverse the progress of Alzheimer’s disease (AD) are still lacking. Previous studies indicated extracts or compounds from Cistanches (ECC) exert a potential neuroprotective effect against AD. Thus, we conducted a preclinical systematic review to assess preclinical evidence and possible mechanisms of ECC in experimental AD. A systematical searching strategy was carried out across seven databases from their inceptions to July 2018. Twenty studies with 1696 rats or mice were involved. Neurobehavioral function indices as primary outcome measures were established by the Morris water maze test (n = 11), step-down test (n = 10), electrical Y-maze test (n = 4), step-through test (n = 3), open field test (n = 2) and passage water maze test (n = 1). Compared with controls, the results of the meta-analysis showed ECC exerted a significant effect in decreasing the escape latency, error times and wrong reaction latency in both the training test and the retention test, and in increasing the exact time and the percentage of time in the platform-quadrant and the number of platform crossings (all P<0.01). In conclusion, ECC exert potential neuroprotective effects in experimental AD, mainly through mechanisms involving antioxidant stress and antiapoptosic effects, inhibiting Aβ deposition and tau protein hyperphosphorylation and promoting synapse protection. Thus, ECC could be a candidate for AD treatment and further clinical trials.

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The Clinical Efficacy and Safety of Stem Cell Therapy for Diabetes Mellitus: A Systematic Review and Meta-Analysis
Yazhen Zhang, Wenyi Chen, Bing Feng, Hongcui Cao
Aging and disease    2020, 11 (1): 141-153.   DOI: 10.14336/AD.2019.0421
Accepted: 10 May 2019

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Diabetes mellitus (DM) is a chronic metabolic disease with high morbidity and mortality. Recently, stem cell-based therapy for DM has shown considerable promise. Here, we undertook a systematic review and meta-analysis of published clinical studies to evaluate the efficacy and safety of stem cell therapy for both type 1 DM (T1DM) and type 2 DM (T2DM). The PubMed, Cochrane Central Register of Controlled Trials, EMBASE, and ClinicalTrials.gov databases were searched up to November 2018. We employed a fixed-effect model using 95% confidence intervals (CIs) when no statistically significant heterogeneity existed. Otherwise, a random-effects statistical model was used. Twenty-one studies met our inclusion criteria: ten T1DM studies including 226 patients and eleven T2DM studies including 386 patients. Stem cell therapy improved C-peptide levels (mean difference (MD), 0.41; 95% CI, 0.06 to 0.76) and glycosylated hemoglobin (HbA1c; MD, -3.46; 95% CI, -6.01 to -0.91) for T1DM patients. For T2DM patients, stem cell therapy improved C-peptide levels (MD, 0.33; 95% CI, 0.07 to 0.59), HbA1c (MD, -0.87; 95% CI, -1.37 to -0.37) and insulin requirements (MD, -35.76; 95% CI, -40.47 to -31.04). However, there was no significant change in fasting plasma glucose levels (MD, -0.52; 95% CI, -1.38 to 0.34). Subgroup analyses showed significant HbA1c and C-peptide improvements in patients with T1DM treated with bone marrow hematopoietic stem cells (BM-HSCs), while there was no significant change in the mesenchymal stem cell (MSC) group. In T2DM, HbA1c and insulin requirements decreased significantly after MSC transplantation, and insulin requirements and C-peptide levels were significantly improved after bone marrow mononuclear cell (BM-MNC) treatment. Stem cell therapy is a relatively safe and effective method for selected individuals with DM. The data showed that BM-HSCs are superior to MSCs in the treatment of T1DM. In T2DM, MSC and BM-MNC transplantation showed favorable therapeutic effects.

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Combined Antioxidant, Anti-inflammaging and Mesenchymal Stem Cell Treatment: A Possible Therapeutic Direction in Elderly Patients with Chronic Obstructive Pulmonary Disease
Shijin Xia, Changxi Zhou, Bill Kalionis, Xiaoping Shuang, Haiyan Ge, Wen Gao
Aging and disease    2020, 11 (1): 129-140.   DOI: 10.14336/AD.2019.0508
Accepted: 11 May 2019

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Chronic Obstructive Pulmonary Disease (COPD) is a worldwide health problem associated with high morbidity and mortality, especially in elderly patients. Aging functions include mitochondrial dysfunction, cell-to-cell information exchange, protein homeostasis and extracellular matrix dysregulation, which are closely related to chronic inflammatory response and oxidation-antioxidant imbalance in the pathogenesis of COPD. COPD displays distinct inflammaging features, including increased cellular senescence and oxidative stress, stem cell exhaustion, alterations in the extracellular matrix, reduced levels of endogenous anti-inflammaging molecules, and reduced autophagy. Given that COPD and inflammaging share similar general features, it is very important to identify the specific mechanisms of inflammaging, which involve oxidative stress, inflammation and lung mesenchymal stem cell function in the development of COPD, especially in elderly COPD patients. In this review, we highlight the studies relevant to COPD progression, and focus on mechanisms associated with inflammaging.

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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
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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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Age-related Impairment of Vascular Structure and Functions
Xu Xianglai, Wang Brian, Ren Changhong, Hu Jiangnan, Greenberg David A., Chen Tianxiang, Xie Liping, Jin Kunlin
Aging and disease    2017, 8 (5): 590-610.   DOI: 10.14336/AD.2017.0430
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Among age-related diseases, cardiovascular and cerebrovascular diseases are major causes of death. Vascular dysfunction is a key characteristic of these diseases wherein age is an independent and essential risk factor. The present work will review morphological alterations of aging vessels in-depth, which includes the discussion of age-related microvessel loss and changes to vasculature involving the capillary basement membrane, intima, media, and adventitia as well as the accompanying vascular dysfunctions arising from these alterations.

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Adipose Stem Cells (ASCs) and Stromal Vascular Fraction (SVF) as a Potential Therapy in Combating (COVID-19)-Disease
Pietro Gentile, Aris Sterodimas
Aging and disease    2020, 11 (3): 465-469.   DOI: 10.14336/AD.2020.0422
Accepted: 22 April 2020

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A recent and interesting study reported improved respiratory activity after intravenous administration of mesenchymal stem cells (MSCs) into patients affected by coronavirus disease 2019 (COVID-19). These outcomes displayed that intravenous infiltration of MSCs is a safe and efficacy treatment for COVID-19 pneumonia, a severe acute respiratory illness caused by the coronavirus 2 (SARS-CoV-2). Only 7 patients were treated, but with extraordinary results, opening a new strategy in COVID-19 therapy. Currently, no specific therapies against SARS-CoV-2 are available. The MSCs therapy outcomes reported, are striking, as these cells inhibit the over-activation of the immune system, promoting endogenous repair, by improving the lung microenvironment after the SARS-CoV-2 infection. The MSCs could represent an effective, autologous and safe therapy, and therefore, sharing these published results, here is reported the potential use possibilities in COVID-19 of the most common MSCs represented by Adipose Stem Cells (ASCs).

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Understanding the Physiological Links Between Physical Frailty and Cognitive Decline
Lina Ma, Piu Chan
Aging and disease    2020, 11 (2): 405-418.   DOI: 10.14336/AD.2019.0521
Accepted: 30 May 2019

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Declines in both physical and cognitive function are associated with increasing age. Understanding the physiological link between physical frailty and cognitive decline may allow us to develop interventions that prevent and treat both conditions. Although there is significant epidemiological evidence linking physical frailty to cognitive decline, a complete understanding of the underpinning biological basis of the two disorders remains fragmented. This narrative review discusses insights into the potential roles of chronic inflammation, impaired hypothalamic-pituitary axis stress response, imbalanced energy metabolism, mitochondrial dysfunction, oxidative stress, and neuroendocrine dysfunction linking physical frailty with cognitive decline. We highlight the importance of easier identification of strategic approaches delaying the progression and onset of physical frailty and cognitive decline as well as preventing disability in the older population.

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Skin Cancer Epidemics in the Elderly as An Emerging Issue in Geriatric Oncology
Garcovich Simone, Colloca Giuseppe, Sollena Pietro, Andrea Bellieni, Balducci Lodovico, Cho William C., Bernabei Roberto, Peris Ketty
Aging and disease    2017, 8 (5): 643-661.   DOI: 10.14336/AD.2017.0503
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Skin cancer is a worldwide, emerging clinical need in the elderly white population, with a steady increase in incidence rates, morbidity and related medical costs. Skin cancer is a heterogeneous group of cancers comprising cutaneous melanoma and non-melanoma skin cancers (NMSC), which predominantly affect elderly patients, aged older than 65 years. Melanoma has distinct clinical presentations in the elderly patient and represents a challenging question in terms of clinical management. NMSC includes the basal cell carcinoma and cutaneous squamous cell carcinoma and presents a wide disease spectrum in the elderly population, ranging from low-risk to high-risk tumours, advanced and inoperable disease. Treatment decisions for NMSC are preferentially based on tumour characteristics, patient’s chronological age and physician’s preferences and operational settings. Several treatment options are available for NMSC, from surgery to non-invasive/medical therapies, but patient-based factors, such as geriatric comorbidities and patient’s life expectancy, do not frequently modulate treatment goals. In melanoma, age-related variations in clinical management are significant and may frequently lead to under-treatment, limiting access to advanced surgical and medical treatments. Clinical decision-making in the care of elderly skin cancer patient should ideally implement a geriatric assessment, prioritizing patient-based factors and efficiently differentiating fit from frail cancer patients. Current clinical practice guidelines for NMSC and melanoma only partially address geriatric aspects of cancer care, such as frailty, limited life-expectancy, geriatric comorbidities and treatment compliance. We review the recent evidence on the scope and problem of skin cancer in the elderly population as well as age-related variations in its clinical management, highlighting the potential role of a geriatric approach in optimizing dermato-oncological care.

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The Peptide-Directed Lysosomal Degradation of CDK5 Exerts Therapeutic Effects against Stroke
Ya-Fan Zhou, Jing Wang, Man-Fei Deng, Bin Chi, Na Wei, Jian-Guo Chen, Dan Liu, Xiaoping Yin, Youming Lu, Ling-Qiang Zhu
Aging and disease    2019, 10 (5): 1140-1145.   DOI: 10.14336/AD.2018.1225
Accepted: 31 December 2018

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The aberrant activation of CDK5 has been implicated in neuronal death in stroke. The goal of this study is to determine whether knocking down CDK5 by a peptide-directed lysosomal degradation approach is therapeutically effective against stroke. We synthesized a membrane-permeable peptide that specifically binds to CDK5 with a chaperone-mediated autophagy targeting motif (Tat-CDK5-CTM) and tested its therapeutic effects on a mouse model of ischemic stroke. Our results showed that Tat-CDK5-CTM blocked the CDK5-NR2B interaction, resulting in the degradation of CDK5, which in turn prevented calcium overload and neuronal death in cultured neurons. Tat-CDK5-CTM also reduced the infarction area and neuronal loss and improved the neurological functions in MCAO (Middle cerebral artery occlusion) mice. The peptide-directed lysosomal degradation of CDK5 is a promising therapeutic intervention for stroke.

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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
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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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Overweight in the Elderly Induces a Switch in Energy Metabolism that Undermines Muscle Integrity
Yaiza Potes, Zulema Pérez-Martinez, Juan C. Bermejo-Millo, Adrian Rubio-Gonzalez, María Fernandez-Fernández, Manuel Bermudez, Jose M. Arche, Juan J. Solano, Jose A. Boga, Mamen Oliván, Beatriz Caballero, Ignacio Vega-Naredo, Ana Coto-Montes
Aging and disease    2019, 10 (2): 217-230.   DOI: 10.14336/AD.2018.0430
Abstract602)   HTML0)    PDF(pc) (1222KB)(1314)       Save

Aging is characterized by a progressive loss of skeletal muscle mass and function (sarcopenia). Obesity exacerbates age-related decline and lead to frailty. Skeletal muscle fat infiltration increases with aging and seems to be crucial for the progression of sarcopenia. Additionally, skeletal muscle plasticity modulates metabolic adaptation to different pathophysiological situations. Thus, cellular bioenergetics and mitochondrial profile were studied in the skeletal muscle of overweight aged people without reaching obesity to prevent this extreme situation. Overweight aged muscle lacked ATP production, as indicated by defects in the phosphagen system, glycolysis and especially mostly by oxidative phosphorylation metabolic pathway. Overweight subjects exhibited an inhibition of mitophagy that was linked to an increase in mitochondrial biogenesis that underlies the accumulation of dysfunctional mitochondria and encourages the onset of sarcopenia. As a strategy to maintain cellular homeostasis, overweight subjects experienced a metabolic switch from oxidative to lactic acid fermentation metabolism, which allows continued ATP production under mitochondrial dysfunction, but without reaching physiological aged basal levels. This ATP depletion induced early signs of impaired contractile function and a decline in skeletal muscle structural integrity, evidenced by lower levels of filamin C. Our findings reveal the main effector pathways at an early stage of obesity and highlight the importance of mitochondrial metabolism in overweight and obese individuals. Exploiting mitochondrial profiles for therapeutic purposes in humans is an ambitious strategy for treating muscle impairment diseases.

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