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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

Abstract43087)   HTML12)    PDF(pc) (1473KB)(20535)       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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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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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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Low level of Vitamin C and dysregulation of Vitamin C transporter might be involved in the severity of COVID-19 Infection
Taylor Patterson,Carlos M Isales,Sadanand Fulzele
Aging and disease    2021, 12 (1): 14-26.   DOI: 10.14336/AD.2020.0918
Accepted: 28 September 2020

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The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has been spreading around the world at an exponential pace, leading to millions of individuals developing the associated disease called COVID-19. Due to the novel nature and the lack of immunity within humans, there has been a collective global effort to find effective treatments against the virus. This has led the scientific community to repurpose Food and Drug Administration (FDA) approved drugs with known safety profiles. Of the many possible drugs, vitamin C has been on the shortlist of possible interventions due to its beneficial role as an immune booster and inherent antioxidant properties. Within this manuscript, a detailed discussion regarding the intracellular function and inherent properties of vitamin C is conducted. It also provides a comprehensive review of published research pertaining to the differences in expression of the vitamin C transporter under several pathophysiologic conditions. Finally, we review recently published research investigating the efficacy of vitamin C administration in treating viral infection and life-threatening conditions. Overall, this manuscript aims to present existing information regarding the extent to which vitamin C can be an effective treatment for COVID-19 and possible explanations as to why it may work in some individuals but not in others.

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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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Mesenchymal Stem Cells for Coronavirus (COVID-19)-Induced Pneumonia: Revisiting the Paracrine Hypothesis with New Hopes?
Selçuk Öztürk, Ayşe Eser Elçin, Yaşar Murat Elçin
Aging and disease    2020, 11 (3): 477-479.   DOI: 10.14336/AD.2020.0403
Accepted: 03 April 2020

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Mesenchymal stem cells (MSCs) bear a promising potential for regenerative medicine therapies and they repair damaged tissue through secretion of immune modulatory and anti-inflammatory molecules acting in a paracrine fashion. Coronavirus disease 2019 (COVID-19) has spread all over the world with high morbidity and mortality rates and there is no specific treatment for this infection. A recent study published in the journal reports that MSC infusion is safe and effective in patients suffering from COVID-19 induced pneumonia. In the light of this study and previous reports, we make additional comments about possible therapeutic effects of MSCs in COVID-19 infection.

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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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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.


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


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.


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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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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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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Ketogenic Diet Ameliorates Cardiac Dysfunction via Balancing Mitochondrial Dynamics and Inhibiting Apoptosis in Type 2 Diabetic Mice
Yongzheng Guo, Cheng Zhang, Fei-Fei Shang, Minghao Luo, Yuehua You, Qiming Zhai, Yong Xia, Luo Suxin
Aging and disease    2020, 11 (2): 229-240.   DOI: 10.14336/AD.2019.0510
Accepted: 01 June 2019
Online available: 01 June 2019

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The ketogenic diet (KD) has been widely used in clinical studies and shown to hace an anti-diabetic effect, but the underlying mechanisms have not been fully elaborated. Our aim was to investigate the effects and the underling mechanisms of the KD on cardiac function in db/db mice. In the present study, db/db mice were subjected to a normal diet (ND) or KD. Fasting blood glucose, cardiac function and morphology, mitochondrial dynamics, oxidative stress, and apoptosis were measured 8 weeks post KD treatment. Compared with the ND, the KD improved glycemic control and protected against diabetic cardiomyopathy in db/db mice, and improved mitochondrial function, as well as reduced oxidative stress were observed in hearts. In addition, KD treatment exerted an anti-apoptotic effect in the heart of db/db mice. Further data showed that the PI3K/Akt pathway was involved in this protective effect. Our data demonstrated that KD treatment ameliorates cardiac dysfunction by inhibiting apoptosis via activating the PI3K-Akt pathway in type 2 diabetic mice, suggesting that the KD is a promising lifestyle intervention to protect against diabetic cardiomyopathy.

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Cell Cycle Deficits in Neurodegenerative Disorders: Uncovering Molecular Mechanisms to Drive Innovative Therapeutic Development
Chitra Joseph,Abubakar Siddiq Mangani,Veer Gupta,Nitin Chitranshi,Ting Shen,Yogita Dheer,Devaraj KB,Mehdi Mirzaei,Yuyi You,Stuart L Graham,Vivek Gupta
Aging and disease    2020, 11 (4): 946-966.   DOI: 10.14336/AD.2019.0923
Accepted: 22 October 2019

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Cell cycle dysregulation has been implicated in the pathogenesis of neurodegenerative disorders. Specialised function obligates neuronal cells to subsist in a quiescent state of cell cycle once differentiated and therefore the circumstances and mechanisms underlying aberrant cell cycle activation in post-mitotic neurons in physiological and disease conditions remains an intriguing area of research. There is a strict requirement of concurrence to cell cycle regulation for neurons to ensure intracellular biochemical conformity as well as interrelationship with other cells within neural tissues. This review deliberates on various mechanisms underlying cell cycle regulation in neuronal cells and underscores potential implications of their non-compliance in neural pathology. Recent research suggests that successful duplication of genetic material without subsequent induction of mitosis induces inherent molecular flaws that eventually assert as apoptotic changes. The consequences of anomalous cell cycle activation and subsequent apoptosis are demonstrated by the increased presence of molecular stress response and apoptotic markers. This review delineates cell cycle events under normal physiological conditions and deficits amalgamated by alterations in protein levels and signalling pathways associated with cell-division are analysed. Cell cycle regulators essentially, cyclins, CDKs, cip/kip family of inhibitors, caspases, bax and p53 have been identified to be involved in impaired cell cycle regulation and associated with neural pathology. The pharmacological modulators of cell cycle that are shown to impart protection in various animal models of neurological deficits are summarised. Greater understanding of the molecular mechanisms that are indispensable to cell cycle regulation in neurons in health and disease conditions will facilitate targeted drug development for neuroprotection.

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Exercise Programs for Muscle Mass, Muscle Strength and Physical Performance in Older Adults with Sarcopenia: A Systematic Review and Meta-Analysis
Wangxiao Bao,Yun Sun,Tianfang Zhang,Liliang Zou,Xiaohong Wu,Daming Wang,Zuobing Chen
Aging and disease    2020, 11 (4): 863-873.   DOI: 10.14336/AD.2019.1012
Accepted: 23 October 2019

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Sarcopenia is an age-related condition that is characterized by progressive and generalized loss of muscle mass and function. Exercise treatment has been the most commonly used intervention among elderly populations. We performed a systematic review and meta-analysis to evaluate the available literature related to the effects of exercise interventions/programs on muscle mass, muscle strength and physical performance in older adults with sarcopenia. We searched PubMed, EMBASE, MEDLINE and the Web of Science for randomized controlled trials and controlled clinical trials exploring exercise in older adults with sarcopenia published through July 2019 without any language restrictions. Pooled analyses were conducted using Review Manager 5.3, with standardized mean differences (SMDs) and fixed-effect models. A total of 3898 titles and abstracts were initially identified, and 22 studies (1041 individuals, 80.75% females, mean age ranged from 60.51 to 85.90 years) were included in the meta-analysis. The exercise programs in the studies consisted of 30 to 80 min of training, with 1 to 5 training sessions weekly for 6 to 36 weeks. Muscle strength (grip strength [SMD 0.57, 95 % CI 0.42 to 0.73, P <0.00001] and timed five chair stands [SMD -0.56, 95 % CI -0.85 to -0.28, P < 0.0001]) and physical performance (gait speed [SMD 0.44, 95 % CI 0.26 to 0.61, P < 0.00001] and the timed up and go test [SMD -0.97, 95 % CI -1.22 to -0.72, P < 0.00001]) showed significant improvement following exercise treatment, while no differences in muscle mass (ASM [SMD 0.15, 95 % CI -0.05 to 0.36, P = 0.15] and ASM/height2 [SMD 0.21, 95 % CI -0.05 to 0.48, P = 0.12]) were detected. Exercise programs showed overall significant positive effects on muscle strength and physical performance but not on muscle mass in sarcopenic older adults.

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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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The Impact of CRISPR-Cas9 on Age-related Disorders: From Pathology to Therapy
Allen Caobi,Rajib Kumar Dutta,Luis D Garbinski,Maria Esteban-Lopez,Yasemin Ceyhan,Mickensone Andre,Marko Manevski,Chet Raj Ojha,Jessica Lapierre,Sneham Tiwari,Tiyash Parira,Nazira El-Hage
Aging and disease    2020, 11 (4): 895-915.   DOI: 10.14336/AD.2019.0927
Accepted: 11 October 2019

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With advances in medical technology, the number of people over the age of 60 is on the rise, and thus, increasing the prevalence of age-related pathologies within the aging population. Neurodegenerative disorders, cancers, metabolic and inflammatory diseases are some of the most prevalent age-related pathologies affecting the growing population. It is imperative that a new treatment to combat these pathologies be developed. Although, still in its infancy, the CRISPR-Cas9 system has become a potent gene-editing tool capable of correcting gene-mediated age-related pathology, and therefore ameliorating or eliminating disease symptoms. Deleting target genes using the CRISPR-Cas9 system or correcting for gene mutations may ameliorate many different neurodegenerative disorders detected in the aging population. Cancer cells targeted by the CRISPR-Cas9 system may result in an increased sensitivity to chemotherapeutics, lower proliferation, and higher cancer cell death. Finally, reducing gene targeting inflammatory molecules production through microRNA knockout holds promise as a therapeutic strategy for both arthritis and inflammation. Here we present a review based on how the expanding world of genome editing can be applied to disorders and diseases affecting the aging population.

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Sirtuins and their Biological Relevance in Aging and Age-Related Diseases
Lijun Zhao,Jianzhong Cao,Kexin Hu,Xiaodong He,Dou Yun,Tanjun Tong,Limin Han
Aging and disease    2020, 11 (4): 927-945.   DOI: 10.14336/AD.2019.0820
Accepted: 22 August 2019

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Sirtuins, initially described as histone deacetylases and gene silencers in yeast, are now known to have many more functions and to be much more abundant in living organisms. The increasing evidence of sirtuins in the field of ageing and age-related diseases indicates that they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. Here, we summarize some of the recent discoveries in sirtuin biology that clearly implicate the functions of sirtuins in the regulation of aging and age-related diseases. Furthermore, human sirtuins are considered promising therapeutic targets for anti-aging and ageing-related diseases and have attracted interest in scientific communities to develop small molecule activators or drugs to ameliorate a wide range of ageing disorders. In this review, we also summarize the discovery and development status of sirtuin-targeted drug and further discuss the potential medical strategies of sirtuins in delaying aging and treating age-related diseases.

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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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COVID-19 and Acute Sarcopenia
Carly Welch,Carolyn Greig,Tahir Masud,Daisy Wilson,Thomas A Jackson
Aging and disease    2020, 11 (6): 1345-1351.   DOI: 10.14336/AD.2020.1014
Accepted: 19 October 2020

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The COVID-19 pandemic has had a devastating global impact, with older adults being most at risk of death from the disease. However, acute sarcopenia occurs in survivors of COVID-19; older adults and the most critically unwell patients are the most at risk. Acute sarcopenia is an under-recognised condition of acute muscle insufficiency, defined by declines in muscle function and/or quantity within six months, usually following a stressor event. This commentary reviews definition and mechanisms of acute sarcopenia in COVID-19 and suggests recommendations for research and clinical practice. Research should now focus on the longer-term consequences of acute sarcopenia in patients who have suffered from COVID-19. At the same time, clinicians need to be increasingly aware of the condition, and measurements of muscle strength, quantity, and physical performance should be embedded into clinical practice. Clinicians should consider the risks of acute sarcopenia when weighing up the risks and benefits of treatment (e.g. dexamethasone), and instigate multidisciplinary treatment including dietetics input.

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A Glimmer of Hope: Maintain Mitochondrial Homeostasis to Mitigate Alzheimer’s Disease
Wenbo Li,Ling Kui,Tsirukis Demetrios,Xun Gong,Min Tang
Aging and disease    2020, 11 (5): 1260-1275.   DOI: 10.14336/AD.2020.0105
Accepted: 10 January 2020

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Mitochondria are classically known to be cellular energy producers. Given the high-energy demanding nature of neurons in the brain, it is essential that the mitochondrial pool remains healthy and provides a continuous and efficient supply of energy. However, mitochondrial dysfunction is inevitable in aging and neurodegenerative diseases. In Alzheimer’s disease (AD), neurons experience unbalanced homeostasis like damaged mitochondrial biogenesis and defective mitophagy, with the latter promoting the disease-defining amyloid β (Aβ) and p-Tau pathologies impaired mitophagy contributes to inflammation and the aggregation of Aβ and p-Tau-containing neurotoxic proteins. Interventions that restore defective mitophagy may, therefore, alleviate AD symptoms, pointing out the possibility of a novel therapy. This review aims to illustrate mitochondrial biology with a focus on mitophagy and propose strategies to treat AD while maintaining mitochondrial homeostasis.

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Geroscience in the Age of COVID-19
Nir Barzilai, James C Appleby, Steven N Austad, Ana Maria Cuervo, Matt Kaeberlein, Christian Gonzalez-Billault, Stephanie Lederman, Ilia Stambler, Felipe Sierra
Aging and disease    2020, 11 (4): 725-729.   DOI: 10.14336/AD.2020.0629
Accepted: 06 July 2020

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The data on COVID-19 is clear on at least one point: Older adults are most vulnerable to hospitalization, disability and death following infection with the novel coronavirus. Therefore, therapeutically addressing degenerative aging processes as the main risk factors appears promising for tackling the present crisis and is expected to be relevant when tackling future infections, epidemics and pandemics. Therefore, utilizing a geroscience approach, targeting aging processes to prevent multimorbidity, via initiating broad clinical trials of potential geroprotective therapies, is recommended.

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Innate and Adaptive Immunity in Aging and Longevity: The Foundation of Resilience
Alexey Moskalev,Ilia Stambler,Calogero Caruso
Aging and disease    2020, 11 (6): 1363-1373.   DOI: 10.14336/AD.2020.0603
Accepted: 02 June 2020

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The interrelation of the processes of immunity and senescence now receives an unprecedented emphasis during the COVID-19 pandemic, which brings to the fore the critical need to combat immunosenescence and improve the immune function and resilience of older persons. Here we review the historical origins and the current state of the science of innate and adaptive immunity in aging and longevity. From the modern point of view, innate and adaptive immunity are not only affected by aging but also are important parts of its underlying mechanisms. Excessive levels or activity of antimicrobial peptides, C-reactive protein, complement system, TLR/NF-κB, cGAS/STING/IFN 1,3 and AGEs/RAGE pathways, myeloid cells and NLRP3 inflammasome, declined levels of NK cells in innate immunity, thymus involution and decreased amount of naive T-cells in adaptive immunity, are biomarkers of aging and predisposition factors for cellular senescence and aging-related pathologies. Long-living species, human centenarians, and women are characterized by less inflamm-aging and decelerated immunosenescence. Despite recent progress in understanding, the harmonious theory of immunosenescence is still developing. Geroprotectors targeting these mechanisms are just emerging and are comprehensively discussed in this article.

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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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A Potential Role for Photobiomodulation Therapy in Disease Treatment and Prevention in the Era of COVID-19
Ann Liebert,Brian Bicknell,Wayne Markman,Hosen Kiat
Aging and disease    2020, 11 (6): 1352-1362.   DOI: 10.14336/AD.2020.0901
Accepted: 08 September 2020

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COVID-19 is an evolving pandemic that has far reaching global effects, with a combination of factors that makes the virus difficult to contain. The symptoms of infection can be devastating or at the least very debilitating for vulnerable individuals. It is clear that the elderly are at most risk of the adverse impacts of the virus, including hospitalization and death. Others at risk are those with comorbidities such as cardiovascular disease and metabolic conditions and those with a hyper-excitable immune response. Treatment options for those with acute responses to the virus are limited and there is an urgent need for potential strategies that can mitigate these severe effects. One potential avenue for treatment that has not been explored is the microbiome gut/lung axis. In addition to those severely affected by their acute reaction to the virus, there is also a need for treatment options for those that are slow to recover from the effects of the infection and also those who have been adversely affected by the measures put in place to arrest the spread of the virus. One potential treatment option is photobiomodulation (PBM) therapy. PBM has been shown over many years to be a safe, effective, non-invasive and easily deployed adjunctive treatment option for inflammatory conditions, pain, tissue healing and cellular energy. We have also recently demonstrated the effectiveness of PBM to alter the gut microbiome. PBM therapy is worthy of consideration as a potential treatment for those most vulnerable to COVID-19, such as the elderly and those with comorbidities. The treatment may potentially be advantageous for those infected with the virus, those who have a slow recovery from the effects of the virus and those who have been denied their normal exercise/rehabilitation programs due to the isolation restrictions that have been imposed to control the COVID-19 pandemic.

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COVID 19 - Clinical Picture in the Elderly Population: A Qualitative Systematic Review
Agnieszka Neumann-Podczaska,Salwan R Al-Saad,Lukasz M Karbowski,Michal Chojnicki,Slawomir Tobis,Katarzyna Wieczorowska-Tobis
Aging and disease    2020, 11 (4): 988-1008.   DOI: 10.14336/AD.2020.0620
Accepted: 03 July 2020

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The SARS-CoV-2 tendency to affect the older individuals more severely, raises the need for a concise summary isolating this age population. Analysis of clinical features in light of most recently published data allows for improved understanding, and better clinical judgement. A thorough search was performed to collect all articles published from 1st of January to 1st of June 2020, using the keywords COVID-19 and SARS-CoV-2 followed by the generic terms elderly, older adults or older individuals. The quality assessment of studies and findings was performed by an adaptation of the STROBE statement and CERQual approach. Excluding duplicates, a total of 1598 articles were screened, of which 20 studies were included in the final analysis, pertaining to 4965 older COVID-19 patients (≥60 years old). Variety in symptoms was observed, with fever, cough, dyspnea, fatigue, or sputum production being the most common. Prominent changes in laboratory findings consistently indicated lymphopenia and inflammation and in some cases organ damage. Radiological examination reveals ground glass opacities with occasional consolidations, bilaterally, with a possible peripheral tendency. An evident fraction of the elderly population (25.7%) developed renal injury or impairment as a complication. Roughly 71.4% of the older adults require supplementary oxygen, while invasive mechanical ventilation was required in almost a third of the reported hospitalized older individuals. In this review, death occurred in 20.0% of total patients with a recorded outcome (907/4531). Variability in confidence of findings is documented. Variety in symptom presentation is to be expected, and abnormalities in laboratory findings are present. Risk for mortality is evident, and attention to the need for supplementary oxygen and possible mechanical ventilation is advised. Further data is required isolating this age population. Presented literature may allow for the construction of better predictive models of COVID-19 in older populations.

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The Application of Artificial Intelligence in the Genetic Study of Alzheimer’s Disease
Rohan Mishra,Bin Li
Aging and disease    2020, 11 (6): 1567-1584.   DOI: 10.14336/AD.2020.0312
Accepted: 16 March 2020

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Alzheimer's disease (AD) is a neurodegenerative disease in which genetic factors contribute approximately 70% of etiological effects. Studies have found many significant genetic and environmental factors, but the pathogenesis of AD is still unclear. With the application of microarray and next-generation sequencing technologies, research using genetic data has shown explosive growth. In addition to conventional statistical methods for the processing of these data, artificial intelligence (AI) technology shows obvious advantages in analyzing such complex projects. This article first briefly reviews the application of AI technology in medicine and the current status of genetic research in AD. Then, a comprehensive review is focused on the application of AI in the genetic research of AD, including the diagnosis and prognosis of AD based on genetic data, the analysis of genetic variation, gene expression profile, gene-gene interaction in AD, and genetic analysis of AD based on a knowledge base. Although many studies have yielded some meaningful results, they are still in a preliminary stage. The main shortcomings include the limitations of the databases, failing to take advantage of AI to conduct a systematic biology analysis of multilevel databases, and lack of a theoretical framework for the analysis results. Finally, we outlook the direction of future development. It is crucial to develop high quality, comprehensive, large sample size, data sharing resources; a multi-level system biology AI analysis strategy is one of the development directions, and computational creativity may play a role in theory model building, verification, and designing new intervention protocols for AD.

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Hypoxia-Induced Degenerative Protein Modifications Associated with Aging and Age-Associated Disorders
Sunil S Adav, Siu Kwan Sze
Aging and disease    2020, 11 (2): 341-364.   DOI: 10.14336/AD.2019.0604
Accepted: 05 June 2019

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Aging is an inevitable time-dependent decline of various physiological functions that finally leads to death. Progressive protein damage and aggregation have been proposed as the root cause of imbalance in regulatory processes and risk factors for aging and neurodegenerative diseases. Oxygen is a modulator of aging. The oxygen-deprived conditions (hypoxia) leads to oxidative stress, cellular damage and protein modifications. Despite unambiguous evidence of the critical role of spontaneous non-enzymatic Degenerative Protein Modifications (DPMs) such as oxidation, glycation, carbonylation, carbamylation, and deamidation, that impart deleterious structural and functional protein alterations during aging and age-associated disorders, the mechanism that mediates these modifications is poorly understood. This review summarizes up-to-date information and recent developments that correlate DPMs, aging, hypoxia, and age-associated neurodegenerative diseases. Despite numerous advances in the study of the molecular hallmark of aging, hypoxia, and degenerative protein modifications during aging and age-associated pathologies, a major challenge remains there to dissect the relative contribution of different DPMs in aging (either natural or hypoxia-induced) and age-associated neurodegeneration.

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Aging-Induced Brain-Derived Neurotrophic Factor in Adipocyte Progenitors Contributes to Adipose Tissue Dysfunction
Hyun-Doo Song, Sang Nam Kim, Abhirup Saha, Sang-Yeop Ahn, Seun Akindehin, Yeonho Son, Yoon Keun Cho, MinSu Kim, Ji-Hyun Park, Young-Suk Jung, Yun-Hee Lee
Aging and disease    2020, 11 (3): 575-587.   DOI: 10.14336/AD.2019.0810
Accepted: 14 August 2019

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Aging-related adipose tissue dysfunction contributes to the progression of chronic metabolic diseases. We investigated the role of age-dependent expression of a neurotrophin, brain-derived neurotrophic factor (BDNF) in adipose tissue. Pro-BDNF expression was elevated in epididymal white adipose tissue (eWAT) with advanced age, which was associated with the reduction in sympathetic innervation. Interestingly, BDNF expression was enriched in PDGFRα+ adipocyte progenitors isolated from eWAT, with age-dependent increase in expression. In vitro pro-BDNF treatment caused apoptosis in adipocytes differentiated from C3H10T1/2 cells, and siRNA knockdown of sortilin mitigated these effects. Tamoxifen-inducible PDGFRα+ cell-specific deletion of BDNF (BDNFPdgfra KO) reduced pro-BDNF expression in eWAT, prevented age-associated declines in sympathetic innervation and mitochondrial content in eWAT, and improved insulin sensitivity. Moreover, BDNFPdgfra KO mice showed reduced expression of aging-induced inflammation and senescence markers in eWAT. Collectively, these results identified the upregulation of pro-BDNF expression in adipocyte progenitors as a feature of visceral white adipose tissue aging and suggested that inhibition of BDNF expression in adipocyte progenitors is potentially beneficial to prevent aging-related adipose tissue dysfunction.

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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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T1-weighted MRI-driven Brain Age Estimation in Alzheimer’s Disease and Parkinson’s Disease
Iman Beheshti, Shiwangi Mishra, Daichi Sone, Pritee Khanna, Hiroshi Matsuda
Aging and disease    2020, 11 (3): 618-628.   DOI: 10.14336/AD.2019.0617
Accepted: 21 July 2019

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Neuroimaging-driven brain age estimation has introduced a robust (reliable and heritable) biomarker for detecting and monitoring neurodegenerative diseases. Here, we computed and compared brain age in Alzheimer’s disease (AD) and Parkinson’s disease (PD) patients using an advanced machine learning procedure involving T1-weighted MRI scans and gray matter (GM) and white matter (WM) models. Brain age estimation frameworks were built using 839 healthy individuals and then the brain estimated age difference (Brain-EAD: chronological age subtracted from brain estimated age) was assessed in a large sample of PD patients (n = 160) and AD patients (n = 129), respectively. The mean Brain-EADs for GM were +9.29 ± 6.43 years for AD patients versus +1.50 ± 6.03 years for PD patients. For WM, the mean Brain-EADs were +8.85 ± 6.62 years for AD patients versus +2.47 ± 5.85 years for PD patients. In addition, PD patients showed a significantly higher WM Brain-EAD than GM Brain-EAD. In a direct comparison between PD and AD patients, we observed significantly higher Brain-EAD values in AD patients for both GM and WM. A comparison of the Brain-EAD between PD and AD patients revealed that AD patients may have a significantly “older-appearing” brain than PD patients.

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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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Stem Cell Based Therapy Option in COVID-19: Is It Really Promising?
Duygu Koyuncu Irmak,Hakan Darıcı,Erdal Karaöz
Aging and disease    2020, 11 (5): 1174-1191.   DOI: 10.14336/AD.2020.0608
Accepted: 07 August 2020

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The COVID-19 patients were first detected in China, in December 2019, then the novel virus with associated pneumonia and other diseases spread quickly to worldwide becoming a serious public health intimidation. Despite all the efforts, the pharmacological agents used for controlling or treating the disease, especially respiratory problems, have not been accomplished so far. Among various treatment options, mesenchymal stem cell-based cellular therapies are being investigated, because of their regeneration ability and multipotency along with other features like immunomodulation, antifibrosis and anti-inflammatory effects. This paper intends to analyze the current clinical trials on stem cell treatment of novel virus, searching and reviewing the available information and the International Clinical Trials Registry Platform (ICTRP) of World Health Organization (WHO). We concluded that the stem cell treatment of COVID-19 is found promising with pilot studies’ results, but still in the early development phase. There is an urgent need for large-scale investigations to confirm and validate the safety and efficacy profile of these therapies with reliable scientific evidence.

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Relationships between Mitochondrial Dysfunction and Neurotransmission Failure in Alzheimer’s Disease
Kan Yin Wong,Jaydeep Roy,Man Lung Fung,Boon Chin Heng,Chengfei Zhang,Lee Wei Lim
Aging and disease    2020, 11 (5): 1291-1316.   DOI: 10.14336/AD.2019.1125
Accepted: 31 March 2020

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Besides extracellular deposition of amyloid beta and formation of phosphorylated tau in the brains of patients with Alzheimer’s disease (AD), the pathogenesis of AD is also thought to involve mitochondrial dysfunctions and altered neurotransmission systems. However, none of these components can describe the diverse cognitive, behavioural, and psychiatric symptoms of AD without the pathologies interacting with one another. The purpose of this review is to understand the relationships between mitochondrial and neurotransmission dysfunctions in terms of (1) how mitochondrial alterations affect cholinergic and monoaminergic systems via disruption of energy metabolism, oxidative stress, and apoptosis; and (2) how different neurotransmission systems drive mitochondrial dysfunction via increasing amyloid beta internalisation, oxidative stress, disruption of mitochondrial permeabilisation, and mitochondrial trafficking. All these interactions are separately discussed in terms of neurotransmission systems. The association of mitochondrial dysfunctions with alterations in dopamine, norepinephrine, and histamine is the prospective goal in this research field. By unfolding the complex interactions surrounding mitochondrial dysfunction in AD, we can better develop potential treatments to delay, prevent, or cure this devastating disease.

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Decreased Naïve T-cell Production Leading to Cytokine Storm as Cause of Increased COVID-19 Severity with Comorbidities
Michael D Schwartz,Stephen G Emerson,Jennifer Punt,Willow D Goff
Aging and disease    2020, 11 (4): 742-745.   DOI: 10.14336/AD.2020.0619
Accepted: 23 June 2020

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Aging, type 2 diabetes, and male gender are major risk factors leading to increased COVID-19 morbidity and mortality. Thymic production and the export of naïve T cells decrease with aging through the effects of androgens in males and in type 2 diabetes. Furthermore, with aging, recovery of naïve T-cell populations after bone marrow transplantation is delayed and associated with an increased risk of chronic graft vs. host disease. Severe COVID-19 and SARS infections are notable for severe T-cell depletion. In COVID-19, there is unique suppression of interferon signaling by infected respiratory tract cells with intact cytokine signaling. A decreased naïve T-cell response likely contributes to an excessive inflammatory response and increases the odds of a cytokine storm. Treatments that improve naïve T-cell production may prove to be vital COVID-19 therapies, especially for these high-risk groups.

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Neuroprotective Effects of Endogenous Secretory Receptor for Advanced Glycation End-products in Brain Ischemia
Yu Shimizu, Ai Harashima, Seiichi Munesue, Masahiro Oishi, Tsuyoshi Hattori, Osamu Hori, Yasuko Kitao, Hiroshi Yamamoto, Nontaphat Leerach, Mitsutoshi Nakada, Yasuhiko Yamamoto, Yasuhiko Hayashi
Aging and disease    2020, 11 (3): 547-558.   DOI: 10.14336/AD.2019.0715
Accepted: 26 July 2019

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The receptor for advanced glycation end-products (RAGE) is expressed on human brain endothelial cells (HBEC) and is implicated in neuronal cell death after ischemia. We report that endogenous secretory RAGE (esRAGE) is a splicing variant form of RAGE that functions as a decoy against ischemia-induced neuronal cell damage. This study demonstrated that esRAGE was associated with heparan sulphate proteoglycans on HBEC. The parabiotic experiments between human esRAGE overexpressing transgenic (Tg), RAGE knockout (KO), and wild-type (WT) mice revealed a significant neuronal cell damage in the CA1 region of the WT side of parabiotic WT→WT mice, but not of Tg→WT mice, 7 days after bilateral common carotid artery occlusion. Human esRAGE was detected around the CA1 neurons in the WT side of the parabiotic Tg→WT pair, but not in the KO side of the Tg→KO pair. To elucidate the dynamic transfer of esRAGE into the brain, we used the blood-brain barrier (BBB) system (PharmaCo-Cell) with or without RAGE knockdown in endothelial cells. A RAGE-dependent transfer of esRAGE was demonstrated from the vascular to the brain side. These findings suggested that esRAGE is associated with heparan sulphate proteoglycans and is transferred into the brain via BBB to exert its neuroprotective effects in ischemia.

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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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Infrapatellar Fat Pad and Knee Osteoarthritis
Ni Zeng,Zhi-Peng Yan,Xin-Yuan Chen,Guo-Xin Ni
Aging and disease    2020, 11 (5): 1317-1328.   DOI: 10.14336/AD.2019.1116
Accepted: 06 December 2019

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Osteoarthritis is the most prevalent arthritis typically characterized by degradation of cartilage. However, its pathogenesis is not fully understood. Currently, osteoarthritis is best considered a disease of the whole “joint organ”. Infrapatellar fat pad (IFP), an adipose tissue near synovium, is now attaching importance to researchers for its inflammatory phenotype. In this narrative review, a large body of evidence has been gathered for the involvement of IFP in the development of knee osteoarthritis. Additionally, the underlying mechanisms of how IFP can be involved in this process have been proposed. However, further investigations are needed to better understand its precise role in this process and its underlying mechanism, and beyond that, to develop new strategies to slow down the degenerative process and explore an effective and timely diagnosis of the disease.

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Immune Characteristics of Patients with Coronavirus Disease 2019 (COVID-19)
Xiaotian Dong, Mengyan Wang, Shuangchun Liu, Jiaqi Zhu, Yanping Xu, Hongcui Cao, Lanjuan Li
Aging and disease    2020, 11 (3): 642-648.   DOI: 10.14336/AD.2020.0317
Accepted: 19 March 2020
Online available: 20 March 2020

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Up to now, little is known about the detailed immune profiles of COVID-19 patients from admission to discharge. In this study we retrospectively reviewed the clinical and laboratory characteristics of 18 COVID-19 patients from January 30, 2020 to February 21, 2020. These patients were divided into two groups; group 1 had a severe acute respiratory syndrome coronavirus 2 nucleic acid-positive duration for more than 15 days (n = 6) and group 2 had a nucleic acid-positive duration for less than 15 days (n = 12). Group 1 patients had lower level of peripheral blood lymphocytes (0.40 vs. 0.78 ×109/L, p = 0.024) and serum potassium (3.36 vs. 3.79 mmol/L, p = 0.043) on admission but longer hospitalization days (23.17 vs. 15.75 days, p < 0.001) compared to Group 2 patients. Moreover, baseline level of lymphocytes (r = -0.62, p = 0.006) was negatively correlated with the nucleic acid-positive duration. Additionally, lymphocytes (420.83 vs. 1100.56 /μL), T cells (232.50 vs. 706.78 /μL), CD4+ T cells (114.67 vs. 410.44 /μL), and CD8+ T cells (94.83 vs. 257.44 /μL) in the peripheral blood analyzed by flow cytometry were significantly different between Group 1and Group 2. Furthermore, there was also a negative correlation between lymphocytes (r = -0.54, p = 0.038) or T cells (r = -0.55, p = 0.034) at diagnosis and the nucleic acid-positive duration, separately. In conclusion, the patients with nucleic acid-positive ≥ 15 days had significantly decreased lymphocytes, T cell and its subsets compared to those who remained positive for less than 15 days.

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Artemisinin Improved Neuronal Functions in Alzheimer's Disease Animal Model 3xtg Mice and Neuronal Cells via Stimulating the ERK/CREB Signaling Pathway
Xia Zhao,Shuai Li,Uma Gaur,Wenhua Zheng
Aging and disease    2020, 11 (4): 801-819.   DOI: 10.14336/AD.2019.0813
Accepted: 12 October 2019

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The most common form of dementia is Alzheimer’s disease which is characterized by memory loss and cognitive disorders. The pathogenesis of Alzheimer’s disease is not known at present but toxicity of amyloid-beta is one of the central hypotheses. Amyloid-beta can stimulate the production of reactive oxygen species (ROS), cause oxidative stress, damage mitochondrial, cause inflammatory reactions and activate apoptosis related factors which lead to the neuronal death. In this study, we found that artemisinin, a first line antimalarial drug used in clinic for decades, improved the cognitive functions in Alzheimer’s disease animal model 3xTg mice. Further study showed that artemisinin reduced the deposition of amyloid-beta and tau protein, reduced the release of inflammation factors and apoptosis factors, and thereby reduced the neuronal cell death. Western blot assay showed that artemisinin stimulated the activation of ERK/CREB signaling pathway. Consistent with these results, artemisinin concentration-dependently promoted the survival of SH-SY5Y cell against toxicity of amyloid-beta protein 1-42 induced ROS accumulation, caspase activation and apoptosis. Artemisinin also stimulated the phosphorylation of ERK1/2 and CREB in SH-SY5Y cells in time and concentration-dependent manner. Inhibition of ERK/CREB pathway attenuated the protective effect of artemisinin. These data put together suggested that artemisinin has the potential to protect neuronal cells in vitro as well as in vivo animal model 3xTg mice via, at least in part, the activation of the ERK/CREB pathway. Our findings also strongly support the potential of artemisinin as a new multi-target drug that can be used for preventing and treating the Alzheimer’s disease.

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Pyroptosis Plays a Role in Osteoarthritis
Senbo An,Huiyu Hu,Yusheng Li,Yihe Hu
Aging and disease    2020, 11 (5): 1146-1157.   DOI: 10.14336/AD.2019.1127
Accepted: 30 November 2019

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Recent studies have revealed novel forms of cell death beyond the canonical types of cellular apoptosis and necrosis, and these novel forms of cell death are induced by extreme microenvironmental factors. Pyroptosis, a type of regulated cell death, occurs when pattern recognition receptors (PRRs) induce the activation of cysteine-aspartic protease 1 (caspase-1) or caspase-11, which can trigger the release of the pyrogenic cytokines interleukin-1β (IL-1β) and IL-18. Osteoarthritis (OA), the most common joint disease worldwide, is characterized by low-grade inflammation and increased levels of cytokines, including IL-1β and IL-18. Additionally, some damaged chondrocytes associated with OA exhibit morphological changes consistent with pyroptosis, suggesting that this form of regulated cell death may contribute significantly to the pathology of OA. This review summarizes the molecular mechanisms of pyroptosis and shows the critical role of NLRP3 (NLR family, pyrin domain containing 3; NLR refers to “nucleotide-binding domain, leucine-rich repeat”) inflammasomes. We also provide evidence describing potential role of pyroptosis in OA, including the relationship with OA risk factors and the contribution to cartilage degradation, synovitis and OA pain.

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Circular RNAs: Promising Biomarkers for Age-related Diseases
Yan-hong Pan,Wei-peng Wu,Xing-dong Xiong
Aging and disease    2020, 11 (6): 1585-1593.   DOI: 10.14336/AD.2020.0309
Accepted: 13 March 2020

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Aging is a complex biological process closely linked with the occurrence and development of age-related diseases. Despite recent advances in lifestyle management and drug therapy, the late diagnosis of these diseases causes severe complications, usually resulting in death and consequently impacting social economies. Therefore, the identification of reliable biomarkers and the creation of effective treatment alternatives for age-related diseases are needed. Circular RNAs (circRNAs) are a novel class of RNA molecules that form covalently closed loops capable of regulating gene expression at multiple levels. Several studies have reported the emerging functional roles of circRNAs in various conditions, providing new perspectives regarding cellular physiology and disease pathology. Notably, accumulating evidence demonstrates the involvement of circRNAs in the regulation of age-related pathologies, including cardio-cerebrovascular disease, neurodegenerative disease, cancer, diabetes, rheumatoid arthritis, and osteoporosis. Therefore, the association of circRNAs with these age-related pathologies highlights their potential as diagnostic biomarkers and therapeutic targets for better disease management. Here, we review the biogenesis and function of circRNAs, with a special focus on their regulatory roles in aging-related pathologies, as well as discuss their potential as biological biomarkers and therapeutic targets for these diseases.

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Mechanism of Ferroptosis: A Potential Target for Cardiovascular Diseases Treatment
Jie Ju,Ya-nan Song,Kun Wang
Aging and disease    2021, 12 (1): 261-276.   DOI: 10.14336/AD.2020.0323
Accepted: 11 April 2020

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Ferroptosis is a form of programmed cell death caused by production of reactive oxygen species and disequilibrium of iron homeostasis. Many chemical compounds and clinical drugs induce ferroptosis in normal and cancer cells, while peroxidation inhibitors, iron chelators, and antioxidants can block ferroptosis. Glutathione peroxidase 4, ferroptosis suppressor protein 1, nuclear factor erythroid 2-related factor 2, and system Xc- are the negative regulators of ferroptosis, whereas nicotinamide adenine dinucleotide phosphate oxidase, p53, mitochondria voltage-dependent anion channel, and cysteinyl-tRNA synthetase function as positive regulators. Ferroptosis plays important roles in pathogen infection and tumor immunology. Recent studies suggest that ferroptosis plays a vital role in the pathogenesis of cardiovascular diseases (CVDs), which seriously threaten human health. Potential therapies designed around ferroptosis may alter the pathological progression of CVDs. Therefore, we redacted an overview of the discovery of ferroptosis, its regulatory mechanisms, and its potential impact on CVDs treatment.

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