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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

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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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Metformin Alters Locomotor and Cognitive Function and Brain Metabolism in Normoglycemic Mice
Wenjun Li, Kiran Chaudhari, Ritu Shetty, Ali Winters, Xiaofei Gao, Zeping Hu, Woo-Ping Ge, Nathalie Sumien, Michael Forster, Ran Liu, Shao-Hua Yang
Aging and disease    2019, 10 (5): 949-963.   DOI: 10.14336/AD.2019.0120
Accepted: 25 January 2019

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Metformin is currently the most effective treatment for type-2 diabetes. The beneficial actions of metformin have been found even beyond diabetes management and it has been considered as one of the most promising drugs that could potentially slow down aging. Surprisingly, the effect of metformin on brain function and metabolism has been less explored given that brain almost exclusively uses glucose as substrate for energy metabolism. We determined the effect of metformin on locomotor and cognitive function in normoglycemic mice. Metformin enhanced locomotor and balance performance, while induced anxiolytic effect and impaired cognitive function upon chronic treatment. We conducted in vitro assays and metabolomics analysis in mice to evaluate metformin’s action on the brain metabolism. Metformin decreased ATP level and activated AMPK pathway in mouse hippocampus. Metformin inhibited oxidative phosphorylation and elevated glycolysis by inhibiting mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) in vitro at therapeutic doses. In summary, our study demonstrated that chronic metformin treatment affects brain bioenergetics with compound effects on locomotor and cognitive brain function in non-diabetic mice.

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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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Enhancement of Mesenchymal Stem Cell-Driven Bone Regeneration by Resveratrol-Mediated SOX2 Regulation
Yoorim Choi, Dong Suk Yoon, Kyoung-Mi Lee, Seong Mi Choi, Myon-Hee Lee, Kwang Hwan Park, Seung Hwan Han, Jin Woo Lee
Aging and disease    2019, 10 (4): 818-833.   DOI: 10.14336/AD.2018.0802
Accepted: 18 September 2018

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Mesenchymal stem cells (MSCs) are an attractive cell source for regenerative medicine. However, MSCs age rapidly during long-term ex vivo culture and lose their therapeutic potential before they reach effective cell doses (ECD) for cell therapy. Thus, a prerequisite for effective MSC therapy is the development of cell culture methods to preserve the therapeutic potential during long-term ex vivo cultivation. Resveratrol (RSV) has been highlighted as a therapeutic candidate for bone disease. Although RSV treatment has beneficial effects on bone-forming cells, in vivo studies are lacking. The current study showed that long-term (6 weeks from primary culture date)-cultured MSCs with RSV induction retained their proliferative and differentiation potential despite reaching ECD. The mechanism of RSV action depends entirely on the SIRT1-SOX2 axis in MSC culture. In a rat calvarial defect model, RSV induction significantly improved bone regeneration after MSC transplantation. This study demonstrated an example of efficient MSC therapy for treating bone defects by providing a new strategy using the plant polyphenol RSV.

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Health and Aging: Unifying Concepts, Scores, Biomarkers and Pathways
Georg Fuellen, Ludger Jansen, Alan A Cohen, Walter Luyten, Manfred Gogol, Andreas Simm, Nadine Saul, Francesca Cirulli, Alessandra Berry, Peter Antal, Rüdiger Köhling, Brecht Wouters, Steffen Möller
Aging and disease    2019, 10 (4): 883-900.   DOI: 10.14336/AD.2018.1030
Accepted: 19 November 2018

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Despite increasing research efforts, there is a lack of consensus on defining aging or health. To understand the underlying processes, and to foster the development of targeted interventions towards increasing one’s health, there is an urgent need to find a broadly acceptable and useful definition of health, based on a list of (molecular) features; to operationalize features of health so that it can be measured; to identify predictive biomarkers and (molecular) pathways of health; and to suggest interventions, such as nutrition and exercise, targeted at putative causal pathways and processes. Based on a survey of the literature, we propose to define health as a state of an individual characterized by the core features of physiological, cognitive, physical and reproductive function, and a lack of disease. We further define aging as the aggregate of all processes in an individual that reduce its wellbeing, that is, its health or survival or both. We define biomarkers of health by their attribute of predicting future health better than chronological age. We define healthspan pathways as molecular features of health that relate to each other by belonging to the same molecular pathway. Our conceptual framework may integrate diverse operationalizations of health and guide precision prevention efforts.

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Adipose-derived Stem Cells Attenuates Diabetic Osteoarthritis via Inhibition of Glycation-mediated Inflammatory Cascade
Navneet Kumar Dubey, Hong-Jian Wei, Sung-Hsun Yu, David F. Williams, Joseph R. Wang, Yue-Hua Deng, Feng-Chou Tsai, Peter D. Wang, Win-Ping Deng
Aging and disease    2019, 10 (3): 483-496.   DOI: 10.14336/AD.2018.0616
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Diabetes mellitus (DM) is well-known to exert complications such as retinopathy, cardiomyopathy and neuropathy. However, in recent years, an elevated osteoarthritis (OA) complaints among diabetics have been observed, portending the risk of diabetic OA. Since formation of advanced glycation end products (AGE) is believed to be the etiology of various diseases under hyperglycemic conditions, we firstly established that streptozotocin-induced DM could potentiate the development of OA in C57BL/6J mouse model, and further explored the intra-articularly administered adipose-derived stem cell (ADSC) therapy focusing on underlying AGE-associated mechanism. Our results demonstrated that hyperglycemic mice exhibited OA-like structural impairments including a proteoglycan loss and articular cartilage fibrillations in knee joint. Highly expressed levels of carboxymethyl lysine (CML), an AGE and their receptors (RAGE), which are hallmarks of hyperglycemic microenvironment were manifested. The elevated oxidative stress in diabetic OA knee-joint was revealed through increased levels of malondialdehyde (MDA). Further, oxidative stress-activated nuclear factor kappa B (NF-κB), the marker of proinflammatory signalling pathway was also accrued; and levels of matrix metalloproteinase-1 and 13 were upregulated. However, ADSC treatment attenuated all OA-like changes by 4 weeks, and dampened levels of CML, RAGE, MDA, NF-κB, MMP-1 and 13. These results suggest that during repair and regeneration, ADSCs inhibited glycation-mediated inflammatory cascade and rejuvenated cartilaginous tissue, thereby promoting knee-joint integrity in diabetic milieu.

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The role of CD2AP in the Pathogenesis of Alzheimer's Disease
Qing-Qing Tao, Yu-Chao Chen, Zhi-Ying Wu
Aging and disease    2019, 10 (4): 901-907.   DOI: 10.14336/AD.2018.1025
Accepted: 08 December 2018

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Alzheimer’s disease (AD) is the most common neurodegenerative disease characterized by irreversible decline in cognition with unclear pathogenesis. Recently, accumulating evidence has revealed that CD2 associated protein (CD2AP), a scaffolding molecule regulates signal transduction and cytoskeletal molecules, is implicated in AD pathogenesis. Several single nucleotide polymorphisms (SNPs) in CD2AP gene are associated with higher risk for AD and mRNA levels of CD2AP are decreased in peripheral lymphocytes of sporadic AD patients. Furthermore, CD2AP loss of function is linked to enhanced Aβ production, Tau-induced neurotoxicity, abnormal neurite structure modulation and reduced blood-brain barrier integrity. This review is to summarize the recent discoveries about the genetics and known functions of CD2AP. The recent evidence concerning the roles of CD2AP in the AD pathogenesis is summarized and CD2AP can be a promising therapeutic target for AD.

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Rejuvenating Strategies of Tissue-specific Stem Cells for Healthy Aging
Min-jun Wang, Jiajia Chen, Fei Chen, Qinggui Liu, Yu Sun, Chen Yan, Tao Yang, Yiwen Bao, Yi-Ping Hu
Aging and disease    2019, 10 (4): 871-882.   DOI: 10.14336/AD.2018.1119
Accepted: 26 November 2018

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Although aging is a physiological process, it has raised interest in the science of aging and rejuvenation because of the increasing burden on the rapidly aging global population. With advanced age, there is a decline in homeostatic maintenance and regenerative responsiveness to the injury of various tissues, thereby contributing to the incidence of age-related diseases. The primary cause of the functional declines that occur along with aging is considered to be the exhaustion of stem cell functions in their corresponding tissues. Age-related changes in the systemic environment, the niche, and stem cells contribute to this loss. Thus, the reversal of stem cell aging at the cellular level might lead to the rejuvenation of the animal at an organismic level and the prevention of aging, which would be critical for developing new therapies for age-related dysfunction and diseases. Here, we will explore the effects of aging on stem cells in different tissues. The focus of this discussion is on pro-youth interventions that target intrinsic stem cell properties, environmental niche component, systemic factors, and senescent cellular clearance, which are promising for developing strategies related to the reversal of aged stem cell function and optimizing tissue repair processes.

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Reactive Astrocytes in Neurodegenerative Diseases
Kunyu Li, Jiatong Li, Jialin Zheng, Song Qin
Aging and disease    2019, 10 (3): 664-675.   DOI: 10.14336/AD.2018.0720
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Astrocytes, the largest and most numerous glial cells in the central nervous system (CNS), play a variety of important roles in regulating homeostasis, increasing synaptic plasticity and providing neuroprotection, thus helping to maintain normal brain function. At the same time, astrocytes can participate in the inflammatory response and play a key role in the progression of neurodegenerative diseases. Reactive astrocytes are strongly induced by numerous pathological conditions in the CNS. Astrocyte reactivity is initially characterized by hypertrophy of soma and processes, triggered by different molecules. Recent studies have demonstrated that neuroinflammation and ischemia can elicit two different types of reactive astrocytes, termed A1s and A2s. However, in the case of astrocyte reactivity in different neurodegenerative diseases, the recently published research issues remain a high level of conflict and controversy. So far, we still know very little about whether and how the function or reactivity of astrocytes changes in the progression of different neurodegenerative diseases. In this review, we aimed to briefly discuss recent studies highlighting the complex contribution of astrocytes in the process of various neurodegenerative diseases, which may provide us with new prospects for the development of an excellent therapeutic target for neurodegenerative diseases.

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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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Emerging Roles of Complement Protein C1q in Neurodegeneration
Kyoungjoo Cho
Aging and disease    2019, 10 (3): 652-663.   DOI: 10.14336/AD.2019.0118
Accepted: 27 January 2019

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The innate immune system is an ancient and primary component system that rapidly reacts to defend the body against external pathogens. C1 is the initial responder of classical pathway of the innate immune system. C1 is comprised of C1q, C1r, and C1s. Among them, C1q is known to interact with diverse ligands, which can perform various functions in physiological and pathophysiological conditions. Because C1q participates in the clearance of pathogens, its interaction with novel receptors is expected to facilitate apoptosis induction, which could prevent the onset or progression of neurodegenerative diseases and could delay the aging process. Because senescence-associated secreting phenotype determinants are generally inflammatory cytokines or immune factors to activate immune cells. In the central nervous system, C1q has diverse neuroprotective roles against pathogens and inflammation. Most of neurodegenerative diseases show region specific pathology feature in the brain. It has been suggested the evidences that the active site and amount of C1q may be disease specific. This review considers currently the emerging and under-recognized roles of C1q in neurodegeneration and highlights the need for further research to clarify these roles. Future studies on the roles of C1q in regulating disease progression should consider these aspects, including the age-dependent onset time of each neurodegenerative disease progression.

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Mitochondrial Creatine Kinase is Decreased in the Serum of Idiopathic Parkinson’s Disease Patients
Jinghui Xu, Xiaodi Fu, Mengqiu Pan, Xiao Zhou, Zhaoyu Chen, Dongmei Wang, Xiaomei Zhang, Qiong Chen, Yanhui Li, Xiaoxian Huang, Guanghui Liu, Jianjun Lu, Yan Liu, Yafang Hu, Suyue Pan, Qing Wang, Qun Wang, Yunqi Xu
Aging and disease    2019, 10 (3): 601-610.   DOI: 10.14336/AD.2018.0615
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Mitochondrial creatine kinase (MtCK) is vital in the process of mitochondrial energy metabolism, and mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson’s disease (PD). Therefore, we speculated that MtCK activity could be altered in the serum of PD patients. However, no studies to date have investigated this specific topic, so we sought to investigate the serum MtCK activities among a cohort of PD patients. 50 patients with PD and 30 age-matched controls were recruited for this study. Serum ubiquitous MtCK (uMtCK) and sarcomeric MtCK (sMtCK) activities were assayed using an immunoinhibition method. Correlations between serum uMtCK/sMtCK activities and clinical features/parameters were explored in the PD group. Our study revealed a significant decrease in the uMtCK activity in the PD group when compared with the control group. No significant difference was found in the serum sMtCK activity between the PD and control groups. There was a significant correlation between serum uMtCK activities and the disease progression rate, duration, and age at onset in PD patients. While no significant relationship was found between the serum uMtCK activities and the Hoehn & Yahr stage or main non-motor symptoms scale. There was a significant decrease in the uMtCK activity in the serum of PD patients, which was associated with the rate of disease progression, duration, and age at onset of disease. Therefore, uMtCK activity in serum offers a useful clue for identification of PD biomarkers.

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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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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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Necrostatin-1 Prevents Necroptosis in Brains after Ischemic Stroke via Inhibition of RIPK1-Mediated RIPK3/MLKL Signaling
Xu-Xu Deng, Shan-Shan Li, Feng-Yan Sun
Aging and disease    2019, 10 (4): 807-817.   DOI: 10.14336/AD.2018.0728
Accepted: 04 September 2018

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Pharmacological studies have indirectly shown that necroptosis participates in ischemic neuronal death. However, its mechanism has yet to be elucidated in the ischemic brain. TNFα-triggered RIPK1 kinase activation could initiate RIPK3/MLKL-mediated necroptosis under inhibition of caspase-8. In the present study, we performed middle cerebral artery occlusion (MCAO) to induce cerebral ischemia in rats and used immunoblotting and immunostaining combined with pharmacological analysis to study the mechanism of necroptosis in ischemic brains. In the ipsilateral hemisphere, we found that ischemia induced the increase of (i) RIPK1 phosphorylation at the Ser166 residue (p-RIPK1), representing active RIPK1 kinase and (ii) the number of cells that were double stained with P-RIPK1 (Ser166) (p-RIPK1+) and TUNEL, a label of DNA double-strand breaks, indicating cell death. Furthermore, ischemia induced activation of downstream signaling factors of RIPK1, RIPK3 and MLKL, as well as the formation of mature interleukin-1β (IL-1β). Treatment with necrostatin-1 (Nec-1), an inhibitor of necroptosis, significantly decreased ischemia-induced increase of p-RIPK1 expression and p-RIPK1+ neurons, which showed protection from brain damage. Meanwhile, Nec-1 reduced RIPK3, MLKL and p-MLKL expression levels and mature IL-1β formation in Nec-1 treated ischemic brains. Our results clearly demonstrated that phosphorylation of RIPK1 at the Ser166 residue was involved in the pathogenesis of necroptosis in the brains after ischemic injury. Nec-1 treatment protected brains against ischemic necroptosis by reducing the activation of RIPK1 and inhibiting its downstream signaling pathways. These results provide direct in vivo evidence that phosphorylated RIPK1 (Ser 166) plays an important role in the initiation of RIPK3/MLKL-dependent necroptosis in the pathogenesis of ischemic stroke in the rodent brain.

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Glial S100A6 Degrades β-amyloid Aggregation through Targeting Competition with Zinc Ions
Zhi-Ying Tian, Chun-Yan Wang, Tao Wang, Yan-Chun Li, Zhan-You Wang
Aging and disease    2019, 10 (4): 756-769.   DOI: 10.14336/AD.2018.0912
Accepted: 20 September 2018

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Evidence has been accumulating that zinc ions can trigger β-amyloid (Aβ) deposition and senile plaque formation in the brain, a pathological hallmark of Alzheimer’s disease (AD). Chelating zinc inhibits Aβ aggregation and may hold promise as a therapeutic strategy for AD. S100A6 is an acidic Ca2+/Zn2+-binding protein found only in a small number of astrocytes in the normal brain. However, in the AD brain, S100A6 is highly expressed in astrocytes around Aβ plaques. The role of the astrocytic S100A6 upregulation in AD is unknown. In the present study, we examined the effects of S100A6 on Aβ plaques and intracellular zinc levels in a mouse model of AD. Chronic exposure to zinc increased Aβ deposition and S100A6 expression, both reversible by the zinc chelator clioquinol, in the brains of amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice. To examine whether exogenous S100A6 could induce Aβ plaque disaggregation through competition for zinc in vitro, we incubated APP/PS1 mouse brain sections with recombinant human S100A6 protein or co-incubated them with human S100A6-expressing cells. Both treatments efficiently reduced the Aβ plaque burden in situ. In addition, treatment with exogenous S100A6 protected cultured COS-7 cells against zinc toxicity. Our results show for the first time that increased S100A6 levels correlate with both Aβ disaggregation and decrease of Aβ plaque-associated zinc contents in brain sections with AD-like pathology. Astrocytic S100A6 in AD may protect from Aβ deposition through zinc sequestration.

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AMPK Signaling Regulates the Age-Related Decline of Hippocampal Neurogenesis
Brian Z Wang, Jane J Yang, Hongxia Zhang, Charity A Smith, Kunlin Jin
Aging and disease    2019, 10 (5): 1058-1074.   DOI: 10.14336/AD.2019.0102
Accepted: 26 January 2019

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The global incidence of age-associated neurological diseases is expected to rise with increasingly greying societies. In the aged brain, there is a dramatic decrease in the number of stem cells, which is a main cause for the decrease in brain function. Intrinsic factors, such as cell metabolism, have been studied but its role in neurogenesis is still unknown. Therefore, this study sought to establish whether AMP-activated protein kinase (AMPK) signaling does indeed regulate hippocampal neurogenesis in the aged brain. We found that i) AMPKα2 was the predominant catalytic subunit in the subgranular and subventricular zones; ii) AMPK activation was at a significantly higher level in the aged vs. young hippocampus; iii) short term (7 days) treatment with selective AMPK signaling inhibitor Compound C (10 mg/kg/day, i.p.) significantly increased the numbers of newborn (BrdU+), Type 2 (MCM2+), and Type 3 (DCX+) neural stem cells, but not Type 1 (GFAP+/Sox2+) cells, in the aged hippocampus. Taken together, our results demonstrate that AMPK signaling plays a critical role in the age-related decline of hippocampal neurogenesis.

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Maintained Properties of Aged Dental Pulp Stem Cells for Superior Periodontal Tissue Regeneration
Linsha Ma, Jingchao Hu, Yu Cao, Yilin Xie, Hua Wang, Zhipeng Fan, Chunmei Zhang, Jinsong Wang, Chu-Tse Wu, Songlin Wang
Aging and disease    2019, 10 (4): 793-806.   DOI: 10.14336/AD.2018.0729
Accepted: 12 September 2018

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Owing to excellent therapeutic potential, mesenchymal stem cells (MSCs) are gaining increasing popularity with researchers worldwide for applications in tissue engineering, and in treatment of inflammation-related and age-related disorders. However, the senescence of MSCs over passaging has limited their clinical application owing to adverse effect on physiological function maintenance of tissues as well as disease treatment. An inflammatory microenvironment is one of the key contributors to MSC senescence, resulting in low regeneration efficiency. Therefore, MSCs with high resistance to cellular senescence would be a benefit for tissue regeneration. Toward this end, we analyzed the senescence properties of different types of stem cells during culture and under inflammation, including dental pulp stem cells (DPSCs), periodontal ligament stem cells (PDLSCs), bone marrow mesenchymal stem cells (BMMSCs), and adipose-derived stem cells (ADSCs). Overall, the DPSCs had higher proliferation rates, lower cellular senescence, and enhanced osteogenesis maintenance compared to those of non-dental MSCs cultured from passage three to six. The expression profiles of genes related to apoptosis, cell cycle, and cellular protein metabolic process (contributing to the cell self-renewal ability and metabolic processes) significantly differed between DPSCs and BMMSCs at passage three. Moreover, DPSCs were superior to BMMSCs with regards to resistance to lipopolysaccharide-induced apoptosis and senescence, with enhanced osteogenesis in vitro, and showed improved periodontal regeneration after injection in a miniature pig periodontitis model in vivo. Overall, the present study indicates that DPSCs show superior resistance to subculture and inflammation-induced senescence and would be suitable stem cells for tissue engineering with inflammation.

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The Prognostic Value of Serum Cytokines in Patients with Acute Ischemic Stroke
Xianmei Li, Siyang Lin, Xiaoli Chen, Wensi Huang, Qian Li, Hongxia Zhang, Xudong Chen, Shaohua Yang, Kunlin Jin, Bei Shao
Aging and disease    2019, 10 (3): 544-556.   DOI: 10.14336/AD.2018.0820
Accepted: 14 September 2018

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The inflammatory response is an unavoidable process and contributes to the destruction of cerebral tissue during the acute ischemic stroke (AIS) phase and has not been addressed fully to date. Insightful understanding of correlation of inflammatory mediators and stroke outcome may provide new biomarkers or therapeutic approaches for ischemic stroke. Here, we prospectively recruited 180 first-ever AIS patients within 72 hrs after stroke onset. We used the National Institutes of Health Stroke Scale (NIHSS) to quantify stroke severity and modified Rankin scale (mRS) to assess the 3-month outcome for AIS patients. Initially, we screened 35 cytokines, chemokines, and growth factors in sera from 75 AIS patients and control subjects. Cytokines that were of interest were further investigated in the 180 AIS patients and 14 heathy controls. We found that IL-1RA, IL-1β, IL-4, IL-5, IL-6, IL-7, IL-9, IL-10, IL-13, IL-15, EGF, G-CSF, Flt-3L, GM-CSF and Fractalkine levels were significantly decreased in severe stroke patients. In particular, IL-1β, IL-4, IL-5, IL-7, IL-9, IL-10, IL-15, G-CSF and GM-CSF were significantly reduced in AIS patients with poor outcome, compared to those with good prognosis. IL-6 was notably higher in the poor outcome group. Only IL-9 level decreased in the large infarct volume group. After adjusting for confounders, we found that IL-5 was an independent protective factor for prognosis in AIS patients with an adjusted OR of 0.042 (P = 0.007), whereas IL-6 was an independent risk predictor for AIS patients with an adjusted OR of 1.293 (P = 0.003). Our study suggests the levels of serum cytokines are related to stroke severity, short-term prognosis and cerebral infarct volume in AIS patients.

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Aging Influences Hepatic Microvascular Biology and Liver Fibrosis in Advanced Chronic Liver Disease
Raquel Maeso-Díaz, Martí Ortega-Ribera, Erica Lafoz, Juan José Lozano, Anna Baiges, Rubén Francés, Agustín Albillos, Carmen Peralta, Juan Carlos García-Pagán, Jaime Bosch, Victoria C Cogger, Jordi Gracia-Sancho
Aging and disease    2019, 10 (4): 684-698.   DOI: 10.14336/AD.2019.0127
Accepted: 18 February 2019

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Advanced chronic liver disease (aCLD) represents a major public health concern. aCLD is more prevalent and severe in the elderly, carrying a higher risk of decompensation. We aimed at understanding how aging may impact on the pathophysiology of aCLD in aged rats and humans and secondly, at evaluating simvastatin as a therapeutic option in aged animals. aCLD was induced in young (1 month) and old (16 months) rats. A subgroup of aCLD-old animals received simvastatin (5 mg/kg) or vehicle (PBS) for 15 days. Hepatic and systemic hemodynamic, liver cells phenotype and hepatic fibrosis were evaluated. Additionally, the gene expression signature of cirrhosis was evaluated in a cohort of young and aged cirrhotic patients. Aged animals developed a more severe form of aCLD. Portal hypertension and liver fibrosis were exacerbated as a consequence of profound deregulations in the phenotype of the main hepatic cells: hepatocytes presented more extensive cell-death and poorer function, LSEC were further capillarized, HSC over-activated and macrophage infiltration was significantly increased. The gene expression signature of cirrhosis significantly differed comparing young and aged patients, indicating alterations in sinusoidal-protective pathways and confirming the pre-clinical observations. Simvastatin administration for 15-day to aged cirrhotic rats improved the hepatic sinusoidal milieu, leading to significant amelioration in portal hypertension. This study provides evidence that aCLD pathobiology is different in aged individuals. As the median age of patients with aCLD is increasing, we propose a real-life pre-clinical model to develop more reliable therapeutic strategies. Simvastatin effects in this model further demonstrate its translational potential.

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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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Statins Induce a DAF-16/Foxo-dependent Longevity Phenotype via JNK-1 through Mevalonate Depletion in C. elegans
Andreas Jahn, Bo Scherer, Gerhard Fritz, Sebastian Honnen
Aging and disease    2020, 11 (1): 60-72.   DOI: 10.14336/AD.2019.0416
Accepted: 19 May 2019

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Statins belong to the most pre-scribed cholesterol lowering drugs in western countries. Their competitive inhibition of the HMG-CoA reductase causes a reduction in the mevalonate pool, resulting in reduced cholesterol biosynthesis, impaired protein prenylation and glycosylation. Recently, a cohort study showed a decreased mortality rate in humans between age 78-90 going along with statin therapy, which is independent of blood cholesterol levels. As C. elegans harbors the mevalonate pathway, but is cholesterol-auxotroph, it is particularly suitable to study cholesterol-independent effects of statins on aging-associated phenotypes. Here, we show that low doses of lovastatin or a mild HMG-CoA reductase knockdown via hmgr-1(RNAi) in C. elegans substantially attenuate aging pigment accumulation, which is a well-established surrogate marker for biological age. Consistently, for two statins we found dosages, which prolonged the lifespan of C. elegans. Together with an observed reduced fertility, slower developmental timing and thermal stress resistance this complex of outcomes point to the involvement of DAF-16/hFOXO3a, the master regulator of stress resistance and longevity. Accordingly, prolonged low-dose statin exposure leads to an increased expression of jnk-1, a known activator of DAF-16. Moreover, the beneficial effects of statins on aging pigments and lifespan depend on DAF-16 and JNK-1, as shown in epistasis analyses. These effects can be reverted by mevalonate supplementation. In conclusion, we describe a lifespan extension in C. elegans, which is conferred via two well-conserved stress-related factors (JNK-1, DAF-16) and results from mevalonate depletion.

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The WNK-SPAK/OSR1 Kinases and the Cation-Chloride Cotransporters as Therapeutic Targets for Neurological Diseases
Huachen Huang, Shanshan Song, Suneel Banerjee, Tong Jiang, Jinwei Zhang, Kristopher T. Kahle, Dandan Sun, Zhongling Zhang
Aging and disease    2019, 10 (3): 626-636.   DOI: 10.14336/AD.2018.0928
Accepted: 02 October 2018

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In recent years, cation-chloride cotransporters (CCCs) have drawn attention in the medical neuroscience research. CCCs include the family of Na+-coupled Cl- importers (NCC, NKCC1, and NKCC2), K+-coupled Cl- exporters (KCCs), and possibly polyamine transporters (CCC9) and CCC interacting protein (CIP1). For decades, CCCs have been the targets of several commonly used diuretic drugs, including hydrochlorothiazide, furosemide, and bumetanide. Genetic mutations of NCC and NKCC2 cause congenital renal tubular disorders and lead to renal salt-losing hypotension, secondary hyperreninemia, and hypokalemic metabolic alkalosis. New studies reveal that CCCs along with their regulatory WNK (Kinase with no lysine (K)), and SPAK (Ste20-related proline-alanine-rich kinase)/OSR1(oxidative stress-responsive kinase-1) are essential for regulating cell volume and maintaining ionic homeostasis in the nervous system, especially roles of the WNK-SPAK-NKCC1 signaling pathway in ischemic brain injury and hypersecretion of cerebrospinal fluid in post-hemorrhagic hydrocephalus. In addition, disruption of Cl- exporter KCC2 has an effect on synaptic inhibition, which may be involved in developing pain, epilepsy, and possibly some neuropsychiatric disorders. Interference with KCC3 leads to peripheral nervous system neuropathy as well as axon and nerve fiber swelling and psychosis. The WNK-SPAK/OSR1-CCCs complex emerges as therapeutic targets for multiple neurological diseases. This review will highlight these new findings.

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A Microcirculatory Theory of Aging
Kunlin Jin
Aging and disease    2019, 10 (3): 676-683.   DOI: 10.14336/AD.2019.0315
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Aging is the progressive decline of physiological functions necessary for survival and reproduction. In gaining a better understanding of the inevitable aging process, the hope is to preserve, promote, or delay healthy aging through the treatment of common age-associated diseases. Although there are theories that try to explain the aging process, none of them seem to fully satisfy. Microcirculation describes blood flow through the capillaries in the circulatory system. The main functions of the microcirculation are the delivery of oxgen and nutrients and the removal of CO2, metabolic debris, and toxins. The microcirculatory impairment or dysfunction over time will result in the accumulation of toxic products and CO2 and loss of nutrition supplementation and O2 in corresponding tissue systems or internal organs, which eventually affect normal tissue and organ functions, leading to aging. Therefore, I propose a microcirculatory theory of aging: aging is the process of continuous impairment of microcirculation in the body.

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Th1 Biased Progressive Autoimmunity in Aged Aire-Deficient Mice Accelerated Thymic Epithelial Cell Senescence
Jie Zhang, Yuqing Wang, Abudureyimujiang Aili, Xiuyuan Sun, Xuewen Pang, Qing Ge, Yu Zhang, Rong Jin
Aging and disease    2019, 10 (3): 497-509.   DOI: 10.14336/AD.2018.0608
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Although autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, are frequently associated with premature aging of the thymus, a direct link is missing between autoimmunity and thymic atrophy. Here we monitored the progression of thymic involution in Aire-deficient mice, in which defective negative selection causes spontaneous and progressive development of autoimmunity. In young and middle-aged mice, Aire deficiency appeared to be protective as supported by the reduced β-gal+ epithelial cells and the enhanced thymic output. However, once the autoimmune phenotype was fully developed in aged Aire-deficient mice, their thymuses underwent accelerated involution. In comparison to the age-matched wildtype littermates, old Aire-deficient mice showed lower numbers of total thymocytes and recent thymic emigrants but more β-gal+ thymic epithelial cells. This phenomenon may partly be attributable to the increased number of activated Th1 cells homing to the thymus. This speculation was further supported by the enhanced thymic aging following repeated challenges with complete Freund’s adjuvant immunization. Taken together, the present study highlights a unique mechanism by which autoimmunity facilitates the senescence of thymic epithelial cells through returning Th1 cells.

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The Metabolic Activity of Caudate and Prefrontal Cortex Negatively Correlates with the Severity of Idiopathic Parkinson’s Disease
Jun-Sheng Chu, Ting-Hong Liu, Kai-Liang Wang, Chun-Lei Han, Yun-Peng Liu, Shimabukuro Michitomo, Jian-Guo Zhang, Tie Fang, Fan-Gang Meng
Aging and disease    2019, 10 (4): 847-853.   DOI: 10.14336/AD.2018.0814
Accepted: 20 September 2018

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Positron emission tomography (PET) scan with tracer [18F]-fluorodeoxy-glucose (18F-FDG) is widely used to measure the glucose metabolism in neurodegenerative disease such as Idiopathic Parkinson’s disease (IPD). Previous studies using 18F-FDG PET mainly focused on the motor or non-motor symptoms but not the severity of IPD. In this study, we aimed to determine the metabolic patterns of 18F-FDG in different stages of IPD defined by Hoehn and Yahr rating scale (H-Y rating scale) and to identify regions in the brain that play critical roles in disease progression. Fifty IPD patients were included in this study. They were 29 men and 21 women (mean±SD, age 57.7±11.1 years, disease duration 4.0±3.8 years, H-Y 2.2±1.1). Twenty healthy individuals were included as normal controls. Following 18F-FDG PET scan, image analysis was performed using Statistical Parametric Mapping (SPM) and Resting-State fMRI Data Analysis Toolkit (REST). The metabolic feature of IPD and regions-of-interests (ROIs) were determined. Correlation analysis between ROIs and H-Y stage was performed. SPM analysis demonstrated a significant hypometabolic activity in bilateral putamen, caudate and anterior cingulate as well as left parietal lobe, prefrontal cortex in IPD patients. In contrast, hypermetabolism was observed in the cerebellum and vermis. There was a negative correlation (p=0.007, r=-0.412) between H-Y stage and caudate metabolic activity. Moreover, the prefrontal area also showed a negative correlation with H-Y (P=0.033, r=-0.334). Thus, the uptake of FDG in caudate and prefrontal cortex can potentially be used as a surrogate marker to evaluate the severity of IPD.

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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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Longevity Effect of Liuwei Dihuang in Both Caenorhabditis Elegans and Aged Mice
Weidong Chen, Jinzeng Wang, Jiahao Shi, Xu Yang, Ping Yang, Ning Wang, Sai Yang, Tianpei Xie, Hua Yang, Mengjie Zhang, Haiyun Wang, Jian Fei
Aging and disease    2019, 10 (3): 578-591.   DOI: 10.14336/AD.2018.0604
Accepted: 21 August 2018
Online available: 21 August 2018

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Liuwei Dihuang (LWDH), a famous traditional Chinese medicine, is widely used in the clinical treatment of aging-related diseases in China. However, its pharmacological mechanisms are not clear. In the present study, we evaluated the lifespan extension effect of LWDH in C. elegans and mice and revealed its underlying mechanisms. The results showed that LWDH significantly extended the lifespan of C. elegans in a dose-dependent manner. LWDH also conferred protection to nematodes against oxidative stress and reduced their fat storage. Genetics analysis and microarray data showed that the longevity effect of LWDH was attributed to the regulation of the innate immune response, proteolysis, lipid metabolism, and the oxidation-reduction process and was dependent on daf-16. Among the six herbs in the formula, Radix Rehmanniae Preparata and Fructus Macrocarpii contributed most to the longevity effect of this medicine, while the other four components had a synergistic effect on the longevity effect of the prescription. The lack of any single herb reduced the efficacy of the complete formula. LWDH also extended the lifespan and reduced both the weight and oxidant stress status in aged mice. Taken together, these results suggested that LWDH might function in a multi-target manner to extend the lifespan in both C. elegans and aged mice, and the best effect was achieved with the complete formula.

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Clinical and Genetic Profiles in Chinese Patients with Huntington’s Disease: A Ten-year Multicenter Study in China
Hong-Lei Li, Xiao-Yan Li, Yi Dong, Yan-Bin Zhang, Hong-Rong Cheng, Shi-Rui Gan, Zhi-Jun Liu, Wang Ni, Jean-Marc Burgunder, X. William Yang, Zhi-Ying Wu
Aging and disease    2019, 10 (5): 1003-1011.   DOI: 10.14336/AD.2018.0911
Accepted: 22 September 2018

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Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder caused by CAG triplet repeats expansion in exon 1 of the Huntingtin gene (HTT). In China, HD is considered to have a low prevalence. The goal of this study was to describe the clinical characteristic and genetic profiles of HD in a Chinese cohort. A total of 322 individuals with expanded CAG repeats were consecutively recruited from the neurologic clinics of three medical centers in Southeastern China between 2008 and 2018. Among them, 80 were pre-symptomatic mutation carriers and 242 were symptomatic patients. The mean age at onset (AAO), defined here as the age at motor symptom onset, of the 242 manifest HD individuals was 40.3 ± 11.9 years and the mean CAG repeat length was 46.1 ± 7.5 in the group of symptomatic patients. Initial symptoms were abnormal movements in 88.8% of the patients with psychiatric symptoms in 6.2%, cognitive impairment in 3.3% and others in 1.7%. The AAO of motor was negatively correlated with the CAG repeat length in an exponential regression analysis (R 2 = 0.74, P<0.001). Analysis of 46 parent-child pairs showed that the CAG repeat length was longer in the offspring group (45.8 ±7.6) than in the parent group (43.8 ±3.0) (p=0.005). Overall, this study provides clinical and genetic profiles in a cohort of Chinese patients with HD, which should contribute to a better understanding of this disorder.

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The Drainage of Interstitial Fluid in the Deep Brain is Controlled by the Integrity of Myelination
Aibo Wang, Rui Wang, Dehua Cui, Xinrui Huang, Lan Yuan, Huipo Liu, Yu Fu, Lei Liang, Wei Wang, Qingyuan He, Chunyan Shi, Xiangping Guan, Ze Teng, Guomei Zhao, Yuanyuan Li, Yajuan Gao, Hongbin Han
Aging and disease    2019, 10 (5): 937-948.   DOI: 10.14336/AD.2018.1206
Accepted: 08 December 2018
Online available: 08 December 2018

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In searching for the drainage route of the interstitial fluid (ISF) in the deep brain, we discovered a regionalized ISF drainage system as well as a new function of myelin in regulating the drainage. The traced ISF from the caudate nucleus drained to the ipsilateral cortex along myelin fiber tracts, while in the opposite direction, its movement to the adjacent thalamus was completely impeded by a barrier structure, which was identified as the converged, compact myelin fascicle. The regulating and the barrier effects of myelin were unchanged in AQP4-knockout rats but were impaired as the integrity of boundary structure of drainage system was destroyed in a demyelinated rat model. We thus proposed that the brain homeostasis was maintained within each ISF drainage division locally, rather than across the brain as a whole. A new brain division system and a new pathogenic mechanism of demyelination are therefore proposed.

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AmpliSeq Transcriptome of Laser Captured Neurons from Alzheimer Brain: Comparison of Single Cell Versus Neuron Pools
Wenjun Deng, Changhong Xing, Rob David , Diego Mastroeni, MingMing Ning, Eng H Lo, Paul D Coleman
Aging and disease    2019, 10 (6): 1146-1158.   DOI: 10.14336/AD.2019.0225
Accepted: 12 April 2019

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Alzheimer’s disease (AD) is the most common cause of dementia in older adults. However, the pathogenesis of AD remains to be fully understood and clinically effective treatments are lacking. Recent advances in single cell RNA sequencing offers an opportunity to characterize the heterogeneity of cell response and explore the molecular mechanism of complex diseases at a single cell level. Here, we present the application of the Ion AmpliSeq transcriptome approach to profile gene expression in single laser captured neurons as well as pooled 10 and 100 neurons from hippocampal CA1 of AD brains versus matching normal aged brains. Our results demonstrated the high sensitivity and high genome coverage of the AmpliSeq transcriptome in single cell sequencing. In addition to capturing the known changes related to AD, our data confirmed the diversity of neuronal profiles in AD brain, which allow the potential identification of single cell response that might be hidden in population analyses. Notably, we also revealed the extensive inhibition of olfactory signaling and confirmed the reduction of neurotransmitter receptors in AD hippocampus. We conclude that although single neuron data show more variance than data from 10 or 100 pooled neurons, single neuron data can be informative. These findings support the utility of the Ion AmpliSeq method for obtaining and analyzing gene expression data from single defined laser captured neurons.

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Total Burden of Cerebral Small Vessel Disease in Recurrent ICH versus First-ever ICH
Mangmang Xu, Yajun Cheng, Quhong Song, Ruozhen Yuan, Shuting Zhang, Zilong Hao, Ming Liu
Aging and disease    2019, 10 (3): 570-577.   DOI: 10.14336/AD.2018.0804
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The relationship between recurrent intracerebral hemorrhage (ICH) and total burden of cerebral small vessel disease (CSVD) is not completely investigated. We aimed to study whether recurrent intracerebral hemorrhage (ICH) had higher CSVD score than first-ever ICH. Lacunes, white matter hyperintensities (WMH), cerebral microbleeds (CMBs), enlarged perivascular spaces (EPVS), cortical superficial siderosis (cSS) and CSVD score were rated on brain magnetic resonance imaging (MRI) in primary ICH patients. Recurrent ICHs were confirmed by reviewing the medical records and MRI scans. Mixed hematomas were defined as follows: deep + lobar, deep + cerebellar, or deep + lobar + cerebellar. Of the 184 patients with primary ICH enrolled (mean age, 61.0 years; 75.5% men), recurrent ICH was present in 45 (24.5%) patients; 26.1% (48/184) had ≥2 hematomas, 93.8% (45/48) of which exhibited recurrent ICH. Mixed hematomas were identified in 8.7% (16/184) of patients and bilateral hematomas in 17.9% (33/184). All mixed hematomas and bilateral hematomas were from cases of recurrent ICH. Patients with mixed etiology-ICH were more likely to have recurrent ICH than patients with cerebral amyloid angiopathy (CAA) or hypertensive angiopathy (HA)-related ICH (36.8% vs17.8%, p=0.008). Multivariate ordinal regression analysis showed that the presence of recurrent ICH (p=0.001), ≥2 hematomas (p=0.002), mixed hematomas (p<0.00001), and bilateral hematomas (p=0.002) were separately significantly associated with a high CSVD score. Recurrent ICH occurs mostly among patients with mixed etiology-ICH and is associated with a higher CSVD burden than first-ever ICH, which needs to be verified by future larger studies.

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Hydroxyurea Facilitates Manifestation of Disease Relevant Phenotypes in Patients-Derived IPSCs-Based Modeling of Late-Onset Parkinson’s Disease
Yuan Tan, Minjing Ke, Zhijian Huang, Cheong-Meng Chong, Xiaotong Cen, Jia-Hong Lu, Xiaoli Yao, Dajiang Qin, Huanxing Su
Aging and disease    2019, 10 (5): 1037-1048.   DOI: 10.14336/AD.2018.1216
Accepted: 08 January 2019

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Induced pluripotent stem cells (iPSCs)-derived dopaminergic neurons might be reset back to the fetal state due to reprogramming. Thus, it is a compelling challenge to reliably and efficiently induce disease phenotypes of iPSCs-derived dopaminergic neurons to model late-onset Parkinson’s disease (PD). Here, we applied a small molecule, hydroxyurea (HU), to promote the manifestation of disease relevant phenotypes in iPSCs-based modeling of PD. We established two iPS cell lines derived from two sporadic PD patients. Both patients-iPSCs-derived dopaminergic neurons did not display PD relevant phenotypes after 6 weeks culture. HU treatment remarkably induced ER stress on patients-iPSCs-derived dopaminergic neurons. Moreover, HU treatment significantly reduced neurite outgrowth, decreased the expression of p-AKT and its downstream targets (p-4EBP1 and p-ULK1), and increased the expression level of cleaved-Caspase 3 in patients-iPSCs-derived dopaminergic neurons. The findings of the present study suggest that HU administration could be a convenient and reliable approach to induce disease relevant phenotypes in PD-iPSCs-based models, facilitating to study disease mechanisms and test drug effects.

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Five-Minute Cognitive Test as A New Quick Screening of Cognitive Impairment in The Elderly
Jie Zhang, Lijun Wang, Xia Deng, Guoqiang Fei, Lirong Jin, Xiaoli Pan, Liuhan Cai, Anthony D Albano, Chunjiu Zhong
Aging and disease    2019, 10 (6): 1258-1269.   DOI: 10.14336/AD.2019.0115
Accepted: 02 March 2019

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This study aims to develop a new evaluation method for quickly and conveniently screening cognitive impairment in the elderly. The five-minute cognitive test (FCT) was designed to capture deficits in five domains of cognitive abilities, including episodic memory, language fluency, time orientation, visuospatial function, and executive function. Subsequently, FCT efficiencies in differentiating normally cognitive ability from cognitive impairment were explored and compared with that of the Mini-Mental Status Evaluation (MMSE). Equipercentile equating method was utilized to create a crosswalk between scores of the FCT and MMSE. Further, the association of scores of the FCT and MMSE with hippocampal volumes was investigated. There were 241 subjects aged 60 years or above enrolled in this study, including 107 adults with cognitive abilities in normal range, 107 patients with mild cognitive impairment (MCI), and 27 patients with mild Alzheimer disease (AD). The AUC of FCT for detection of cognitive impairment (MCI and mild AD) was 0.885 (95% CI 0.838 to 0.922). The sensitivity and specificity of FCT for the diagnosis of cognitive impairment were 80.6% and 84.11 %, respectively. FCT’s diagnostic performance was superior to that of MMSE in the same cohort. Mean completion time of FCT was 339.9 ± 67.7 seconds (5-6 min). In addition, a conversion table between scores on the FCT and MMSE was created. Further, the FCT scores were positively correlated with hippocampal volumes. The FCT is a novel, reliable, and valid cognitive screening test for the detection of dementia at early stages.

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Genetic Interaction of APOE and FGF1 is Associated with Memory Impairment and Hippocampal Atrophy in Alzheimer’s Disease
Ya-Ting Chang, Hiroaki Kazui, Manabu Ikeda, Chi-Wei Huang, Shu-Hua Huang, Shih-Wei Hsu, Wen-Neng Chang, Chiung-Chih Chang
Aging and disease    2019, 10 (3): 510-519.   DOI: 10.14336/AD.2018.0606
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The APOE and fibroblast growth factor 1 (FGF1) have both been associated with amyloid β accumulation and neurodegeneration. Investigation the effect of APOE-FGF1 interactions on episodic memory (EM) deficits and hippocampus atrophy (HA) might elucidate the complex clinical-pathological relationship in Alzheimer’s disease (AD). EM performance and hippocampal volume (HV) were characterized in patients with mild AD based on APOE-ε4 carrier status (APOE-ε4 carriers versus non-carriers) and FGF1 single nucleotide polymorphism (FGF1-rs34011-GG versus FGF1-rs34011-A-allele carriers). The clinical-pathological relationships within each genotypic group (ε4+/GG-carrier, ε4+/A-allele-carrier, ε4-/GG-carrier and ε4-/A-allele-carrier) were analyzed. There were no significant differences between the FGF1-rs34011-GG and FGF1-rs34011-A-allele carriers for the level of EM performance or HV (p> 0.05). The bilateral HV was significantly smaller and EM impairment was significantly worse in ε4+/GG-carrier than in ε4-/A-allele-carrier, and an interaction effect of APOE (APOE-ε4 carriers versus non-carriers) with FGF1 (FGF1-rs34011-GG versus FGF1-rs34011-A-allele carriers) predicted EM impairment (F4,92= 3.516, p= 0.018) and structural changes in voxel-based morphometry. Our data shows that concurrent consideration of APOE and FGF1 polymorphisms might be required to understand the clinical-pathological relationship in AD.

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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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Deficiency of tPA Exacerbates White Matter Damage, Neuroinflammation, Glymphatic Dysfunction and Cognitive Dysfunction in Aging Mice
Peng Yu, Poornima Venkat, Michael Chopp, Alex Zacharek, Yi Shen, Linlin Liang, Julie Landschoot-Ward, Zhongwu Liu, Rongcai Jiang, Jieli Chen
Aging and disease    2019, 10 (4): 770-783.   DOI: 10.14336/AD.2018.0816
Accepted: 27 August 2018
Online available: 26 August 2018

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Tissue plasminogen activator (tPA) is a serine protease primarily involved in mediating thrombus breakdown and regulating catabolism of amyloid-beta (Aβ). The aim of this study is to investigate age-dependent decline of endogenous tPA and the effects of tPA decline on glymphatic function and cognitive outcome in mice. Male, young (3m), adult (6m) and middle-aged (12m) C57/BL6 (wild type) and tPA knockout (tPA-/-) mice were subject to a battery of cognitive tests and white matter (WM) integrity, neuroinflammation, and glymphatic function were evaluated. Adult WT mice exhibit significantly decreased brain tPA level compared to young WT mice and middle-aged WT mice have significantly lower brain tPA levels than young and adult WT mice. Middle-aged WT mice exhibit significant neuroinflammation, reduced WM integrity and increased thrombin deposition compared to young and adult mice, and increased blood brain barrier (BBB) permeability and reduced cognitive ability compared to young WT mice. In comparison to adult WT mice, adult tPA-/- mice exhibit significant BBB leakage, decreased dendritic spine density, increased thrombin deposition, neuroinflammation, and impaired functioning of the glymphatic system. Compared to age-matched WT mice, adult and middle-aged tPA-/- mice exhibit significantly increased D-Dimer expression and decreased perivascular Aquaporin-4 expression. Compared to age-matched WT mice, young, adult and middle-aged tPA-/- mice exhibit significant cognitive impairment, axonal damage, and increased deposition of amyloid precursor protein (APP), Aβ, and fibrin. Endogenous tPA may play an important role in contributing to aging induced cognitive decline, axonal/WM damage, BBB disruption and glymphatic dysfunction in the brain.

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Verapamil Ameliorates Motor Neuron Degeneration and Improves Lifespan in the SOD1G93A Mouse Model of ALS by Enhancing Autophagic Flux
Xiaojie Zhang, Sheng Chen, Kaili Lu, Feng Wang, Jiangshan Deng, Zhouwei Xu, Xiuzhe Wang, Qinming Zhou, Weidong Le, Yuwu Zhao
Aging and disease    2019, 10 (6): 1159-1173.   DOI: 10.14336/AD.2019.0228
Accepted: 03 March 2019

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Amyotrophic lateral sclerosis (ALS) is a progressive, paralytic disorder caused by selective degeneration of motor neurons in the brain and spinal cord. Our previous studies indicated that abnormal protein aggregation and dysfunctional autophagic flux might contribute to the disease pathogenesis. In this study, we have detected the role of the Ca2+ dependent autophagic pathway in ALS by using the L-type channel Ca2+ blocker, verapamil. We have found that verapamil significantly delayed disease onset, prolonged the lifespan and extended disease duration in SOD1G93A mice. Furthermore, verapamil administration rescued motor neuron survival and ameliorated skeletal muscle denervation in SOD1G93A mice. More interestingly, verapamil significantly reduced SOD1 aggregation and improved autophagic flux, which might be mediated the inhibition of calpain 1 activation in the spinal cord of SOD1G93A mice. Furthermore, we have demonstrated that verapamil reduced endoplasmic reticulum stress and suppressed glia activation in SOD1G93A mice. Collectively, our study indicated that verapamil is neuroprotective in the ALS mouse model and the Ca2+-dependent autophagic pathway is a possible therapeutic target for the treatment of ALS.

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BDNF Alleviates Neuroinflammation in the Hippocampus of Type 1 Diabetic Mice via Blocking the Aberrant HMGB1/RAGE/NF-κB Pathway
Rongrong Han, Zeyue Liu, Nannan Sun, Shu Liu, Lanlan Li, Yan Shen, Jianbo Xiu, Qi Xu
Aging and disease    2019, 10 (3): 611-625.   DOI: 10.14336/AD.2018.0707
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Diabetes is a systemic disease that can cause brain damage such as synaptic impairments in the hippocampus, which is partly because of neuroinflammation induced by hyperglycemia. Brain-derived neurotrophic factor (BDNF) is essential in modulating neuroplasticity. Its role in anti-inflammation in diabetes is largely unknown. In the present study, we investigated the effects of BDNF overexpression on reducing neuroinflammation and the underlying mechanism in mice with type 1 diabetes induced by streptozotocin (STZ). Animals were stereotactically microinjected in the hippocampus with recombinant adeno-associated virus (AAV) expressing BDNF or EGFP. After virus infection, four groups of mice, the EGFP+STZ, BDNF+STZ, EGFP Control and BDNF Control groups, received STZ or vehicle treatment as indicated. Three weeks later brain tissues were collected. We found that BDNF overexpression in the hippocampus significantly rescued STZ-induced decreases in mRNA and protein expression of two synaptic plasticity markers, spinophilin and synaptophysin. More interestingly, BDNF inhibited hyperglycemia-induced microglial activation and reduced elevated levels of inflammatory factors (TNF-α, IL-6). BDNF blocked the increase in HMGB1 levels and specifically, in levels of one of the HMGB1 receptors, RAGE. Downstream of HMGB1/RAGE, the increase in the protein level of phosphorylated NF-κB was also reversed by BDNF in STZ-treated mice. These results show that BDNF overexpression reduces neuroinflammation in the hippocampus of type 1 diabetic mice and suggest that the HMGB1/RAGE/NF-κB signaling pathway may contribute to alleviation of neuroinflammation by BDNF in diabetic mice.

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