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Cover Illustration
2020, Vol.11  No.6
<b><span style="font-size:9.0pt;font-family:"">Figure 1. Mechanisms of acute sarcopenia development with COVID-19. <span> </span></span></b><span style="font-size:9.0pt;font-family:"">Precipitating factors for acute sarcopenia with COVID-19 are demonstrated by pathways and predisposing factors are shown separately. <i>MPB = Muscle Protein Breakdown; MPS = Muscle Protein Synthesis</i></span>

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  • Table of Content
      01 December 2020, Volume 11 Issue 6 Previous Issue   
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    Commentary Article
    Of Cross-immunity, Herd Immunity and Country-specific Plans: Experiences from COVID-19 in India
    Sankha Shubhra Chakrabarti,Upinder Kaur,Anup Singh,Suddhachitta Chakrabarti,Manigreeva Krishnatreya,Bimal Kumar Agrawal,Amit Mittal,Amit Singh,Rahul Khanna,Indrajeet Singh Gambhir,Kunlin Jin,Sasanka Chakrabarti
    Aging and disease. 2020, 11 (6): 1339-1344.   DOI: 10.14336/AD.2020.1104
    Abstract   HTML   PDF (436KB) ( 271 )

    India has witnessed a high number of COVID-19 cases, but mortality has been quite low, and most cases have been asymptomatic or mild. In early April, we had hypothesized a low COVID-19 mortality in India, based on the concept of cross-immunity. The presence of cross-immunity is presumed to lead to a milder course of disease and allow the time necessary for the development of adaptive immunity by the body to eliminate the virus. Evidence supporting our hypothesis has started showing up. Multiple studies have shown the generation of different T cell subsets and B cells responding to epitopes of viral proteins, especially of the spike protein, as a part of adaptive immunity against SARS-CoV-2. Cross-reactive T-cells have been demonstrated in patients who have been previously exposed to endemic coronaviruses. The interplay of cross-immunity and herd immunity is apparent in the COVID-19 scenario in India from the presence of a large number of asymptomatic or mild cases, a low infection-fatality ratio and a generally flat curve of percentage positivity of cases with respect to total testing, both in periods of strict lock-down and step-wise unlocking. It seems that cross-immunity resulted in faster generation of herd immunity. Although the initial restrictive measures such as lockdown prevented the rapid spread of the outbreak, further extension of such measures and overly expensive ones such as enhanced testing in India will result in a huge burden on the health economics as well as the society. Hence, we propose a restructuring of the health services and approach to COVID-19. The restructured health services should move away from indiscriminate testing, isolation and quarantine, and instead, the emphasis should be on improving facilities for testing and management of only critical COVID cases and the replacement of complete lockdowns by the selective isolation and quarantine of susceptible persons such as the aged and those with co-morbidities. In the process of describing India-specific plans, we emphasize why the development of country-specific plans for tackling epidemics is important, instead of adopting a “one policy fits all” approach.

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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
    Abstract   HTML   PDF (374KB) ( 644 )

    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 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
    Abstract   HTML   PDF (448KB) ( 545 )

    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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    Opinion Article
    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
    Abstract   HTML   PDF (641KB) ( 895 )

    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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    Orginal Article
    Hippocampal Neural Stem Cell Grafting after Status Epilepticus Alleviates Chronic Epilepsy and Abnormal Plasticity, and Maintains Better Memory and Mood Function
    Bharathi Hattiangady,Ramkumar Kuruba,Bing Shuai,Remedios Grier,Ashok K Shetty
    Aging and disease. 2020, 11 (6): 1374-1394.   DOI: 10.14336/AD.2020.1020
    Abstract   HTML   PDF (2003KB) ( 397 )

    Hippocampal damage after status epilepticus (SE) leads to multiple epileptogenic changes, which lead to chronic temporal lobe epilepsy (TLE). Morbidities such as spontaneous recurrent seizures (SRS) and memory and mood impairments are seen in a significant fraction of SE survivors despite the administration of antiepileptic drugs after SE. We examined the efficacy of bilateral intra-hippocampal grafting of neural stem/progenitor cells (NSCs) derived from the embryonic day 19 rat hippocampi, six days after SE for restraining SE-induced SRS, memory, and mood impairments in the chronic phase. Grafting of NSCs curtailed the progression of SRS at 3-5 months post-SE and reduced the frequency and severity of SRS activity when examined at eight months post-SE. Reduced SRS activity was also associated with improved memory function. Graft-derived cells migrated into different hippocampal cell layers, differentiated into GABA-ergic interneurons, astrocytes, and oligodendrocytes. Significant percentages of graft-derived cells also expressed beneficial neurotrophic factors such as the fibroblast growth factor-2, brain-derived neurotrophic factor, insulin-like growth factor-1 and glial cell line-derived neurotrophic factor. NSC grafting protected neuropeptide Y- and parvalbumin-positive host interneurons, diminished the abnormal migration of newly born neurons, and rescued the reelin+ interneurons in the dentate gyrus. Besides, grafting led to the maintenance of a higher level of normal neurogenesis in the chronic phase after SE and diminished aberrant mossy fiber sprouting in the dentate gyrus. Thus, intrahippocampal grafting of hippocampal NSCs shortly after SE considerably curbed the progression of epileptogenic processes and SRS, which eventually resulted in less severe chronic epilepsy devoid of significant cognitive and mood impairments.

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    Serum Occludin as a Biomarker to Predict the Severity of Acute Ischemic Stroke, Hemorrhagic Transformation, and Patient Prognosis
    Weili Li,Zhifeng Qi,Huining Kang,Xuzhen Qin,Haiqing Song,Xueqin Sui,Yi Ren,Xunming Ji,Qingfeng Ma,Ke Jian Liu
    Aging and disease. 2020, 11 (6): 1395-1406.   DOI: 10.14336/AD.2020.0119
    Abstract   HTML   PDF (766KB) ( 513 )

    Blood-brain barrier (BBB) damage plays an important role in overall brain injury following acute ischemic stroke (AIS). We investigated the potential utility of serum occludin, a BBB damage biomarker, in predicting the severity of AIS, hemorrhagic transformation (HT) and patient prognosis. A total of 243 patients, suspected of suffering an AIS and admitted to the emergency room at Xuanwu Hospital between November 2018 to March 2019, were enrolled in this study. Serum occludin levels were measured by enzyme linked immunosorbent assay and clinical data were collected from each patient. Receiver operating characteristic curves (ROC) were used to analyze the relationship between serum occludin and AIS. Multiple logistic regression analysis was used to analyze the relationship between serum occludin and stroke prognosis. Serum occludin levels were significantly elevated in acute stroke cases compared with those with stroke-like symptoms (P<0.001). In the moderate and severe cerebral infarction (CI) groups, serum occludin levels were significantly higher than those in the mild CI group (P<0.001). Patients with HT had higher occludin levels than non-HT patients (P<0.05). In addition, serum occludin level of patients with poor prognosis was significantly higher than that of the patients with good prognosis for non-reperfusion therapy. The ROC curve showed that serum occludin could reasonably predict HT and poor prognosis. Moreover, serum occludin were independently associated with 90-day poor prognosis. These findings suggest that the serum occludin levels could be used to identify early acute stroke cases and may predict the severity of AIS and HT as well as the prognosis at 90 days.

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    The Mechanism of Downregulated Interstitial Fluid Drainage Following Neuronal Excitation
    Yuanyuan Li,Hongbin Han,Kuangyu Shi,Dehua Cui,Jun Yang,Ian Leigh Alberts,Lan Yuan,Guomei Zhao,Rui Wang,Xianjie Cai,Ze Teng
    Aging and disease. 2020, 11 (6): 1407-1422.   DOI: 10.14336/AD.2020.0224
    Abstract   HTML   PDF (2511KB) ( 979 )

    The drainage of brain interstitial fluid (ISF) has been observed to slow down following neuronal excitation, although the mechanism underlying this phenomenon is yet to be elucidated. In searching for the changes in the brain extracellular space (ECS) induced by electrical pain stimuli in the rat thalamus, significantly decreased effective diffusion coefficient (DECS) and volume fraction (α) of the brain ECS were shown, accompanied by the slowdown of ISF drainage. The morphological basis for structural changes in the brain ECS was local spatial deformation of astrocyte foot processes following neuronal excitation. We further studied aquaporin-4 gene (APQ4) knockout rats in which the changes of the brain ECS structure were reversed and found that the slowed DECS and ISF drainage persisted, confirming that the down-regulation of ISF drainage following neuronal excitation was mainly attributable to the release of neurotransmitters rather than to structural changes of the brain ECS. Meanwhile, the dynamic changes in the DECS were synchronized with the release and elimination processes of neurotransmitters following neuronal excitation. In conclusion, the downregulation of ISF drainage following neuronal excitation was found to be caused by the restricted diffusion in the brain ECS, and DECS mapping may be used to track the neuronal activity in the deep brain.

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    Reparative Effects of Stem Cell Factor and Granulocyte Colony-Stimulating Factor in Aged APP/PS1 Mice
    Xingzhi Guo,Yanying Liu,David Morgan,Li-Ru Zhao
    Aging and disease. 2020, 11 (6): 1423-1443.   DOI: 10.14336/AD.2020.0201
    Abstract   HTML   PDF (2841KB) ( 433 )

    Alzheimer’s disease (AD), characterized by the accumulation of β-amyloid (Aβ) plaques and tau neurofibrillary tangles in the brain, neuroinflammation and neurodegeneration, is the most common form of neurodegenerative disease among the elderly. No effective treatment is available now in restricting the pathological progression of AD. The aim of this study is to determine the therapeutic efficacy of stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) (SCF+G-CSF) in aged APPswe/PS1dE9 (APP/PS1) mice. SCF+G-CSF was subcutaneously injected for 12 days to 25-month-old male APP/PS1 mice. We observed that SCF+G-CSF treatment reduced the Aβ plaques in both the cortex and hippocampus. SCF+G-CSF treatment increased the association of TREM2+/Iba1+ cells with Aβ plaques and enhanced Aβ uptake by Iba1+ and CD68+cells in the brains of aged APP/PS1 mice. Importantly, cerebral expression area of P2RY12+and TMEM119+ homeostatic microglia and the branches of P2RY12+ homeostatic microglia were increased in the SCF+G-CSF-treated aged APP/PS1 mice. SCF+G-CSF treatment also decreased NOS-2 and increased IL-4 in the brains of aged APP/PS1 mice. Moreover, the loss of MAP2+dendrites and PSD-95+post-synapses and the accumulation of aggregated tau in the brains of aged APP/PS1 mice were ameliorated by SCF+G-CSF treatment. Furthermore, the density of P2RY12+ microglia was negatively correlated with Aβ deposits, but positively correlated with the densities of MAP2+ dendrites and PSD-95+ puncta in the brains of aged APP/PS1 mice. These findings reveal the therapeutic potential of SCF+G-CSF treatment in ameliorating AD pathology at the late stage.

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    Rationale and Methodology of The PopulatION HEalth and Eye Disease PRofile in Elderly Singaporeans Study [PIONEER]
    Preeti Gupta,Ryan Eyn Kidd Man,Eva K Fenwick,Amudha Aravindhan,Alfred TL Gan,Sahil Thakur,Bao Lin Pauline Soh,Joanne M Wood,Alex A Black,Angelique Chan,David Ng,Teoh Khim Hean,Edwin Goh,Chong Foong-Fong Mary,Jenny Loo,Ciaran Gerard Forde,Charumathi Sabanayagam,Ching-Yu Cheng,Tien Yin Wong,Ecosse L Lamoureux
    Aging and disease. 2020, 11 (6): 1444-1458.   DOI: 10.14336/AD.2020.0206
    Abstract   HTML   PDF (1263KB) ( 247 )

    To describe the rationale, design and methodology of a geographically-representative and population-based study investigating the epidemiology, impact, personal and economic burden of age-related eye diseases, declining visual and other sensory systems in Asians aged >60 years in Singapore.PIONEER (The PopulatION HEalth and Eye Disease PRofilE in Elderly Singaporeans Study) is currently a cross-sectional study targeting 3152 Chinese, Malay and Indian adults who are Singapore citizens or permanent residents aged 60 years and older living across Singapore. The study is intended to be longitudinal, with several waves of data planned to be collected in the future. The sampling frame consisted of 7000 names derived from age, gender and ethnicity-stratified random sampling of individuals >60 years. Selected individuals were invited via letters, home visits, and telephone calls for a clinical assessment at the Singapore Eye Research Institute. Individuals with limited mobility were examined in a custom-designed mobile eye clinic. Questionnaires were subsequently administered at participants’ homes by trained interviewers in their preferred language. A total of 3,299 participants (from East, West, North and South Singapore) were approached from December 2017 to November 2019. Of these, 953 (28.5%) were deemed ineligible. Out of 2,346 eligible participants, 904 (38.5%) refused, and 1,442 (61.5%) attended our clinical testing protocol, giving an initial response rate of 61.5%. Of these, 1,170 (81%) were cognitively able to complete the questionnaire assessment. The mean age±SD of our participants was 73.8±8.6 years; n=798 (55.3%) were female; and 828 (57.4%) were of Chinese ethnicity. The findings from this study will allow a deeper understanding of the risk factors and impact of aging in Asian populations, particularly in relation to the visual function and other functional system.

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    Alteration of Metabolic Profile and Potential Biomarkers in the Plasma of Alzheimer’s Disease
    Yaping Shao,Yang Ouyang,Tianbai Li,Xinyao Liu,Xiaojiao Xu,Song Li,Guowang Xu,Weidong Le
    Aging and disease. 2020, 11 (6): 1459-1470.   DOI: 10.14336/AD.2020.0217
    Abstract   HTML   PDF (1592KB) ( 802 )

    The expending of elderly population worldwide has resulted in a dramatic rise in the incidence of chronic diseases such as Alzheimer’s disease (AD). Inadequate understanding of the mechanisms underlying AD has hampered the development of efficient tools for definitive diagnosis and curative interventions. Previous studies have attempted to discover reliable biomarkers of AD, but these biomarkers can only be measured through invasive (neuropathological markers in cerebrospinal fluid) or expensive (positron emission tomography scanning or magnetic resonance imaging) techniques. Metabolomics is a high-throughput technology that can detect and catalog large numbers of small metabolites and may be a useful tool for characterization of AD and identification of biomarkers. In this study, we used ultra-performance liquid chromatography-mass spectrometry based untargeted metabolomics to measure the concentrations of plasma metabolites in a cohort of subjects with AD (n=44) and cognitively normal controls (Ctrl, n=94). The AD group showed marked reductions in levels of polyunsaturated fatty acids, acyl-carnitines, degradation products of tryptophan, and elevated levels of bile acids compared to the Ctrl group. We then validated the results using an independent cohort that included subjects with AD (n=30), mild cognitive impairment (MCI, n=13), healthy controls (n=43), and non-AD neurological disease controls (NDC, n=31). We identified five metabolites comprising cholic acid, chenodeoxycholic acid, allocholic acid, indolelactic acid, and tryptophan that were able to distinguish patients with AD from both Ctrl and NDC with satisfactory sensitivity and specificity. The concentrations of these metabolites were significantly correlated with disease severity. Our results also suggested that altered bile acid profiles in AD and MCI might indicate early risk for the development of AD. These findings may allow for development of new approaches for diagnosis of AD and may provide novel insights into AD pathogenesis.

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    Premature CD4+ T Cells Senescence Induced by Chronic Infection in Patients with Acute Coronary Syndrome
    Ming Cao,Lei Ruan,Yi Huang,Jinli Wang,Jinhua Yan,Yu Sang,Shanshan Li,Guan Wang,Xiaofen Wu
    Aging and disease. 2020, 11 (6): 1471-1480.   DOI: 10.14336/AD.2020.0203
    Abstract   HTML   PDF (807KB) ( 313 )

    Acquired immune responses mediated by CD4+ T cells contribute to the initiation and progression of acute coronary syndrome (ACS). ACS patients show acquired immune system abnormalities that resemble the characteristics of autoimmune dysfunction described in the elderly. This study aimed to investigate the role of premature CD4+ T cells senescence in ACS and the underlying mechanism. We compared the immunological status of 25 ACS patients, 15 young healthy individuals (C1), and 20 elderly individuals with absence of ACS (C2). The percentages of CD4+ T lymphocyte subsets (including naïve, regulatory, memory and effector T cells) in peripheral blood were analyzed. In ACS patients, a significant expansion of CD4+CD28null effector T cells and a decline of CD4+CD25+CD62L+Treg cells were observed. In addition, patients with ACS showed an accelerated loss of CD4+CD45RA+CD62L+ naïve T cells and a compensatory increase in the number of CD4+CD45RO+ memory T cells. ACS patients demonstrated no significant difference in frequency of T cell receptor excision circles (TRECs) compared to age-matched healthy volunteers. The expression of p16Ink4a was increased while CD62L was decreased in CD4+CD28null T cells of ACS patients. Compared to healthy donors, ACS patients demonstrated the lowest telomerase activity in both CD4+CD28+and CD4+CD28null T cells. The serum levels of C-reactive protein, Cytomegalovirus IgG, Helicobactor pylori IgG and Chlamydia pneumonia IgG were significantly higher in ACS patients. The results suggested that the percentage of CD4+ T cell subpopulations correlated with chronic infection, which contributes to immunosenescence. In conclusion, chronic infection induced senescence of premature CD4+T cells, which may be responsible for the development of ACS.

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    Review Article
    COVID-19 in Elderly Adults: Clinical Features, Molecular Mechanisms, and Proposed Strategies
    Ya Yang,Yalei Zhao,Fen Zhang,Lingjian Zhang,Lanjuan Li
    Aging and disease. 2020, 11 (6): 1481-1495.   DOI: 10.14336/AD.2020.0903
    Abstract   HTML   PDF (528KB) ( 408 )

    Coronavirus disease 2019 (COVID-19) is causing problems worldwide. Most people are susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but elderly populations are more susceptible. Elevated susceptibility and death rates in elderly COVID-19 patients, especially those with age-related complications, are challenges for pandemic prevention and control. In this paper, we review the clinical features of elderly patients with COVID-19 and explore the related molecular mechanisms that are essential for the exploration of preventive and therapeutic strategies in the current pandemic. Furthermore, we analyze the feasibility of currently recommended potential novel methods against COVID-19 among elderly populations.

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    Pituitary Adenylate Cyclase-Activating Polypeptide: A Promising Neuroprotective Peptide in Stroke
    Yuanjian Fang,Reng Ren,Hui Shi,Lei Huang,Cameron Lenahan,Qin Lu,Lihui Tang,Yi Huang,Jiping Tang,Jianmin Zhang,John H Zhang
    Aging and disease. 2020, 11 (6): 1496-1512.   DOI: 10.14336/AD.2020.0626
    Abstract   HTML   PDF (614KB) ( 367 )

    The search for viable, effective treatments for acute stroke continues to be a global priority due to the high mortality and morbidity. Current therapeutic treatments have limited effects, making the search for new treatments imperative. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a well-established cytoprotective neuropeptide that participates in diverse neural physiological and pathological activities, such as neuronal proliferation, differentiation, and migration, as well as neuroprotection. It is considered a promising treatment in numerous neurological diseases. Thus, PACAP bears potential as a new therapeutic strategy for stroke treatment. Herein, we provide an overview pertaining to the current knowledge of PACAP, its receptors, and its potential neuroprotective role in the setting of stroke, as well as various mechanisms of neuroprotection involving ionic homeostasis, excitotoxicity, cell edema, oxidative stress, inflammation, and cell death, as well as the route of PACAP administration.

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    Influence of BDNF Genetic Polymorphisms in the Pathophysiology of Aging-related Diseases
    Rodrigo Urbina-Varela,María Inés Soto-Espinoza,Romina Vargas,Luis Quiñones,Andrea del Campo
    Aging and disease. 2020, 11 (6): 1513-1526.   DOI: 10.14336/AD.2020.0310
    Abstract   HTML   PDF (452KB) ( 314 )

    For the first time in history, most of the population has a life expectancy equal or greater than 60 years. By the year 2050, it is expected that the world population in that age range will reach 2000 million, an increase of 900 million with respect to 2015, which poses new challenges for health systems. In this way, it is relevant to analyze the most common diseases associated with the aging process, namely Alzheimer´s disease, Parkinson Disease and Type II Diabetes, some of which may have a common genetic component that can be detected before manifesting, in order to delay their progress. Genetic inheritance and epigenetics are factors that could be linked in the development of these pathologies. Some researchers indicate that the BDNF gene is a common factor of these diseases, and apparently some of its polymorphisms favor the progression of them. In this regard, alterations in the level of BDNF expression and secretion, due to polymorphisms, could be linked to the development and/or progression of neurodegenerative and metabolic disorders. In this review we will deepen on the different polymorphisms in the BDNF gene and their possible association with age-related pathologies, to open the possibilities of potential therapeutic targets.

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    Intra-arterial Cold Saline Infusion in Stroke: Historical Evolution and Future Prospects
    Longfei Wu,Mitchell Huber,Di Wu,Jian Chen,Ming Li,Yuchuan Ding,Xunming Ji
    Aging and disease. 2020, 11 (6): 1527-1536.   DOI: 10.14336/AD.2020.0325
    Abstract   HTML   PDF (355KB) ( 381 )

    Acute ischemic stroke (AIS) is a perpetual threat to life and functionality due to its high morbidity and mortality. In the past several decades, therapeutic hypothermia has garnered interest as an effective neuroprotective method in the setting of AIS. However, traditional hypothermic methods have been criticized for their low cooling efficiency and side effects. Intra-arterial cold saline infusion (IA-CSI), as a novel hypothermic method, not only minimizes these side effects, but is also perfectly integrated with widely accepted recanalization modalities in AIS, thereby serving as a promising prospect for clinical translation. In this article, we review the historical development of IA-CSI, summarize major studies of IA-CSI in rodents, large animals, and humans to date, and suggest insight into future development prospects in the field of AIS. We hope that this article will provide inspiration for the future application of hypothermia in AIS patients.

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    Oxidative Stress at the Crossroads of Aging, Stroke and Depression
    Anwen Shao,Danfeng Lin,Lingling Wang,Sheng Tu,Cameron Lenahan,Jianmin Zhang
    Aging and disease. 2020, 11 (6): 1537-1566.   DOI: 10.14336/AD.2020.0225
    Abstract   HTML   PDF (1278KB) ( 657 )

    Epidemiologic studies have shown that in the aging society, a person dies from stroke every 3 minutes and 42 seconds, and vast numbers of people experience depression around the globe. The high prevalence and disability rates of stroke and depression introduce enormous challenges to public health. Accumulating evidence reveals that stroke is tightly associated with depression, and both diseases are linked to oxidative stress (OS). This review summarizes the mechanisms of OS and OS-mediated pathological processes, such as inflammation, apoptosis, and the microbial-gut-brain axis in stroke and depression. Pathological changes can lead to neuronal cell death, neurological deficits, and brain injury through DNA damage and the oxidation of lipids and proteins, which exacerbate the development of these two disorders. Additionally, aging accelerates the progression of stroke and depression by overactive OS and reduced antioxidant defenses. This review also discusses the efficacy and safety of several antioxidants and antidepressants in stroke and depression. Herein, we propose a crosstalk between OS, aging, stroke, and depression, and provide potential therapeutic strategies for the treatment of stroke and depression.

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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
    Abstract   HTML   PDF (463KB) ( 759 )

    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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    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
    Abstract   HTML   PDF (524KB) ( 572 )

    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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    A Perspective on Roles Played by Immunosenescence in the Pathobiology of Alzheimer's Disease
    Yan Zhao,Jun-Kun Zhan,Youshuo Liu
    Aging and disease. 2020, 11 (6): 1594-1607.   DOI: 10.14336/AD.2020.0205
    Abstract   HTML   PDF (589KB) ( 382 )

    Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder. Aging is the most significant risk factor for late-onset AD. The age-associated changes in the immune system are termed immunosenescence. A close connection between immunosenescence and AD is increasingly recognized. This article provides an overview of immunosenescence and evidence for its role in the pathogenesis of AD and possible mechanisms as well as the outlook for drug development.

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    The Critical Role of SIRT1 in Parkinson’s Disease: Mechanism and Therapeutic Considerations
    Xuan Li,Ya Feng,Xi-Xi Wang,Daniel Truong,Yun-Cheng Wu
    Aging and disease. 2020, 11 (6): 1608-1622.   DOI: 10.14336/AD.2020.0216
    Abstract   HTML   PDF (698KB) ( 1009 )

    Silence information regulator 1 (SIRT1), a member of the sirtuin family, targets histones and many non-histone proteins and participates in various physiological functions. The enzymatic activity of SIRT1 is decreased in patients with Parkinson’s disease (PD), which may reduce their ability to resist neuronal damage caused by various neurotoxins. As far as we know, SIRT1 can induce autophagy by regulating autophagy related proteins such as AMP-activated protein kinase, light chain 3, mammalian target of rapamycin, and forkhead transcription factor 1. Furthermore, SIRT1 can regulate mitochondrial function and inhibit oxidative stress mainly by maintaining peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in a deacetylated state and thus maintaining a constant level of PGC-1α. Other studies have demonstrated that SIRT1 may play a role in the pathophysiology of PD by regulating neuroinflammation. SIRT1 deacetylases nuclear factor-kappa B and thus reduces its transcriptional activity, inhibits inducible nitric oxide synthase expression, and decreases tumor necrosis factor-alpha and interleukin-6 levels. SIRT1 can also upregulate heat shock protein 70 by deacetylating heat shock factor 1 to increase the degradation of α-synuclein oligomers. Few studies have focused on the relationship between SIRT1 single nucleotide polymorphisms and PD risk, so this topic requires further research. Based on the neuroprotective effects of SIRT1 on PD, many in vitro and in vivo experiments have demonstrated that some SIRT1 activators, notably resveratrol, have potential neuroprotective effects against dopaminergic neuronal damage caused by various neurotoxins. Thus, SIRT1 plays a critical role in PD development and might be a potential target for PD therapy.

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    Pathological Mechanisms and Potential Therapeutic Targets of Pulmonary Arterial Hypertension: A Review
    Ying Xiao,Pei-Pei Chen,Rui-Lin Zhou,Yang Zhang,Zhuang Tian,Shu-Yang Zhang
    Aging and disease. 2020, 11 (6): 1623-1639.   DOI: 10.14336/AD.2020.0111
    Abstract   HTML   PDF (680KB) ( 551 )

    Pulmonary arterial hypertension (PAH) is a progressive cardiovascular disease characterized by pulmonary vasculature reconstruction and right ventricular dysfunction. The mortality rate of PAH remains high, although multiple therapeutic strategies have been implemented in clinical practice. These drugs mainly target the endothelin-1, prostacyclin and nitric oxide pathways. Management for PAH treatment includes improving symptoms, enhancing quality of life, and extending survival rate. Existing drugs developed to treat the disease have resulted in enormous economic and healthcare liabilities. The estimated cost for advanced PAH has exceeded $200,000 per year. The pathogenesis of PAH is associated with numerous molecular processes. It mainly includes germline mutation, inflammation, dysfunction of pulmonary arterial endothelial cells, epigenetic modifications, DNA damage, metabolic dysfunction, sex hormone imbalance, and oxidative stress, among others. Findings based on the pathobiology of PAH may have promising therapeutic outcomes. Hence, faced with the challenges of increasing healthcare demands, in this review, we attempted to explore the pathological mechanisms and alternative therapeutic targets, including other auxiliary devices or interventional therapies, in PAH. The article will discuss the potential therapies of PAH in detail, which may require further investigation before implementation.

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    Serine and Metabolism Regulation: A Novel Mechanism in Antitumor Immunity and Senescence
    Qi Wu,Xinyue Chen,Juanjuan Li,Shengrong Sun
    Aging and disease. 2020, 11 (6): 1640-1653.   DOI: 10.14336/AD.2020.0314
    Abstract   HTML   PDF (633KB) ( 415 )

    As one of the nonessential amino acids (NEAAs), serine is involved in the anabolism of multiple macromolecular substances by participating in one-carbon unit metabolism. Thus, rapidly proliferating cells such as tumor cells and activated immune cells are highly dependent on serine. Serine supports the proliferation of various immune cells through multiple pathways to enhance the antitumor immune response. Moreover, serine influences aging specificity in an epigenetic and metabolic manner. In this review, we focus on recent advances in the relationship between serine metabolism, antitumor immunity, and senescence. The metabolic regulation of serine seems to be a key point of intervention in antitumor immunity and aging-related disease, providing an opportunity for several novel therapeutics.

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Kunlin Jin, M.D., Ph.D., Professor
Ashok K. Shetty, Ph.D., Professor
David A. Greenberg, M.D., Ph.D., Professor
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