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Cover Illustration
2020, Vol.11  No.3
<b><span style="font-size:9.0pt;font-family:"color:#3B3B3B;background:white;">Figure 3. Characteristic 3D morphological alterations of the thoracic spinal cord microvasculature at different time points after surgery to induce chronic compression.</span></b><span style="font-size:9.0pt;font-family:"color:#3B3B3B;background:white;"> <b>(A-C)</b> Representative 3D cross-sectional images of the spinal cord microvasculature after 1 and 6 months of chronic compression. <b>(D-F) </b>Pseudocolored image of the spinal cord microvasculature correlated with vessel thickness at the corresponding time point after compression surgery. </span>

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  • Table of Content
      09 May 2020, Volume 11 Issue 3 Previous Issue   
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    Editorial
    Adipose Stem Cells (ASCs) and Stromal Vascular Fraction (SVF) as a Potential Therapy in Combating (COVID-19)-Disease
    Pietro Gentile, Aris Sterodimas
    Aging and disease. 2020, 11 (3): 465-469.   DOI: 10.14336/AD.2020.0422
    Abstract   HTML   PDF (235KB) ( 782 )

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

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    Short Communication
    Molecular Aging Markers in Patients with Klinefelter Syndrome
    Eva Pohl, Sina Muschal, Sabine Kliesch, Michael Zitzmann, Julia Rohayem, Jörg Gromoll, Sandra Laurentino
    Aging and disease. 2020, 11 (3): 470-476.   DOI: 10.14336/AD.2019.0801
    Abstract   HTML   PDF (458KB) ( 292 )

    Molecular aging markers provide the opportunity for biological age determination in humans and to study factors, such as genetic determinants, affecting the ageing process. In males with Klinefelter syndrome (KS, non-mosaic karyotype 47, XXY), which is the most common sex chromosome aneuploidy, age-related morbidity and mortality are increased, and a significantly reduced life span has been observed. The aim of this study was to investigate whether Klinefelter patients exhibit molecular signs of premature ageing. We studied, specifically, age-associated DNA methylation patterns (by pyrosequencing) and relative telomere length (TL; by quantitative polymerase chain reaction) in blood in a cohort of Klinefelter patients (n=178 and 266 for DNA methylation and TL, respectively) aged 18-71 years and compared them to the data of age-matched healthy male (n = 184 and 196 for DNA methylation and TL, respectively) and female controls (n = 50). Age-associated DNA methylation patterns were not indicative of accelerated ageing in Klinefelter men. Significantly longer telomeres were found in the young Klinefelter subjects aged 18-24 years (mean=1.51 vs. 1.09 and 1.26 in female and male controls, respectively). However, telomere length in subsequent age groups showed no difference to controls. Gonosomal aneuploidy in Klinefelter syndrome is associated with higher baseline TL at adolescent age, but comparable TL with progressive age in other age groups.

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    Commentary
    Mesenchymal Stem Cells for Coronavirus (COVID-19)-Induced Pneumonia: Revisiting the Paracrine Hypothesis with New Hopes?
    Selçuk Öztürk, Ayşe Eser Elçin, Yaşar Murat Elçin
    Aging and disease. 2020, 11 (3): 477-479.   DOI: 10.14336/AD.2020.0403
    Abstract   HTML   PDF (299KB) ( 748 )

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

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    Perspective
    COVID-19 in India: Are Biological and Environmental Factors Helping to Stem the Incidence and Severity?
    Sankha Shubhra Chakrabarti, Upinder Kaur, Anindita Banerjee, Upasana Ganguly, Tuhina Banerjee, Sarama Saha, Gaurav Parashar, Suvarna Prasad, Suddhachitta Chakrabarti, Amit Mittal, Bimal Kumar Agrawal, Ravindra Kumar Rawal, Robert Chunhua Zhao, Indrajeet Singh Gambhir, Rahul Khanna, Ashok K Shetty, Kunlin Jin, Sasanka Chakrabarti
    Aging and disease. 2020, 11 (3): 480-488.   DOI: 10.14336/AD.2020.0402
    Abstract   HTML   PDF (726KB) ( 897 )

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

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    Opinion
    Whole-lung Low Dose Irradiation for SARS-Cov2 Induced Pneumonia in the Geriatric Population: An Old Effective Treatment for a New Disease? Recommendation of the International Geriatric Radiotherapy Group
    Pedro C Lara, Nam P Nguyen, David Macias-Verde, Javier Burgos-Burgos, Meritxell Arenas, Alice Zamagni, Vincent Vinh-Hung, Brigitta G Baumert, Micaela Motta, Arthur Sun Myint, Marta Bonet, Tiberiu Popescu, Te Vuong, Gokula Kumar Appalanaido, Lurdes Trigo, Ulf Karlsson, Juliette Thariat
    Aging and disease. 2020, 11 (3): 489-493.   DOI: 10.14336/AD.2020.0506
    Abstract   HTML   PDF (300KB) ( 386 )

    A cytokine storm induced by SARS-Cov2 may produce pneumonitis which may be fatal for older patients with underlying lung disease. Hyper-elevation of Interleukin1 (IL-1), Tumor necrosis factor-1alfa (TNF-1 alfa), and Interleukin 6 (IL-6) produced by inflammatory macrophage M1 may damage the lung alveoli leading to severe pneumonitis, decreased oxygenation, and potential death despite artificial ventilation. Older patients may not be suitable candidates for pharmaceutical intervention targeting IL-1/6 blockade or artificial ventilation. Low dose total lung (LDTL) irradiation at a single dose of 50 cGy may stop this cytokine cascade, thus preventing, and/or reversing normal organs damage. This therapy has been proven in the past to be effective against pneumonitis of diverse etiology and could be used to prevent death of older infected patients. Thus, LDRT radiotherapy may be a cost-effective treatment for this frail patient population whom radiation -induced malignancy is not a concern because of their advanced age. This hypothesis should be tested in future prospective trials.

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    Orginal Article
    Longitudinal Association of Telomere Attrition with the Effects of Antihypertensive Treatment and Blood Pressure Lowering
    Shuyuan Zhang, Rongxia Li, Yunyun Yang, Yu Chen, Shujun Yang, Jian Li, Cunjin Wu, Tao Kong, Tianlong Liu, Jun Cai, Li Fu, Yanan Zhao, Rutai Hui, Weili Zhang
    Aging and disease. 2020, 11 (3): 494-508.   DOI: 10.14336/AD.2019.0721
    Abstract   HTML   PDF (814KB) ( 382 )

    Leukocytes telomere length has been associated with hypertension, but, whether longitudinal telomeres change could serve as a useful predictive tool in hypertension remains uncertain. This study aimed to examine the longitudinal trajectory of leukocytes telomere length in a population-based prospective study of 1,108 individuals with hypertension. Leukocytes telomere length were measured at baseline and again after a median 2.2 (range 1.5-2.4) years of follow-up. Age as an independent predictor was inversely associated with baseline telomeres and follow-up telomeres. Annual telomere attrition rate was calculated as (follow-up telomeres-baseline telomeres)/follow-up years, and participants were categorized into the shorten and the lengthen groups. Results showed that telomere lengthening was significantly correlated with decreased systolic blood pressure (SBP) (β=-3.28; P=0.02) and pulse pressure (PP) (β=-2.53; P=0.02), and the differences were respectively -3.3 mmHg (95%CI, -6.2 to -0.3; P=0.03) in ∆SBP and -2.4 mmHg (95%CI, -4.9 to -0.1; P=0.04) in ∆PP between two groups after adjustment for vascular risk factors and baseline blood pressures. When stratified by age and gender, the correlations were observed in women and patients ≤60 years. Furthermore, among patients using calcium channel blocker (CCB) and angiotensin receptor blocker (ARB), those with telomeres lengthening showed a significantly lower level of ∆SBP and ∆PP. There was no correlation between telomere attrition and incidence of cardiovascular events. Our data indicated that increased telomere length of leukocytes was associated with decreased SBP and PP, particularly for patients who received CCB and ARB, supporting that telomere attrition may provide new sight in clinical intervention for hypertension.

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    COVID-19 Virulence in Aged Patients Might Be Impacted by the Host Cellular MicroRNAs Abundance/Profile
    Sadanand Fulzele, Bikash Sahay, Ibrahim Yusufu, Tae Jin Lee, Ashok Sharma, Ravindra Kolhe, Carlos M Isales
    Aging and disease. 2020, 11 (3): 509-522.   DOI: 10.14336/AD.2020.0428
    Abstract   HTML   PDF (793KB) ( 1542 )

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

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    Mib2 Deficiency Inhibits Microglial Activation and Alleviates Ischemia-Induced Brain Injury
    Xiaoheng Li, Yajin Liao, Yuan Dong, Shuoshuo Li, Fengchao Wang, Rong Wu, Zengqiang Yuan, Jinbo Cheng
    Aging and disease. 2020, 11 (3): 523-535.   DOI: 10.14336/AD.2019.0807
    Abstract   HTML   PDF (1613KB) ( 344 )

    Neuroinflammation plays a critical role in ischemia-induced brain injury. Mib2, an E3 ubiquitin ligase, has been reported to regulate Notch signaling and participate in the peripheral immune system. However, the roles of Mib2 in the nervous system are not well characterized. In this study, we show that Mib2 is involved in lipopolysaccharide (LPS)- and oxygen-glucose deprivation (OGD)-induced microglial activation. Mechanistically, Mib2 interacts with the IKK complex and regulates the activation of NF-κB signaling, thus modulating Notch1 transcription in the microglia. Furthermore, we generated a microglia-specific Mib2 knockout mice and found that microglia-specific deletion of Mib2 significantly alleviates ischemia-induced neuroinflammation and brain injury. Taken together, our results reveal a critical role of Mib2 in microglial activation and ischemia-induced brain injury, thus providing a potential target for the treatment of stroke.

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    Cellular and Molecular Biomarkers Indicate Premature Aging in Pseudoxanthoma Elasticum Patients
    Janina Tiemann, Thomas Wagner, Olivier M Vanakker, Matthias van Gils, José-Luis Bueno Cabrera, Bettina Ibold, Isabel Faust, Cornelius Knabbe, Doris Hendig
    Aging and disease. 2020, 11 (3): 536-546.   DOI: 10.14336/AD.2019.0610
    Abstract   HTML   PDF (651KB) ( 256 )

    The molecular processes of aging are very heterogenic and not fully understood. Studies on rare progeria syndromes, which display an accelerated progression of physiological aging, can help to get a better understanding. Pseudoxanthoma elasticum (PXE) caused by mutations in the ATP-binding cassette sub-family C member 6 (ABCC6) gene shares some molecular characteristics with such premature aging diseases. Thus, this is the first study trying to broaden the knowledge of aging processes in PXE patients. In this study, we investigated aging associated biomarkers in primary human dermal fibroblasts and sera from PXE patients compared to healthy controls. Determination of serum concentrations of the aging biomarkers eotaxin-1 (CCL11), growth differentiation factor 11 (GDF11) and insulin-like growth factor 1 (IGF1) showed no significant differences between PXE patients and healthy controls. Insulin-like growth factor binding protein 3 (IGFBP3) showed a significant increase in serum concentrations of PXE patients older than 45 years compared to the appropriate control group. Tissue specific gene expression of GDF11 and IGFBP3 were significantly decreased in fibroblasts from PXE patients compared to normal human dermal fibroblasts (NHDF). IGFBP3 protein concentration in supernatants of fibroblasts from PXE patients were decreased compared to NHDF but did not reach statistical significance due to potential gender specific variations. The minor changes in concentration of circulating aging biomarkers in sera of PXE patients and the significant aberrant tissue specific expression seen for selected factors in PXE fibroblasts, suggests a link between ABCC6 deficiency and accelerated aging processes in affected peripheral tissues of PXE patients.

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    Neuroprotective Effects of Endogenous Secretory Receptor for Advanced Glycation End-products in Brain Ischemia
    Yu Shimizu, Ai Harashima, Seiichi Munesue, Masahiro Oishi, Tsuyoshi Hattori, Osamu Hori, Yasuko Kitao, Hiroshi Yamamoto, Nontaphat Leerach, Mitsutoshi Nakada, Yasuhiko Yamamoto, Yasuhiko Hayashi
    Aging and disease. 2020, 11 (3): 547-558.   DOI: 10.14336/AD.2019.0715
    Abstract   HTML   PDF (847KB) ( 380 )

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

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    Oxyphylla A Promotes Degradation of α-Synuclein for Neuroprotection via Activation of Immunoproteasome
    Hefeng Zhou, Shengnan Li, Chuwen Li, Xuanjun Yang, Haitao Li, Hanbing Zhong, Jia-Hong Lu, Simon Ming-Yuen Lee
    Aging and disease. 2020, 11 (3): 559-574.   DOI: 10.14336/AD.2019.0612
    Abstract   HTML   PDF (2036KB) ( 477 )

    Parkinson’s disease (PD), the second most common neurodegenerative disorder, is neuropathologically characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and the presence of Lewy bodies in surviving neurons. α-synuclein (α-syn) is the major component of Lewy bodies and its deposition in neurons is critical pathological event in the pathogenesis of PD. Herein, we reported that Oxyphylla A, a novel lead compound from the fruit of Alpinia oxyphylla, significantly promoted α-syn degradation in a cellular PD model. When exploring the molecular pathways, we found that Oxyphylla A promoted α-syn degradation in a ubiquitin proteasome system (UPS)-dependent and autophagy-independent manner. We further confirmed that Oxyphylla A enhanced UPS activity by upregulating 20S subunit PSMB8 expression. A mechanism study revealed that Oxyphylla A activated the PKA/Akt/mTOR pathway to trigger PSMB8 expression and enhance UPS activity. Finally, we illustrated that Oxyphylla A alleviated the accumulation of both Triton-soluble and Triton-insoluble forms of α-syn and protected against α-syn-induced neurotoxicity in A53T α-syn transgenic mice. These findings suggest that the activation of UPS, via small molecular UPS enhancers including Oxyphylla A, may be a therapeutic strategy for intervention against PD and related diseases.

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    Aging-Induced Brain-Derived Neurotrophic Factor in Adipocyte Progenitors Contributes to Adipose Tissue Dysfunction
    Hyun-Doo Song, Sang Nam Kim, Abhirup Saha, Sang-Yeop Ahn, Seun Akindehin, Yeonho Son, Yoon Keun Cho, MinSu Kim, Ji-Hyun Park, Young-Suk Jung, Yun-Hee Lee
    Aging and disease. 2020, 11 (3): 575-587.   DOI: 10.14336/AD.2019.0810
    Abstract   HTML   PDF (1819KB) ( 483 )

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

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    Renoprotective Effect of a Dipeptidyl Peptidase-4 Inhibitor on Aging Mice
    Tae H Ban, Eun N Kim, Min Y Kim, Ji H Lim, Jong H Lee, Hyung D Kim, Hye E Yoon, Cheol W Park, Bum S Choi
    Aging and disease. 2020, 11 (3): 588-602.   DOI: 10.14336/AD.2019.0620
    Abstract   HTML   PDF (2057KB) ( 290 )

    Dipeptidyl peptidase 4 (DPP-4) inhibitors exert pleiotropic effects beyond glycemic control. We investigated the renoprotective effects of DPP-4 inhibitors on aging mice mediated by the renin-angiotensin system (RAS). C57BL/6 mice were divided into three groups: the two-month-old mice (YM group), the eighteen-month-old mice (AM group) and the eighteen-month-old, linagliptin-treated mice (AM + LIN group). Renal function was improved, based on serum creatinine and cystatin-C levels (p < 0.05 compared with the AM group for both parameters). Fibrotic areas and the levels of proteins related to fibrosis improved in the AM + LIN group (p < 0.001 compared with the AM group for all parameters). In the AM + LIN group, the DPP-4-positive area and activity and expressions of DPP-4 were decreased (p < 0.05 compared with the AM group for all parameters). The levels of proteins related to the RAS, including prorenin receptor, angiotensin-converting enzyme, angiotensin II and angiotensin 1 receptor, were decreased in the AM + LIN group (p < 0.05, p < 0.01, p < 0.05, and p < 0.01 compared with the AM group, respectively). NADPH oxidase 2 and NADPH oxidase 4 levels decreased in the AM + LIN group (p < 0.001 compared with the AM group for both proteins), whereas the levels of endothelial nitric oxide synthase (eNOS) phosphorylated at serine1177 and superoxide dismutase 1 were increased (p < 0.01 compared with the AM group for both proteins). DPP-4 inhibitors may exert renoprotective effects via prorenin receptor/angiotensin-converting enzyme/angiotensin II/angiotensin 1 receptor axis.

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    SRμCT Reveals 3D Microstructural Alterations of the Vascular and Neuronal Network in a Rat Model of Chronic Compressive Thoracic Spinal Cord Injury
    Liyuan Jiang, Yong Cao, Zhen Liu, Shuangfei Ni, Jun Liu, Yoon Ha, Zixiang Luo, Chengjun Li, Shaohua Liu, Jingsong Li, Xianzhen Yin, Tianding Wu, Hongbin Lu, Jianzhong Hu
    Aging and disease. 2020, 11 (3): 603-617.   DOI: 10.14336/AD.2019.0529
    Abstract   HTML   PDF (1252KB) ( 393 )

    The complex pathology of chronic thoracic spinal cord compression involves vascular and neuroarchitectural repair processes that are still largely unknown. In this study, we used synchrotron radiation microtomography (SRμCT) to quantitatively characterize the 3D temporal-spatial changes in the vascular and neuronal network after chronic thoracic spinal cord compression in order to obtain further insights into the pathogenesis of this disease and to elucidate its underlying mechanisms. Direct 3D characterization of the spinal cord microvasculature and neural microstructure of the thoracic spinal cord was successfully reconstructed. The significant reduction in vasculature and degeneration of neurons in the thoracic spinal cord visualized via SRμCT after chronic compression were consistent with the changes detected by immunofluorescence staining. The 3D morphological measurements revealed significant reductions of neurovascular parameters in the thoracic spinal cord after 1 month of compression and became even worse after 6 months without relief of compression. In addition, the distinct 3D morphological twist and the decrease in branches of the central sulcal artery after chronic compression vividly displayed that these could be the potential triggers leading to blood flow reduction and neural deficits of the thoracic spinal cord. Our findings propose a novel methodology for the 3D analysis of neurovascular repair in chronic spinal cord compression, both qualitatively and quantitatively. The results indicated that compression simultaneously caused vascular dysfunction and neuronal network impairment, which should be acknowledged as concurrent events after chronic thoracic spinal cord injury. Combining neuroprotection with vasoprotection may provide promising therapeutic targets for chronic thoracic spinal cord compression.

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    T1-weighted MRI-driven Brain Age Estimation in Alzheimer’s Disease and Parkinson’s Disease
    Iman Beheshti, Shiwangi Mishra, Daichi Sone, Pritee Khanna, Hiroshi Matsuda
    Aging and disease. 2020, 11 (3): 618-628.   DOI: 10.14336/AD.2019.0617
    Abstract   HTML   PDF (961KB) ( 762 )

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

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    Lactulose Suppresses Osteoclastogenesis and Ameliorates Estrogen Deficiency-Induced Bone Loss in Mice
    Xiao Chen, Zheng Zhang, Yan Hu, Jin Cui, Xin Zhi, Xiaoqun Li, Hao Jiang, Yao Wang, Zhengrong Gu, Zili Qiu, Xin Dong, Yuhong Li, Jiacan Su
    Aging and disease. 2020, 11 (3): 629-641.   DOI: 10.14336/AD.2019.0613
    Abstract   HTML   PDF (1244KB) ( 468 )

    Postmenopausal osteoporosis is characterized by excess osteoclastogenesis which leads to net bone loss and brittle fractures. Studies have demonstrated that estrogen deficiency-associated bone loss is microbiota-dependent and could be prevented by probiotics and prebiotics. In this study, we report that orally administered lactulose (20 g/kg, 6 weeks) orally administered significantly inhibited osteoclastogenesis, bone resorption, and prevented ovariectomy (OVX)-induced bone loss in mice. Lactulose increased intestinal Claudin 2, 3 and 15, compared to the OVX group, and lowered pro-osteoclastogenic cytokines levels including tumor necrosis factor-α, interleukin(IL)-6, receptor activator of nuclear factor kappa-Β ligand (RANKL), and IL-17 as well as increased the anti-inflammatory cytokine IL-10 in the intestine, peripheral blood, and bone marrow. Lactulose significantly preserved the number of Foxp3+ Treg cells in the intestines compared with that in OVX mice. Lactulose altered the composition of intestinal microbiota measured by 16s rDNA sequencing and increased intestinal and serum short-chain fatty acids (SCFAs) levels including acetate, propionate and butyrate which were decreased in OVX mice as measured by gas chromatography. Oral administration of lactulose for 2 weeks significantly lowered the level of bone resorption marker C-telopeptide of type 1 collagen-1 in healthy male young volunteers (aging 20-25 years). In conclusion, lactulose inhibited osteoclastogenesis and bone resorption by altering the intestinal microbiota and increasing SCFAs. Lactulose could serve as an ideal therapeutic agent for postmenopausal osteoporosis.

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    Immune Characteristics of Patients with Coronavirus Disease 2019 (COVID-19)
    Xiaotian Dong, Mengyan Wang, Shuangchun Liu, Jiaqi Zhu, Yanping Xu, Hongcui Cao, Lanjuan Li
    Aging and disease. 2020, 11 (3): 642-648.   DOI: 10.14336/AD.2020.0317
    Abstract   HTML   PDF (624KB) ( 688 )

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

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    Review
    Management of The Elderly Cancer Patients Complexity: The Radiation Oncology Potential
    Giuseppe Colloca, Luca Tagliaferri, Beatrice Di Capua, Maria Antonietta Gambacorta, Vito Lanzotti, Andrea Bellieni, Silvio Monfardini, Lodovico Balducci, Roberto Bernabei, William C Cho, Vincenzo Valentini
    Aging and disease. 2020, 11 (3): 649-657.   DOI: 10.14336/AD.2019.0616
    Abstract   HTML   PDF (386KB) ( 337 )

    Radiation oncology has the potential to be an excellent option for the frail elderly cancer patients because of its limited systemic toxicities. It can be effective for curative, prophylactic, disease control or palliative purposes. Currently about 60% of all cancer patients undergoing active treatment at some point receive radiation treatment. However, though widely used, there are limited clinical trials strictly designed for the elderly. This paper will review the key points in the assessment and treatment of elderly cancer patient including quality of life, active life expectancy, cognitive performance, frailty, sarcopenia and how the new technologies can help to reach the key goal of maintaining autonomy and independence for the elderly cancer patient.

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    Dementia Risk in Type 2 Diabetes Patients: Acarbose Use and Its Joint Effects with Metformin and Pioglitazone
    Chin-Hsiao Tseng
    Aging and disease. 2020, 11 (3): 658-667.   DOI: 10.14336/AD.2019.0621
    Abstract   HTML   PDF (901KB) ( 239 )

    This population-based retrospective cohort study investigated dementia risk associated with acarbose in patients with type 2 diabetes mellitus by using Taiwan’s National Health Insurance database. A cohort of 15,524 matched pairs of ever and never users of acarbose based on propensity score matching was enrolled from new-onset type 2 diabetes patients from 1999 to 2006. Patients who were alive on January 1, 2007, were followed up for dementia until December 31, 2011. Adjusted hazard ratios were estimated using Cox proportional hazards models. The results revealed that the incident case numbers (incidence rates) of dementia were 264 (407.19 per 100,000 person-years) for never users and 231 (337.94 per 100,000 person-years) for ever users. The hazard ratio for ever users versus never users was 0.841 (95% confidence interval, 0.704-1.005) and 0.918 (0.845-0.998) for every 1-year increment of cumulative duration of acarbose therapy. Subgroup analyses showed that the reduced risk associated with acarbose was only observed in women (adjusted hazard ratio, 0.783; 95% confidence interval, 0.618-0.992) and in non-users of metformin (adjusted hazard ratio, 0.635; 95% confidence interval, 0.481-0.837). A model comparing different combinations of acarbose, metformin, and pioglitazone suggested that users of all three drugs had the lowest risk of dementia (hazard ratio, 0.406; 95% confidence interval, 0.178-0.925). In conclusion, reduced risk of dementia associated with acarbose is observed in the female sex and in non-users of metformin. Moreover, users of all three drugs (acarbose, metformin, and pioglitazone) have the lowest risk of dementia.

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    Comorbid Chronic Diseases are Strongly Correlated with Disease Severity among COVID-19 Patients: A Systematic Review and Meta-Analysis
    Hong Liu, Shiyan Chen, Min Liu, Hao Nie, Hongyun Lu
    Aging and disease. 2020, 11 (3): 668-678.   DOI: 10.14336/AD.2020.0502
    Abstract   HTML   PDF (983KB) ( 1071 )

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

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    Parkinson Disease and Orthostatic Hypotension in the Elderly: Recognition and Management of Risk Factors for Falls
    Peter A LeWitt, Steve Kymes, Robert A Hauser
    Aging and disease. 2020, 11 (3): 679-691.   DOI: 10.14336/AD.2019.0805
    Abstract   HTML   PDF (512KB) ( 1261 )

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

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    Implications of Long Non-Coding RNAs in Age-Altered Proteostasis
    Cristina-Sorina Catana, Catalina-Angela Crișan, Dana Opre, Ioana Berindan-Neagoe
    Aging and disease. 2020, 11 (3): 692-704.   DOI: 10.14336/AD.2019.0814
    Abstract   HTML   PDF (770KB) ( 502 )

    This review aims to summarize the current knowledge on how lncRNAs are influencing aging and cancer metabolism. Recent research has shown that senescent cells re-enter cell-cycle depending on intrinsic or extrinsic factors, thus restoring tissue homeostasis in response to age-related diseases (ARDs). Furthermore, maintaining proteostasis or cellular protein homeostasis requires a correct quality control (QC) of protein synthesis, folding, conformational stability, and degradation. Long non-coding RNAs (lncRNAs), transcripts longer than 200 nucleotides, regulate gene expression through RNA-binding protein (RBP) interaction. Their association is linked to aging, an event of proteostasis collapse. The current review examines approaches that lead to recognition of senescence-associated lncRNAs, current methodologies, potential challenges that arise from studying these molecules, and their crucial implications in clinical practice.

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    The Critical Role of Nurr1 as a Mediator and Therapeutic Target in Alzheimer’s Disease-related Pathogenesis
    Seong Gak Jeon, Anji Yoo, Dong Wook Chun, Sang Bum Hong, Hyunju Chung, Jin-il Kim, Minho Moon
    Aging and disease. 2020, 11 (3): 705-724.   DOI: 10.14336/AD.2019.0718
    Abstract   HTML   PDF (790KB) ( 966 )

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

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  Editors-in-Chief  
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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