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Cover Illustration
2019, Vol.10  No.6
<b><span style="font-size:9.0pt;font-family:"">Effects of verapamil on skeletal muscle pathology in </span><span style="font-size:9.0pt;font-family:"">SOD1<sup>G93A </sup>mice.</span></b><span style="font-size:9.0pt;font-family:""> NADH staining of gastrocnemius muscle sections. n = 3 per group. Arrows indicate significant grouped atrophic fibers and hematoxylin inclusions. Scale bar = 100 μm.. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test. All values are presented as mean ± SEM. <sup>**</sup>P </span><span style="font-size:9.0pt;font-family:"">< </span><span style="font-size:9.0pt;font-family:"">0.01, compared with WT-Con group;</span>& [Detail] ...

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  • Table of Content
      01 December 2019, Volume 10 Issue 6 Previous Issue    Next Issue
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    Orginal Article
    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
    Abstract   HTML   PDF (1540KB) ( 1253 )

    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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    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
    Abstract   HTML   PDF (1342KB) ( 1243 )

    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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    Novel Role of Lck in Leptin-Induced Inflammation and Implications for Renal Aging
    Dae Hyun Kim, June Whoun Park, Hyoung Oh Jeong, Bonggi Lee, Ki Wung Chung, Yujeong Lee, Hee Jin Jung, Min Kyung Hyun, A Kyoung Lee, Byeong Moo Kim, Byung Pal Yu, Hae Young Chung
    Aging and disease. 2019, 10 (6): 1174-1186.   DOI: 10.14336/AD.2019.0218
    Abstract   HTML   PDF (904KB) ( 858 )

    Aging is associated with increased fat mass and elevated serum leptin levels (hyperleptinemia), causing proinflammation in the kidneys where it plays a primary role in the removal of endogenous leptin from the circulation. Lymphocyte-specific kinase (Lck) is a positive regulator of inflammatory signaling and a potential treatment target for age-related diseases, but its role in leptin signaling is unknown. Here, we investigated how Lck influences hyperleptinemia-induced inflammation in kidney tissues from 6- and 21-month-old rats. Results indicate that Lck expression and activation increased significantly in aged rat kidneys, especially at renal tubules. Furthermore, we identified interactions between Lck and short leptin-receptor isoforms, suggesting that Lck is a protein tyrosine kinase regulating leptin signaling. We further investigated whether increased Lck expression in renal tubular epithelial cells and macrophage infiltration are associated with leptin-induced inflammation. We then demonstrated that leptin activates Lck and proinflammatory transcription factors (STAT3 and NF-κB), while Lck knockdown modulates the expression of both transcription factors. Collectively, these data implicate that Lck leads to development of leptin-induced renal inflammation during aging. Inhibition of this protein tyrosine kinase may therefore be an appropriate therapeutic option for protection against age-related hyperleptinemia.

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    Astragalus Polysaccharide Extends Lifespan via Mitigating Endoplasmic Reticulum Stress in the Silkworm, Bombyx mori
    Jiangbo Song, Min Chen, Zhiquan Li, Jianfei Zhang, Hai Hu, Xiaoling Tong, Fangyin Dai
    Aging and disease. 2019, 10 (6): 1187-1198.   DOI: 10.14336/AD.2019.0515
    Abstract   HTML   PDF (964KB) ( 1124 )

    The traditional Chinese medicine Astragalus polysaccharide (APS) has been widely used to improve glucose homeostasis and immunoregulator properties. In recent years, it has also been shown to extend the lifespan of Caenorhabditis elegans; however, the underlying molecular mechanisms are not fully understood. Here, our study shows that APS could significantly extend adult stage, mean, and maximum lifespan of the silkworm, Bombyx mori and increase body weight without affecting food intake and fecundity. Meanwhile, the activities of glutathione S-transferase and superoxide dismutase are significantly enhanced, and the reaction oxygen species content is reduced concomitantly. Moreover, the activity of lysozyme is increased dramatically. In addition, APS rescues the shortened lifespan by Bacillus thuringiensis infection in silkworm. Furthermore, the transcription of the crucial genes involved in endoplasmic reticulum stress is upregulated upon the endoplasmic reticulum stress stimulation. APS also significantly ameliorates endoplasmic reticulum stress in silkworm cell line and in vivo. Together, the results of this study indicate that APS can prolong the silkworm lifespan by mitigating endoplasmic reticulum stress. This study improves our understanding of the molecular mechanism of APS-induced lifespan extension and highlights the importance of the silkworm as an experimental animal for evaluating the effects and revealing the mechanisms in lifespan extension of traditional Chinese medicine.

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    Genetic Spectrum and Variability in Chinese Patients with Amyotrophic Lateral Sclerosis
    Zhi-Jun Liu, Hui-Xia Lin, Qiao Wei, Qi-Jie Zhang, Cong-Xin Chen, Qing-Qing Tao, Gong-Lu Liu, Wang Ni, Aaron D Gitler, Hong-Fu Li, Zhi-Ying Wu
    Aging and disease. 2019, 10 (6): 1199-1206.   DOI: 10.14336/AD.2019.0215
    Abstract   HTML   PDF (476KB) ( 1654 )

    Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by selective impairment of upper and lower motor neurons. We aimed to investigate the genetic spectrum and variability in Chinese patients with ALS. A total of 24 familial ALS (FALS) and 21 early-onset sporadic ALS (SALS) of Chinese ancestry were enrolled. Targeted next-generation sequencing (NGS) was performed in the probands, followed by verification by Sanger sequencing and co-segregation analysis. Clinical features of patients with pathogenic or likely pathogenic variants were present. The mutation frequency of ALS-related genes was then analyzed in Chinese population. In this cohort, 17 known mutations (9 SOD1, 5 FUS, 2 TARDBP and one SETX) were identified in 14 FALS and 6 early-onset SALS. Moreover, 7 novel variants (SOD1 c.112G>C, OPTN c.811C>T, ERBB4 c.965T>A, DCTN1 c.1915C>T, NEFH c.2602G>A, NEK1 c.3622G>A, and TAF15 c.1535G>A) were identified. In southeastern Chinese FALS, the mutation frequency of SOD1, FUS, and TARDBP was 52.9%, 8.8%, 8.8% respectively. In early-onset SALS, FUS mutations were the most common (22.6%). In Chinese ALS cases, p.H47R is most frequent SOD1 mutations, while p.R521 is most common FUS mutation and p.M337V is most common TARDBP mutation. Our results revealed that mutations in SOD1, FUS and TARDBP are the most common cause of Chinese FALS, while FUS mutations are the most common cause of early-onset SALS. The genetic spectrum is different between Chinese ALS and Caucasian ALS.

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    TNFα-induced Up-regulation of Ascl2 Affects the Differentiation and Proliferation of Neural Stem Cells
    Zhongfeng Liu, Xuan Wang, Kewen Jiang, Xunming Ji, Y. Alex Zhang, Zhiguo Chen
    Aging and disease. 2019, 10 (6): 1207-1220.   DOI: 10.14336/AD.2018.1028
    Abstract   HTML   PDF (1722KB) ( 2178 )

    The molecular mediators underlying the effects of inflammation on neural stem cells (NSCs) are not fully characterized. In this study, we identified Ascl2 as a downstream basic helix-loop-helix (bHLH) transcription factor in NSCs following exposure to TNFα. Under normal conditions, Ascl2 expression is inhibited at post-transcriptional levels by miR-26a, which targets the 3’ untranslated region (UTR) of Ascl2. Upon exposure to TNFα, miR-26a expression is reduced, which leads to up-regulation of Ascl2. Overexpression of Ascl2 promotes neuronal differentiation, reduces proliferation, and increases the level of cleaved CASPASE 3 in NSCs, as observed in the in vitro and in ovo experiments. Ascl2 may serve in NSCs as a standby factor that readily responds to TNFα, which is often induced in inflammatory situations. In a chronic inflammatory condition with consistent up-regulation of TNFα, overexpression of Ascl2 may inhibit neurogenesis as a net result.

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    Entorhinal Cortex Atrophy in Early, Drug-naive Parkinson’s Disease with Mild Cognitive Impairment
    Xiuqin Jia, Zhijiang Wang, Tao Yang, Ying Li, Shuai Gao, Guorong Wu, Tao Jiang, Peipeng Liang
    Aging and disease. 2019, 10 (6): 1221-1232.   DOI: 10.14336/AD.2018.1116
    Abstract   HTML   PDF (982KB) ( 1808 )

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

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    Autophagy Activation is Associated with Neuroprotection in Diabetes-associated Cognitive Decline
    Yanqing Wu, Libing Ye, Yuan Yuan, Ting Jiang, Xin Guo, Zhouguang Wang, Ke Xu, Zeping Xu, Yanlong Liu, Xingfeng Zhong, Junmin Ye, Hongyu Zhang, Xiaokun Li, Jian Xiao
    Aging and disease. 2019, 10 (6): 1233-1245.   DOI: 10.14336/AD.2018.1024
    Abstract   HTML   PDF (1787KB) ( 1554 )

    Autophagy is a lysosome-dependent cellular catabolic mechanism that mediates the turnover of dysfunctional organelles and aggregated proteins. It has a neuroprotective role on neurodegenerative diseases. Here, we hypothesized that autophagy may also have a neuroprotective role in diabetes-associated cognitive decline (DACD). In current study, we found that db/db mice display cognitive decline with inferior learning and memory function. The accumulation of β-amyloid1-42 (Aβ1-42), which is a characteristic of Alzheimer’s disease (AD), was markedly higher in the prefrontal cortex (PFC), cornu ammon1 (CA1), and dentate gyrus (DG) areas of the hippocampus in db/db mice. Moreover, BDNF and microtubule associated protein 2 (MAP2) levels were lower in the hippocampus of db/db mice. However, there was no noticeable differences in the level of apoptosis in the hippocampus between control (CON) mice and db/db mice. Markers of autophagy in the hippocampus were elevated in db/db mice. The expression levels of ATG5, ATG7, and LC3B were higher, and the level of P62 was lower. An autophagy inhibitor, 3-MA, and ATG7 siRNA significantly reversed the activation of autophagy in vitro, which was accompanied with a higher level of apoptosis. Taken together, our current study suggests that diabetes is associated with cognitive decline, and activation of autophagy has a neuroprotective role in DACD.

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    Disability Transitions and Health Expectancies among Elderly People Aged 65 Years and Over in China: A Nationwide Longitudinal Study
    Chengbei Hou, Yuan Ma, Xinghua Yang, Lixin Tao, Deqiang Zheng, Xiangtong Liu, Xiaonan Wang, Xia Li, Wei Wang, Xianghua Fang, Xiuhua Guo
    Aging and disease. 2019, 10 (6): 1246-1257.   DOI: 10.14336/AD.2019.0121
    Abstract   HTML   PDF (774KB) ( 1070 )

    Disability has become a critical issue among elderly populations, yet limited large-scale research related to this issue has been conducted in China, an aging society. This study explored sex and urban-rural differences in disability transitions and life expectancies among older adults in China. Data were collected from the Chinese Longitudinal Health Longevity Survey (CLHLS), which enrolled people aged 65 and older and was conducted in randomly selected counties and cities across 22 provinces in China. Disability was diagnosed based on basic activities of daily living (BADLs) and instrumental activities of daily living (IADLs). Several individual characteristics were assessed, including sociodemographic factors (age, sex and region, etc.) and health behaviors (currently smoking, currently drinking, etc.). Multistate models were applied to analyze the transition rates among 4 states: no disability, mild disability, severe disability and death. The transition rates from disabled states to the no-disability state were found to decrease markedly with age. The rates of recovery from mild disability in rural areas were higher than those in urban areas. Rural elderly individuals lived shorter lives than their urban counterparts, but they tended to live with better functional status, spending a larger fraction of their remaining life with less severe disability. Based on these findings, devoting more attention and resources to rural areas may help less severely disabled people recuperate and prevent severe disability. The study provides insights into health plan strategies to help guide the allocation of limited resources.

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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
    Abstract   HTML   PDF (1314KB) ( 1236 )

    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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    Frailty Predicts an Increased Risk of End-Stage Renal Disease with Risk Competition by Mortality among 165,461 Diabetic Kidney Disease Patients
    Chia-Ter Chao, Jui Wang, Jenq-Wen Huang, Ding-Cheng Chan, Kuo-Liong Chien
    Aging and disease. 2019, 10 (6): 1270-1281.   DOI: 10.14336/AD.2019.0216
    Abstract   HTML   PDF (836KB) ( 964 )

    To examine the effect of frailty on diabetic kidney disease patients’ risk of progression to end-stage renal disease (ESRD), mortality, and adverse episodes, as whether frailty modifies their risk of developing ESRD and other adverse outcomes remains unclear. We identified 165,461 DKD patients from the Longitudinal Cohort of Diabetes Patients in Taiwan (n=840,000) between 2004 and 2010, classifying them into those without frailty or with 1, 2 and ≥3 frailty components based on a modified version of FRAIL scale. Using Cox proportional hazard regression analysis, we examined the long-term risk of developing ESRD along with their risk of mortality, supplemented by a competing risk analysis against mortality. Among all participants, 66.2% (n=109,586), 27.2% (n=44,986), 5.9% (n=9,799), and 0.7% (n=1090) patients did not have or had 1, 2, and ≥3 frailty components, respectively. After a 4.1-year follow-up, 4.2% patients developed ESRD and 18.5% died. Cox proportional hazard modeling revealed that patients with 1, 2, and ≥3 frailty components had increased risks of developing ESRD (for 1, 2, and ≥3 components, hazard ratio [HR] 1.13, 1.18, and 1.2, respectively) and mortality (HR 1.25, 1.41, and 1.34, respectively), with. 9% and 16% risk elevations for ESRD and mortality per component increase. Competing risk analysis showed that frailty-induced ESRD risk was attenuated partially by mortality in those with moderate frailty. The receipt of palliative care did not attenuate this risk. Frailty increased the risk of ESRD based on a dose-response relationship among DKD patients with risk competition by mortality.

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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
    Abstract   HTML   PDF (394KB) ( 2474 )

    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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    The Potential Markers of Circulating microRNAs and long non-coding RNAs in Alzheimer's Disease
    Yanfang Zhao, Yuan Zhang, Lei Zhang, Yanhan Dong, Hongfang Ji, Liang Shen
    Aging and disease. 2019, 10 (6): 1293-1301.   DOI: 10.14336/AD.2018.1105
    Abstract   HTML   PDF (628KB) ( 3240 )

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

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    Interplay between Exosomes and Autophagy in Cardiovascular Diseases: Novel Promising Target for Diagnostic and Therapeutic Application
    Jinfan Tian, Sharif Popal Mohammad, Yingke Zhao, Yanfei Liu, Keji Chen, Yue Liu
    Aging and disease. 2019, 10 (6): 1302-1310.   DOI: 10.14336/AD.2018.1020
    Abstract   HTML   PDF (361KB) ( 2292 )

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

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    Neurological Manifestation of Incretin-Based Therapies in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis
    Le Gao, Shuqing Yu, Andrea Cipriani, Shanshan Wu, Yi Huang, Zilu Zhang, Jun Yang, Yixin Sun, Zhirong Yang, Sanbao Chai, Yuan Zhang, Linong Ji, Siyan Zhan, Feng Sun
    Aging and disease. 2019, 10 (6): 1311-1319.   DOI: 10.14336/AD.2019.0303
    Abstract   HTML   PDF (932KB) ( 1561 )

    As a new class of antidiabetic drug, incretin-based therapies, which include dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have raised concerns about symptoms of withdrawal in patients with type 2 diabetes mellitus (T2DM), such as dizziness and headache. To systematically evaluate whether incretin-based therapies may lead to dizziness and headache in patients with T2DM compared to other traditional antidiabetic drugs or placebo. We searched Medline, Embase, the Cochrane library, and clinicaltrials.gov from inception through June 23, 2017, to identify randomized controlled trials of the safety of DPP-4Is or GLP-1 RAs versus placebo or other antidiabetic drugs in T2DM patients. We used the network meta-analysis under the frequentist framework to compare the association between multiple antidiabetic drugs and dizziness and headache. A total of 233 clinical trials with nine treatments and 147,710 patients were included: two incretin-based therapies, one placebo, and six traditional antidiabetic drugs (metformin, insulin, sulfonylurea, thiazolidinediones, alpha-glucosidase inhibitor, and sodium-glucose co-transporter 2). Compared to insulin, thiazolidinediones, or placebo, GLP-1 RAs statistically significantly increased the risk of dizziness (odds ratios [ORs]: 1.92, 1.57, and 1.40, respectively) and headache (ORs: 1.34, 1.41, and 1.18, respectively). DPP-4Is increased the risk of headache (OR: 1.22, 95% confidence interval [CI]: 1.02 to 1.46; moderate quality) and dizziness (OR: 1.46, 95% CI: 1.05 to 2.03; moderate quality) compared to insulin. Of the incretin-based therapies, DPP-4Is had a lower risk of dizziness than GLP-1 RAs (OR: 0.76, 95% CI: 0.67 to 0.87; high quality). Ranking probability analysis indicated that GLP-1 RAs may have the greatest risk of both dizziness and headache among the nine treatments (22.5% and 23.4%, respectively), whereas DPP-4Is were in the middle (46.2% and 45.0%, respectively). Incretin-based therapies increase the risk of dizziness and headache compared to insulin, thiazolidinediones, and placebo.

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    Short Communications
    The Long-lasting Radioprotective Effect of Caffeic Acid in Mice Exposed to Total Body Irradiation by Modulating Reactive Oxygen Species Generation and Hematopoietic Stem Cell Senescence-Accompanied Long-term Residual Bone Marrow Injury
    Hyun-Jaung Sim, Govinda Bhattarai, Joshua Lee, Jeong-Chae Lee, Sung-Ho Kook
    Aging and disease. 2019, 10 (6): 1320-1327.   DOI: 10.14336/AD.2019.0208
    Abstract   HTML   PDF (1054KB) ( 979 )

    Total body irradiation (TBI) serves as an effectively curative therapy for cancer patients and adversely causes long-term residual bone marrow (BM) injury with premature senescence of hematopoietic stem cells (HSCs), which is mediated by increased production of reactive oxygen species (ROS). In the present study, we investigated how the exposure time of TBI in a mouse model affects HSCs and whether the treatment of caffeic acid (CA), a known dietary phenolic antioxidant, has a radioprotective effect. Single (S)-TBI at a sublethal dose (5 Gy) caused relatively higher induction of mitochondrial ROS and senescence-related factors in HSCs than those in hematopoietic progenitor cells (HPCs) and Lineage-Sca-1+c-Kit+ (LSK) cells, as well as reduced clonogenic formation and donor cell-derived reconstituting capacity. Repetitive double (D)-TBI (two months after the S-TBI at a dose of 5Gy) further weakened HSPC function via mitochondrial ROS accumulation and senescence-associated β-galactosidase (SA-β-gal) activity. Oral administration of CA (20 mg/kg) five times before and once immediately after TBI ameliorated ROS generation and TBI-induced HSC senescence and its radioprotective effect was long lasting in S-TBI mice but not in D-TBI mice. Further, supplementation of CA also induced apoptotic cell death of colon cancer cells. Collectively, these findings indicate that CA has a dual effect, ameliorating HSC senescence-accompanied long-term BM injury in S-TBI mice and stimulating apoptotic cell death of colon cancer cells.

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    Aging, Alzheimer’s Disease and Dysfunctional Glycolysis; Similar Effects of Too Much and Too Little
    Alan R Hipkiss
    Aging and disease. 2019, 10 (6): 1328-1331.   DOI: 10.14336/AD.2019.0611
    Abstract   HTML   PDF (288KB) ( 1540 )

    Aging and much related dysfunction can be delayed by decreased glycolysis, however dysfunctional glycolysis appears to play a causative role in Alzheimer’s disease (AD). It is proposed here that this apparent contradiction can be reconciled by suggesting that both over-use and inhibition of the glycolytic enzyme triosephosphate isomerase can limit NADH generation and increase protein glycation. It is also suggested that excessive glycolysis in erythrocytes may provide a source of systemic methylglyoxal and glycated alpha-synuclein, both of which accelerate aging onset and neurodegeneration.

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Kunlin Jin, M.D., Ph.D., Professor
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