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Aging, light sensitivity and circadian health
Sarah L. Chellappa
doi : 10.18632/aging.203806
Volume 13, Issue 24, pp: 25604—25606
Parathyroid hormone signaling in mature osteoblasts/osteocytes protects mice from age-related bone loss
Yuhei Uda1, * , Vaibhav Saini2, * , Christopher A. Petty1 , Majed Alshehri1 , Chao Shi1,3 , Jordan M. Spatz2,4 , Roberto Santos1 , Carly M. Newell1 , Tim Y. Huang1 , Alejandro Kochen1 , Ji W. Kim1 , Christodoulos K. Constantinou1 , Hiroaki Saito5 , Kathryn D. Held6 , Eric Hesse5 , Paola Divieti Pajevic1,2
doi : 10.18632/aging.203808
Volume 13, Issue 24, pp: 25607—25642
Aging is accompanied by osteopenia, characterized by reduced bone formation and increased bone resorption. Osteocytes, the terminally differentiated osteoblasts, are regulators of bone homeostasis, and parathyroid hormone (PTH) receptor (PPR) signaling in mature osteoblasts/osteocytes is essential for PTH-driven anabolic and catabolic skeletal responses. However, the role of PPR signaling in those cells during aging has not been investigated. The aim of this study was to analyze the role of PTH signaling in mature osteoblasts/osteocytes during aging. Mice lacking PPR in osteocyte (Dmp1-PPRKO) display an age-dependent osteopenia characterized by a significant decrease in osteoblast activity and increase in osteoclast number and activity. At the molecular level, the absence of PPR signaling in mature osteoblasts/osteocytes is associated with an increase in serum sclerostin and a significant increase in osteocytes expressing 4-hydroxy-2-nonenals, a marker of oxidative stress. In Dmp1-PPRKO mice there was an age-dependent increase in p16Ink4a/Cdkn2a expression, whereas it was unchanged in controls. In vitro studies demonstrated that PTH protects osteocytes from oxidative stress-induced cell death. In summary, we reported that PPR signaling in osteocytes is important for protecting the skeleton from age-induced bone loss by restraining osteoclast’s activity and protecting osteocytes from oxidative stresses.
Healthy memory aging - the benefits of regular daily activities increase with age
Olga Krakovska1 , Gregory J. Christie4 , Faranak Farzan5,6 , Andrew Sixsmith1 , Martin Ester2 , Sylvain Moreno3,4
doi : 10.18632/aging.203753
Volume 13, Issue 24, pp: 25643—25652
As the number of older adults increases, so does the pressure on health care systems due to age-related disorders. Attempts to reduce cognitive decline have focused on individual interventions such as exercise or diet, with limited success. This study adopted a different approach by investigating the impact of combined daily activities on memory decline. We used data from the National Institute of Aging’s Health and Retirement Study to explore two new questions: does combining activities affect memory decline, and if yes, does this impact change across the lifespan? We created a new machine learning model using 33 daily activities and involving 3210 participants. Our results showed that the effect of combined activities on memory decline was stronger than any individual activity’s impact. Moreover, this effect increased with age, whereas the importance of historical factors such as education, and baseline memory decreased. The present findings point out the importance of selecting multiple, diverse activities for older adults as they age. These results could have a significant impact on aging health policies promoting new programs such as social prescribing.
Maternal adverse childhood experiences before pregnancy are associated with epigenetic aging changes in their children
Jamaji C. Nwanaji-Enwerem1,2,3,4 , Lars Van Der Laan3,4 , Katherine Kogut5 , Brenda Eskenazi3,4,5,6 , Nina Holland3,4,5 , Julianna Deardorff5,6 , Andres Cardenas3,4,5
doi : 10.18632/aging.203776
Volume 13, Issue 24, pp: 25653—25669
Emerging research suggests associations of physical and psychosocial stressors with epigenetic aging. Although this work has included early-life exposures, data on maternal exposures and epigenetic aging of their children remain sparse. Using longitudinally collected data from the California, Salinas Valley CHAMACOS study, we examined relationships between maternal Adverse Childhood Experiences (ACEs) reported up to 18 years of life, prior to pregnancy, with eight measures (Horvath, Hannum, SkinBloodClock, Intrinsic, Extrinsic, PhenoAge, GrimAge, and DNAm telomere length) of blood leukocyte epigenetic age acceleration (EAA) in their children at ages 7, 9, and 14 years (N = 238 participants with 483 observations). After adjusting for maternal chronological age at delivery, pregnancy smoking/alcohol use, parity, child gestational age, and estimated leukocyte proportions, higher maternal ACEs were significantly associated with at least a 0.76-year increase in child Horvath and Intrinsic EAA. Higher maternal ACEs were also associated with a 0.04 kb greater DNAm estimate of telomere length of children. Overall, our data suggests that maternal preconception ACEs are associated with biological aging in their offspring in childhood and that preconception ACEs have differential relationships with EAA measures, suggesting different physiologic utilities of EEA measures. Studies are necessary to confirm these findings and to elucidate potential pathways to explain these relationships, which may include intergenerational epigenetic inheritance and persistent physical and social exposomes.
Chronobiological activity of cysteinyl leukotriene receptor 1 during basal and induced autophagy in the ARPE-19 retinal pigment epithelial cell line
Andreas Koller1 , Julia Preishuber-Pflügl1 , Christian Runge1 , Anja-Maria Ladek1 , Susanne Maria Brunner1 , Ludwig Aigner2 , Herbert Reitsamer1 , Andrea Trost1
doi : 10.18632/aging.203787
Volume 13, Issue 24, pp: 25670—25693
Autophagy is an important cellular mechanism for maintaining cellular homeostasis, and its impairment correlates highly with age and age-related diseases. Retinal pigment epithelial (RPE) cells of the eye represent a crucial model for studying autophagy, as RPE functions and integrity are highly dependent on an efficient autophagic process. Cysteinyl leukotriene receptor 1 (CysLTR1) acts in immunoregulation and cellular stress responses and is a potential regulator of basal and adaptive autophagy. As basal autophagy is a dynamic process, the aim of this study was to define the role of CysLTR1 in autophagy regulation in a chronobiologic context using the ARPE-19 human RPE cell line.
Age-dependent expression changes of circadian system-related genes reveal a potentially conserved link to aging
Emanuel Barth1 , Akash Srivastava1,2,3 , Diane Wengerodt3 , Milan Stojiljkovic3 , Hubertus Axer3 , Otto W. Witte3 , Alexandra Kretz3, * , Manja Marz1,2,4,5, *
doi : 10.18632/aging.203788
Volume 13, Issue 24, pp: 25694—25716
The circadian clock system influences the biology of life by establishing circadian rhythms in organisms, tissues, and cells, thus regulating essential biological processes based on the day/night cycle. Circadian rhythms change over a lifetime due to maturation and aging, and disturbances in the control of the circadian system are associated with several age-related pathologies.
Calcification in Werner syndrome associated with lymphatic vessels aging
Hideyuki Ogata1 , Shinsuke Akita1 , Sanae Ikehara2,3 , Kazuhiko Azuma3 , Takashi Yamaguchi3 , Maihulan Maimaiti2 , Yoshiro Maezawa4,5 , Yoshitaka Kubota1 , Koutaro Yokote4,5 , Nobuyuki Mitsukawa1 , Yuzuru Ikehara2,3
doi : 10.18632/aging.203789
Volume 13, Issue 24, pp: 25717—25728
In addition to the symptoms of aging, the main symptoms in Werner syndrome (WS), a hereditary premature aging disease, include calcification of subcutaneous tissue with solid pain and refractory skin ulcers. However, the mechanism of calcification in WS remains unclear. In this study, the histological analysis of the skin around the ulcer with calcification revealed an accumulation of calcium phosphate in the lymphatic vessels. Moreover, the morphological comparison with the lymphatic vessels in PAD patients with chronic skin ulcers demonstrated the ongoing lymphatic remodeling in WS patients because of the narrow luminal cross-sectional area (LA) of the lymphatic vessels but the increment of lymphatic microvessels density (MLVD). Additionally, fluorescence immunohistochemical analysis presented the cytoplasmic distribution and the accumulation of WRN proteins in endothelial cells on remodeling lymphatic vessels. In summary, these results point out a relationship between calcification in lymphatic vessels and the remodeling of lymphatic vessels and suggest the significance of the accumulation of WRN mutant proteins as an age-related change in WS patients. Thus, cytoplasmic accumulation of WRN protein can be an indicator of the decreasing drainage function of the lymphatic vessels and the increased risk of skin ulcers and calcification in the lymphatic vessels.
Factors influencing serum neurofilament light chain levels in normal aging
Marisa Koini1 , Lukas Pirpamer1 , Edith Hofer1,2 , Arabella Buchmann3 , Daniela Pinter3 , Stefan Ropele3 , Christian Enzinger3,4 , Pascal Benkert5 , David Leppert5 , Jens Kuhle5 , Reinhold Schmidt1, * , Michael Khalil3, *
doi : 10.18632/aging.203790
Volume 13, Issue 24, pp: 25729—25738
Serum neurofilament light (sNfL) is a promising marker for neuro-axonal damage and it is now well known that its levels also increase with higher age. However, the effect of other determinants besides age is still poorly investigated. We therefore aimed to identify factors influencing the sNfL concentration by analysing a large set of demographical, life-style and clinical variables in a normal aging cohort.
Small molecules for cell reprogramming: a systems biology analysis
Anna Knyazer1, * , Gabriela Bunu2, * , Dmitri Toren2 , Teodora Bucaciuc Mracica2 , Yael Segev1 , Marina Wolfson1 , Khachik K. Muradian3 , Robi Tacutu2 , Vadim E. Fraifeld1,3
doi : 10.18632/aging.203791
Volume 13, Issue 24, pp: 25739—25762
If somatic stem cells would be able to maintain their regenerative capacity over time, this might, to a great extent, resolve rejuvenation issues. Unfortunately, the pool of somatic stem cells is limited, and they undergo cell aging with a consequent loss of functionality. During the last decade, low molecular weight compounds that are able to induce or enhance cell reprogramming have been reported. They were named “Small Molecules” (SMs) and might present definite advantages compared to the exogenous introduction of stemness-related transcription factors (e.g. Yamanaka’s factors). Here, we undertook a systemic analysis of SMs and their potential gene targets. Data mining and curation lead to the identification of 92 SMs. The SM targets fall into three major functional categories: epigenetics, cell signaling, and metabolic “switchers”. All these categories appear to be required in each SM cocktail to induce cell reprogramming. Remarkably, many enriched pathways of SM targets are related to aging, longevity, and age-related diseases, thus connecting them with cell reprogramming. The network analysis indicates that SM targets are highly interconnected and form protein-protein networks of a scale-free topology. The extremely high contribution of hubs to network connectivity suggests that (i) cell reprogramming may require SM targets to act cooperatively, and (ii) their network organization might ensure robustness by resistance to random failures. All in all, further investigation of SMs and their relationship with longevity regulators will be helpful for developing optimal SM cocktails for cell reprogramming with a perspective for rejuvenation and life span extension.
Retinal drusen in patients with chronic myeloproliferative blood cancers are associated with an increased proportion of senescent T cells and signs of an aging immune system
Charlotte Liisborg1,2 , Vibe Skov3 , Lasse Kjær3 , Hans Carl Hasselbalch2,3 , Torben Lykke Sørensen1,2
doi : 10.18632/aging.203803
Volume 13, Issue 24, pp: 25763—25777
The cause of age-related macular degeneration (AMD) is unknown, but evidence indicates that both innate and adaptive immunity play a role in the pathogenesis. Our recent work has investigated AMD in patients with myeloproliferative neoplasms (MPNs) since they have increased drusen and AMD prevalence. We have previously found increased levels of chronic low-grade inflammation (CLI) in MPN patients with drusen (MPNd) compared to MPN patients with normal retinas (MPNn). CLI and AMD are both associated with aging, and we, therefore, wanted to study immunosenescence markers in MPNd, MPNn, and AMD. The purpose was to identify differences between MPNd and MPNn, which might reveal novel information relevant to drusen pathophysiology and thereby the AMD pathogenesis. Our results suggest that MPNd have a T cell differentiation profile resembling AMD and more effector memory T cells than MPNn. The senescence-associated-secretory-phenotype (SASP) is associated with effector T cells. SASP is thought to play a role in driving CLI seen with advancing age. Senescent cells with SASP may damage healthy tissue, including the eye tissues affected in AMD. The finding of increased effector cells in MPNd could implicate a role for adaptive immunity and senescent T cells together with increased CLI in drusen pathophysiology.
PKMYT1, exacerbating the progression of clear cell renal cell carcinoma, is implied as a biomarker for the diagnosis and prognosis
Juan Chen1, * , Xiaoliang Hua2,3,4, * , Heying Chen1 , Xiangmin Qiu1 , Haibing Xiao2,3,4 , Shengdong Ge2,3,4 , Chaozhao Liang2,3,4 , Qin Zhou1
doi : 10.18632/aging.203759
Volume 13, Issue 24, pp: 25778—25798
Clear cell renal cell carcinoma (ccRCC) is one of the most lethal urological malignancies with high tumor heterogeneity, and reliable biomarkers are still needed for its diagnosis and prognosis. WEE family kinases function as key regulators of the G2/M transition, have essential roles in maintaining cellular genomic stability and have the potential to be promising therapeutic targets in various tumors. However, the roles of WEE family kinases in ccRCC remain undetermined. In the present study, we first explored multiple public datasets and found that PKMYT1 was up-regulated in both RCC tumors and cell lines. Expression levels of PKMYT1 were highly associated with pathological stage and grade. Kaplan-Meier curves showed that high PKMYT1 expression was associated with lower overall survival and disease-free survival. Receiver operating characteristic curves revealed that the expression of PKMYT1 could better distinguish ccRCC from normal samples. Functional enrichment analysis demonstrated that cell cycle- related pathways and epithelial to mesenchymal transition (EMT) might be potential mechanisms of PKMYT1 in ccRCC tumorigenesis. Moreover, knockdown of PKMYT1 in vitro attenuated the proliferation, migration and invasion of RCC cell lines, promoted cell apoptosis and prevented the EMT phenotype in vitro. In conclusion, our study demonstrated that PKMYT1 has the potential to act as a diagnostic and prognostic biomarker for RCC patients. Targeting PKMYT1 may be considered as a new potential therapeutic method and direction in RCCs.
DNA methylation of ARHGAP30 is negatively associated with ARHGAP30 expression in lung adenocarcinoma, which reduces tumor immunity and is detrimental to patient survival
Sheng Hu1 , Wenxiong Zhang1 , Jiayue Ye1 , Yang Zhang1 , Deyuan Zhang1 , Jinhua Peng1 , Dongliang Yu1 , Jianjun Xu1 , Yiping Wei1
doi : 10.18632/aging.203762
Volume 13, Issue 24, pp: 25799—25845
Rho-GTPase activating protein 30 (ARHGAP30) can enhance the intrinsic hydrolysis of GTP and regulates Rho-GTPase negatively. The relationship between ARHGAP30 expression and lung adenocarcinoma is unclear. Therefore, the present study aimed to assess the differences in expression of ARHGAP30 between lung adenocarcinoma tissues and normal tissues and the relationship between DNA methylation and ARHGAP30 expression in lung adenocarcinoma. To determine the role of ARHGAP30 expression in the prognosis and survival of patients with lung adenocarcinoma, gene set enrichment analysis of ARHGAP30 was performed, comprising analyses of Kyoto Encyclopedia of Genes and Genomes pathways, Panther pathways, Reactome pathways, Wikipathways, Gene Ontology, Kinase Target Network, Transcription Factor Network, and a protein-protein interaction network. The association of ARHGAP30 expression with tumor-infiltrating lymphocytes, immunostimulators, major histocompatibility complex molecules, chemokines, and chemokine receptors in lung adenocarcinoma tissues was also analyzed. DNA methylation of ARHGAP30 correlated negatively with ARHGAP30 expression. Patients with lung adenocarcinoma with high DNA methylation of ARHGAP30 had poor prognosis. The prognosis of patients with lung adenocarcinoma with low ARHGAP30 expression was also poor. ARHGAP30 expression in lung adenocarcinoma correlated positively, whereas methylation of ARHGAP30 correlated negatively, with levels of tumor infiltrating lymphocytes. Gene set enrichment analysis revealed that many pathways associated with ARHGAP30 should be studied to improve the diagnosis, treatment, and prognosis of lung adenocarcinoma. We speculated that DNA methylation of ARHGAP30 suppresses ARHGAP30 expression, which reduces tumor immunity, leading to poor prognosis for patients with lung adenocarcinoma.
The risk of distant metastases in patients with gynecologic cancers after surgery: a population-based study
Yi-Hsuan Hsiao1,2,3 , Pei-Ni Chen4,5 , Min-Chien Hsin4,5 , Po-Hui Wang4,6 , Jing-Yang Huang4,5 , Shun-Fa Yang4,5
doi : 10.18632/aging.203773
Volume 13, Issue 24, pp: 25846—25858
The aim of the study was to determine the risk of distant metastases in patients with gynecologic cancers after surgery, including cervical, uterine and ovarian cancers. This is a retrospective study evaluating gynecologic cancer from 2009 to 2014 using population-based administrative datasets from the Health and Welfare Data Science Center (HWDC) and from The National Health Informatics Project (NHIP). A total of 1,464 gynecologic cancer patients, including 321 cervical cancer patients, 724 uterine cancer patients and 419 ovarian cancer patients, were analyzed retrospectively from 2009 to 2014. Among the cervical cancer patients, 173 (53.89%) received surgery only and 148 (46.11%) received surgery with radiotherapy /chemotherapy. Among the uterus cancer patients, 425(58.70%) received surgery only and 299 (41.3%) received surgery with radiotherapy /chemotherapy. Among the ovarian cancer patients, 81 (19.33%) received surgery only and 338 (80.67%) received surgery with radiotherapy/chemotherapy. Among patients with brain, liver or lung metastasis, cervical cancer patients have more cumulative metastasis-free survival than those ovarian cancer (p=0.0041). In analyzing liver metastasis based on primary cancer sites, cervical cancer patients and uterine cancer cases have more cumulative metastasis- free survival than those ovarian cancer (p<0.0001). In conclusion, ovarian cancer patients have higher risk of liver metastasis than cervical or uterine cancer. There were significantly different of pathological stage for cumulative metastasis-free survival among gynecologic cancer patients with brain or liver or lung metastasis. Pathological T stage remains the main predictive for distant metastasis of gynecologic cancer.
Identification and functional analysis of lncRNAs and mRNAs between tumorigenesis and metastasis in CRC
Hongtao Liu1, * , Yuan Tian2, * , Jiaxi Li1, * , Guoxia Zhang1 , Qun Liu1 , Min Yang1 , Longtao Yue1 , Qiwei Cao1 , Guihui Zhang1 , Yuxia Cheng1 , Na Kong1 , Lei Fang1 , Shoupeng Li1 , Qing Sun1
doi : 10.18632/aging.203775
Volume 13, Issue 24, pp: 25859—25885
The role of long non-coding RNAs (lncRNAs) in colorectal cancer (CRC) tumorigenesis and metastasis remains poorly characterized. The aim of this study was to identify novel lncRNAs and their functions in CRC progression. Through microarray analysis of paired normal colorectal mucosa (NM), primary tumor (PT), and metastatic lymph node (MLN) tissues, lncRNA and mRNA expression patterns were identified. Further bioinformatic analyses were performed to compare the biological functions of lncRNAs between tumorigenesis and metastasis of CRC, which was further verified by TCGA-COAD and GSE82236. The expression of lncRNA MIR29B2CHG93 in paired CRC tissues was detected in a cohort of CRC patients. The effects of lncRNA MIR29B2CHG93 on proliferation, migration, and invasion were determined by in vitro experiments. We found that tumorigenesis-associated lncRNAs predominantly participated in the regulation of the EMT/P53/PI3K-Akt/KRAS signaling pathway as well as the processes related to cell cycle and cell mitosis, while metastasis-associated lncRNAs mainly regulated blood vessel morphogenesis and immune-related biological processes. Compared to the TCGA and GSE datasets, seven tumorigenesis-associated lncRNAs and eight metastasis-associated lncRNAs were identified. LncRNA MIR29B2CHG93 knockdown remarkably suppressed tumor growth and metastasis in vitro, which acted as a tumor promoter in CRC. The lncRNA MIR29B2CHG93 was significantly upregulated in CRC tissues and was indicator of unfavorable clinical outcome in CRC. These results revealed novel lncRNAs that provide new insights for an in-depth understanding of CRC progression. In particular, this study identified a novel lncRNA MIR29B2CHG93 in CRC progression, which might be a potential biomarker for diagnosis, prognosis and metastasis-prediction in CRC.
Structural, functional and molecular pathogenesis of pelvic organ prolapse in patient and Loxl1 deficient mice
Yu Li1,2,3 , Nanfang Nie1,2,3 , Lin Gong1,2,3 , Fangyuan Bao2,3 , Chengrui An2,3 , Hongxia Cai1,2,3 , Xudong Yao2,4 , Yanshan Liu1,2,3 , Chunbo Yang5 , Bingbing Wu2,4 , XiaoHui Zou1,2,3
doi : 10.18632/aging.203777
Volume 13, Issue 24, pp: 25886—25902
Pelvic organ prolapse is a worldwide health problem to elderly women. Understanding its pathogenesis and an ideal animal model are crucial to developing promising treatments. The present study aimed to investigate new clinical significance and detailed mechanism of pelvic organ prolapse by comparing the structural, functional and molecular dysfunctions of pelvic organ prolapse in patient and Loxl1 deficient mice. Our results showed that human vagina tissues from prolapsed site showed disarranged collagen and elastic fibers compared with the non-prolapse tissue. A gene ontology (GO) analysis of differentially expressed genes revealed molecular changes mainly related to inflammatory response and extracellular matrix (ECM) organization. While the mice lacking Loxl1 developed stable POP phenotype and disordered ECM structure in histology. Such Loxl1 knockout mice exhibited a significantly urinary dysfunction and decreased mechanical properties of the pelvic floor tissues, implying that POP in human condition might be induced by progressively decreased mechanics of pelvic tissues following ECM catabolism. Similarly, we not only identified significant up-regulated ECM catabolism processes and down-regulated ECM synthesis processes, but also characterized high level of inflammatory response in vagina tissue of the Loxl1 deficient mice. Thus, all these pathological changes in the POP mice model was consistent with those of the clinical elderly patients. These findings provide new insight into remodeling of POP by LOXL1 regulation and be of great importance to develop combination treatments of ECM metabolism and inflammation regulation strategy.
METTL14 benefits the mesenchymal stem cells in patients with steroid-associated osteonecrosis of the femoral head by regulating the m6A level of PTPN6
Cheng Cheng1, * , Haoping Zhang2, * , Jia Zheng1 , Yi Jin1 , Donghui Wang1 , Zhipeng Dai1
doi : 10.18632/aging.203778
Volume 13, Issue 24, pp: 25903—25919
Imbalanced osteogenic/adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is considered the core pathological characteristic of steroid-associated osteonecrosis of the femoral head (SONFH). N6-Methyladenosine (m6A) is the most common type of RNA modification in eukaryotic cells and participates in various physiological and pathological processes. However, the relationship between m6A modification and SONFH has not been reported. In the present study, we aimed to explore the roles of m6A modifications and methyltransferase METTL14 in SONFH. Our results showed that the m6A levels were down-regulated in femoral head tissues and BMSCs from SONFH patients, and this effect was attributed to the reduction of METTL14. Furthermore, METTL14 overexpression in BMSCs from SONFH patients enhanced cell proliferation and osteogenic differentiation. We further identified PTPN6 as the downstream target of METTL14 by mRNA sequencing. Mechanistically, METTL14 regulated PTPN6 expression by increasing PTPN6 mRNA stability in an m6A-dependent manner. Moreover, PTPN6 knockdown abrogated the beneficial effects of METTL14 overexpression on BMSCs. Additionally, we found that METTL14 activated the Wnt signaling pathway, and this effect was caused by the interaction of PTPN6 and GSK-3?. In conclusion, we elucidated the functional roles of METTL14 and m6A methylation in SONFH BMSCs and identified a novel RNA regulatory mechanism, providing a potential therapeutic target for SONFH.
LDH-A inhibitors as remedies to enhance the anticancer effects of PARP inhibitors in ovarian cancer cells
Jiangdong Xiang1 , Lina Zhou1 , Yinyan He1 , Sufang Wu1
doi : 10.18632/aging.203780
Volume 13, Issue 24, pp: 25920—25930
Ovarian cancer is one of the most lethal gynecologic malignancies. It has been shown that PARP inhibitors can selectively target BRCA-mutated ovarian cancer and exert some effects on ovarian cancer without BRCA mutations. However, the mechanism is still unclear. In this study, wild-type BRCA ovarian cancer cells (A2780 and SKOV3) were used. Our results showed that using a PARP inhibitor (olaparib or AG14361) alone significantly inhibited the proliferation of A2780 cells but negligibly inhibited the proliferation of SKOV3 cells. We used RNA sequencing to explore differentially expressed genes and found that PARP inhibitors increased LDH-A in SKOV3 cells, which was confirmed by RT-PCR. Oxamate (a specific inhibitor of LDH-A) was used to investigate whether LDH-A inhibition enhances the suppressive effects of PARP inhibitors on ovarian cancer without BRCA mutations. CCK-8 assays, scratch assays and Transwell assays were used to determine cell proliferation, cell migration ability and invasion ability, respectively. Both olaparib and AG14361 significantly inhibited the proliferation/invasion ability of A2780 cells but not SKOV3 cells. Inhibition of LDH-A can remarkably promote the inhibitory effects of PARP inhibitors on both A2780 and SKOV3 cells. Thus, high expression level of LDH-A influenced the suppressive effects of PARP inhibitors on ovarian cancer with wild-type BRCA, and LDH-A inhibition notably enhanced this effect.
NAD+ improved experimental autoimmune encephalomyelitis by regulating SIRT1 to inhibit PI3K/Akt/mTOR signaling pathway
Jinli Wang1 , Xueqin Song1 , Guojun Tan1 , Pengtao Sun1 , Li Guo1 , Ning Zhang1 , Jueqiong Wang1 , Bin Li2
doi : 10.18632/aging.203781
Volume 13, Issue 24, pp: 25931—25943
To investigate the effect of NAD+ on thymus autophagy in experimental autoimmune encephalomyelitis (EAE) mice through SIRT1.
Global, regional, and national burden of age-related hearing loss from 1990 to 2019
Jinyu Man1,2 , Hui Chen2,3 , Tongchao Zhang1,2 , Xiaolin Yin1,2 , Xiaorong Yang2,3 , Ming Lu1,2,3
doi : 10.18632/aging.203782
Volume 13, Issue 24, pp: 25944—25959
The global distribution and temporal trend of age-related hearing loss (ARHL) are unknown, and we aimed to investigate magnitudes and temporal trends of ARHL burden and its influencing factors at the national, regional, and global levels. Based on the information of Global Burden of Disease Study 2019, we calculated the estimated annual percentage change to quantify the global, regional, and national temporal trends of age-standardized rates (ASRs) of ARHL by gender, age, and severity. The number of prevalent cases and disability-adjusted life years (DALYs) of ARHL increased from 751.50 million and 22.01 million in 1990 to 1456.66 million and 40.24 million in 2019, respectively. Except for a few countries such as Niger and Burkina Faso, the age-standardized prevalence rate and age-standardized DALYs rate showed a downward trend in most countries and regions. Mild ARHL accounted for the largest proportion in all ARHL, and only mild ARHL showed an upward trend in ASRs. In most regions, the proportion of ARHL disease burden attributable to occupational noise showed a downward trend in the past 30 years. In 2019, ARHL disease burden attributable to occupational noise declined with the increase of socio-demographic index in countries. Although the ASR of ARHL in most parts of the world is declining, the absolute disease burden of ARHL is still heavy. Understanding the real-time disease burden of ARHL and its temporal trend is of great significance for formulating more effective preventive measures and reducing the ARHL burden.
A novel pyroptosis-related gene signature to predict outcomes in laryngeal squamous cell carcinoma
Chongchang Zhou1,2 , Guowen Zhan3 , Yangli Jin4 , Jianneng Chen5 , Zhisen Shen1,2 , Yi Shen1,2 , Hongxia Deng1,2
doi : 10.18632/aging.203783
Volume 13, Issue 24, pp: 25960—25979
Pyroptosis, a pro-inflammatory form of programmed cell death, is associated with carcinogenesis and progression. However, there is little information concerning pyroptosis-related genes (PRGs) in laryngeal squamous cell carcinoma (LSCC). Herein, we aim to explore the prognostic value of PRGs in LSCC. The expression and clinical data of 47 PRGs in LSCC patients were obtained from The Cancer Genome Atlas. A novel prognostic PRG signature was constructed using least absolute shrinkage and selection operator analysis. Receiver operating characteristic (ROC) curves were drawn, and Kaplan-Meier survival Cox proportional hazard regression analyses were performed to measure the predictive capacity of the PRG signature. Furthermore, we constructed a six-PRG signature to divide LSCC patients into high- and low-risk groups. Patients in the high-risk group had worse overall survival than the low-risk group. The area under the time-dependent ROC curve was 0.696 for 1 year, 0.784 for 3 years, and 0.738 for 5 years. We proved that the PRGs signature was an independent predictor for LSCC. Functional enrichment analysis indicated that several immune-related pathways were significantly enriched in the low-risk group. Consistent with this, patients with low-risk scores had higher immune scores and better immunotherapeutic responses than the high-risk group. In conclusion, we established a novel PRGs signature that can predict outcome and response to immunotherapy of LSCC, pyroptosis may be a potential target for LSCC.
Identification of a competing endogenous RNA network related to immune signature in clear cell renal cell carcinoma
Yuke Zhang1 , Jiangwen Dai2 , Weifeng Huang3 , Qingsong Chen4 , Wei Chen5 , Qiying He1 , Feng Chen6 , Peng Zhang1
doi : 10.18632/aging.203784
Volume 13, Issue 24, pp: 25980—26002
Clear cell renal cell carcinoma (ccRCC) is a fatal cancer of the urinary system. Long non-coding RNAs (lncRNAs) act as competitive endogenous RNAs (ceRNAs) involving the ccRCC progression. However, the relationship between the ceRNA network and immune signature is largely unknown. In this study, the ccRCC-related gene expression profiles retrieved from the TCGA database were used first to identify the differentially expressed genes through differential gene expression analysis and weighted gene co-expression network analysis. The interaction among differentially expressed lncRNAs, miRNAs, and mRNAs were matched using public databases. As a result, a ceRNA network was developed that contained 144 lncRNAs, 23 miRNAs, as well as 62 mRNAs. Four of 144 lncRNAs including LINC00943, SRD5A3-AS1, LINC02345, and U62317.3 were identified through LASSO regression and Cox regression analyses, and were used to create a prognostic risk model. Then, the ccRCC samples were divided into the high- and low-risk groups depending on their risk scores. ROC curves, Kaplan-Meier survival analysis, and the survival risk plots indicated that the predictive performance of our developed risk model was accurate. Moreover, the CIBERSORT algorithm was used to measure the infiltration levels of immune cells in the ccRCC samples. The further genomic analysis illustrated a positive correlation between most immune checkpoint blockade-related genes and the risk score. In conclusion, the present findings effectually contribute to the comprehensive understanding of the ccRCC pathogenesis, and may offer a reference for developing novel therapeutic and prognostic biomarkers.
Network pharmacology reveals the potential mechanism of Baiying Qinghou decoction in treating laryngeal squamous cell carcinoma
Kun Gao1,2 , Yanan Zhu3 , Hui Wang4 , Xianwei Gong5 , Zhiyong Yue1,2 , Aiai Lv3 , Xuanchen Zhou1,2
doi : 10.18632/aging.203786
Volume 13, Issue 24, pp: 26003—26021
Baiying Qinghou as a traditional Chinese medicine decoction shows anticancer property on laryngeal squamous cell carcinoma. However, little is known about the precise mechanism of Baiying Qinghou detection against laryngeal squamous cell carcinoma.
LINC00839 knockdown restrains the metastatic behavior of nasopharyngeal carcinoma by sponging miR-454-3p
Feng Ying Zhang1, * , Xia Li2, * , Ting Ting Huang1 , Mei Ling Xiang1 , Lin Lin Sun1 , Zhao Lan Sun3
doi : 10.18632/aging.203792
Volume 13, Issue 24, pp: 26022—26033
Long intergenic non-coding RNA 00839 (LINC00839) has been verified as a pro-metastasis factor in malignancies. However, the significance of LINC00839 in nasopharyngeal carcinoma (NPC) has yet to be illuminated, as well as its underlying mechanism. Here, we disclosed that LINC00839 is highly expressed in NPC. Deletion of LINC00839 suppresses NPC cells rapid growth, invasive capacity and EMT in vitro. Besides, LINC00839 is identified as a “sponge” for miR-454-3p, and upregulation of LINC00839 reverses miR-454-3p-mediated inhibition of aggressiveness in NPC cells. Furthermore, the expression of cellular-mesenchymal epithelial transition factor (c-Met), the downstream target of miR-454-3p, is downregulated by LINC00839 knockdown in NPC cells. In vivo, LINC00839 knockdown retards the tumor growth of NPC cells in the xenografted mice model. Collectively, attenuation of LINC00839 expression attenuates the aggressive properties of NPC cells via directly sponging the miR-454-3p and regulating c-Met expression.
rTMS alleviates AD-induced cognitive impairment by inhibitng apoptosis in SAMP8 mouse
Zheng Bao1,2 , Li Bao4 , Na Han2 , Yueyun Hou2 , Fumin Feng1,3
doi : 10.18632/aging.203796
Volume 13, Issue 24, pp: 26034—26045
This study sought to investigate whether repetitive transcranial magnetic stimulation (rTMS) could alleviate cognitive dysfunction in SAMP8 mice by reducing cell apoptosis and activating the cAMP/PKA/CREB signalling pathway. A total of 40 SAMP8 mice were randomly assigned to the SAMP8 group (n=20), and rTMS treatment group (rTMS+SAMP8, n=20); additionally, 20 homologous and normal aged SAMR1 mice were used as the control group(n=20). The Morris water maze and Y maze tests were applied to evaluate spatial learning and memory ability. Haematoxylin and eosin (HE) staining and terminal-deoxynucleotidyl transferase-mediated nick end labelling (TUNEL) were used to observe the changes in neurons in the cortex and hippocampus. Western blotting and RT-PCR were used to detect signalling related proteins. rTMS significantly improved spatial learning and memory deficits and morphological abnormalities in the hippocampus region of the hippocampus. In addition, rTMS reduced apoptosis of neurons caused by AD and the expression of pro-apoptotic proteins (Caspase-3 and Bax) and increased the expression of an antiapoptotic protein (Bcl-2). Furthermore, rTMS activated the cAMP/PKA/CREB signalling pathway. These results showed that rTMS could ameliorate cognitive deficits in AD mice by inhibiting apoptosis via activation the cAMP/PKA/CREB signalling pathway.
An immune-related lncRNA risk coefficient model to predict the outcomes in clear cell renal cell carcinoma
Cheng Tang1, * , GenYi Qu1, * , Yong Xu1 , Guang Yang1 , Jiawei Wang1 , Maolin Xiang1
doi : 10.18632/aging.203797
Volume 13, Issue 24, pp: 26046—26062
Using model algorithms, we constructed an immune-related long non-coding RNAs (lncRNAs) risk coefficient model to predict outcomes for patients with clear cell renal cell carcinoma (ccRCC) to understand the infiltration of tumor immune cells and the sensitivity to immune-targeted drugs.
Tertiary lymphoid structure stratifies glioma into three distinct tumor subtypes
Xingwang Zhou1 , Wenyan Li1 , Jie Yang1 , Xiaolan Qi2 , Yimin Chen1 , Hua Yang1 , Liangzhao Chu1
doi : 10.18632/aging.203798
Volume 13, Issue 24, pp: 26063—26094
Tertiary lymphoid structure (TLS), also known as ectopic lymphoid organs, are found in cancer, chronic inflammation, and autoimmune diseases. However, the heterogeneity of TLS in gliomas is unclear. Therefore, it is necessary to identify TLS differences and define TLS subtypes.
Knockdown hsa_circ_0063526 inhibits endometriosis progression via regulating the miR-141-5p / EMT axis and downregulating estrogen receptors
Zhangming Wei1,2,3, * , Yi Hu4, * , Xiang He1,2,3, * , Mengmeng Zhang3 , Xinyue Zhang3 , Yali Wang5 , Xiaoling Fang3 , Liping Li1,2
doi : 10.18632/aging.203799
Volume 13, Issue 24, pp: 26095—26117
Endometriosis can cause severe social burdens. Abnormal circular RNA levels have been found to lead to changes of related gene expression, thereby mediating the occurrence and development of a series of diseases, including endometriosis. The role of circRNA in endometriosis is still in its infancy. This study will explore the role of circRNA hsa_circ_0063526 with microRNA-141-5p in the development of endometriosis. The expression levels of genes were detected by RT-qPCR. Transwell, wound-healing, and EdU assays were performed on the End1 / E6E7 cell line from the endometriosis patient. PCR and immunohistochemistry were used to detect the expression of candidate regulatory genes in ectopic lesions in an endometriosis mice model. The expression level of hsa_circ_0063526 in ectopic tissue of endometriosis patients was significantly higher than control (P<0.05), The expression levels of hsa_circ_0063526 and miRNA-141-5P in ectopic tissue of endometriosis were negatively correlated (P<0.05). Knockdown of hsa_circ_0063526 inhibited the invasion, migration, and proliferation ability of End1 / E6E7 cell; the inhibition of microRNA-141-5p rescued this inhibition (P <0.05). In vivo experiments showed that miR-141-5p and si-hsa_circ_0063526 treatment reduced lesion size and regulated endometriosis genes. Our data suggest that hsa_circ_0063526 and miR-141-5p are possible biomarkers and therapeutic targets for endometriosis.
Tumor microenvironment characterization in esophageal cancer identifies prognostic relevant immune cell subtypes and gene signatures
Yuhong Zhang1 , Minqi Zhu2 , Junxian Mo2 , Lei Xian3
doi : 10.18632/aging.203800
Volume 13, Issue 24, pp: 26118—26136
Esophageal cancer (ESCA) is a common malignancy in the digestive system with a high mortality rate and poor prognosis. Tumor microenvironment (TME) plays an important role in the tumorigenesis, progression and therapy resistance of ESCA, whereas its role in predicting clinical outcomes has not been fully elucidated. In this study, we comprehensively estimated the TME infiltration patterns of 164 ESCA patients using Gene Set Variation Analysis (GSVA) and identified 4 key immune cells (natural killer T cell, immature B cell, natural killer cell, and type 1 T helper cell) associated with the prognosis of ESCA patients. Besides, two TME groups were defined based on the TME patterns with different clinical outcomes. According to the expression gene set between two TME groups, we built a model to calculate TMEscore based on the single-sample gene-set enrichment analysis (ssGSEA) algorithm. TMEscore systematically correlated the TME groups with genomic characteristics and clinicopathologic features. In conclusion, our data provide a novel TMEscore which can be regarded as a reliable index for predicting the clinical outcomes of ESCA.
miR-545 promotes colorectal cancer by inhibiting transferring in the non-normal ferroptosis signaling
Sixin Zheng1, * , Lingling Hu2, * , Qingwen Song2, * , Yuqiang Shan1 , Guang Yin1 , Hanzhang Zhu1 , Wencheng Kong1 , Chunhua Zhou1
doi : 10.18632/aging.203801
Volume 13, Issue 24, pp: 26137—26147
In this study, we examined whether and how miR-545 modulates ferroptosis in colorectal cancer (CRC). HT-29 and HCT-116 human CRC cell viability was examined using a CCK-8 assay and malondialdehyde (MDA) and Fe2+ levels were measured after treatment with the ferroptosis inducers Eradicator of Ras and ST (erastin) and Ras selective lethal 3 (RSL3) with or without miR-545 overexpression or knockdown vectors. Our results demonstrate that miR-545 overexpression inhibited, while miR-545 knockdown further increased, erastin and RSL3-induced upregulation of MDA, reactive oxygen species (ROS), and Fe2+ levels. Similarly, miR-545 overexpression partially reversed, while miR-545 knockdown enhanced, the erastin and RSL3-induced reduction in HT-29 and HCT-116 cell survival rates. Transferrin (TF) was identified as a target gene of miR-545. To determine whether miR-545 suppresses ferroptosis via TF, we overexpressed TF in HT-29 and HCT-116 cells. We found that TF overexpression blocked miR-545-induced changes in ROS, MDA, and Fe2+ levels in HT-29 and HCT-116 cells, thereby inducing CRC cell death. An in vivo assay showed that inhibition of miR-545 decreased tumor growth in nude mice treated with erastin. Together, these findings indicate that miR-545 promotes CRC cell survival by suppressing TF.
Free fatty acids-induced neutrophil extracellular traps lead to dendritic cells activation and T cell differentiation in acute lung injury
Wei Chen1,2, * , Hong Chen1,2, * , Zhi-Tao Yang3 , En-Qiang Mao3 , Ying Chen3 , Er-Zhen Chen3
doi : 10.18632/aging.203802
Volume 13, Issue 24, pp: 26148—26160
This study aimed to investigate whether free fatty acids (FFAs) could induce the release of neutrophil extracellular traps (NETs), as well as the mechanism of FFAs-induced NETs in acute lung injury (ALI). FFAs were used to induce NETs production. The reactive oxygen species (ROS) production was detected after FFA and NADPH oxidase inhibitor treatments. The association between FFAs-induced NETs and the activation of p38, ERK, and JNK pathways was investigated. The effect of FFAs-induced NETs on the dendritic cells (DCs) activation and T cell differentiation was investigated. FFAs could induce neutrophils to produce NETs. FFAs significantly promoted ROS production and increased the expression of ERK, p38 and JNK, and treatment of the inhibitors of NAPDH oxidase (DPI), p38 (SB202190), ERK1/2 (U0126) and JNK (SP600125) inhibited FAAs-induced NETs production. FFAs induced NETs could promote DCs activation and consequently led to the differentiation of primary CD4+ T cells into Th1 and Th17 cells and the release of IL-1?, IL-12 and TNF-?. FFAs are capable of inducing NETs via NOX, ERK, p38 and JNK pathways. FFA-induced NETs further lead to DCs activation and T cell differentiation, which can well explain the mechanism of ALI caused by FFAs.
Coupling of serum CK20 and hyper-methylated CLIP4 as promising biomarker for colorectal cancer diagnosis: from bioinformatics screening to clinical validation
Zhongjian Liu1,2, * , Hui Tang1,2, * , Wen Zhang1,2 , Jinli Wang1,2 , Lilan Wan1,2 , Xisha Li1,2 , Yuping Ji3 , Na Kong3 , Yanfang Zhang3 , Jiangang Wang3 , Zhang Fan3 , Qiang Guo1,2
doi : 10.18632/aging.203804
Volume 13, Issue 24, pp: 26161—26179
Colorectal cancer (CRC) is one of the most common and lethal malignancies. The identification of minimally invasive and precise biomarkers is an urgent need for the early diagnosis of CRC. Through bioinformatics analysis of 395 CRC tissues and 63 CRC cell lines, CK18, CK20, de-methylated HPDL and hyper-methylated CLIP4 were identified as candidate serum biomarkers. Then, a training cohort consisting of 60 CRC, 30 colorectal adenomas (CA) and 33 healthy controls and a validation cohort consisting of 60 CRC, 30 CA and 30 healthy controls were enrolled. In the training cohort, enzyme-linked immunosorbent assay (ELISA) showed that CK18 and CK20 were all significantly higher in CRC and CA. CK18 diagnosed CRC with 46.67% sensitivity and 87.3% specificity; CK20 diagnosed CRC with 28.33% sensitivity and 90.47% specificity. Methylation-specific PCR (MSP) indicated that de-methylated HPDL and hyper-methylated CLIP4 were significantly detected in CRC and CA. De-methylated HPDL diagnosed CRC with 36.67% sensitivity and 93.65% specificity and hyper-methylated CLIP4 with 73.33% sensitivity and 84.13% specificity. Random combined analysis suggested that CK20/hyper-methylated CLIP4 diagnosed CRC with 91.67% sensitivity and 82.54% specificity. In the validation cohort, CK20 diagnosed CRC with 36.7% sensitivity and 88.3% specificity and hyper-methylated CLIP4 with 80% sensitivity and 85% specificity. CK20/hyper-methylated CLIP4 diagnosed CRC with 95% sensitivity and 81.7% specificity. Compared with serum biomarkers reported before, CK20/hyper-methylated CLIP4 possessed the potential to be a new effective and precise diagnostic biomarker for CRC.
NAP1L1 promotes proliferation and chemoresistance in glioma by inducing CCND1/CDK4/CDK6 expression through its interaction with HDGF and activation of c-Jun
Zigui Chen1,2, * , Yingying Xie1,2 , Hongcheng Luo3 , Ye Song4 , Tianshi Que4 , Rentong Hu3 , Huatuo Huang3 , Kunxiang Luo5 , Chuanyu Li5 , Chengjian Qin5 , Chuanhua Zheng5 , Weiyi Fang1,2 , Longyang Liu1,2 , Hao Long1,4 , Qisheng Luo1,5
doi : 10.18632/aging.203805
Volume 13, Issue 24, pp: 26180—26200
The prognosis of glioma is poor as its pathogenesis and mechanisms underlying cisplatin chemoresistance remain unclear. Nucleosome assembly protein 1 like 1 (NAP1L1) is regarded as a hallmark of malignant tumors. However, the role of NAP1L1 in glioma remains unknown. In this study, we aimed to investigate the molecular functions of NAP1L1 in glioma and its involvement in cisplatin chemoresistance, if any. NAP1L1 was found to be upregulated in samples from The Cancer Genome Atlas (TCGA) database. Immunohistochemistry indicated that NAP1L1 and hepatoma-derived growth factor (HDGF) were enhanced in glioma as compared to the para-tumor tissues. High expressions of NAP1L1 and HDGF were positively correlated with the WHO grade, KPS, Ki-67 index, and recurrence. Moreover, NAP1L1 expression was also positively correlated with the HDGF expression in glioma tissues. Functional studies suggested that knocking down NAP1L1 could significantly inhibit glioma cell proliferation both in vitro and in vivo, as well as enhance the sensitivity of glioma cells to cisplatin (cDDP) in vitro. Mechanistically, NAP1L1 could interact with HDGF at the protein level and they co-localize in the cytoplasm. HDGF knockdown in NAP1L1-overexpressing glioma cells significantly inhibited cell proliferation. Furthermore, HDGF could interact with c-Jun, an oncogenic transcription factor, which eventually induced the expressions of cell cycle promoters, CCND1/CDK4/CDK6. This finding suggested that NAP1L1 could interact with HDGF, and the latter recruited c-Jun, a key oncogenic transcription factor, that further induced CCND1/CDK4/CDK6 expression, thereby promoting proliferation and chemoresistance in glioma cells. High expression of NAP1L1 in glioma tissues indicated shorter overall survival in glioma patients.
