Aging

Aging is associated with an increased susceptibility to adverse inflammatory conditions such as sepsis and cytokine storm. We hypothesized that senescent cells (SnCs) play a central role in this age-associated pathology in part due to their expression of the senescence-associated secretory phenotype (SASP), which may prime SnCs to inflammatory stimulation. To test this hypothesis, we examined the expression of various inflammatory cytokines and chemokines at the levels of gene transcription and protein production in various SnCs in vitro in response to lipopolysaccharide (LPS), interleukin-1? (IL1?), and tumor necrosis factor ? (TNF?) stimulation. We found that SnCs not only expressed higher basal levels of various inflammatory cytokines and chemokines as a manifestation of the SASP, but more importantly exhibited hyper-activation of the induction of a variety of inflammatory mediators in response to LPS, IL1? and TNF? stimulation as compared with non-SnCs. This senescence-associated hyper-activation is likely mediated in part via the p38MAPK (p38) and NF?B pathways because LPS stimulation elicited significantly higher levels of p38 phosphorylation and NF?B p65 nuclear translation in SnCs when compared to their non-senescent counterparts and inhibition of these pathways with losmapimod (a p38 specific inhibitor) and BMS-345541 (a selective NF?B inhibitor) attenuated LPS-induced expression of IL6, TNF?, CCL5, and IL1? mRNA in SnCs. These findings suggest that SnCs may play an important role in the age-related increases in the susceptibility to developing an exacerbated inflammatory response and highlight the potential to use senotherapeutics to ameliorate the severity of various devastating inflammatory conditions in the elderly.

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Features of age-related response to sleep deprivation: in vivo experimental studies

Maria Novozhilova1 , Tatiana Mishchenko1 , Elena Kondakova1 , Tatiana Lavrova1 , Maria Gavrish1 , Svetlana Aferova1 , Claudio Franceschi2 , Maria Vedunova1

doi : 10.18632/aging.203372

Volume 13, Issue 15 pp 19108—19126

Insomnia is currently considered one of the potential triggers of accelerated aging. The frequency of registered sleep-wake cycle complaints increases with age and correlates with the quality of life of elderly people. Nevertheless, whether insomnia is actually an age-associated process or whether it acts as an independent stress-factor that activates pathological processes, remains controversial. In this study, we analyzed the effects of long-term sleep deprivation modeling on the locomotor and orienting-exploratory activity, spatial learning abilities and working memory of C57BL/6 female mice of different ages. We also evaluated the modeled stress influence on morphological changes in brain tissue, the functional activity of the mitochondrial apparatus of nerve cells, and the level of DNA methylation and mRNA expression levels of the transcription factor HIF-1? (Hif1) and age-associated molecular marker PLIN2. Our findings point to the age-related adaptive capacity of female mice to the long-term sleep deprivation influence. For young (1.5 months) mice, the modeled sleep deprivation acts as a stress factor leading to weight loss against the background of increased food intake, the activation of animals’ locomotor and exploratory activity, their mnestic functions, and molecular and cellular adaptive processes ensuring animal resistance both to stress and risk of accelerated aging development. Sleep deprivation in adult (7-9 months) mice is accompanied by an increase in body weight against the background of active food intake, increased locomotor and exploratory activity, gross disturbances in mnestic functions, and decreased adaptive capacity of brain cells, that potentially increasing the risk of pathological reactions and neurodegenerative processes.

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The life in a gradient: calcium, the lncRNA SPRR2C and mir542/mir196a meet in the epidermis to regulate the aging process

Sven Breunig1,2, * , Veronika Wallner2, * , Katharina Kobler2 , Herbert Wimmer2 , Peter Steinbacher2 , Maria Karolin Streubel2 , Johannes Bischof2,3 , Jutta Duschl2 , Claudia Neuhofer2 , Wolfgang Gruber2 , Fritz Aberger4 , Michael Breitenbach2 , Elisabeth Russe5 , Gottfried Wechselberger5 , Albert Duranton6 , Klaus Richter2 , Mark Rinnerthaler2

doi : 10.18632/aging.203385

Volume 13, Issue 15 pp 19127—19144

The turnover of the epidermis beginning with the progenitor cells in the basal layer to the fully differentiated corneocytes is tightly regulated by calcium. Calcium more than anything else promotes the differentiation of keratinocytes which implies the need for a calcium gradient with low concentrations in the stratum basale and high concentrations in the stratum granulosum. One of the hallmarks of skin aging is a collapse of this gradient that has a direct impact on the epidermal fitness. The rise of calcium in the stratum basale reduces cell proliferation, whereas the drop of calcium in the stratum granulosum leads to a changed composition of the cornified envelope. We showed that keratinocytes respond to the calcium induced block of cell division by a large increase of the expression of several miRNAs (hsa-mir542-5p, hsa-mir125a, hsa-mir135a-5p, hsa-mir196a-5p, hsa-mir491-5p and hsa-mir552-5p). The pitfall of this rescue mechanism is a dramatic change in gene expression which causes a further impairment of the epidermal barrier. This effect is attenuated by a pseudogene (SPRR2C) that gives rise to a lncRNA. SPRR2C specifically resides in the stratum granulosum/corneum thus acting as a sponge for miRNAs.

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Epigenetic age prediction in semen – marker selection and model development

Aleksandra Pisarek1 , Ewelina Po?piech1 , Antonia Heidegger2 , Catarina Xavier2 , Anna Papie?3 , Danuta Piniewska-Róg4 , Vivian Kalamara5 , Ramya Potabattula6 , Micha? Bochenek1 , Marta Sikora-Polaczek7 , Aneta Macur8 , Anna Wo?niak9 , Jaros?aw Janeczko8 , Christopher Phillips10 , Thomas Haaf6 , Joanna Pola?ska3 , Walther Parson2,11 , Manfred Kayser5 , Wojciech Branicki1,9 , on behalf of the VISAGE Consortium

doi : 10.18632/aging.203399

Volume 13, Issue 15 pp 19145—19164

DNA methylation analysis is becoming increasingly useful in biomedical research and forensic practice. The discovery of differentially methylated sites (DMSs) that continuously change over an individual’s lifetime has led to breakthroughs in molecular age estimation. Although semen samples are often used in forensic DNA analysis, previous epigenetic age prediction studies mainly focused on somatic cell types. Here, Infinium MethylationEPIC BeadChip arrays were applied to semen-derived DNA samples, which identified numerous novel DMSs moderately correlated with age. Validation of the ten most age-correlated novel DMSs and three previously known sites in an independent set of semen-derived DNA samples using targeted bisulfite massively parallel sequencing, confirmed age-correlation for nine new and three previously known markers. Prediction modelling revealed the best model for semen, based on 6 CpGs from newly identified genes SH2B2, EXOC3, IFITM2, and GALR2 as well as the previously known FOLH1B gene, which predict age with a mean absolute error of 5.1 years in an independent test set. Further increases in the accuracy of age prediction from semen DNA will require technological progress to allow sensitive, simultaneous analysis of a much larger number of age correlated DMSs from the compromised DNA typical of forensic semen stains.

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Endothelium-specific deletion of amyloid-? precursor protein exacerbates endothelial dysfunction induced by aging

Livius V. d’Uscio1 , Zvonimir S. Katusic1

doi : 10.18632/aging.203401

Volume 13, Issue 15 pp 19165—19185

The physiological function of amyloid precursor protein (APP) in the control of endothelial function during aging is unclear. Aortas of young (4-6 months old) and aged (23-26 months old) wild-type (WT) and endothelium-specific APP-deficient (eAPP?/?) mice were used to study aging-induced changes in vascular phenotype. Unexpectedly, aging significantly increased protein expression of APP in aortas of WT mice but not in aortas of eAPP?/? mice thereby demonstrating selective upregulation APP expression in vascular endothelium of aged aortas. Most notably, endothelial dysfunction (impairment of endothelium-dependent relaxations) induced by aging was significantly exacerbated in aged eAPP?/? mice aortas as compared to age-matched WT mice. Consistent with this observations, endothelial nitric oxide synthase (eNOS) protein expression was significantly decreased in aged eAPP?/? mice as compared to age matched WT mice. In addition, protein expression of cyclooxygenase 2 and release of prostaglandins were significantly increased in both aged WT and eAPP?/? mice. Notably, treatment with cyclooxygenase inhibitor, indomethacin, normalized endothelium-dependent relaxations in aged WT mice, but not in aged eAPP?/? mice. In aggregate, our findings support the concept that aging-induced upregulation of APP in vascular endothelium is an adaptive response designed to protect and preserve expression and function of eNOS.

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Health trajectories after age 60: the role of individual behaviors and the social context

Amaia Calderón-Larrañaga1 , Xiaonan Hu1 , Miriam Haaksma2 , Debora Rizzuto1,3 , Laura Fratiglioni1,3 , Davide L. Vetrano1,4

doi : 10.18632/aging.203407

Volume 13, Issue 15 pp 19186—19206

This study aimed to detect health trajectories after age 60, and to explore to what extent individual and social factors may contribute to healthier aging.

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Hedgehog dysregulation contributes to tissue-specific inflammaging of resident macrophages

Mahamat Babagana1, * , Kyu-Seon Oh1, * , Sayantan Chakraborty1, * , Alicja Pacholewska1,2, * , Mohammad Aqdas1 , Myong-Hee Sung1

doi : 10.18632/aging.203422

Volume 13, Issue 15 pp 19207—19229

Age-associated low-grade sterile inflammation, commonly referred to as inflammaging, is a recognized hallmark of aging, which contributes to many age-related diseases. While tissue-resident macrophages are innate immune cells that secrete many types of inflammatory cytokines in response to various stimuli, it is not clear whether they have a role in driving inflammaging. Here we characterized the transcriptional changes associated with physiological aging in mouse resident macrophage populations across different tissues and sexes. Although the age-related transcriptomic signatures of resident macrophages were strikingly tissue-specific, the differentially expressed genes were collectively enriched for those with important innate immune functions such as antigen presentation, cytokine production, and cell adhesion. The brain-resident microglia had the most wide-ranging age-related alterations, with compromised expression of tissue-specific genes and relatively exaggerated responses to endotoxin stimulation. Despite the tissue-specific patterns of aging transcriptomes, components of the hedgehog (Hh) signaling pathway were decreased in aged macrophages across multiple tissues. In vivo suppression of Hh signaling in young animals increased the expression of pro-inflammatory cytokines, while in vitro activation of Hh signaling in old macrophages, in turn, suppressed the expression of these inflammatory cytokines. This suggests that hedgehog signaling could be a potential intervention axis for mitigating age-associated inflammation and related diseases. Overall, our data represent a resourceful catalog of tissue-specific and sex-specific transcriptomic changes in resident macrophages of peritoneum, liver, and brain, during physiological aging.

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LncRNA LINC01305 promotes cervical cancer progression through KHSRP and exosome-mediated transfer

Xianxia Huang1 , Xuemei Liu1 , Bo Du1 , Xueling Liu1 , Mei Xue1 , Qingxin Yan1 , Xiaohong Wang1 , Qian Wang2

doi : 10.18632/aging.202565

Volume 13, Issue 15 pp 19230—19242

Cervical cancer (CC) is one of the deadliest female malignancies worldwide. Long non-coding RNAs (lncRNAs) are essential regulators for cancer progression. This study aimed to elucidate the role of lncRNA LINC01305 in the progression of CC. We found where LINC01305 was expressed in CC tissues and its correlation with the survival rate of CC patients. Functional experiments were performed to elucidate the effect of LINC01305 on CC. The results showed that LINC01305 was increased in CC tumor tissues and was correlated with a lower survival rate. The overexpression and knockdown of LINC01305 enhanced and inhibited the progression of CC, respectively. Additionally, the upregulation of LINC01305 promoted tumor growth in xenograft mice. Moreover, the effect of LINC01305 on CC was mediated through interacting with the RNA-binding protein, KHSRP. Furthermore, LINC01305 was mainly distributed in exosomes and was transferred to recipient cells to enhance CC progression. Lastly, LINC01305 may participate in the regulation of the stemness of CC. Taken together, the results suggest that LINC01305 promotes the progression of CC through KHSRP and that LINC01305 is released through exosomes and is involved in the stemness of CC. This study sheds light on the molecular mechanism underlying the progression of CC.

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Glioma stem cell-derived exosomal miR-944 reduces glioma growth and angiogenesis by inhibiting AKT/ERK signaling

Jianxin Jiang1, *,# , Jun Lu1, *,# , Xiaolin Wang1 , Bing Sun1 , Xiaoxing Liu1 , Yasuo Ding1, & , Guangzhong Gao1, &

doi : 10.18632/aging.203243

Volume 13, Issue 15 pp 19243—19259

In this study, we investigated the regulatory role of exosomal microRNA-944 (miR-944) derived from glioma stem cells (GSCs) in glioma progression and angiogenesis. Bioinformatics analysis showed that miR-944 levels were significantly lower in high-grade gliomas (HGGs) than low-grade gliomas in the Chinese Glioma Genome Atlas and The Cancer Genome Atlas datasets. The overall survival rates were significantly shorter for glioma patients expressing low miR-944 levels than high miR-944 levels. GSC-derived exosomal miR-944 significantly decreased in vitro proliferation, migration, and tube formation by human umbilical vein endothelial cells (HUVECs). Targetscan and dual luciferase reporter assays demonstrated that miR-944 directly targets the 3’UTR of VEGFC. In vivo mouse studies demonstrated that injection of agomiR-944 directly into tumors 3 weeks after xenografting glioma cells significantly reduced tumor growth and angiogenesis. GSC-derived exosomal miR-944 significantly reduced VEGFC levels and suppressed activation of AKT/ERK signaling pathways in HUVECs and xenograft glioma cell tumors. These findings demonstrate that GSC-derived exosomal miR-944 inhibits glioma growth, progression, and angiogenesis by suppressing VEGFC expression and inhibiting the AKT/ERK signaling pathway.

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Downregulation of lncRNA SBF2-AS1 inhibits hepatocellular carcinoma proliferation and migration by regulating the miR-361-5p/TGF-?1 signaling pathway

Yan-Hui Wu1 , Bin Yu2 , Wei-Xun Chen1 , Xi Ai1 , Wei Zhang1 , Wei Dong1 , Ya-Jie Shao3

doi : 10.18632/aging.203248

Volume 13, Issue 15 pp 19260—19271

SBF2-AS1 is an oncogenic long non-coding RNA (lncRNA). However, its role and mechanism in hepatocellular carcinoma (HCC) is still not completely clear. The HepG2, Hep3B, Bel-7402 and HL-7702 cell lines were used in our experiments. The CCK-8 kit and EdU staining were applied to detect cell viability and multiplication. The wound healing and Boyden chamber cell migration assays were employed to test the migration ability of cells. The levels of TGF-?1 mRNA, lncRNA SBF2-AS1, and miR-361-5p were assessed by real-time PCR. TGF-?1 protein levels were evaluated by western blotting. The direct interaction between miR-361-5p and TGF-?1 was determined by luciferase reporter assays. A xenograft mouse model (XMM) was established to comprehensively study the effect and mechanisms of lncRNA SBF2-AS1. lncRNA SBF2-AS1 concentration in HCC cells exceeded that in a normal hepatocyte cell line. The downregulation of lncRNA SBF2-AS1 upregulated miR-361-5p levels in HCC cells. And, miR-361-5p negatively regulate TGF-?1 expression in HCC cells. The suppression of miR-361-5p attenuated the influence of lncRNA SBF2-AS1 downregulation on the viability, proliferation, and migration capability of HCC cells. Further, the downregulation of lncRNA SBF2-AS1 inhibited neoplasm growth in an XMM of HCC. Simultaneously, miR-361-5p was upregulated and TGF-?1 was downregulated after lncRNA SBF2-AS1 knocked down. In conclusion, downregulation of lncRNA SBF2-AS1 inhibits HCC proliferation and migration through the regulation of the miR-361-5p/TGF-?1 signaling pathway.

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lncRNA ANRIL aggravates the chemoresistance of pancreatic cancer cells to gemcitabine by targeting inhibition of miR-181a and targeting HMGB1-induced autophagy

Lei Wang1 , Rongrong Bi2 , Lei Li1 , Kun Zhou1 , Hang Yin1

doi : 10.18632/aging.203251

Volume 13, Issue 15 pp 19272—19281

Recent studies focus on long noncoding RNAs (lncRNA) as crucial regulators of cancer biology that contribute to essential cancer cell functions such as cell proliferation, apoptosis, and metastasis. In pancreatic cancer, several lncRNAs have been mentioned as important actors in tumorigenesis. However, the function of lncRNA ANRIL (named as ANRIL as follows) in pancreatic cancer has not been elucidated. In the present study, we show that ANRIL was up-regulated while miR-181a was down-regulated in pancreatic cancer tissues and HMGB1 was highly expressed. Knockdown of ANRIL in pancreatic cancer repressed cellular proliferation, invasion, migration, and reduced chemotherapy resistance to gemcitabine. ANRIL was negatively correlated with miR-181a, while overexpression of miR-181a could reverse the effect. For further mechanism research, we found that miR-181a aimed to HMGB1 which activated cell autophagy. Taken together, our results implicate that the ANRIL, by targeting miR-181a, activates the HMGB1-induced cell autophagy, which is thought to be critical for oncogenesis.

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Evaluation of the cargo contents and potential role of extracellular vesicles in osteoporosis

Jifeng Xu1 , Yu Chen1 , Dongsheng Yu1 , Li Zhang1 , Xiaofan Dou1 , Gang Wu2 , Yaping Wang3 , Shuijun Zhang1

doi : 10.18632/aging.203264

Volume 13, Issue 15 pp 19282—19292

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). Extracellular vesicles (EVs) remain unexplored in the context of osteoporosis. Towards this, EVs were isolated from plasma of a discovery cohort with 8 non-osteoporotic and 8 osteoporotic individuals, and nanoparticle tracking analysis (NTA) revealed a significantly higher EV concentration in osteoporotic individuals (P = 0.003). Moreover, EVs concentration showed a linear correlation with bone mineral density (BMD) values (linear correlation coefficient r = 0.9542, deviation from zero, p < 0.001). Results using a mouse model of osteoporosis confirmed that the number of EVs in mice from hindlimb unloading group was significantly higher than that from the age-matched control group (p = 0.015). TaqMan Real-Time PCR demonstrated that miR-335-5p, -320a, -483-5p, and miR-21-5p, were significantly higher expressed in osteoporotic patients compared with non-osteoporotic individuals. Quantitative real-time PCR shown that Wnt1, Wnt5a, Wnt7a, and Wnt9a mRNAs were lower expressed in osteoporosis derived EVs. In vitro functional assay indicated that osteoporosis derived EVs resulted in reduced mineralization in SaOS-2 cells. In conclusion, these results suggest that osteoporosis increased the secretion of EVs which carry higher expression of miRNAs and decreased expression of Wnt signals, further decreased the mineralization capacity in human osteoblasts.

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Apremilast ameliorates IL-1?-induced dysfunction in epidermal stem cells

Yuxi Jia1, * , Xiangru Chen1, * , Jing Sun1

doi : 10.18632/aging.203265

Volume 13, Issue 15 pp 19293—19305

Skin tissue is the natural barrier that protects our body, the damage of which can be repaired by the epidermal stem cells (ESCs). However, external factors abolish the self-repair ability of ESCs by inducing oxidative stress and severe inflammation. Apremilast is a small molecular inhibitor of phosphodiesterase 4 that was approved for the treatment of psoriasis. In the present study, the protective property of Apremilast against IL-1?-induced dysfunction on epidermal stem cells, as well as the preliminary mechanism, will be investigated.

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LncRNA-HAGLR motivates triple negative breast cancer progression by regulation of WNT2 via sponging miR-335-3p

Liting Jin1, * , Chenggang Luo2, * , Xinhong Wu1 , Manxiu Li1 , Shun Wu1 , Yaojun Feng1

doi : 10.18632/aging.203272

Volume 13, Issue 15 pp 19306—19316

Triple negative breast cancer (TNBC) is a group of highly heterogeneous mixed breast cancer at the level of gene expression profile. Therefore, it is of great clinical significance to explore the molecular mechanism of TNBC and find a targeted therapeutic approach from the molecular level.

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The deubiquitinase OTUD3 stabilizes ACTN4 to drive growth and metastasis of hepatocellular carcinoma

Peiyi Xie1, * , Yanglin Chen2, * , Hongfei Zhang3, * , Guichao Zhou4 , Qing Chao5 , Jiangwen Wang6 , Yue Liu6 , Jiayu Fang6 , Jing Xie6 , Jing Zhen6 , Zhiyuan Wang7, & , Liang Hao8 , Da Huang9, &

doi : 10.18632/aging.203293

Volume 13, Issue 15 pp 19317—19338

OTU domain-containing protein 3 (OTUD3), a deubiquitinating enzyme, has been shown to participate in progression of multiple malignancies. The accurate function of OTUD3 in hepatocellular carcinoma (HCC) progression remains elusive. We found that OTUD3 was significantly overexpressed in HCC, and higher OTUD3 expression was correlated with larger tumor size, more distant metastasis, and worse TNM stage. A series of gain- and loss-of-function assays were also performed to examine the oncogenic function of OTUD3 in promoting HCC cell growth and metastasis in vitro. Using a xenograft mouse model, we showed that OTUD3 accelerated HCC progression in vivo. Furthermore, alpha-actinin 4 (ACTN4) was identified as a downstream target of OTUD3 through mass spectrometry analysis, and the ACTN4 protein level was significantly related to OTUD3 expression. Additionally, OTUD3 directly bound with ACTN4 and deubiquitinated ACTN4 to stabilize it. Finally, ACTN4 was found to be essential for OTUD3-mediated HCC proliferation and metastasis in vitro and in vivo. Collectively, our findings identify the oncogenic role of OTUD3 in HCC and suggest that OTUD3 can be considered as a pivotal prognostic biomarker and a potential therapeutic target.

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Characterization of familial hypercholesterolemia in Taiwanese ischemic stroke patients

Hsin Tung1,2,3 , Hsueh-Ju Lin4 , Po-Lin Chen5,6 , Tsai-Jung Lu4 , Pei-Pei Jhan4 , Jun-Peng Chen7 , Yi-Ming Chen4,8 , Chen-Chin Wu3,5 , Yung-Yang Lin1,9,10 , Tzu-Hung Hsiao4,11,12

doi : 10.18632/aging.203320

Volume 13, Issue 15 pp 19339—19351

Familial hypercholesterolemia (FH) is a common genetic disorder characterized by a lifelong elevated low-density lipoprotein cholesterol (LDL-C) level. The relationship between FH and ischemic stroke is still controversial. We enrolled ischemic stroke patients prospectively in our neurological ward, and divided them into two groups according to LDL-C levels with a threshold of 130 mg/dl. Targeted sequencing was performed in all stroke patients for LDLR, APOB, and PCSK9 genes. The fifty-eight high-LDL subjects were older, prevalence of previous myocardial infarction/stroke history was lower, and the first stroke age was older compared with values in the sixty-three low-LDL cases. The prevalence of FH in Han-Chinese stroke patients was 5.0%, and was 10.3% in those with a higher LDL-C level. We identified six carriers, who had higher percentages of large vessel stroke subtype (66.7% vs. 15.4%) and transient ischemic attack (33.3% vs. 3.8%), previous myocardial infarction/stroke history (50.0% vs. 11.5%), statin use (50.0% vs. 11.5%), and increased carotid intima-media thickness (IMT) (0.9-1.2mm vs.0.7-9.0mm) compared with the other hypercholesterolemic patients without pathogenic variants. Ischemic stroke patients carrying FH pathogenic variants seemed to have a higher risk for large artery stroke and transient ischemic attack. The IMT exam could be useful to screen for FH in hypercholesterolemic stroke patients.

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Identification of immune-related genes that predict prognosis and risk of bladder cancer: bioinformatics analysis of TCGA database

Liqiang Guo1 , Qiong Wu2 , Zhen Ma3 , Mingzhen Yuan4, *,& , Shengtian Zhao5, *

doi : 10.18632/aging.203333

Volume 13, Issue 15 pp 19352—19374

Bladder cancer (BLCA) is the major tumor of the urinary system, and immune-related genes (IRGs) contribute significantly to its initiation and prognosis.

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THBS4/integrin ?2 axis mediates BM-MSCs to promote angiogenesis in gastric cancer associated with chronic Helicobacter pylori infection

LingNan He1 , WeiJun Wang1 , HuiYing Shi1 , Chen Jiang1 , HaiLing Yao1 , YuRui Zhang1 , Wei Qian1 , Rong Lin1

doi : 10.18632/aging.203334

Volume 13, Issue 15 pp 19375—19396

BM-MSCs contribute to Helicobacter pylori (H. pylori)-induced gastric cancer, but their mechanism is still unclear. The aim of our study was to investigate the specific role and mechanism of BM-MSCs in H. pylori-induced gastric cancer.

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Association between CTLA-4 gene polymorphism and risk of rheumatoid arthritis: a meta-analysis

Chuankun Zhou1 , Shutao Gao2 , Xi Yuan1 , Zixing Shu1 , Song Li1 , Xuying Sun1 , Jun Xiao1 , Hui Liu3

doi : 10.18632/aging.203349

Volume 13, Issue 15 pp 19397—19414

Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) gene polymorphisms may be involved in the risk of Rheumatoid arthritis (RA). However, evidence for the association remains controversial. Therefore, we performed a meta-analysis to confirm the relationship between CTLA-4 gene polymorphisms and RA. The pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of association. Stratified analysis was conducted by ethnicity. In total, 66 case-control studies including 21681 cases and 23457 controls were obtained. For rs3087243 polymorphism, significant association was detected in Asians (A vs. G: OR=0.77, 95%CI=0.65-0.90, P=0.001; AA vs. GG: OR=0.67, 95%CI=0.48-0.94, P=0.02) and Caucasians (A vs. G: OR=0.89, 95%CI=0.86-0.93, P<0.00001; AA vs. GG: OR=0.81, 95%CI=0.75-0.88, P<0.00001). For rs231775 polymorphism, significant association was observed in the overall (G vs. A: OR =1.16, 95%CI=1.08-1.25, P<0.0001; GG vs. AA: OR=1.29, 95%CI=1.12-1.50, P=0.0006), and in Asians (G vs. A: OR=1.27, 95%CI=1.10-1.47, P=0.001; GG vs. AA: OR=1.58, 95%CI=1.24-2.01, P=0.0002), but not in Caucasians. However, there was no association between rs5742909 polymorphism and RA. This meta-analysis confirmed that rs3087243 and rs231775 polymorphism were associated with the risk of RA in both overall population and ethnic-specific analysis, but there was no association between rs5742909 polymorphism and RA risk.

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Development and validation of an intra-tumor heterogeneity-related signature to predict prognosis of bladder cancer: a study based on single-cell RNA-seq

Ranran Zhou1,2 , Jingjing Liang3 , Qi Chen1,2 , Hu Tian1,2 , Cheng Yang1,2 , Cundong Liu1,2

doi : 10.18632/aging.203353

Volume 13, Issue 15 pp 19415—19441

Intra-tumor heterogeneity (ITH) was a potential mechanism of progression and drug resistance in bladder cancer (BCa). However, the understanding of ITH in BCa remains insufficient. Single-cell RNA sequencing (scRNA-seq) profiles of 2075 cells were analyzed, and 2940 cell markers were screened. The ITH of 396 cases was evaluated, and 96 ITH-related genes were identified. Based on the gene-pair strategy, 96 genes were cyclically paired, and an 8-gene-pair model was successfully established to evaluate the overall survival of BCa through Lasso and multivariate Cox regressions. The risk model showed high predictive value in the training dataset (n = 396, p = 0) and external validation datasets (n = 165, p = 2.497e-02; n = 224, p = 3.423e-02). The model was also valuable for the prediction of clinical treatment outcomes. Totally, a prognostic model based on scRNA-seq and ITH was successfully constructed and validated in large cohorts, providing novel clues for ITH study of BCa.

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CC16-TNF-? negative feedback loop formed between Clara cells and normal airway epithelial cells protects against diesel exhaust particles exposure-induced inflammation

Ting Hu1 , Fenglan Sun1 , Xinjuan Yu1 , Qinghai Li1 , Long Zhao1 , Wanming Hao1, & , Wei Han1

doi : 10.18632/aging.203356

Volume 13, Issue 15 pp 19442—19459

CC16 is almost exclusively expressed in non-ciliated epithelial Clara cells, and widely used as a Clara cell marker. Diesel exhaust particles (DEPs), the fine particulate matters produced by diesel engines, cause or exacerbate airway-related diseases. Our previous study documented that DEP inhibits the CC16 expression in the immortalized mouse Clara cell line through methylation of C/EBP? promoter. However, the molecular mechanism by which DEP regulates CC16 secretion is unclear. Here, we isolated CC16 containing Clara cells (CC16+) from human distal lung, and found that DEP inhibited CC16 secretion from CC16+ cells via methylation of C/EBP? and inhibition of Munc18b transcription. CC16+ cell conditioned media containing different concentrations of CC16 was prepared and used for culture of airway epithelial cells BEAS-2B with no expression of CC16. A positive correlation was observed between CC16 level and DEP-induced autophagy activity, and a negative correlation between CC16 level and DEP-induced pro-inflammatory cytokine TNF-?, IL-6, and IL-8 level, suggesting that CC16 might mitigate DEP-induced inflammation via promoting autophagy in BEAS-2B cells. This result was further confirmed by adding recombinant CC16 to BEAS-2B cells exposed to DEP. Moreover, CC16 level was significantly increased when CC16+ cells were cultured in BEAS-2B cell conditioned medium containing TNF-? or the normal medium supplemented with recombinant TNF-?, suggesting that TNF-? induced CC16 production and secretion from CC16+ cells. Collectively, these data point that CC16 and TNF-? form a negative feedback loop, and this negative feedback loop between Clara cells and normal airway epithelial cells protects against DEP exposure-induced inflammation.

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Pedunculoside protects against LPS-induced mastitis in mice by inhibiting inflammation and maintaining the integrity of blood-milk barrier

Xingchi Kan1, * , Guiqiu Hu1, * , Bingxu Huang1, * , Wenjin Guo1, * , Yaping Huang1 , Yingsheng Chen1 , Ping Xu1 , Xiangyu Cai1 , Shoupeng Fu1 , Juxiong Liu1

doi : 10.18632/aging.203357

Volume 13, Issue 15 pp 19460—19474

Mastitis is a disease that seriously threatens the health of the mammary gland after delivery. Pedunculoside (PE) is the main bioactive component of Aquifoliaceae. The purpose of this experiment is to explore the effects of PE on mastitis and its underlying mechanisms. Our research results showed that PE could significantly inhibit the increase in the levels of inflammatory mediators such as TNF-?, IL-6, IL-1?, MPO and iNOS during mastitis. Mechanism studies have found that PE could significantly inhibit the phosphorylation of AKT protein and binds to the ASP-184 site. Further research found that PE also inhibited the activation of AKT's downstream pro-inflammatory signals NF-?B and MAPK. In addition, PE effectively promote the expression of tight junction proteins occludin and claudin-3 during inflammation, maintaining the integrity of the blood-milk barrier. In summary, our research shows that PE inhibits the phosphorylation of AKT/NF-?B and MAPK signals; It also relieves mastitis by repairing the blood-milk barrier.

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FK506 binding protein 10: a key actor of collagen crosslinking in clear cell renal cell carcinoma

Yubai Zhang1,4 , Yue Yin2 , Sijia Liu3 , Lei Yang1,4 , Changhua Sun4 , Ruihua An1

doi : 10.18632/aging.203359

Volume 13, Issue 15 pp 19475—19485

Clear cell renal cell carcinoma (ccRCC) is the most common type of malignant tumor in the kidney. With numbers of patients whose physical condition or tumor stage not suitable for radical surgery, they only have a narrow choice of using VEGF/mTOR targeted drugs to control their tumors, but ccRCC often shows resistance to these drugs. Therefore, identifying a new therapeutic target is of urgent necessity. In this study, for the first time, we concluded from bioinformatics analyses and in vitro research that FK506 binding protein 10 (FKBP10), together with its molecular partner Lysyl hydroxylase 2 (LH2/PLOD2), participate in the process of type I collagen synthesis in ccRCC via regulating crosslinking of pro-collagen chains. Our findings may provide a potential therapeutic target to treat ccRCC in the future.

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A combined hypoxia and immune gene signature for predicting survival and risk stratification in triple-negative breast cancer

Xia Yang1,2 , Xin Weng1,2 , Yajie Yang1,2 , Meng Zhang1,2 , Yingjie Xiu1,2 , Wenfeng Peng1,2 , Xuhui Liao1,2 , Meiquan Xu1,2 , Yanhua Sun1,2 , Xia Liu1,2

doi : 10.18632/aging.203360

Volume 13, Issue 15 pp 19486—19509

Increasing evidence showed that the clinical significance of the interaction between hypoxia and immune status in tumor microenvironment. However, reliable biomarkers based on the hypoxia and immune status in triple-negative breast cancer (TNBC) have not been well established. This study aimed to explore a gene signature based on the hypoxia and immune status for predicting prognosis, risk stratification, and individual treatment in TNBC.

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UHPLC-MS-based metabolomics and chemoinformatics study reveals the neuroprotective effect and chemical characteristic in Parkinson’s disease mice after oral administration of Wen-Shen-Yang-Gan decoction

Guoxue Zhu1,3, * , Wang Wang2, * , Chang Chen1,4 , Lili Tang1 , Yan Liang1 , Zhennian Zhang1 , Yan Lu1 , Yang Zhao1, &

doi : 10.18632/aging.203361

Volume 13, Issue 15 pp 19510—19528

Parkinson’s disease (PD), the typical neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). However, no therapeutic agent used currently could slow down neuronal cell loss so as to decelerate or halt the progression of PD. Traditional Chinese medicine (TCM) has been utilized to treat the dysfunction of the autonomic nervous system. Wen-Shen-Yang-Gan decoction (WSYGD) has a good effect on the clinical treatment of PD with constipation. However, it is not clear which ingredients and what mechanism are responsible for the therapeutic effect. In this study, the pharmacodynamic study of WSYGD in PD mice was applied. Concurrently, a novel method for the identification of metabolic profiles of WSYGD has been developed. Finally, we found that WSYGD could protect the PD mice induced by rotenone. The underlying mechanism of the protective effect may be related to the reduction of the DA neurons apoptosis via reducing inflammatory reaction. By virtue of UPLC-MS and chemoinformatics method, 35 prototype compounds and 27 metabolites were filtered out and tentatively characterized. In conclusion, this study provides an insight into the metabolism of WSYGD in vivo to enable understanding of the metabolic process and therapeutic mechanism of PD.

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Brain reactivity to emotional stimuli in women with premenstrual dysphoric disorder and related personality characteristics

Mingzhou Gao1,2,3, * , Mingqi Qiao1,2,3, * , Li An4 , Guangbin Wang5 , Jieqiong Wang2,3 , Chunhong Song6 , Fengqin Wei1,3 , Yanhong Yu1,2,3 , Tao Gong5 , Dongmei Gao1,2,3

doi : 10.18632/aging.203363

Volume 13, Issue 15 pp 19529—19541

Premenstrual dysphoric disorder (PMDD) is a psychiatric condition that is associated with the menstrual cycle. Elucidation of the neural regulation mechanisms of brain reactivity to emotional stimuli among women with PMDD may inform PMDD treatment.

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Physical exercise prevents age-related heart dysfunction induced by high-salt intake and heart salt-specific overexpression in Drosophila

Deng-Tai Wen1,2 , Lan Zheng1 , Kai Lu1 , Wen-Qi Hou2

doi : 10.18632/aging.203364

Volume 13, Issue 15 pp 19542—19560

A long-term high-salt intake (HSI) seems to accelerate cardiac aging and age-related diseases, but the molecular mechanism is still not entirely clear. Exercise is an effective way to delay cardiac aging. However, it remains unclear whether long-term exercise (LTE) can protect heart from aging induced by high-salt stress. In this study, heart CG2196(salt) specific overexpression (HSSO) and RNAi (HSSR) was constructed by using the UAS/hand-Gal4 system in Drosophila. Flies were given exercise and a high-salt diet intervention from 1 to 5 weeks of age. Results showed that HSSR and LTE remarkably prevented heart from accelerated age-related defects caused by HSI and HSSO, and these defects included a marked increase in heart period, arrhythmia index, malondialdehyde (MDA) level, salt expression, and dTOR expression, and a marked decrease in fractional shortening, SOD activity level, dFOXO expression, PGC-1? expression, and the number of mitochondria and myofibrils. The combination of HSSR and LTE could better protect the aging heart from the damage of HSI. Therefore, current evidences suggested that LTE resisted HSI-induced heart presenility via blocking CG2196(salt)/TOR/oxidative stress and activating dFOXO/PGC-1?. LTE also reversed heart presenility induced by cardiac-salt overexpression via activating dFOXO/PGC-1? and blocking TOR/oxidative stress.

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Effect of age as a continuous variable in early-stage endometrial carcinoma: a multi-institutional analysis in China

Shuai Sun1, * , Lijuan Zou3, * , Tiejun Wang4, * , Zi Liu5 , Jianli He6 , Xiaoge Sun7 , Wei Zhong8 , Fengju Zhao9 , Xiaomei Li10 , Sha Li11 , Hong Zhu12 , Zhanshu Ma13 , Wenhui Wang1 , Meng Jin14 , Fuquan Zhang1 , Xiaorong Hou1 , Lichun Wei2 , Ke Hu1

doi : 10.18632/aging.203367

Volume 13, Issue 15 pp 19561—19574

To explore the effect of age at diagnosis as a continuous variable on survival and treatment choice of patients with early-stage endometrial carcinoma (EC).

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Plasmatic exosome-derived circRNAs panel act as fingerprint for glioblastoma

Dongyan Xia1 , Xuhui Gu1

doi : 10.18632/aging.203368

Volume 13, Issue 15 pp 19575—19586

Circular RNAs (circRNAs) have recently emerged as a new class of RNAs, highly enriched in the brain and very stable within cells, exosomes and body fluids. In this study, we aimed to screen the exosome derived circRNAs in glioblastoma multiforme (GBM) and investigate whether these circRNAs could predict GBM as potential biomarkers. The exosome was extracted from the plasma of GBM patients and healthy volunteers and validated by immunoblotting. The circRNA microarray was employed with three samples in each group to screen the dysregulated circRNAs isolated from the exosome. Five circRNAs were first selected as candidates with the upregulated level in exosome isolated from the plasma of GBM. Further validation found that only hsa_circ_0055202, hsa_circ_0074920 and hsa_circ_0043722 were consistent with training set. The Receiver operating characteristic (ROC) curve also revealed a high diagnostic ability an area under ROC curve value (AUC) for single circRNA and combined. The AUC for hsa_circ_0055202, hsa_circ_0074920, hsa_circ_0043722 and the combined was 0.810, 0.670, 0.938 and 0.988 in training set. For the validation set, the AUC was 0.850, 0.625, 0.750 and 0.925. The three circRNAs were further investigated with stable expression in human plasma samples. In conclusion, the exosome derived hsa_circ_0055202, hsa_circ_0074920 and hsa_circ_0043722 might be the potential biomarker for predicting the GBM.

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LncRNA AC136007.2 alleviates cerebral ischemic-reperfusion injury by suppressing autophagy

Na Liu1 , Aini Peng1 , Haiyan Sun2 , Yuansu Zhuang1 , Ming Yu3 , Qun Wang1 , Jinping Wang1

doi : 10.18632/aging.203369

Volume 13, Issue 15 pp 19587—19597

Differential expression and diagnostic significance of the long noncoding RNA (lncRNA) AC136007.2 has been reported in patients with acute ischemic stroke (AIS). However, its role on disease progression and outcome remains unclear. Here, we employed an oxygen-glucose deprivation/reperfusion (OGD/R) model in neuronal SH-SY5Y cells and performed middle cerebral artery occlusion (MCAO) surgery in rats to investigate the function of AC136007.2 in ischemia-reperfusion (I/R) injury. AC136007.2 expression was determined by RT-qPCR and cell viability was examined using CCK-8, Edu, LDH, and apoptosis assays. Pro-inflammatory cytokine expression was assessed using ELISA. OGD/R downregulated AC136007.2 expression in SH-SY5Y cells, decreased viability by inducing apoptosis, and stimulated secretion of TNF-?, IL-6, and IL-1?. In turn, lentivirus-mediated AC136007.2 overexpression significantly reversed these phenomena. LC3 immunofluorescence and western blotting analyses of LC3-I/II and Beclin-1 expression and AMPK/mTOR phosphorylation status showed that AC136007.2 suppressed autophagy in SH-SY5Y cells via inactivation of AMPK/mTOR signaling. Notably, incubation with the AMPK activator AICAR abolished the pro-survival effect of AC136007.2 upon OGD/R treatment. Importantly, intraventricular injection of AC136007.2 significantly reduced cerebral infarction and brain edema in MCAO rats, as shown by TTC staining and water content measurements. We conclude that AC136007.2 alleviates cerebral I/R injury by suppressing AMPK/mTOR-dependent autophagy.

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Computational research of mTORC1 inhibitor on cerebral ischemia-reperfusion injury

Hui Li1, *,# , Wenzhuo Yang3, *,# , Zhenhua Wang3 , Xu Wang1 , Yulei Hao1 , Jianxin Xi3 , Han Lu3 , Zhishan Du3 , Jiachun Feng1, * , Bao Zhang2, * , Di Ma1, *

doi : 10.18632/aging.203371

Volume 13, Issue 15 pp 19598—19613

Ischemic stroke contributes to more than 80% of all strokes and has the four characteristics of high prevalence, high disability, high mortality, and high recurrence. Stroke is a preventable and controllable disease. In addition to controlling the primary disease, effective prevention and control measures need to be given to the occurrence and development of stroke. With the development and progress of modern treatment methods for ischemic stroke, the mortality and disability rate have decreased significantly. At present, the main treatment methods for ischemic stroke include thrombolysis, thrombus removal at the ultra-early stage, and treatment of improving collateral circulation in the acute phase. However, the ultra-early and early blood reperfusion involves reperfusion injury, which will cause secondary nerve damage, which is called cerebral ischemia/reperfusion injury (CIRI). Studies have found that autophagy is involved in the entire process of CIRI and can reduce the damage of CIRI. The mammalian target of Rapamycin (mTORC1) is the primary signal pathway regulating autophagy. And the mTORC1 inhibitor, Rapamycin, has been proved to exert neuroprotective effects in the ultra-early and early cerebral ischemia-reperfusion. Therefore, screening and designing mTORC1 inhibitors is very important to control reperfusion injury and reduce neuronal death and apoptosis. In this research, plenty of computer-assisted was applied to virtually screen and select potential mTORC1’s inhibitors. We used Libdock to screen the structure and performed toxicity predictions, ADME (absorption, distribution, metabolism, excretion) to predict small molecules’ pharmacological and toxicological properties. To assess the binding mechanism and affinity between the mTORC1 dimer and the ligand, molecular docking was performed. Then, the pharmacophore of small molecules in the docking conformation with the protein was supplemented by Schrodinger. Additionally, molecular dynamics simulations were conducted to assess if the ligand-receptor complex was stable in a natural environment. Furthermore, an experiment was performed to verify the inhibitory effect of compound 1 and compound 2 on mTOR protein. All in all, the study provides a hand of candidate drugs as well as pharmacological properties, which can play an essential role in mTORC1 inhibitors.

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Global, regional, and national burden of blindness and vision loss due to common eye diseases along with its attributable risk factors from 1990 to 2019: a systematic analysis from the global burden of disease study 2019

Xiaorong Yang1,2 , Hui Chen1,2 , Tongchao Zhang3 , Xiaolin Yin3 , Jinyu Man3 , Qiufeng He3 , Ming Lu1,2,3

doi : 10.18632/aging.203374

Volume 13, Issue 15 pp 19614—19642

To map the magnitudes and temporal trends of blindness and vision loss (BVL) due to common eye diseases along with its attributable risk factors at the national, regional, and global levels. The annual burden of BVL in 204 countries and territories was extracted from the Global Burden of Disease Study 2019. The estimated annual percentage change (EAPC) and causes composition change were calculated to quantify the temporal trends of BVL-related disease burden by sex, region, and eye disease. The global disability-adjusted life years (DALYs) of BVL increased from 12.44 million in 1990 to 22.56 million in 2019, with a slightly decreased rate from 3.03 to 2.78 per 1000 population (EAPC = -0.30). About 29.6% of BVL-related DALYs worldwide were caused by cataract, followed by refraction disorders (29.1%), near vision loss (21.7%), other vision loss (13.7%), glaucoma (3.3%), and age-related macular degeneration (2.5%) in 2019. The age-standardized DALYs rates due to each eye disease type in most regions were decreased, especially in countries with high burden and high-middle socio-demographic index. Moreover, the contribution of smoking and air pollution from solid fuels to BVL burden decreased, however, the age-standardized burden of BVL attributed to high body-mass index and high fasting plasma glucose elevated gradually across almost all regions. The temporal trend of BVL burden due to specific eye diseases varies remarkably by region, sex and age. Understanding the real-time patterns of BVL burden is crucial for formulating more effective and targeted prevention and healthcare strategies to decrease the BVL burden.

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The protective effect of allicin on myocardial ischemia-reperfusion by inhibition of Ca2+ overload-induced cardiomyocyte apoptosis via the PI3K/GRK2/PLC-?/IP3R signaling pathway

Tong Gao1,2 , Peng Yang2 , Dongliang Fu2 , Mengru Liu1,2 , Xinyi Deng2,3 , Mingjing Shao2 , Jiangquan Liao2 , Hong Jiang2 , Xianlun Li1,2,3

doi : 10.18632/aging.203375

Volume 13, Issue 15 pp 19643—19656

To investigate the protective effect and mechanism of allicin on myocardial ischemia-reperfusion (MI/R) injury.

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Diagnostic performance of microRNAs in testicular germ cell tumors: a systematic review and meta-analysis

Xi-Yi Zhao1, * , Yu-Lu Gao1,2, * , Dan-Feng Li1 , Hong-Chao Liu1 , Rui-Fang Zhu3 , Chang-Tai Zhu1

doi : 10.18632/aging.203376

Volume 13, Issue 15 pp 19657—19677

The sensitivity (Sen) of classic biomarkers for the diagnosis of testicular germ cell tumors (TGCTs) is currently low. Previous studies have shown the diagnostic potential of microRNAs (miRNAs) for TGCTs; however, the results of these studies are inconsistent. Therefore, we conducted a systematic review and meta-analysis to evaluate their diagnostic value. PubMed, EMBASE, Cochrane Library, and Web of Science databases were systematically searched until September 30, 2020 and 18 trials from 11 studies involving 2,068 participants were included in this meta-analysis. Using a bivariate mixed-effects meta-analysis model, the pooled Sen, specificity (Spe), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) with 95% confidence interval values of total miRNAs were 0.83 (0.73–0.90), 0.95 (0.89–0.98), 15.79 (7.41–33.66), 0.18 (0.11–0.29), 87.13 (41.99–180.82), and 0.95 (0.93–0.97), respectively; however, the observed values of single miR-371a-3p were ?0.84 (0.76–0.90), 0.95 (0.91–0.98), 18.41 (9.69–34.97), 0.17 (0.11–0.26), 111.56 (47.72–260.80), and?0.97 (0.95–0.98), respectively. Subgroup analysis revealed that miRNAs that included miR-371a-3p showed higher predictive performance than those that did not (P < 0.05). This research identified that miR-371a-3p has a high diagnostic value for TGCTs, except teratoma.

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Identification of inflammation-related DNA methylation biomarkers in periodontitis patients based on weighted co-expression analysis

Pengcheng Wang1,2 , Bingbing Wang3 , Zheng Zhang4 , Zuomin Wang2, &

doi : 10.18632/aging.203378

Volume 13, Issue 15 pp 19678—19695

Evidence from past research has shown that DNA methylation plays a key role in the pathogenesis of periodontitis, regulating gene expression levels and thereby affecting the occurrence of various diseases. Three sample sets of methylation data and gene expression data were downloaded from Gene Expression Omnibus (GEO) database. A diagnostic classifier is established based on gene expression data and CpG methylation data. Abnormal expression of immune-related pathways and methyltransferase-related genes in patients with periodontitis was detected. A total of 8,029 differentially expressed CpG (DMP) was annotated to the promoter region of 4,940 genes, of which 295 immune genes were significantly enriched. The CpG sites of 23 differentially co-expressed immune gene promoter regions were identified, and 13 CpG were generally hypermethylated in healthy group samples, while some were methylated in most patients. Five CpGs were screened as robust periodontitis biomarkers. The accuracy in the training data set, the two external verification data sets, and in the transcriptome was 95.5%, 80% and 78.3%, and 82.6%, respectively. This study provided new features for the diagnosis of periodontitis, and contributed to the personalized treatment of periodontitis.

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Immune cell infiltration-associated signature in colon cancer and its prognostic implications

Dan Deng1,2, * , Xin Luo1, * , Sifang Zhang2 , Zhijie Xu3,4

doi : 10.18632/aging.203380

Volume 13, Issue 15 pp 19696—19709

Tumor immune cell infiltration (ICI) has been reported in various studies to be correlated with tumor diagnosis, clinical treatment sensitivity and prognosis. It is an important direction to study the characteristics of immune cell infiltration and develop new prognostic markers to improve the treatment of colon cancer. In this paper, we systematically analyzed the ICI characteristics and obtained three ICI clusters. Then, the ICI scores were constructed and its prognostic implications were discussed. From the results, the ICI score patterns were linked to a great survival difference (p<0.001). A high ICI score was characterized by a higher fraction of plasma cells, CD8+ T cells, memory resting CD4+ T cells, monocytes, eosinophils and dendritic cells, which had better prognosis. Macrophages and neutrophils were increased in low ICI score patients with decreased overall survival. Immune checkpoint molecules (PDCD1, CD274, LAG3, IDO1, CTLA-4, TIGHT and HAVCR2) were found to be significantly overexpressed in the low ICI score subgroup. In addition, we also studied the correlation between the tumor mutation burden (TMB) and ICI score. This study indicated the ICI score could serve as a potential prognostic biomarker for colon cancer patients’ immunotherapy.

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Active wearable device utilization improved physical performance and IGF-1 among community-dwelling middle-aged and older adults: a 12-month prospective cohort study

Wei-Ju Lee1,2 , Li-Ning Peng1,3 , Ming-Hsien Lin1,3 , Ching-Hui Loh1,4 , Liang-Kung Chen1,3,5

doi : 10.18632/aging.203383

Volume 13, Issue 15 pp 19710—19721

Wearable devices provide real-time and patient-powered data that enable the development of personalized health promotion and management programs. This study aimed to explore the clinical benefits of using the wearable device and to examine associated factors, utilization patterns on health status. 319 community-living adults aged 50-85 years were enrolled and clinically followed for 12 months. Participants were categorized into 3 groups based on the wearable device utilization patterns (active: >30 days of use, non-active: <3 days of use, usual: 3-30 days of use). 128 (40.1%) and 98(30.7%) were active and usual wearable device users, and no significant differences in the baseline demographic characteristics and functional status were noted across groups. Higher cognitive performance was significantly associated with the wearable device use (OR: 1.3,95%CI: 1.1-1.5, p=0.005). Multivariable linear regression showed that 0.16 m/s increase in walking speed among active users, which was significantly higher than non-active users (p=0.034). Compared to usual users, active users had higher average daily, weekday, and holiday step counts. The walking speed increased for 0.03 m/s when participants walked 1,000 more daily step counts (p=0.020). Active use of wearable devices substantially increased walking speed, which suggested better functional outcomes and survival benefits in the future.

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The role of age at menarche and age at menopause in Alzheimer’s disease: evidence from a bidirectional mendelian randomization study

Mingli Li1,2,3,4,5, * , Jiali Lin1,2,3,4,5, * , Shuang Liang1,2,3,4,5, * , Zefeng Chen1,2,3,4,5 , Yulan Bai1,2,3,4,5 , Xinyang Long1,2,3,4,5 , Shengzhu Huang1,2,3,4,5 , Zengnan Mo1,2,3,4,6

doi : 10.18632/aging.203384

Volume 13, Issue 15 pp 19722—19749

The association between endogenous estrogen exposure and Alzheimer’s disease (AD) remains inconclusive in previous observational studies, and few Mendelian randomization (MR) studies have focused on their causality thus far. We performed a bidirectional MR study to clarify the causality and causal direction of age at menarche and age at menopause, which are indicators of endogenous estrogen exposure, on AD risk. We obtained all genetic datasets for the MR analyses using publicly available summary statistics based on individuals of European ancestry from the IEU GWAS database. The MR analyses indicated no significant causal relationship between the genetically determined age at menarche (outlier-adjusted inverse variance weighted odds ratio [IVWOR] = 0.926; 95% confidence interval [CI], 0.803-1.066) or age at menopause (outlier-adjusted IVWOR = 0.981; 95% CI, 0.941-1.022) and AD risk. Similarly, AD did not show any causal association with age at menarche or age at menopause. The sensitivity analyses yielded similar results. In contrast, an inverse association was detected between age at menarche and body mass index (BMI, outlier-adjusted IVW ? = -0.043; 95% CI, -0.077 to -0.009). Our bidirectional MR study provides no evidence for a causal relationship between the genetically determined age at menarche or age at menopause and AD susceptibility, or vice versa. However, earlier menarche might be associated with higher adult BMI.

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Dual inhibition of FGFR4 and BCL-xL inhibits multi-resistant ovarian cancer with BCL2L1 gain

Ting Guo1 , Chao Gu1 , Bin Li1 , Congjian Xu1

doi : 10.18632/aging.203386

Volume 13, Issue 15 pp 19750—19759

Overexpression of BCL2L1 (BCL-xL) was associated with platinum resistance in ovarian cancer (OvCa). However, role of copy number (CN) gain of BCL2L1 in OvCa remains elusive.

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miRNA-221-3p derived from M2-polarized tumor-associated macrophage exosomes aggravates the growth and metastasis of osteosarcoma through SOCS3/JAK2/STAT3 axis

Wei Liu1 , Qiuping Long1 , Wei Zhang1 , Dehui Zeng1 , Bingbing Hu1 , Shengyao Liu2 , Li Chen1

doi : 10.18632/aging.203388

Volume 13, Issue 15 pp 19760—19775

Enhanced infiltration of M2-polarized tumor-associated macrophages (TAMs) is linked to osteosarcoma (OS) metastasis and growth. Here, we aim to explore a novel miR-221-3p shuttled by M2-TAM exosomes in the growth and metastasis of OS cells.

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Exosomal lncRNA LINC01711 facilitates metastasis of esophageal squamous cell carcinoma via the miR-326/FSCN1 axis

Mei-Ling Xu1 , Tian-Cheng Liu2 , Feng-Xiang Dong2 , Ling-Xin Meng1 , Ai-Xia Ling3 , Shan Liu1

doi : 10.18632/aging.203389

Volume 13, Issue 15 pp 19776—19788

Esophageal cancer is a malignant tumor with a five-year survival rate of less than 20%. Early diagnosis and exploration of esophageal cancer pathogenesis are of great significance for the treatment and prognosis of esophageal cancer. Long non-coding RNA (lncRNA) plays a vital role in the occurrence and development of different types of tumors. However, the role of exosome LncRNA in esophageal squamous cell carcinoma (ESCC) is rarely reported. In this study, we detected high expression of lncRNA LINC01711 in ESCC tissues and was associated with poor prognosis. Silencing LINC01711 can inhibit the proliferation, migration, invasion, and growth of ESCC cell lines, and induce apoptosis. Linc01711 was identified as a competitive endogenous RNA that suppressed miR-326, and up-regulated the expression of fascin actin-bundling protein 1 (FSCN1). Besides, in vivo experiments showed that the administration of exosome-derived LINC01711 (LINC01711-Exo) promoted the growth of tumors in nude mice. In general, exosomal LINC01711 promoted the proliferation, migration, and invasion of esophageal cancer cells by up-regulating FSCN1 and down-regulating miR-326, thus improved the occurrence and development of ESCC.

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Comprehensive analysis of new prognostic signature based on ferroptosis-related genes in clear cell renal cell carcinoma

Bin Zheng1,2,3, * , Zhihong Niu1,2,3, * , Shubin Si4 , Guiting Zhao2,3 , Jianwei Wang5 , Zhongshun Yao2,3 , Fajuan Cheng6,7 , Wei He2,3

doi : 10.18632/aging.203390

Volume 13, Issue 15 pp 19789—19804

Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor and the most common subtype of RCC. Ferroptosis is a novel form of regulated cell death, and ferroptosis-related genes (FRGs) have been associated with the prognosis of patients with certain cancers. However, the detailed prognostic correlation between FRGs and ccRCC has not yet been elucidated. To address this, the current study used The Cancer Genome Atlas (TCGA) dataset to explore 64 FRGs and determine their prognostic value in ccRCC. Results showed that 52 out of the 64 genes displayed significantly different expression levels in tumor tissue, and 35 out of the 52 differentially expressed genes (DEGs) were associated with overall survival. Subsequently, a four-gene prognostic signature (CD44, DPP4, NCOA4 and SLC7A11) was constructed and could successfully distinguish ccRCC patients with different prognosis in TCGA train and test sets. Furthermore, clinical ccRCC samples from our medical center were used to verify the application value of the new prognostic signature through immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR). Biological functional analysis implied that immune-related functions and pathways were enriched in the TCGA cohort and the immune status scores were significantly different between high- and low-risk sets. These results suggest that the four ferroptosis-related regulatory genes can act as reliable prognostic biomarkers of ccRCC, and might be exploited as potential targets of therapeutic strategies.

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MiR-195-5p and miR-205-5p in extracellular vesicles isolated from diabetic foot ulcer wound fluid decrease angiogenesis by inhibiting VEGFA expression

Jing Liu1, * , Jiahuan Wang1, * , Wan Fu1 , Xiaoyi Wang1 , Hongxing Chen1 , Xiaoying Wu1 , Guojuan Lao1 , Yuxi Wu1 , Mengdie Hu1 , Chuan Yang1 , Li Yan1 , Meng Ren1

doi : 10.18632/aging.203393

Volume 13, Issue 15 pp 19805—19821

Diabetic foot ulcers are recalcitrant to healing, and poor angiogenesis is considered as the main contributing factor. We aimed to explore the effect of extracellular vesicles (EVs) derived from wound fluids on new vessel formation in diabetic foot ulcers. EVs were isolated from wound fluids of diabetic foot ulcers (DF-EVs). The inhibitory effect of DF-EVs on human umbilical vein endothelial cells (HUVECs) and wound healing was tested. To elucidate the potential mechanism of these effects, we screened the differentially expressed microRNAs (miRNAs) in DF-EVs via microarray analysis and verified the upregulation of miR-195-5p and miR-205-5p in DF-EVs via quantitative real-time polymerase chain reaction (qRT-PCR). Further dual-luciferase reporter assays and overexpression experiments proved these two miRNAs inhibited the expression of vascular endothelial growth factor A (VEGFA) directly to the 3? untranslated region (UTR) of VEGFA and, in turn, promoted an inhibitory effect of DF-EVs on angiogenesis and wound healing in patients with diabetic foot ulcers. Our study shows EVs in the wound fluids of diabetic foot ulcer lesions carrying antiangiogenic miR-195-5p and miR-205-5p negatively regulated angiogenesis and wound healing in patients with diabetic foot.

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Circular RNA ZNF609 drives tumor progression by regulating the miR-138-5p/SIRT7 axis in melanoma

Quan Liu1, * , Wei Cui1, * , Chao Yang2 , Li-Ping Du1

doi : 10.18632/aging.203394

Volume 13, Issue 15 pp 19822—19834

Melanoma serves as a prevailing and lethal skin malignancy with high mortality and a growing number of patients globally. Circular RNAs (circRNAs), as a type of emerging cellular regulator, are involved in the modulation of melanoma. Nevertheless, the function of circZNF609 in melanoma development remains obscure. In this study, we were interested in the effect and the underlying mechanism of circZNF609 on DNA damage during melanoma progression. The circZNF609 depletion significantly suppressed melanoma cell invasion, migration, and proliferation, and stimulated apoptosis. Meanwhile, comet assays showed that the tail length and ?H2AX levels were elevated by circZNF609 depletion. Mechanically, circZNF609 sponged miR-138-5p and miR-138-5p targeted SIRT7 in the melanoma cells. The SIRT7 overexpression and miR-138-5p inhibitor could reverse circZNF609 depletion-mediated DNA damage and malignant progression in melanoma cells. Functionally, CircZNF609 promoted cell growth of melanoma in the nude mice. Consequently, we conclude that circZNF609 suppresses DNA damage and potentially enhances melanoma progression at the experimental condition by modulating the miR-138-5p/SIRT7 axis. Our finding provides new insights into the mechanism by which circZNF609 modulates the development of melanoma. CircZNF609 and miR-138-5p may be utilized as therapeutic targets for melanoma.

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Bisphosphonates and breast cancer survival: a meta-analysis and trial sequential analysis of 81508 participants from 23 prospective epidemiological studies

YuPeng Liu1, * , Shu Zhao2, * , YuXue Zhang3, * , Justina Ucheojor Onwuka4 , QingYuan Zhang2, & , XiaoDong Liu1

doi : 10.18632/aging.203395

Volume 13, Issue 15 pp 19835—19866

We assessed the effect of bisphosphonates (BPs) on breast cancer (BCa) patient survival and explored how long the effect can persist after treatment.

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Efficacy of graphene oxide-loaded cationic antimicrobial peptide AWRK6 on the neutralization of endotoxin activity and in the treatment of sepsis

Bo Song1 , Hongli Zhao2 , Haiyan Yang1 , Shengji Wang3

doi : 10.18632/aging.203397

Volume 13, Issue 15 pp 19867—19877

This study is to assess the therapeutic effect of graphene oxide (GO) loaded with AWRK6 on endotoxin-induced sepsis.

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CCL2 associated with CD38 expression during ex vivo expansion in human cord blood-derived hematopoietic stem cells

Chao-Ling Yao1,2,3, * , Poyin Huang4,5,6,7, * , Tsai-Chi Liu8 , Yung-Kai Lin9,10 , Ching-Yun Chen8 , Yi-Ting Lai2 , Tzu?Yun Chin8 , Tsung-Yu Tseng3 , Yi-Chiung Hsu8

doi : 10.18632/aging.203398

Volume 13, Issue 15 pp 19878—19893

To date, different experimental strategies have been developed for the ex vivo expansion of human hematopoietic stem cells (HSCs) for clinical applications. However, differences in the genomic function of expanded HSCs under different culture systems remain unclear. In this study, we compared the gene expression profiles of HSCs in ex vivo expanded serum (10% FBS, fetal bovine serum) and serum-free culture systems and analyzed the molecular functions of differentially expressed genes using microarray chips. We identified 839 differentially expressed genes between the two culture systems. These genes were enriched in the TNF -regulated inflammatory pathway in an FBS culture system. In addition, the mRNA expression of CCL2 (C-C motif chemokine ligand 2), TNF (tumor necrosis factor) and FOS (FBJ murine osteosarcoma viral oncogene homolog) was validated by RT-qPCR. Our data revealed that ex vivo expansion of HSCs using the FBS culture system induces an inflammatory response and high CD38 expression, indicating that this system might activate an inflammatory pathway and induce expression of the cancer marker CD38 during ex vivo expansion of HSCs. This study provides a transcriptional profile and new insights into the genomic functions of HSCs under different expanded cultures.

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Establishing a three-miRNA signature as a prognostic model for colorectal cancer through bioinformatics analysis

Yiming Wang1, * , Lumi Huang1, * , Nan Shan2 , Huiwen Ma1 , Songmei Lu1 , Xingyue Chen1 , Hao Long3

doi : 10.18632/aging.203400

Volume 13, Issue 15 pp 19894—19907

Identification of more promising microRNAs (miRNAs) are being extensively studied with respect to colorectal cancer (CRC), since CRC is the leading cause of cancer deaths and most common malignant tumors worldwide. A series of colon cancer (CCa) samples from The Cancer Genome Atlas (TCGA) were analyzed to provide a new perspective into this field.

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A circular RNA, circSMARCA5, inhibits prostate cancer proliferative, migrative, and invasive capabilities via the miR-181b-5p/miR-17-3p-TIMP3 axis

Xin Xie1, * , Fu-Kang Sun1, * , Xin Huang1 , Cheng-He Wang1 , Jun Dai1 , Ju-Ping Zhao1 , Chen Fang1 , Wei He1

doi : 10.18632/aging.203408

Volume 13, Issue 15 pp 19908—19919

SMARCA5 (circSMARCA5) is involved in the occurrence of different cancers, but its role in prostate cancer carcinogenesis and metastatic transformation remains elusive. Thus, we evaluated the circSMARCA5 functional relevance in prostate cancer and its associated molecular mechanism. First, circSMARCA5 expression and function in this cancer were evaluated. To determine the miR-181b-5p/miR-17-3p target and clarify how circSMARCA5 regulates the miR-181b-5p-TIMP3 and miR-17-3p-TIMP3 axis, RNA immunoprecipitation, biotin-coupled microRNA capture, luciferase reporter, Western blot, and quantitative real-time PCR assays were employed. In primary and metastatic prostate cancer tissues, circSMARCA5 was significantly downregulated compared with normal controls. Functionally, circSMARCA5 exhibited a suppressive effect on prostate cancer cells' metastasis and growth. At the molecular level, circSMARCA5 could affect the tissue inhibitor of metalloproteinases 3 (TIMP3) expression through miR-181b-5p or miR-17-3p interactions. Moreover, lysine acetyltransferase 5 (KAT5) induced circSMARCA5 biogenesis and regulated the miR-181b-5p-TIMP3 and miR-17-3p-TIMP3 axis. These results suggested that targeting circSMARCA5-miR-181b-5p-TIMP3 and circSMARCA5-miR-17-3p-TIMP3 axis might be a novel therapeutic strategy for prostate cancer.

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Cellular senescence in lymphoid organs and immunosenescence

Vivekananda Budamagunta1,2,3 , Thomas C. Foster1,2 , Daohong Zhou1,3

doi : 10.18632/aging.203405

Volume 13, Issue 15 pp 19920—19941

Immunosenescence is a multi-faceted phenomenon at the root of age-associated immune dysfunction. It can lead to an array of pathological conditions, including but not limited to a decreased capability to surveil and clear senescent cells (SnCs) and cancerous cells, an increased autoimmune responses leading to tissue damage, a reduced ability to tackle pathogens, and a decreased competence to illicit a robust response to vaccination. Cellular senescence is a phenomenon by which oncogene-activated, stressed or damaged cells undergo a stable cell cycle arrest. Failure to efficiently clear SnCs results in their accumulation in an organism as it ages. SnCs actively secrete a myriad of molecules, collectively called senescence-associated secretory phenotype (SASP), which are factors that cause dysfunction in the neighboring tissue. Though both cellular senescence and immunosenescence have been studied extensively and implicated in various pathologies, their relationship has not been greatly explored. In the wake of an ongoing pandemic (COVID-19) that disproportionately affects the elderly, immunosenescence as a function of age has become a topic of great importance. The goal of this review is to explore the role of cellular senescence in age-associated lymphoid organ dysfunction and immunosenescence, and provide a framework to explore therapies to rejuvenate the aged immune system.

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Correction for: Establishing immune scoring model based on combination of the number, function, and phenotype of lymphocytes

Guoxing Tang1 , Xu Yuan1 , Ying Luo1 , Qun Lin1 , Zhishui Chen2,3 , Xue Xing4 , Huijuan Song1 , Shiji Wu1 , Hongyan Hou1 , Jing Yu5 , Liyan Mao6 , Weiyong Liu1 , Feng Wang1 , Ziyong Sun1

doi : 10.18632/aging.203423

Volume 13, Issue 15 pp 19942—19944

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Correction for: Supplementary research on K150del variant of activated protein C

Wen-Yi Lin1 , Liang Tang1 , Xuan Lu1 , Yu Hu1

doi : 10.18632/aging.203437

Volume 13, Issue 15 pp 19945

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Correction for: RNA-seq reveals the diverse effects of substrate stiffness on epidermal ovarian cancer cells

Xiaoxu Yang1, * , Guohui Wang1, * , Xiaolei Huang1 , Min Cheng2 , Yangyang Han1

doi : 10.18632/aging.203438

Volume 13, Issue 15 pp 19946—19947

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