Meeting Report: Aging Research and Drug Discovery

Esther Meron1, * , Maria Thaysen1, * , Suzanne Angeli2 , Adam Antebi3 , Nir Barzilai4,5 , Joseph A. Baur6 , Simon Bekker-Jensen1 , Maria Birkisdottir7,8 , Evelyne Bischof9 , Jens Bruening10 , Anne Brunet11 , Abigail Buchwalter12 , Filipe Cabreiro13,14 , Shiqing Cai15 , Brian H. Chen16,17 , Maria Ermolaeva18 , Collin Y. Ewald19 , Luigi Ferrucci20 , Maria Carolina Florian21 , Kristen Fortney22 , Adam Freund23 , Anastasia Georgievskaya24 , Vadim N. Gladyshev25 , David Glass26 , Tyler Golato27 , Vera Gorbunova28 , Jan Hoejimakers29 , Riekelt H. Houtkooper30 , Sibylle Jager31 , Frank Jaksch32 , Georges Janssens30 , Martin Borch Jensen33 , Matt Kaeberlein34 , Gerard Karsenty35 , Peter de Keizer36 , Brian Kennedy2,37,38 , James L. Kirkland39 , Michael Kjaer40 , Guido Kroemer41 , Kai-Fu Lee42 , Jean-Marc Lemaitre43 , David Liaskos44 , Valter D. Longo45 , Yu-Xuan Lu3 , Michael R. MacArthur46 , Andrea B. Maier38,47,48 , Christina Manakanatas49 , Sarah J. Mitchell46 , Alexey Moskalev50,51 , Laura Niedernhofer52 , Ivan Ozerov53 , Linda Partridge3 , Emmanuelle Passegué54 , Michael A. Petr1,55 , James Peyer56 , Dina Radenkovic57 , Thomas A. Rando58 , Suresh Rattan59 , Christian G. Riedel60 , Lenhard Rudolph18 , Ruixue Ai61 , Manuel Serrano62 , Björn Schumacher14 , David A. Sinclair63 , Ryan Smith64 , Yousin Suh65 , Pam Taub66 , Alexandre Trapp25 , Anne-Ulrike Trendelenburg67 , Dario Riccardo Valenzano3,18 , Kris Verburgh68 , Eric Verdin2 , Jan Vijg4 , Rudi G.J. Westendorp69 , Alessandra Zonari70 , Daniela Bakula1 , Alex Zhavoronkov53 , Morten Scheibye-Knudsen1

doi : 10.18632/aging.203859

Volume 14, Issue 2 pp 530—543

Aging is the single largest risk factor for most chronic diseases, and thus possesses large socioeconomic interest to continuously aging societies. Consequently, the field of aging research is expanding alongside a growing focus from the industry and investors in aging research. This year’s 8th Annual Aging Research and Drug Discovery (ARDD) meeting was organized as a hybrid meeting from August 30th to September 3rd 2021 with more than 130 attendees participating on-site at the Ceremonial Hall at University of Copenhagen, Denmark, and 1800 engaging online. The conference comprised of presentations from 75 speakers focusing on new research in topics including mechanisms of aging and how these can be modulated as well as the use of AI and new standards of practices within aging research. This year, a longevity workshop was included to build stronger connections with the clinical community.

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Severe versus common COVID-19: an early warning nomogram model

Yanxin Chang1,2, * , Xuying Wan2,3, * , Xiaohui Fu2,4, * , Ziyu Yang3,5 , Zhijie Lu2,6 , Zhenmeng Wang2,6 , Li Fu2,7 , Lei Yin2,4 , Yongjie Zhang4 , Qian Zhang2,7

doi : 10.18632/aging.203832

Volume 14, Issue 2 pp 544—556

The wide spread of coronavirus disease 2019 is currently the most rigorous health threat, and the clinical outcomes of severe patients are extremely poor. In this study, we establish an early warning nomogram model related to severe versus common COVID-19. A total of 1059 COVID-19 patients were analyzed in the primary cohort and divided into common and severe according to the guidelines on the Diagnosis and Treatment of COVID-19 by the National Health Commission of China (7th version). The clinical data were collected for logistic regression analysis to assess the risk factors for severe versus common type. Furthermore, 123 COVID-19 patients were reviewed as the validation cohort to assess the performance of this model. Multivariate logistic analysis revealed that age, dyspnea, lymphocyte count, C-reactive protein and interleukin-6 were independent factors for prewarning the severe type occurrence. Then, the early warning nomogram model including these risk factors for inferring the severe disease occurrence out of common type of COVID-19 was constructed. The C-index of this nomogram in the primary cohort was 0.863, 95% confidence interval (CI) (0.836–0.889). Meanwhile, in the validation cohort, the C-index of this nomogram was 0.889, 95% CI (0.828–0.950). In both the primary cohort and validation cohorts, the calibration curve showed good agreement between prediction and actual probability. The early warning model shows that data at the very beginning including age, dyspnea, lymphocyte count, CRP, and IL-6 may prewarn the severe disease occurrence to some extent, which could help clinicians early and timely treatment.

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Association between tocilizumab treatment and clinical outcomes of COVID-19 patients: a systematic review and meta-analysis

Jingwen Peng1,3 , Xiaodong She1,3 , Huan Mei1,3 , Hailin Zheng1,3 , Meihua Fu1,3 , Guanzhao Liang1,3 , Qiong Wang1,3 , Weida Liu1,2,3

doi : 10.18632/aging.203834

Volume 14, Issue 2 pp 557—571

To explore and summarize the association between treatment with tocilizumab and clinical outcomes in COVID-19 patients. We performed a systematic review and meta-analysis (10 RCTs including 3378 patients in the tocilizumab group and 3142 patients in the control group). We systematically searched PubMed and MedRxiv for all RCTs as of June 1, 2021, to assess the benefits and harms of tocilizumab to treat patients with COVID-19. All analyses were carried out using RevMan version 5.4.1. There were nine RCTs published in peer-reviewed journals and one RCTs published as a preprint. The summary RR for all-cause mortality with tocilizumab was 0.89 (95% CI= 0.82-0.96, P= 0.003). There was no significant between-trial heterogeneity (I2= 28%, P= 0.19). However, all peer-reviewed RCTs showed no significant associations between treatment with tocilizumab and reductions in all-cause mortality. We notably found that tocilizumab significantly reduced the rate of intubation or death in patients with COVID-19 with 3 RCTs. Across the 8 RCTs, the summary RR for discharge with tocilizumab was 1.10 (95% CI= 1.03-1.16, P< 0.00001). There was no significant association of tocilizumab with harm on other patient-relevant clinical outcomes, including increasing secondary infection risk, patients of adverse events, or patients of serious adverse events. Tocilizumab significantly increased the rate of hospital discharges in COVID-19 patients. Still, it did not decrease all-cause mortality or increase the risk of secondary infections, patients of adverse events, or patients for serious adverse events. Evidence that tocilizumab affects clinical outcomes in patients with COVID-19 requires further proof.

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Combination of dasatinib and quercetin improves cognitive abilities in aged male Wistar rats, alleviates inflammation and changes hippocampal synaptic plasticity and histone H3 methylation profile

Adam Krzystyniak1, * , Malgorzata Wesierska2, * , Gregory Petrazzo1 , Agnieszka Gadecka1 , Magdalena Dudkowska1 , Anna Bielak-Zmijewska1 , Grazyna Mosieniak1 , Izabela Figiel3 , Jakub Wlodarczyk3 , Ewa Sikora1

doi : 10.18632/aging.203835

Volume 14, Issue 2 pp 572—595

Aging is associated with cognitive decline and accumulation of senescent cells in various tissues and organs. Senolytic agents such as dasatinib and quercetin (D+Q) in combination have been shown to target senescent cells and ameliorate symptoms of aging-related disorders in mouse models. However, the mechanisms by which senolytics improve cognitive impairments have not been fully elucidated particularly in species other than mice. To study the effect of senolytics on aging-related multifactorial cognitive dysfunctions we tested the spatial memory of male Wistar rats in an active allothetic place avoidance task. Here we report that 8 weeks treatment with D+Q alleviated learning deficits and memory impairment observed in aged animals. Furthermore, treatment with D+Q resulted in a reduction of the peripheral inflammation measured by the levels of serum inflammatory mediators (including members of senescent cell secretome) in aged rats. Significant improvements in cognitive abilities observed in aged rats upon treatment with D+Q were associated with changes in the dendritic spine morphology of the apical dendritic tree from the hippocampal CA1 neurons and changes in the level of histone H3 trimethylation at lysine 9 and 27 in the hippocampus. The beneficial effects of D+Q on learning and memory in aged rats were long-lasting and persisted at least 5 weeks after the cessation of the drugs administration. Our results expand and provide new insights to the existing knowledge associated with effects of senolytics on alleviating age-related associated cognitive dysfunctions.

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Five years of exercise intervention at different intensities and development of white matter hyperintensities in community dwelling older adults, a Generation 100 sub-study

Anette Arild1 , Torgil Vangberg2,3 , Hanne Nikkels4 , Stian Lydersen5 , Ulrik Wisløff6,7 , Dorthe Stensvold6,7 , Asta K. Håberg1,4

doi : 10.18632/aging.203843

Volume 14, Issue 2 pp 596—622

We investigated if a five-year supervised exercise intervention with moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT) versus control; physical activity according to national guidelines, attenuated the growth of white matter hyperintensities (WMH). We hypothesized that supervised exercise, in particular HIIT, reduced WMH growth. Older adults from the general population participating in the RCT Generation 100 Study were scanned at 3T MRI at baseline (age 70–77), and after 1-, 3- and 5-years. At each follow-up, cardiorespiratory fitness was measured with ergospirometry, and physical activity plus clinical data collected. Manually delineated total WMH, periventricular (PWMH), deep (DWMH), and automated total white matter hypointensity volumes were obtained. No group by time interactions were present in linear mixed model analyses with the different WMH measurements as outcomes. In the combined exercise (MICT&HIIT) group, a significant group by time interaction was uncovered for PWMH volume, with a larger increase in the MICT&HIIT group. Cardiorespiratory fitness at the follow-ups or change in cardiorespiratory fitness over time were not associated with any WMH measure. Contrary to our hypothesis, taking part in MICT or HIIT over a five-year period did not attenuate WMH growth compared to being in a control group following national physical activity guidelines.

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A catalogue of omics biological ageing clocks reveals substantial commonality and associations with disease risk

Erin Macdonald-Dunlop1 , Nele Taba2,3 , Lucija Klari?4 , Azra Frkatovi?5 , Rosie Walker6 , Caroline Hayward4 , Tõnu Esko2,7 , Chris Haley4 , Krista Fischer2,8 , James F. Wilson1,4, * , Peter K. Joshi1, *

doi : 10.18632/aging.203847

Volume 14, Issue 2 pp 623—659

Biological age (BA), a measure of functional capacity and prognostic of health outcomes that discriminates between individuals of the same chronological age (chronAge), has been estimated using a variety of biomarkers. Previous comparative studies have mainly used epigenetic models (clocks), we use ~1000 participants to compare fifteen omics ageing clocks, with correlations of 0.21-0.97 with chronAge, even with substantial sub-setting of biomarkers. These clocks track common aspects of ageing with 95% of the variance in chronAge being shared among clocks. The difference between BA and chronAge - omics clock age acceleration (OCAA) - often associates with health measures. One year’s OCAA typically has the same effect on risk factors/10-year disease incidence as 0.09/0.25 years of chronAge. Epigenetic and IgG glycomics clocks appeared to track generalised ageing while others capture specific risks. We conclude BA is measurable and prognostic and that future work should prioritise health outcomes over chronAge.

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Comparing qPCR and DNA methylation-based measurements of telomere length in a high-risk pediatric cohort

Waylon J. Hastings1 , Laura Etzel1 , Christine M. Heim1,2 , Jennie G. Noll3 , Emma J. Rose3,4 , Hannah M.C. Schreier1 , Chad E. Shenk3,5 , Xin Tang1 , Idan Shalev1

doi : 10.18632/aging.203849

Volume 14, Issue 2 pp 660—677

Various approaches exist to assess population differences in biological aging. Telomere length (TL) is one such measure, and is associated with disease, disability and early mortality. Yet, issues surrounding precision and reproducibility are a concern for TL measurement. An alternative method to estimate TL using DNA methylation (DNAmTL) was recently developed. Although DNAmTL has been characterized in adult and elderly cohorts, its utility in pediatric populations remains unknown. We examined the comparability of leukocyte TL measurements generated using qPCR (absolute TL; aTL) to those estimated using DNAmTL in a high-risk pediatric cohort (N = 269; age: 8–13 years, 83% investigated for maltreatment). aTL and DNAmTL measurements were correlated with one another (r = 0.20, p = 0.001), but exhibited poor measurement agreement and were significantly different in paired-sample t-tests (Cohen’s d = 0.77, p < 0.001). Shorter DNAmTL was associated with older age (r = ?0.25, p < 0.001), male sex (? = ?0.27, p = 0.029), and White race (? = ?0.74, p = 0.008). By contrast, aTL was less strongly associated with age (r = ?0.13, p = 0.040), was longer in males (? = 0.31, p = 0.012), and was not associated with race (p = 0.820). These findings highlight strengths and limitations of high-throughput measures of TL; although DNAmTL replicated hypothesized associations, aTL measurements were positively skewed and did not replicate associations with external validity measures. These results also extend previous research in adults and suggest that DNAmTL is a sensitive TL measure for use in pediatric populations.

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Targeting regulation of ATP synthase 5 alpha/beta dimerization alleviates senescence

Yun Haeng Lee1, * , Doyoung Choi2, * , Geonhee Jang2 , Ji Yun Park1 , Eun Seon Song1 , Haneur Lee1 , Myeong Uk Kuk1 , Junghyun Joo1 , Soon Kil Ahn1 , Youngjoo Byun2 , Joon Tae Park1

doi : 10.18632/aging.203858

Volume 14, Issue 2 pp 678—707

Senescence is a distinct set of changes in the senescence-associated secretory phenotype (SASP) and leads to aging and age-related diseases. Here, we screened compounds that could ameliorate senescence and identified an oxazoloquinoline analog (KB1541) designed to inhibit IL-33 signaling pathway. To elucidate the mechanism of action of KB1541, the proteins binding to KB1541 were investigated, and an interaction between KB1541 and 14–3–3? protein was found. Specifically, KB1541 interacted with 14–3–3? protein and phosphorylated of 14–3–3? protein at serine 58 residue. This phosphorylation increased ATP synthase 5 alpha/beta dimerization, which in turn promoted ATP production through increased oxidative phosphorylation (OXPHOS) efficiency. Then, the increased OXPHOS efficiency induced the recovery of mitochondrial function, coupled with senescence alleviation. Taken together, our results demonstrate a mechanism by which senescence is regulated by ATP synthase 5 alpha/beta dimerization upon fine-tuning of KB1541-mediated 14–3–3? protein activity.

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S-Klotho level and physiological markers of cardiometabolic risk in healthy adult men

Agnieszka ?ela?niewicz1 , Judyta Nowak-Kornicka1 , Bogus?aw Paw?owski1

doi : 10.18632/aging.203861

Volume 14, Issue 2 pp 708—727

S-Klotho is perceived as a biomarker of healthy aging that has been shown to be inversely associated with cardiometabolic risk in elderly individuals. The aim of this study was to test if s-Klotho level is associated with cardiometabolic risk markers in younger healthy men in order to verify the possible role of s-Klotho level as an early marker of cardiometabolic risk. A cross-sectional study was conducted among 186 healthy men (Mage=35.33, SDage=3.47) from a Western urban population. Serum basal levels of s-Klotho, lipid profile, homocysteine, glycemia markers, C-reactive protein, liver transaminases and creatinine were evaluated. Also, blood pressure was measured and cardiometabolic risk score and homeostatic model assessment for insulin resistance (HOMA-IR) were calculated. Testosterone and cortisol levels, self-reported psychological stress, physical activity, smoking in the past, alcohol use and body adiposity were controlled for. We found no relationship between levels of s-Klotho and physiological markers of cardiometabolic risk in the studied population. The results were similar when controlled for adiposity, testosterone level, physical activity, alcohol use and smoking in the past. We suggest that s-Klotho level is not an early marker of cardiometabolic risk in younger middle-aged healthy men.

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Influence of age and sex on microRNA response and recovery in the hippocampus following sepsis

Asha Rani1 , Jolie Barter1 , Ashok Kumar1 , Julie A. Stortz2 , McKenzie Hollen2 , Dina Nacionales2 , Lyle L. Moldawer2 , Philip A. Efron2 , Thomas C. Foster1,3

doi : 10.18632/aging.203868

Volume 14, Issue 2 pp 728—746

Sepsis, defined as a dysregulated host immune response to infection, is a common and dangerous clinical syndrome. The excessive host inflammatory response can induce immediate and persistent cognitive decline, which can be worse in older individuals. Sex-specific differences in the outcome of infectious diseases and sepsis appear to favor females. We employed a murine model to examine the influence of age and sex on the brain's microRNA (miR) response following sepsis. Young and old mice of both sexes underwent cecal ligation and puncture (CLP) with daily restraint stress. Expression of hippocampal miR was examined in age- and sex-matched controls at 1 and 4 days post-CLP. Few miR were modified in a similar manner across age or sex and these few miR were generally associated with neuroprotection against inflammation. Similar to previous work examining transcription, young females exhibited a better recovery of the miR profile from day 1 to day 4, relative to young males and old females. For young males and all female groups, the initial response mainly involved a decrease in miR expression. In contrast, old males exhibited only upregulated miR on day 1 and day 4 and many of the miR upregulated on day 1 and day 4 were linked to neurodegeneration, increased neuroinflammation, and cognitive impairment. The results emphasize age and sex differences in epigenetic mechanisms that likely contribute to susceptibility or resilience to cognitive impairment due to sepsis.

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Overexpression of chaperonin containing TCP1 subunit 7 has diagnostic and prognostic value for hepatocellular carcinoma

Xinghua Huang1,2, * , Huaxiang Wang1,3, * , Fengfeng Xu1,2, * , Lizhi Lv1,2 , Ruling Wang3 , Bin Jiang3 , Tingting Liu2,4 , Huanzhang Hu1,2 , Yi Jiang1,2

doi : 10.18632/aging.203809

Volume 14, Issue 2 pp 747—769

Chaperonin containing TCP1 subunit 7 (CCT7) regulates the expression of many tumor-related proteins. We investigated the diagnostic and prognostic value of CCT7 expression for hepatocellular carcinoma (HCC). In datasets from The Cancer Genome Atlas and the Gene Expression Omnibus, CCT7 mRNA levels were greater in HCC tissues than adjacent normal tissues, and these results were validated using immunohistochemistry. In patients with early-stage disease and low alpha-fetoprotein expression, CCT7 expression was still higher in HCC tissues than normal tissues. Receiver operating characteristic curve analyses indicated that CCT7 expression had better diagnostic value than alpha-fetoprotein for HCC patients with early-stage disease and low alpha-fetoprotein expression. The positive predictive value of CCT7 expression was higher than that of alpha-fetoprotein expression. Higher CCT7 mRNA and protein levels were independent risk factors for poorer overall and recurrence-free survival in HCC patients. Greater methylation of the CpG site cg19515186 was associated with better overall survival in HCC patients. Genes co-expressed with CCT7 were upregulated in HCC and associated with poorer overall survival. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analyses demonstrated that CCT7 expression correlated with spliceosome signaling. These findings demonstrate that CCT7 has diagnostic and prognostic value for HCC.

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Impact of marital status on survival in patients with stage 1A NSCLC

Liu Huang1, * , Shu Peng2, * , Chenyu Sun3 , Lian Chen1 , Qian Chu1 , Sudip Thapa1 , Vanisha Chummun4 , Lu Zhang1 , Peng Zhang1 , Eric L. Chen3 , Ce Cheng5 , Yuan Chen1

doi : 10.18632/aging.203838

Volume 14, Issue 2 pp 770—779

To study how marital status influences overall survival (OS) in patients with stage IA non-small cell lung cancer (NSCLC). And whether the result is valid in different time periods.

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Integrin ?E?7 is involved in the intestinal barrier injury of sepsis

Jia-Kui Sun1,2 , Qian Zhang1 , Xiao Shen2 , Jing Zhou1 , Xiang Wang2 , Su-Ming Zhou1, & , Xin-Wei Mu2

doi : 10.18632/aging.203839

Volume 14, Issue 2 pp 780—788

IL-9-producing CD4(+) T (Th9) cell was related to acute intestinal barrier injury in sepsis. Integrin ?E?7 was an important lymphocyte homing receptor on the surface of intestinal Th9 cells. However, the roles of ?E?7 in the intestinal injury caused by Th9 cells were not clear in sepsis.

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A dynamic model to predict long-term outcomes in patients with prolonged disorders of consciousness

Junwei Kang1 , Lianghua Huang1 , Yunliang Tang1 , Gengfa Chen1 , Wen Ye1 , Jun Wang1 , Zhen Feng1

doi : 10.18632/aging.203840

Volume 14, Issue 2 pp 789—799

It is important to predict the prognosis of patients with prolonged disorders of consciousness (DOC). This study established and validated a nomogram and corresponding web-based calculator to predict outcomes for patients with prolonged DOC.

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The interaction protein of SORBS2 in myocardial tissue to find out the pathogenic mechanism of LVNC disease

Chunyan Li1, * , Yang Zheng3, * , Ying Liu1 , Guo Hong Jin1 , Haizhou Pan4 , Fenghui Yin5 , Jun Wu1,2, &

doi : 10.18632/aging.203841

Volume 14, Issue 2 pp 800—810

Left ventricular noncompaction cardiomyopathy (LVNC) is a cardiac disorder characterized by an excessive trabecular meshwork of deep intertrabecular recesses within the ventricular myocardium. Sorbin and SH3 domain-containing protein 2 (SORBS2) converges on the actin and microtubule cytoskeleton. Here, we investigated the proteins interacting with SORBS2 to elucidate the pathogenic mechanism of LVNC. As reported in previous studies, SORBS2 enhances the occurrence of LVNC by potentiating heart failure, but the specific mechanism remains unclear.

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Immunological significance of survival-related alternative splicing in uveal melanoma

Deqian Kong1 , Li Li1 , Huajun Wang1 , Ke Li1 , Guangying Zheng1

doi : 10.18632/aging.203842

Volume 14, Issue 2 pp 811—825

Uveal melanoma (UM) is a highly malignant intraocular tumor. The imbalance of alternative splicing (AS) is a landmark of tumor initiation and progression. However, there are few studies of AS in UM. Thus, this study aimed to identify a new AS-based prognostic signature and reveal its relationship with tumor-infiltrating immune cells. Univariable Cox regression analysis identified survival-related AS events. The prognostic signature was constructed using the univariable and multivariable Cox regression analyses. Kaplan-Meier survival analysis, the proportional hazard model, and receiver operating characteristic curves verified its prognostic value. Single-sample gene set enrichment analysis was used to analyze immune cell enrichment. The correlation of the risk score with tumor-infiltrating immune cells and immune checkpoint blockade (ICB) genes was examined. We screened 2886 survival-related AS events, of which five were selected to build a prognostic predictor. The risk score was positively relevant with ICB key targets (HAVCR2, IDO1, and PDCD1) and the infiltration of T cells, MDSC, and activated B cells. We provided novel and effective indices, including a risk score and clinical nomogram, for prognostic prediction in UM and discussed the potential relationship between survival-related AS events and immune cell infiltration, which is crucial for developing immune-targeted therapy to improve prognosis.

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A new signature based on alternative polyadenylation for prognostic prediction and therapeutic responses in low-grade glioma

Yuzhi Wang1, * , Yunfei Xu2, * , Yi Zhang3

doi : 10.18632/aging.203844

Volume 14, Issue 2 pp 826—844

Evidence from research supports the significant role of alternative polyadenylation (APA) in the development of cancer. The aim of this study is to explore the prognostic and therapeutic value of APA events for patients with low-grade gliomas (LGG).

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Tumor microenvironment-related multigene prognostic prediction model for breast cancer

Kai Hong1 , Yingjue Zhang2 , Lingli Yao1 , Jiabo Zhang3 , Xianneng Sheng3 , Yu Guo3

doi : 10.18632/aging.203845

Volume 14, Issue 2 pp 845—868

Breast cancer is an invasive disease with complex molecular mechanisms. Prognosis-related biomarkers are still urgently needed to predict outcomes of breast cancer patients.

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Novel necroptosis-related gene signature for predicting the prognosis of pancreatic adenocarcinoma

Zixuan Wu1 , Xuyan Huang1 , Minjie Cai2 , Peidong Huang3 , Zunhui Guan4

doi : 10.18632/aging.203846

Volume 14, Issue 2 pp 869—891

Pancreatic adenocarcinoma (PAAD) is a deadly digestive system tumor with a poor prognosis. Recently, necroptosis has been considered as a type of inflammatory programmed cell death. However, the expression of necroptosis-related genes (NRGs) in PAAD and their associations with prognosis remain unclear. NRGs’ prediction potential in PAAD samples from The TCGA and GEO datasets was investigated. The prediction model was constructed using Lasso regression. Co-expression analysis showed that gene expression was closely related to necroptosis. NRGs were shown to be somewhat overexpressed in high-risk people even when no other clinical symptoms were present, indicating that they may be utilized in a model to predict PAAD prognosis. GSEA showed immunological and tumor-related pathways in the high-risk group. Based on the findings, immune function and m6A genes differ significantly between the low-risk and high-risk groups. MET, AM25C, MROH9, MYEOV, FAM111B, Y6D, and PPP2R3A might be related to the oncology process for PAAD patients. Moreover, CASKIN2, TLE2, USP20, SPRN, ARSG, MIR106B, and MIR98 might be associated with low-risk patients with PAAD. NRGs and the relationship of the immune function, immune checkpoints, and m6A gene expression with NRGs in PAAD may be considered as potential therapeutic targets that should be further studied.

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The effect of QiangGuYin on osteoporosis through the AKT/mTOR/autophagy signaling pathway mediated by CKIP-1

Yifeng Yuan1, * , Jiangang Sun1, * , Hang Zhou1, * , Shen Wang1, * , Caijian He1, * , Tianpeng Chen1 , Mouhao Fang1 , Shaohua Li1 , Shifa Kang1 , Xiaosheng Huang1 , Binbin Tang2 , Bocheng Liang2 , Yingdelong Mao2 , Jianyou Li3 , Xiaolin Shi2, & , Kang Liu2, &

doi : 10.18632/aging.203848

Volume 14, Issue 2 pp 892—906

Osteoporosis is a systemic bone disease characterized by decreased bone mass and deterioration of bone microstructure, which leads to increased bone fragility and increased risk of fractures. Casein kinase 2 interacting protein 1 (CKIP-1, also known as PLEKHO1) is involved in the biological process of bone formation, differentiation and apoptosis, and is a negative regulator of bone formation. QiangGuYin (QGY) is a famous TCM formula that has been widely used in China for the clinical treatment of postmenopausal osteoporosis for decades, but the effect in regulating CKIP-1 on osteoporosis is not fully understood. This study aimed to explore the potential mechanism of CKIP-1 participating in autophagy in bone cells through the AKT/mTOR signaling pathway and the regulatory effect of QGY. The results in vivo showed that QGY treatment can significantly improve the bone quality of osteoporotic rats, down-regulate the expression of CKIP-1, LC3II/I and RANKL, and up-regulated the expression of p62, p-AKT/AKT, p-mTOR/mTOR, RUNX2 and OPG. It is worth noting that the results in vitro confirmed that CKIP-1 interacts with AKT. By up-regulating the expression of Atg5 and down-regulating the p62, the level of LC3 (autophagosome) is increased, and the cells osteogenesis and differentiation are inhibited. QGY inhibits the combination of CKIP-1 and AKT in osteoblasts, activates the AKT/mTOR signaling pathway, inhibits autophagy, and promotes cell differentiation, thereby exerting an anti-osteoporosis effect. Therefore, QGY targeting CKIP-1 to regulate the AKT/mTOR-autophagy signaling pathway may represent a promising drug candidate for the treatment of osteoporosis.

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A radiomics model predicts the response of patients with advanced gastric cancer to PD-1 inhibitor treatment

Zhiwen Liang1, *,# , Ai Huang1, *,# , Linfang Wang2, *,# , Jianping Bi3 , Bohua Kuang1 , Yong Xiao2 , Dandan Yu1 , Ma Hong1 , Tao Zhang1

doi : 10.18632/aging.203850

Volume 14, Issue 2 pp 907—922

Programmed cell death 1 (PD1) inhibitors have shown promising treatment effects in advanced gastric cancer, the beneficiary population not definite. This study aimed to construct an individualized radiomics model to predict the treatment benefits of PD-1 inhibitors in gastric cancer. Patients with advanced gastric cancer treated with PD-1 inhibitors were randomly divided into a training set (n = 58) and a validation set (n = 29). CT imaging data were extracted from medical records, and an individual radiomics nomogram was generated based on the imaging features and clinicopathological risk factors. Discrimination performance was evaluated by Harrell’s c-index and receiver operator characteristic (ROC) curve analyses. The areas under the ROC curves (AUCs) were analyzed to predict anti-PD-1 efficacy and survival. We found that the radiomics nomogram could predict the response of gastric cancer to anti-PD-1 treatment. The AUC was 0.865 with a 95% CI of 0.812-0.828 in the training set, while the AUC was 0.778 with a 95% CI of 0.732–0.776 in the validation set. The diagnostic performance of the radiomics was significantly higher than that of the clinical factors (p < 0.01). Patients with a low risk of disease progression discriminated by the radiomics nomogram had longer progression-free survival than those with a high risk (6.5 vs. 3.2 months, HR 1.99, 95% CI: 1.19-3.31, p = 0.009). The radiomics nomogram based on CT imaging features and clinical risk factors could predict the treatment benefits of PD-1 inhibitors in advanced gastric cancer, enabling it to guide decision-making regarding clinical treatment.

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Age-related alterations of brain metabolic network based on [18F]FDG-PET of rats

Xin Xue1, *,# , Jia-Jia Wu2, *,# , Bei-Bei Huo1 , Xiang-Xin Xing1,2 , Jie Ma1 , Yu-Lin Li1 , Mou-Xiong Zheng2,3 , Xu-Yun Hua2,3 , Jian-Guang Xu1,2,4

doi : 10.18632/aging.203851

Volume 14, Issue 2 pp 923—942

Using animal models to study the underlying mechanisms of aging will create a critical foundation from which to develop new interventions for aging-related brain disorders. Aging-related reorganization of the brain network has been described for the human brain based on functional, metabolic and structural connectivity. However, alterations in the brain metabolic network of aging rats remain unknown. Here, we submitted young and aged rats to [18F]fluorodeoxyglucose with positron emission tomography (18F-FDG PET) and constructed brain metabolic networks. The topological properties were detected, and the network robustness against random failures and targeted attacks was analyzed for age-group comparison. Compared with young rats, aged rats showed reduced betweenness centrality (BC) in the superior colliculus and a decreased degree (D) in the parietal association cortex. With regard to network robustness, the brain metabolic networks of aged rats were more vulnerable to simulated damage, which showed significantly lower local efficiency and clustering coefficients than those of the young rats against targeted attacks and random failures. The findings support the idea that aged rats have similar aging-related changes in the brain metabolic network to the human brain and can therefore be used as a model for aging studies to provide targets for potential therapies that promote healthy aging.

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The oncogenic role of treacle ribosome biogenesis factor 1 (TCOF1) in human tumors: a pan-cancer analysis

Wei Gu1 , Le Sun1 , Jian Wang1 , Xiaowei Chen1

doi : 10.18632/aging.203852

Volume 14, Issue 2 pp 943—960

Treacle ribosome biogenesis factor 1 (TCOF1) plays a crucial role in multiple processes, including ribosome biogenesis, DNA damage response (DDR), mitotic regulation, and telomere integrity. However, its role in cancers remains unclear. We aimed to visualize the expression, prognostic, and mutational landscapes of TCOF1 across cancers and to explore its association with immune infiltration. In this work, we integrated information from TCGA and GEO to explore the differential expression and prognostic value of TCOF1. Then, the mutational profiles of TCOF1 in cancers were investigated. We further determined the correlation between TCOF1 and immune cell infiltration levels. Additionally, we determined correlations among certain immune checkpoints, microsatellite instability, tumor mutational burden (TMB), and TCOF1. Potential pathways of TCOF1 in tumorigenesis were analyzed as well. In general, tumor tissue had a higher expression level of TCOF1 than normal tissue. The prognostic value of TCOF1 was multifaceted, depending on type of cancer. TCOF1 was correlated with tumor purity, CD8+ T cells, CD4+ T cells, B cells, neutrophils, macrophages, and dendritic cells (DCs) in 6, 14, 16, 12, 20, 13, and 17 cancer types, respectively. TCOF1 might act on ATPase activity, microtubule binding, tubulin binding, and catalytic activity (on DNA), and participate in tumorigenesis through “cell cycle” and “cellular-senescence” pathways. TCOF1 could affect pan-cancer prognosis and was correlated with immune cell infiltration. “Cell cycle” and “cellular-senescence” pathways were involved in the functional mechanisms of TCOF1, a finding that awaits further experimental validation.

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Integrative bioinformatics and experimental analysis revealed TEAD as novel prognostic target for hepatocellular carcinoma and its roles in ferroptosis regulation

Xinxin Ren1, * , Xiang Wang2, * , Yuanliang Yan2 , Xi Chen2 , Yuan Cai3 , Qiuju Liang2 , Bi Peng3 , Zhijie Xu3,4 , Qingchun He5,6 , Fanhua Kang7 , Jianbo Li7 , Wenqin Zhang7 , Qianhui Hong7 , Jinwu Peng3,7 , Muzhang Xiao8

doi : 10.18632/aging.203853

Volume 14, Issue 2 pp 961—974

Transcriptional enhanced associate domain (TEAD) family consists of four members TEAD1/2/3/4 that regulate cell growth, stem cell functions and organ development. As the downstream of Hippo signaling pathway, TEAD family is involved in the progression of several cancers. However, the precise biology functions of TEAD family in hepatocellular carcinoma (HCC) have not been reported yet.

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The prevalence of small intestinal bacterial overgrowth in diabetes mellitus: a systematic review and meta-analysis

Xin Feng1 , Xiao-Qing Li2, &

doi : 10.18632/aging.203854

Volume 14, Issue 2 pp 975—988

We conducted this systematic review and meta-analysis to estimate the prevalence of SIBO in diabetic patients and to determine the association between SIBO and diabetes.

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A novel pyroptosis-related signature predicts prognosis and response to treatment in breast carcinoma

Haochen Yu1,2 , Yong Fu3 , Zhenrong Tang1 , Linshan Jiang1 , Chi Qu1 , Han Li1 , Zhaofu Tan1 , Dan Shu1 , Yang Peng1 , Shengchun Liu1

doi : 10.18632/aging.203855

Volume 14, Issue 2 pp 989—1013

Pyroptosis is a new form of programmed cell death (PCD), also known as cellular inflammatory necrosis. Its discovery has resulted in a novel approach to the progression and medication resistance of breast cancer (BC). However, there is still a significant gap in the investigation of pyroptosis-related genes in BC.

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A comprehensive analysis of age-related metabolomics and transcriptomics reveals metabolic alterations in rat bone marrow mesenchymal stem cells

Xiao Yu1 , Hui Sun1 , Xingyu Gao1 , Chang Zhang1 , Yanan Sun1 , Huan Wang1 , Haiying Zhang1 , Yingai Shi1 , Xu He1

doi : 10.18632/aging.203857

Volume 14, Issue 2 pp 1014—1032

The functions of stem cells decline progressively with aging, and some metabolic changes occur during the process. However, the molecular mechanisms of stem cell aging remain unclear. In this study, the combined application of metabolomics and transcriptomics technologies can effectively describe the possible molecular mechanisms of rat bone marrow mesenchymal stem cell (BMSC) senescence. Metabolomic profiles revealed 23 differential metabolites which were abundant in “glycerophospholipid metabolism”, “linoleic acid metabolism” and “biosynthesis of unsaturated fatty acids”. In addition, transcriptomics analysis identified 590 genes with enormously differential expressions in young and old BMSCs. KEGG enrichment analyses showed that metabolism-related pathways in BMSC senescence had stronger responses. Furthermore, the integrated analysis of the interactions between the differentially expressed genes (DEGs) and metabolites indicated the differential genes related to lipid metabolism of Scd, Scd2, Dgat2, Fads2, Lpin1, Gpat3, Acaa2, Lpcat3, Pcyt2 and Pla2g4a may be closely associated with the aging of BMSCs. Finally, Scd2 was identified as the most significant DEG, and Scd2 over-expression could alleviate cellular senescence in aged BMSCs. In conclusion, this work provides a validated understanding that the DEGs and metabolites related to lipid metabolism present more apparent changes in the senescence of rat BMSCs.

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Pan-cancer analysis reveals NUP37 as a prognostic biomarker correlated with the immunosuppressive microenvironment in glioma

Ya He1, * , Jingang Li2, * , Lan Shen3, * , Hui Zhou2 , Wei Fei2 , Guangliang Zhang2 , Zhen Li2 , Fei Wang2 , Yuetao Wen2, &

doi : 10.18632/aging.203862

Volume 14, Issue 2 pp 1033—1047

Nucleoporin 37 kDa (NUP37), a member of the nucleoporin family, has been reported to regulate the proliferation and apoptosis of several tumor types. However, its role in the tumor immune microenvironment is unclear. Here, we evaluated the expression, methylation, copy number alteration, and prognostic significance of NUP37 using RNA-seq and clinical data from The Cancer Genome Atlas. We observed higher expression of NUP37 in 28 of 29 tumor types, and high NUP37 expression predicted worse survival status of patients in 15 tumors. Using data from the cBioportal database, we described the gene variation of NUP37 in glioma and pan-cancer. We further assessed the role of NUP37 in the tumor immune microenvironment using immune infiltration data. NUP37 expression was positively associated with the infiltration levels of immunosuppressive cells, such as nTregs, iTregs, and tumor-associated macrophages, and negatively correlated with immune killer cells, such as CD8+ T and NK cells across cancers. Furthermore, NUP37 expression was associated with immune checkpoints and immune regulation-related genes. The half-maximal inhibitory concentrations of anti-cancer drugs were obtained from the Genomics of Drug Sensitivity in the Cancer database. The correlation between half-maximal inhibitory concentration and NUP37 expression was evaluated. The patients with the evaluated expression of NUP37 were resistant to several anti-cancer drugs. These results suggest that NUP37 is a potential oncogene and prognostic biomarker in glioma and pan-cancer. Tumor tissues with high NUP37 expression exist in a relatively immunosuppressive microenvironment and are resistant to several anti-cancer drugs.

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Acquired resistance for immune checkpoint inhibitors in cancer immunotherapy: challenges and prospects

Xunrui Chen1, * , Wenhui Zhang2, * , Wenyan Yang3 , Min Zhou4, & , Feng Liu1

doi : 10.18632/aging.203833

Volume 14, Issue 2 pp 1048—1064

Drug resistance has become an obstacle to the further development of immunotherapy in clinical applications and experimental studies. In the current review, the acquired resistance to immunotherapy was examined. The mechanisms of acquired resistance were based on three aspects as follows: The change of the tumor functions, the upregulated expression of inhibitory immune checkpoint proteins, and the effects of the tumor microenvironment. The combined use of immunotherapy and other therapies is performed to delay acquired resistance. A comprehensive understanding of acquired drug resistance may provide ideas for solving this dilemma.

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Correction for: Glaucocalyxin B inhibits cartilage inflammatory injury in rheumatoid arthritis by regulating M1 polarization of synovial macrophages through NF-?B pathway

Chenyang Han1, * , Yi Yang1, * , Yongjia Sheng1 , Jin Wang1 , Xiaohong Zhou2 , Wenyan Li1 , Li Guo2 , Caiqun Zhang1 , Qiao Ye3

doi : 10.18632/aging.203864

Volume 14, Issue 2 pp 1065—1066

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Correction for: Curcumin in combination with homoharringtonine suppresses lymphoma cell growth by inhibiting the TGF-?/Smad3 signaling pathway

Yu Zhang1 , Jingjing Xiang1 , Ni Zhu1 , Hangping Ge1 , Xianfu Sheng1 , Shu Deng1 , Junfa Chen1 , Lihong Yu2 , Yan Zhou2 , Jianping Shen1

doi : 10.18632/aging.203870

Volume 14, Issue 2 pp 1067

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