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  • Research Perspective

    Brown adipose tissue enhances exercise performance and healthful longevity

    Relevance score: 5.270863
    Dorothy E. Vatner, Jie Zhang, Stephen F. Vatner
    Keywords: brown adipose tissue, white adipose tissue, healthful longevity, exercise, regulator of G protein signaling 14
    Published in Aging on December 18, 2024
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  • Editorial

    Aging gracefully: time and space matter

    Relevance score: 4.2499533
    Charline Roy, Laurent Molin, Florence Solari
    Keywords: DAF-2/insulin-IGF-1 receptor pathway, tissue-specific, muscle aging, lifespan
    Published in Aging on May 25, 2023
  • Research Paper Volume 14, Issue 8 pp 3607-3616

    Association of CIDEB gene promoter methylation with overweight or obesity in adults

    Relevance score: 5.316716
    Zhiguang Ping, Zhaoyan Guo, Ming Lu, Yanzi Chen, Li Liu
    Keywords: CIDEB, DNA methylation, obesity, adipose tissue, haplotype
    Published in Aging on April 27, 2022
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  • Research Paper Volume 13, Issue 15 pp 19207-19229

    Hedgehog dysregulation contributes to tissue-specific inflammaging of resident macrophages

    Relevance score: 5.171119
    Mahamat Babagana, Kyu-Seon Oh, Sayantan Chakraborty, Alicja Pacholewska, Mohammad Aqdas, Myong-Hee Sung
    Keywords: tissue-resident macrophages, inflammation, inflammaging, transcriptomics, aging
    Published in Aging on August 14, 2021
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  • Research Paper Volume 13, Issue 11 pp 14590-14603

    Prevalence of proliferating CD8+ cells in normal lymphatic tissues, inflammation and cancer

    Relevance score: 4.3824406
    Niclas C. Blessin, Raed Abu-Hashem, Tim Mandelkow, Wenchao Li, Ronald Simon, Claudia Hube-Magg, Christina Möller-Koop, Melanie Witt, Alice Schmidt, Franziska Büscheck, Christoph Fraune, Andreas M. Luebke, Katharina Möller, Frank Jacobsen, Florian Lutz, Maximilian Lennartz, Stefan Steurer, Guido Sauter, Doris Höflmayer, Maria Christina Tsourlakis, Andrea Hinsch, Eike Burandt, Waldemar Wilczak, Sarah Minner, Till S. Clauditz
    Keywords: tumor infiltrating lymphocytes, CD8+ cytotoxic T cells, tumor microenvironment, lymphatic tissue, colorectal cancer
    Published in Aging on June 3, 2021
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  • Research Paper Volume 12, Issue 24 pp 24894-24913

    Obesity induced by high-fat diet is associated with critical changes in biological and molecular functions of mesenchymal stromal cells present in visceral adipose tissue

    Relevance score: 5.171119
    Mustafa Burak Acar, Şerife Ayaz-Güner, Giovanni Di Bernardo, Hüseyin Güner, Ayşegül Murat, Gianfranco Peluso, Servet Özcan, Umberto Galderisi
    Keywords: mesenchymal stromal cells, visceral adipose tissue, senescence
    Published in Aging on December 27, 2020
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  • Research Paper Volume 12, Issue 21 pp 21186-21201

    Landscape of transcription and expression regulated by DNA methylation related to age of donor and cell passage in adipose-derived mesenchymal stem cells

    Relevance score: 4.1757107
    Guan-Ming Lu, Yong-Xian Rong, Zhi-Jie Liang, Dong-lin Hunag, Yan-Fei Ma, Zhi-Zhai Luo, Fang-Xiao Wu, Xin-Heng Liu, Yu Liu, Steven Mo, Zhong-Quan Qi, Hong-Mian Li
    Keywords: adipose-derived mesenchymal stem cells, tissue regeneration, WGCNA, regenerative medicine, TCGAbiolinks
    Published in Aging on October 31, 2020
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  • Research Paper Volume 12, Issue 16 pp 16195-16210

    Cortical aging – new insights with multiparametric quantitative MRI

    Relevance score: 4.1757107
    Alexander Seiler, Sophie Schöngrundner, Benjamin Stock, Ulrike Nöth, Elke Hattingen, Helmuth Steinmetz, Johannes C. Klein, Simon Baudrexel, Marlies Wagner, Ralf Deichmann, René-Maxime Gracien
    Keywords: cortical aging, tissue microstructure, quantitative MRI, surface-based analysis, iron deposition
    Published in Aging on August 27, 2020
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    Scatterplots illustrating the relationship between global cortical qMRI parameters/cortical thickness and age. (A) relationship between T1 and age; (B) relationship between PD and age; (C–E) relationships of T2, T2* and T2' with age; (F) relationship between cortical thickness and age. ms: milliseconds; p.u.: percentage units; mm: millimeters.



    Cortical clusters indicating a significant association between age and cortical quantitative T1 values. The scale bar displays the level of significance. Cold colors demonstrate a negative association with age in the respective regions. L: left; R: right; Lat.: lateral; Med.: medial.



    Cortical clusters exhibiting a significant relationship between age and cortical quantitative T2 (A) and T2′ values (B). The scale bar displays the level of significance. Hot colors demonstrate a positive and cold colors a negative association with age in the respective regions. L: left; R: right; Lat.: lateral; Med.: medial.



    Cortical clusters indicating a significant relationship between age and cortical thickness. The scale bar indicates the level of significance. Cold colors demonstrate a negative association with age in the respective regions. L: left; R: right; Lat.: lateral; Med.: medial.



    Scatterplots illustrating the relationship between regional cortical qMRI parameters/cortical thickness and age in the cortical subregions (lobes). (A) relationship between T1 and age; (B) relationship between PD and age; (C–E) relationships of T2, T2* and T2' with age; (F) relationship between cortical thickness and age. In each plot, the four different colors denote the respective cortical subregions. ms: milliseconds; p.u.: percentage units; mm: millimeters.



  • Priority Research Paper Volume 12, Issue 16 pp 15882-15905

    Senolytic activity of small molecular polyphenols from olive restores chondrocyte redifferentiation and promotes a pro-regenerative environment in osteoarthritis

    Relevance score: 5.2979965
    Marta Varela-Eirín, Paula Carpintero-Fernández, Agustín Sánchez-Temprano, Adrián Varela-Vázquez, Carlos Luis Paíno, Antonio Casado-Díaz, Alfonso Calañas Continente, Virginia Mato, Eduardo Fonseca, Mustapha Kandouz, Alfonso Blanco, José Ramón Caeiro, María D. Mayán
    Keywords: senescence, dedifferentiation, osteoarthritis, connexin43, tissue regeneration
    Published in Aging on August 3, 2020
    Show abstract

    Downregulation of Cx43 during chondrogenesis improves differentiation towards chondrocytes. (A) Treatment of OACs with oleuropein (Oleu) or olive extract (OE) for 2 h significantly downregulates Cx43 protein detected by western-blot and flow cytometry. Median fluorescence intensity (MFI) ratios of oleuropein and OE treatments with respect to their untreated controls of each experiment are represented (n=10 independent experiments, P=0.0003). (B) Differentiation capacity of hMSCs isolated from bone marrow grown in adipogenic (top, 21 days) or osteogenic (bottom, 21 days) medium supplemented with 10 μM oleuropein or 10 μM OE. hMSCs cultured in growth medium were used as a control. Top, adipogenic evaluation by oil red O for lipid staining and by PPARγ gene expression. Data represent the ratio of cells containing lipid deposits to the total number of cells (n=3 independent experiments, P<0.0001). Values were normalized to hMSCs differentiated in adipogenic medium without treatment (AM). On the right, PPARγ gene expression (n=4 independent experiments, P<0.0001). Alizarin red staining was used to detect calcium deposits for osteogenic differentiation. Values were obtained by counting red pixels and normalized to those of hMSCs differentiated in osteogenic medium without treatment (OM) (n=4-6 independent experiments, P=0.0317). OSTCN gene expression was measured to confirm osteogenic differentiation (n=4 independent experiments, P=0.0055). (C) Differentiation capacity of hMSCs isolated from bone marrow grown in chondrogenic medium as micromasses for 30 days. Representative images for Col2A1. The quantification is shown on the right (n=5–6 micromasses from independent experiments, P=0.0423). Chondrogenesis was also evaluated by ACAN gene expression quantification (n=3–4 independent experiments, P<0.0001). (D) Cx43 protein levels in hMSCs, isolated from bone marrow and from inguinal fat, differentiated for 7 and 14 days in the presence of chondrogenic medium (CM) in comparison to untreated hMSCs cultured in normal growth medium (GM). (E) Cx43 RNA expression of hMSCs cultured for 14 days in the presence of chondrogenic medium (CM) alone or supplemented with 10 μM oleuropein. Data were normalized to HPRT-1 levels (n=5-6 independent experiments, P<0.0001). (F) Cx43 protein levels were analyzed by western blot in OACs differentiated for 7 days in the presence of chondrogenic medium (CM), supplemented with 10 μM oleuropein. The graph represents the quantification from 3 independent experiments (P=0.0004). Data is expressed as mean±SD, one-way ANOVA; *P<0.05, **P<0.01 and ***P<0.0001.



    Downregulation of Cx43 by oleuropein decreases GJIC and improves the phenotype of OACs. (A) Oleuropein (Oleu) treatment significantly decreases GJIC evaluated by an SL/DT assay when OACs were exposed with this molecule for 2 h (top, n=6 independent experiments; Student’s t test, P<0.0001). The results were confirmed by calcein transfer by flow cytometry (n=4 independent experiments; Student’s t test, P=0.0037). (B) Graph showing the effect of oleuropein on GJIC when healthy chondrocytes (N) were exposed to 10 μM oleuropein compared with OACs (n=5 independent experiments; one-way ANOVA, P=0.0004). (C) OACs cultured for 7 days with 10 μM Oleu showed reduced expression of the mesenchymal markers CD105 and CD166, analyzed by flow cytometry. Student’s t test, P=0.0039 (CD105) and P=0.0022 (CD166), n=6 independent experiments. CD166 levels were also analyzed by western blot (n=3 independent experiments, Student’s t test, P=0.0046). (D) Downregulation of Cx43 increased Col2A1, detected by immunofluorescence in OACs treated with 10 μM oleuropein. Graphs represent the corrected total cell fluorescence (CTCF) of Cx43 and Col2a1 (n=4 independent experiments). Student’s t test, P<0.0001 (Cx43), and P=0.0007 (Col2a1). (E) mRNA levels of IL-1ß, IL-6, COX-2 and MMP-3 of OACs cultured in normal medium (UT) exposed to 10 μM oleuropein for 2 h. n=4–7 independent experiments. Student’s t test: P= 0.033 (IL-1ß), P<0.0001 (IL-6), P=0.1013 (COX-2), P=0.0466 (MMP-3). (F) IL-6 detected by ELISA when OACs were treated with oleuropein for 72 h (n=4 independent experiments, Student’s t test, P=0.0345). IL-6 (n=3 independent experiments) and COX-2 (n=4 independent experiments) protein levels detected by western-blot in OACs treated with 10 μM oleuropein for 72 h. Student’s t test, P=0.0193 (IL-6), P=0.0141 (COX-2). Data is expressed as mean±SD; *P<0.05, **P<0.01 and ***P<0.0001.



    Oleuropein treatment enhances chondrocyte redifferentiation. (A) Immunohistochemistry of Col2A1 (4-6 independent experiments; one-way ANOVA, P=0.0019) and toluidine blue staining of proteoglycan subunits (n=6 independent experiments; one-way ANOVA, P=0.059) indicate significant enrichment in ECM components in OACs micromasses grown in 3D culture for 30 days in chondrogenic medium (CM) when supplemented with 10 μM oleuropein (Oleu) or OE. (B) Cx43 protein levels detected by western blot (and normalized to Ponceau staining) are reduced when OACs micromasses are exposed to CM supplemented with 10 μM oleuropein or OE for 21 days (n=3 independent experiments; one-way ANOVA, P=0.0328). (C) Oil red staining showing reduced OACs dedifferentiation upon exposure to Oleu or OE in adipogenic medium (n=5 independent experiments; one-way ANOVA, P=0.0001). (D) Nuclear levels of Twist-1 were decreased in OACs cultured with 10 μM oleuropein for 2 h. Lamin A was used as a loading control (n=3 independent experiments; Student’s t test, P=0.001). (E) Cx43 protein levels in primary OACs after 1-h treatment with oleuropein or oligomycin. Western blot represents n=4 independent experiments. Quantification is shown on the right (one-way ANOVA, P=0.0036). On the right, immunofluorescence for Twist-1 (red) in primary OACs treated with 5 μg/ml oligomycin and 10 μM oleuropein for 1 h. The graph represents the percentage of cells with Twist-1 nuclear localization (n=4 independent experiments; one-way ANOVA, P=0.0067). (F) The mRNA expression of the EMT markers Twist-1, N-Cadherin and Vimentin in OACs treated with 10 μM oleuropein for 2 h. Data were normalized to HPRT-1 levels. n= 5 independent experiments; Student’s t test: P<0.0001 (Twist-1), P= 0.0011 (N-Cad), P=0.0209 (Vim). Data is expressed as mean±SD; *P<0.05, **P<0.01 and ***P<0.0001.



    Oleuropein modulates the Cx43 promoter activity in chondrocytes. (A) Treatment with 10 μM oleuropein for 2 h decreases Cx43 protein levels in T/C-28a2 cells (n=4 independent experiments, Student’s t test, P=0.0012), but this effect was not observed in the same cell line overexpressing Cx43 (pIRES-Cx43)(n=3 independent experiments, Student’s t test, P=0.0624). (B) Luciferase reporter assay indicating that oleuropein inhibits Cx43 promoter activity. The graphs indicate the normalized luminescence activity in the T/C-28a2 transfected with a pGL3-basic plasmid containing 300 base pairs of Cx43 promoter ligated to the luciferase gene. Cells were cultured in DMEM with 10% FBS (UT) and with 5 μg/ml oligomycin or 10 μM oleuropein for 1 h as indicated (n=4 independent experiments; one-way ANOVA, P=0.0012). On the right, Cx43 gene expression under 5 μg/ml oligomycin and 10 μM oleuropein treatment in OACs treated for 1 h (n=4 independent experiments; one-way ANOVA, P=0.0002). Data were normalized to HPRT-1 levels. (C) Immunofluorescence assays of Cx43 in OACs treated with 10 μM oleuropein or 5 μg/ml oligomycin for 1 h. Data were normalized to the untreated condition (n=3 independent experiments; one-way ANOVA, P<0.0001). Data is expressed as mean±SD; *P<0.05, **P<0.01 and ***P<0.0001.



    Cx43 downregulation by oleuropein decreased chondrocyte senescence. (A) SA-βGal activity detected by flow cytometry in OACs treated with 10 μM oleuropein (Oleu) for 7 and 14 days (n=3–7 independent experiments; one-way ANOVA, P<0.0001). (B) The graphs show the comparative analysis of SA-βGal activity measured by flow cytometry of OACs exposed for 24 h to 10 μM oleuropein or 5 μg/ml oligomycin as indicated (n=5 independent experiments; one-way ANOVA, P=0.0003). On the right, SA-βGal activity determined by X-Gal cleavage and cell staining (blue), evaluated by microscopy in OACs treated for 7 days with 10 μM oleuropein or 5 μg/ml oligomycin (n=3 independent experiments; one-way ANOVA, P<0.0001). (C) p16 mRNA expression of OACs treated with 10 μM oleuropein for 2 h. Data were normalized to HPRT-1 levels (n=5 independent experiments; Student’s t test, P=0.0002). (D) Western blot of p53 (n=3 independent experiments), p21 (n=3 independent experiments) and p16 (n=4 independent experiments) in OACs treated with 10 μM oleuropein for 2 h. α-tubulin was used as a loading control. Student’s t test, P=0.001 (p53), P=0.0278 (p21), P=0.0286 (p16). (E) Cell proliferation evaluated by immunofluorescence of Ki-67 in T/C-28a2 chondrocytes treated with 10 μM palbociclib and/or 10 μM oleuropein for 24 h. Images represent n= 3 independent experiments. One-way ANOVA, P=0.0434 (UT vs Palbo); P=0.0096 (Palbo vs Palbo+Oleu). (F) Downregulation of Cx43 by oleuropein attenuates IL-6 and COX-2 upregulation when OACs are exposed to oligomycin for 1 h (n=3–9 independent experiments; one-way ANOVA). (G) Western blot (n=3 independent experiments) shows the effect of 10 μM oleuropein and 10 ng/mL TNFα treatments (for 1 h) on Cx43 protein levels in OACs (one-way ANOVA, P=0.0018). On the right, NF-κB detected by immunofluorescence in OACs treated with 10 ng/mL TNFα for 1 h. This effect is partially abolished by 1-h 10 μM oleuropein treatment. The graph represents the cell percentage with nuclear NF-κB staining (n=7 independent experiments; one-way ANOVA, P=0.0055). (H) Nuclear levels of NF-kß in OACs cultured with 10 μM oleuropein for 2 h. Lamin A was used as a loading control (n=3 independent experiments; Student’s t test, P=0.0021). Data is expressed as mean±SD; *P<0.05, **P<0.01 and ***P<0.0001.



    Oleuropein treatment decreased cellular senescence in synoviocytes and bone cells isolated from patients. (A) Cx43 protein levels analyzed by western blot in synoviocytes treated with 10 μM oleuropein for 2 h (n=7 independent experiments, P=0.0313). (B) Treatment of synoviocytes with 10 μM of oleuropein for 7 days detected by SA-βGal activity (n=4 independent experiments, P<0.0001). (C) p16 mRNA levels of synoviocytes treated with 10 μM oleuropein for 2 h. Data were normalized to HPRT-1 levels (n= 4 independent experiments, P<0.0001). On the right, mRNA levels of IL-1ß, IL-6 and COX-2 of synoviocytes cultured in normal medium (DMEM 10% FBS) and exposed to 10 μM oleuropein for 2 h. Data were normalized to HPRT-1 levels. N=4 independent experiments, P<0.0001 (IL-1ß), P=0.0024 (IL-6), P=0.0025 (COX-2). (D) Cx43 protein levels analyzed by western blot in bone cells treated with 10 μM oleuropein for 2 h (n=4 independent experiments, P=0.0319). (E) 10 μM of oleuropein treatment for 7 days reduces senescence levels in bone cells as detected by SA-βGal and flow cytometry (n=3 independent experiments, P=0.0149). (F) p16 mRNA expression of bone cells treated with 10 μM oleuropein for 2 h. Data were normalized to HPRT-1 levels (n= 4 independent experiments, P=0.002). On the right, mRNA levels of IL-1ß, IL-6 and COX-2 of bone cells cultured in normal medium (DMEM 10% FBS) exposed to 10 μM oleuropein for 2 h. Data were normalized to HPRT-1 levels. N=3-4 independent experiments. P=0.0463 (IL-1ß), P=0.0077 (IL-6), P=0.0002 (COX-2). Data is expressed as mean±SD, Student’s t test; *P<0.05, **P<0.01 and ***P<0.0001.



    Cx43 overactivity contributes to disease progression. Cx43 overexpression leads to accumulation of dedifferentiated and senescent cells involved in disease progression in OA patients. These phenotypic changes results in the synthesis of ECM remodeling factors involved in tissue degradation (MMPs) and proinflammatory factors, such as IL-1ß and IL-6, which facilitate the dedifferentiation and reprogramming of neighboring cells. These factors may further spread senescence and dedifferentiation to surrounding tissues contributing to joint degeneration. Downregulation of Cx43 by oleuropein treatment contributes to the elimination of senescent cells and redifferentiation of osteoarthritic chondrocytes into fully differentiated cells, able to support the ECM composition and restoring the regenerative capacity of the tissue. However, oleuropein may have other targets that may contribute to the drug effect. In addition, oleuropein treatment might improve the effectiveness of stem cell therapy, by promoting chondrogenic and osteogenic differentiation, and by inhibiting adipogenesis.



  • Editorial Volume 12, Issue 14 pp 13845-13846

    Alpha-ketoglutarate for adipose tissue rejuvenation

    Relevance score: 4.3561254
    Qiyu Tian, Xiangdong Liu, Min Du
    Keywords: alpha-ketoglutarate, aging, DNA methylation, stem cells, brown adipose tissue
    Published in Aging on July 29, 2020
  • Priority Research Paper Volume 12, Issue 10 pp 8790-8819

    Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin

    Relevance score: 4.1975837
    Melod Mehdipour, Colin Skinner, Nathan Wong, Michael Lieb, Chao Liu, Jessy Etienne, Cameron Kato, Dobri Kiprov, Michael J. Conboy, Irina M. Conboy
    Keywords: blood exchange, therapeutic plasma exchange, multi-tissue rejuvenation, rejuvenation by dilution
    Published in Aging on May 30, 2020
    Show abstract

    The Power of an experiment is determined by the Effect Size. (Top) According to the ES and Variance in comparing young, old and old rejuvenated cohorts in our 2003-2020 studies we show that with these parameters N=4 justifies independence in our samples and larger N does not significantly improve on this justification. (Bottom) If hypothetical samples have high variance (and thus normalized effect size is reduced), then more samples (higher N) are needed to procure similar power in an experiment. Generally, an increase of sample size is needed for increasing the Power to discern less-tangible phenomena that are not statistically detectable without such N increase.



    Rejuvenation of adult myogenesis, and albumin-independent effects of TPE. One day after the NBE, muscle was injured at two sites per TA by cardiotoxin; 5 days later muscle was isolated and cryosectioned at 10 μm. (A) Representative H&E and eMyHC IF images of the injury site. Scale bar = 50 μm. (B) Regenerative index: the number of centrally nucleated myofibers per total nuclei. OO vs. ONBE p = 0.000001, YY vs ONBE non-significant p = 0.4014; Fibrotic index: white devoid of myofibers areas. OO vs ONBE p = 0.000048, YY vs YNBE non-significant p = 0.1712. Minimal Feret diameter of eMyHC+ myofibers is normalized to the mean of YY [9]. OO vs. ONBE p= 3.04346E-05, YY vs. YNBE p=0.009. Data-points are TA injury sites of 4-5 YNBE and 5 ONBE animals. Young and Old levels (detailed in Supplementary Figure 1) are dashed lines. Representative images for YY versus YNBE cohorts are shown in Supplementary Figure 6. (C) Automated microscopy quantification of HSA dose response, as fold difference in BrdU+ cells from OPTI-MEM alone (0 HSA). There was no enhancement of myogenic proliferation at 1-16% HSA. N=6. (D) Meta-Express quantification of BrdU+ cells by automated high throughput microscopy for myoblasts cultured with 4% PreTPE versus PostTPE serum and (E) for these cells cultured with 4% of each: PreTPE serum + HSA or PostTPE serum + HSA. Significant increase in BrdU positive cells is detected in every subject 1, 2, 3, and 4 for TPE-treated serum (p=0.011, <0.0001, <0.0001, 0.0039, respectively), as well as for TPE-treated serum when 4%HSA is present (p<0.0001, <0.0001, <0.0001, =0.009 respectively). N=6. (F) Scatter plot with Means and SEM of all Pre-TPE, Post-TPE, +/- HSA cohorts shows significant improvement in proliferation in Pre TPE as compared to and Post TPE cohorts (p*=0.033), as well as Pre+HSA and Post+HSA cohorts (p*=0.0116). In contrast, no significant change was observed when comparing Pre with Pre+HSA (p=0.744) or Post with Post+HSA (p=0.9733). N=4 subjects X 6 independent assays for each, at each condition. (G) Representative BrdU IF and Hoechst staining in sub-regions of one of the 9 sites that were captured by the automated microscopy. Blood serum from old individuals diminished myogenic cell proliferation with very few BrdU+ cells being visible (illustrated by one positive cell in Pre-TPE and arrowhead pointing to the corresponding nucleus); TPE abrogated this inhibition but HSA did not have a discernable effect.



    Neurogenesis of aged mice is enhanced by one procedure of neutral blood exchange. (A) Immunofluorescence was performed to assay for proliferative Ki67-positive cells in the subgranular zone (SGZ) of the dentate gyrus (DG). Representative images of Ki67(red)+/Hoechst (blue)+ cells in the DG are shown for OO and ONBE mice. (B) Quantification of the number of Ki67+/Hoechst+ cells per SGZ of the DG (extrapolated from serial sections that span the entire hippocampus). ONBE mice have a ~8-fold increase in the number of these cells when compared to OO (****p-value = 0.0000145). The number of these proliferating neural precursor cells in the SGZ of YY mice is not significantly different from that of ONBE mice (N.S. p-value = 0.15235). A trend for ~44% increase in YNBE mice as compared to the YY mice, is not statistically significant (N.S. = 0.20123). Isotype-matched IgG negative control confirms low non-specific fluorescence. N=4 for YY and OO, N=6 for YNBE and N=7 for ONBE. Scale bar is 50-micron. Representative images for YY versus YNBE cohorts are shown in Supplementary Figure 6. These data demonstrate that hippocampal neurogenesis improves in old mice after just one NBE, e.g. without young blood or its fractions, and that young mice do not decline in this parameter when their blood plasma is diluted through the NBE.



    Liver adiposity and fibrosis are reduced in old mice after a single procedure of neutral blood exchange. Histological analysis (Oil Red-O and Masson’s trichome staining) of 10 μm liver sections from uninjured mice collected at 6 days after NBE. (A) Representative images of lipid droplets (fat) stained with Oil Red-O and Collagen (fibrosis) stained blue with Masson’s trichome show that NBE visibly reduced fat and fibrosis of old livers. (B) Adiposity Index (red pixels per section) and (C). Fibrotic index (numbers of fibrotic clusters per section) were determined as in [9] and by shown here trichrome. Adiposity: YY-YNBE NS p= 0.8, YY-ONBE *p= 0.04, OO-ONBE ***p= 0.0004. N=4 YY and OO, N=8 YNBE and ONBE. Fibrosis: YY-YNBE NS p= 0.7, YY-ONBE *p= 0.012, OO-ONBE ****p= 0.00001. N=8. All quants are represented as % of OO control. Scale bar=50 μm. Representative images for YY versus YNBE cohorts and of albumin/Hoechst are shown in Supplementary Figure 6.



    Comparative NBE/TPE proteomics. Serum levels of 308 mouse proteins (Raybiotech #L-308) and 507 human proteins (Raybiotech #L-507) were assayed. After background subtraction, total intensities for each protein (assayed in duplicates for each sample) were normalized to the internal array background control as fold-increments, with a sensitivity cut-off of 2-fold; these normalized intensities were expressed, as a fraction of the internal array positive control. (A) t-SNE clustering of mouse proteins grouped by class of treatment: OO and YY isochronic controls were compared to each other (left) and OO was compared to ONBE (right). Differences between YY vs. OO and OO vs. ONBE proteomes are outlined. (B) Distinct grouping of OO, YY and ONBE proteomes is shown in the t-SNE plot with identities of proteins in clusters 1-4 specified below. Power analysis for independence of X, X and Y marked proteins from these clusters, is shown in Supplementary Figure 4. (C) Heatmap on mouse proteins illustrates significant differences between OO and ONBE cohorts (proteins are grouped on their main function, as indicated). (D) Old human serum proteome before TPE (Before-B) and 1 month after a single procedure of TPE (After-A): t-SNE clustering of human proteins grouped by class of treatment. TPE resulted in a clear and robust change in the molecular composition of the systemic milieu as compared to the Before-TPE. (E) Heat map on human proteins illustrates significant differences between S1,2,3 B and S1, 2, 3 A (before versus after TPE) cohorts (proteins are grouped on their main function, as indicated). Proteins in dashed boxes are the same between mouse and human in Heatmaps. A general elevation (not decrease) of most systemic proteins at 6 days after the NBE and at 1 month after the TPE was observed.



    Model of the dilution effect in resetting of circulatory proteome. System: A induces itself (A, red), and C (blue); A represses B (green), C represses A. A dilution of an age-elevated protein (A, at D1: initial dilution event), breaks the autoinduction and diminishes the levels of A (event 1, red arrow); the secondary target of A (B, at event 2 green arrow), then becomes de-repressed and elevated (B induces B is postulated); the attenuator of A (C, at event 3 blue arrow), has a time-delay (TD) of being diminished, as it is intracellular and was not immediately diluted, and some protein levels persist even after the lower induction of C by A. C decreases (no longer induced by A), and a re-boot of A results in the re-induction of C by A (event 4 blue arrow) leading to the secondary decrease of A signaling intensity/autoinduction, and a secondary upward wave of B (events 5 red arrow and 6 green arrow, respectively).



  • Priority Research Paper Volume 12, Issue 10 pp 8766-8789

    Muscle-dependent regulation of adipose tissue function in long-lived growth hormone-mutant mice

    Relevance score: 4.5035853
    Xinna Li, Jacquelyn A. Frazier, Edward Spahiu, Madaline McPherson, Richard A. Miller
    Keywords: aging, growth hormone, uncoupling protein 1 (UCP1), adipose tissue, inflammation
    Published in Aging on May 28, 2020
    Show abstract

    Effects of global deletion of Growth Hormone Receptor (GKO mouse) on the expression of UCP1 in adipose tissue. (A) Total RNAs were isolated from interscapular (brown fat), mesenteric, inguinal and perigonadal adipose tissues of 24-week-old wild type littermate control mice (WT) and GKO mice. mRNA levels of UCP1 (brown and beige fat marker) were measured by qRT-PCR. Data (mean ± SEM; n = 4) were normalized by the amount of GAPDH mRNA and expressed relative to the corresponding male WT value. *P < 0.05 versus WT. (B) Cell lysate was prepared from interscapular (brown fat), inguinal and perigonadal adipose tissues of 24-week-old WT and GKO mice. Protein levels of UCP1 (brown and beige fat marker) were then measured by western blotting. Representative gel images are shown. (C) Relative protein expression was normalized to β-actin levels. Values are mean ±SEM (n = 4).



    Expression of UCP1 in adipose tissue of Snell Dwarf mice (dw). (A) RNA was isolated from brown fat, mesenteric, inguinal and perigonadal adipose tissues of 24-week-old littermate control (WT) mice and Snell Dwarf mice (dw). mRNA levels of UCP1 were measured by qRT-PCR. Data (mean ± SEM; n = 4) were normalized by the amount of GAPDH mRNA and expressed relative to the corresponding male WT value. *P < 0.05 versus WT. (B) Cell lysate was prepared from brown fat, inguinal and perigonadal adipose tissues of 24-week-old WT and dw mice, and protein levels of UCP1 were measured by western blotting. Representative gel images are shown. (C) Relative protein expression was normalized to β-actin levels. Values are mean ±SEM (n = 4).



    Effects of liver-specific deletion of GHR (LKO mice) on the expression of UCP1 in adipose tissue. (A) Total RNAs were isolated from brown fat, mesenteric, inguinal and perigonadal adipose tissues of 24-week-old WT mice and LKO mice. mRNA levels of UCP1 were measured by qRT-PCR. Data (mean ± SEM; n = 4) were normalized by the amount of GAPDH mRNA and expressed relative to the corresponding male WT value. *P < 0.05 versus WT. (B) Cell lysate was isolated from interscapular (brown fat), inguinal and perigonadal adipose tissues of 24-week-old WT mice and LKO mice, and protein levels of UCP1 were measured by western blotting. Representative gel images are shown. (C) Relative protein expression was normalized to β-actin levels. Values are mean ±SEM (n = 4).



    Effects of fat-specific deletion of GHR (FKO mice) on the expression of UCP1 in adipose tissue. (A) Total RNAs were isolated from brown fat, mesenteric, inguinal and perigonadal adipose tissues of 24-week-old WT mice and FKO mice. mRNA levels of UCP1 were measured by qRT-PCR. Values were normalized by the amount of GAPDH mRNA and expressed relative to the corresponding male WT value. *P < 0.05 versus WT. (B) Cell lysate was isolated from interscapular (BAT), inguinal and perigonadal adipose tissues of 24-week-old WT mice and FKO mice, and protein levels of UCP1 were measured by western blotting. Representative gel images are shown. (C) Relative protein expression was normalized to β-actin levels. Values are mean ±SEM (n = 4).



    Effects of muscle-specific deletion of GHR (MKO mice) on the expression of UCP1 in adipose tissue. (A) Total RNA was isolated from brown fat, mesenteric, inguinal and perigonadal adipose tissues of 24-week-old WT mice and MKO mice. mRNA levels of UCP1 were measured by qRT-PCR. Values were normalized by the amount of GAPDH mRNA and expressed relative to the corresponding male WT value. *P < 0.05 versus WT. (B) Cell lysate was isolated from interscapular (brown fat), inguinal and perigonadal adipose tissues of 24-week-old WT mice and MKO mice, and protein levels of UCP1 were measured by western blotting. Representative gel images are shown. (C) Relative protein expression was normalized to β-actin levels. Values are mean ±SEM (n = 4).



    Effects of global deletion of GHR (GKO mice) on adipose tissue macrophage infiltration and macrophage M1-M2 polarization. (A) Quantitative RT-PCR analysis of total RNA isolated from interscapular (brown fat), inguinal and perigonadal adipose tissues of 24-week-old WT and GKO mice for M1 macrophage markers (iNOS) and M2 macrophage markers (Arg1) mRNAs. Data (mean ± SEM; n = 4) were normalized by the amount of GAPDH mRNA and expressed relative to the corresponding male WT value. *P < 0.05, **P < 0.01 versus WT. (B) Cell lysate was isolated from interscapular (brown fat), inguinal and perigonadal adipose tissues of 24-week-old WT and GKO mice. The protein levels of iNOS and Arg1 were measured by western blotting. (C) Relative protein expression was normalized to β-actin levels. Values are mean ±SEM (n = 4).



    Adipose tissue macrophage infiltration and macrophage M1-M2 polarization of long-lived mice (DW and GKO). (A) Quantitative RT-PCR analysis of total RNA isolated from brown fat, inguinal and perigonadal adipose tissues of 24-week-old GKO mice and WT littermate mice for IL-6, TNFα, MCP-1 mRNAs. Values were normalized by the amount of GAPDH mRNA and expressed relative to the corresponding male WT value. *P < 0.05 versus WT. (B) Quantitative RT-PCR analysis of total RNA isolated from brown fat, inguinal and perigonadal adipose tissues of 24-week-old dw mice and WT mice for IL-6, TNFα, MCP-1 mRNAs. Data (mean ± SEM; n = 4) are expressed relative to the corresponding male WT value. *P < 0.05 versus WT.



    Adipose tissue macrophage infiltration and macrophage M1-M2 polarization of tissue-specific GHR KO mice (LKO, MKO and FKO). The three left panels show relative protein expression (Arginase1 and iNOS) in brown fat, inguinal and perigonadal adipose tissues of 24-week-old LKO (A), MKO (B), and FKO (C) was normalized to β-actin levels. Values are mean ±SEM (n = 4). *P < 0.05 versus WT. M = males; F = females. The three right panels show quantitative RT-PCR analysis of total RNA isolated from brown fat, inguinal and perigonadal adipose tissues of 24-week-old LKO (A), MKO (B), and FKO (C) mice and WT mice for IL-6, TNFα, MCP-1 mRNAs. Data (mean ± SEM; n = 4) were normalized by the amount of GAPDH mRNA and expressed relative to the corresponding male WT value. *P < 0.05 versus WT.



    Plasma irisin levels and expression of FNDC5 in muscle tissue of WT and mutant mice (DW, GKO, LKO, MKO and FKO). (A) Irisin content was measured by ELISA assay on plasma samples of 24-week-old WT and mutant mice model (DW, GKO, LKO, MKO and FKO). Data are shown as mean ± SEM for each group (n = 6). *P < 0.05 versus WT. (B) Cell lysate was prepared from gastrocnemius muscle of 24-week-old WT and mutant mice (DW, GKO, LKO, MKO and FKO), and protein levels of FNDC5 were measured by western blotting. Representative gel images are shown. (C) Relative protein expression was normalized to β-actin levels. Values are mean ±SEM (n = 4). *P < 0.05 versus WT.



  • Research Paper Volume 12, Issue 8 pp 6928-6946

    AKT3 deficiency in M2 macrophages impairs cutaneous wound healing by disrupting tissue remodeling

    Relevance score: 4.3561254
    Song Gu, Hanhao Dai, Xilian Zhao, Chang Gui, Jianchao Gui
    Keywords: cutaneous wound healing, M2 macrophage, tissue remodeling, AKT3, AKT signaling
    Published in Aging on April 14, 2020
    Show abstract

    Impaired tissue remodeling and re-epithelization in delayed cutaneous wound tissue. (A) Histological staining of cutaneous wound tissue (200×). (a) H&E staining of sustained inflammatory cells and disordered tissue organization in the delayed cutaneous wound. (b) Masson staining of collagenous (blue) and muscular (red) fibers. Less staining was observed in the delayed wound tissue. (c) EVG staining of elastic fibers. Less staining occurred in the delayed wound tissue. (B) IHC and TUNEL staining of cutaneous wound tissue (200×). (a) CK-5 and PCNA expression levels are reduced in the delayed wound tissue. (b) Increased apoptosis (green cells) occurred in the delayed wound tissue. All the experiments were repeated at least three times.



    Transcriptome analysis for normal and delayed cutaneous wound tissue. (A, B) Cluster analysis for cutaneous wound tissue (normal wound tissue, n = 5; delayed wound tissue, n = 8). (A) Heatmap and (B) volcano plot for cutaneous wound tissue collected 28 days post-injury. (C) Gene expression profiles of normal and delayed cutaneous wound tissue generated by gene ontology (GO) analysis. (D) KEGG pathway analysis showed that the ECM-associated pathway was significantly enriched. Abbreviation: BB, biological process; CC, cellular component; MF, molecular function. All the experiments were repeated at least three times.



    Downregulation of AKT3, COL1A1, and COL11A1 in delayed cutaneous wound tissue. (A) Venn diagram of the KEGG pathway. (a) Venn analysis identified 35 genes that were enriched in PI3K-AKT signaling, ECM-receptor interactions, and focal adhesion. (b) The heatmap expression profile of the 35 changed genes. (B) Venn diagram of GO analysis for the tissue remodeling-associated biological functions. AKT3, COL1A1, and COL11A1 were enriched. (Ca–d) Gene set enrichment analysis (GSEA) of cutaneous wound tissue. The genes associated with (a) cell adhesion molecules, (b) collagen metabolic processes, (c) focal adhesion, and (d) extracellular structural organization were negatively enriched in the delayed cutaneous wound tissue. (D) IHC staining of AKT3, COL1A1, and COL11A1 in cutaneous wound tissue (200 x). The levels of all three proteins were reduced in the delayed wound tissue. (E) Decreased AKT3, COL1A1, and COL11A1 protein levels in delayed cutaneous wound tissue. (F) Total AKT3 and phosphorylated-Ser472 AKT3 levels were decreased in delayed cutaneous wound tissue. All the experiments were repeated at least three times.



    Loss of AKT3 in M2 macrophages inhibited extracellular COL1A1 and COL11A1 expression. (A) GSEA showed that negatively enriched genes were associated with PI3K-AKT signaling and phagosomes in delayed cutaneous wound tissue. (B) Heatmap of the top 10 genes related to PI3K-AKT signaling and phagosomes; AKT3 was downregulated in both functional enrichment sets in the delayed cutaneous wound tissue. (C) Immunofluorescence of cutaneous wound tissue (n = 6). CD68- (green) and CD206-(red) positive M2 macrophages were reduced in the delayed cutaneous wound tissue. AKT3 (pink) was decreased in the M2 macrophages. (D) qRT-PCR showed decreased AKT3 mRNA expression in the delayed cutaneous wound tissue-derived M2 macrophages. (E) Western blotting verified the reduction and loss of AKT3 in M2 macrophages from delayed cutaneous wound tissue. (F) Immunofluorescence of COL1A1 and COL11A1 in CD68-positive macrophages in cutaneous wound tissue. (a) Decreased CD68-positive macrophage infiltration and COL1A1 protein expression were observed in delayed cutaneous wound tissue. (b) Decreased COL11A1 protein expression also accompanied the reduced CD68-positive macrophage infiltration. All the experiments were repeated at least three times.



    AKT3 knockdown in M2 macrophages suppressed proliferation and migration as well as COL1A1 and COL11A1 expression ex vivo. (A) Schematic of the M2 macrophage-HSF co-culture model. (B) Total AKT3 and associated phosphorylated AKT3Ser472 levels in THP-1-derived M2 macrophages following AKT3 knockdown. (C–D) CCK-8 assay of the co-culture model. (C) Proliferation of co-cultured HSFs was impaired following AKT3 knockdown in THP-1-derived M2 macrophages. (D) M2 macrophages isolated from delayed cutaneous wound tissue also lost their ability to facilitate HSF proliferation compared to M2 macrophages derived from normal wound tissue. (E, F) EdU assay of the co-culture model. (E) DNA replication induced by M2 macrophages in HSFs was abrogated by AKT3 knockdown in these macrophages. (F) M2 macrophages from delayed cutaneous wound tissue were incapable of promoting HSF DNA replication. (G, H) Transwell migration assay of the co-culture model. (G) HSF migration was impaired after co-culture with AKT3 knockdown in THP-1-derived M2 macrophages. (H) M2 macrophages isolated from delayed cutaneous wound tissue could not promote HSF migration. (I) COL1A1 and COL11A1 protein levels were increased in HSFs co-cultured with THP-1-derived M2 macrophages. AKT3 knockdown in the M2 macrophages decreased COL1A1 and COL11A1 expression in the co-cultured HSFs. (J) M2 macrophages from delayed cutaneous wound tissue were incapable of inducing COL1A1 and COL11A1 expression in co-cultured HSFs compared to normal wound tissue-derived M2 macrophages. All the experiments were repeated at least three times.



    Loss of AKT3 delayed cutaneous wound healing in mice. (A) Schematic of AKT3 knockout in mice. (B) Western blotting for AKT3 levels in AKT3+/+ and AKT3-/- mice (n = 6). (C) AKT3 knockout delayed cutaneous wound healing in mice by days 7 and 14 post-injury. (Da–c) Histological staining of mouse cutaneous wound tissue. (a) H&E staining showed more inflammatory cells in the wound tissue of AKT3-/- mice and incomplete tissue integrity (n = 6). (b) Masson staining showed the numbers of collagenous and muscular fibers were reduced in the wound tissue of AKT3-/- mice (n = 6). (c) EVG staining showed that number of elastin fibers were decreased in the wound tissue of AKT3-/- mice (n = 6). (E) IF staining showed the F40/80 and CD206 expression in mouse cutaneous wound tissue. All the experiments were repeated at least three times.



    M2 macrophages from AKT3-/- mice failed to promote cell proliferation and migration ex vivo. (A) TGF-β and IL-10 mRNA levels were decreased in delayed cutaneous wound tissue 7th and 14th day post-injury in mice (n = 3). (B) Western blotting demonstrated the loss of AKT3 in M2 macrophages from AKT3-/- mice. (C, D) CCK-8 and EdU assays demonstrated that M2 macrophages from AKT3-/- mice were incapable of promoting JB6 cell proliferation (C) or DNA replication (D), respectively. (E) Transwell migration assay showed M2 macrophages from AKT3-/- mice could not promote JB6 cell migration. (F) COL1A1 and COL11A1 protein levels in JB6 were not increased by co-culture with M2 macrophages from AKT3-/- mice. (G) The schematic illustration of the role of M2 macrophage AKT3 deficiency in delayed cutaneous wound healing. All the experiments were repeated at least three times.



  • Research Paper Volume 12, Issue 5 pp 4371-4378

    Vitamin D levels are prognostic factors for connective tissue disease associated interstitial lung disease (CTD-ILD)

    Relevance score: 4.3561254
    Yujuan Gao, Qi Zhao, Xiaohua Qiu, Yi Zhuang, Min Yu, Jinghong Dai, Hourong Cai, Xin Yan
    Keywords: Vitamin D, connective tissue disease associated interstitial lung disease, prognosis
    Published in Aging on March 12, 2020
    Show abstract

    The level of 25(OH)D in the healthy control, IPF and CTD-ILD. (A) The mean level of 25(OH)D was 16.06±4.33 ng/ml in the CTD-ILD group, 25.18±7.43 ng/ml in the IPF group and 27.33±5.30 ng/ml in the control group. The serum 25(OH)D levels were obviously lower in patients with CTD-ILD compared with the IPF group (P < 0.05) and the control group (P < 0.05). (B) The CTD-ILD groups were divided into two subgroups: anti-MDA5 antibody-positive and anti-MDA5 antibody-negative groups. A statistically significant difference in vitamin D levels was found in the two subgroups(P=0.006).



    Correlation between vitamin D and lung function changes in patients with CTD-ILD. (A) The Δ25(OH)D(%) was positively correlated with ΔFVC(%) (r=0.559, P=0.001); (B) The Δ25(OH)D(%) was positively correlated with ΔFEV1(%) (r=0.559, P=0.001); (C) The Δ25(OH)D(%) was positively correlated with ΔDLCO-SB(%)(r = 0.559, P=0.001).



    Survival of CTD-ILD patients in high 25(OH)D level group and low 25(OH)D level group. Using a median of serum 25(OH)D (14.98) as a standard, 85 patients with CTD-ILD were divided into high-level and low-level groups. The median survival time of patients with high serum 25(OH)D level in was 16.5 months (95%CI 14.6~18.4 months), significantly longer than the patients with low-level 25(OH)D level group (14.0 months, 95%CI 11.1 to 16.9 months) (P=0.007).



  • Research Paper Volume 12, Issue 4 pp 3807-3827

    Risk score based on expression of five novel genes predicts survival in soft tissue sarcoma

    Relevance score: 3.706203
    Hui-Yun Gu, Chao Zhang, Jia Guo, Min Yang, Hou-Cheng Zhong, Wei Jin, Yang Liu, Li-Ping Gao, Ren-Xiong Wei
    Keywords: soft tissue sarcoma, least absolute shrinkage and selection operator regression analysis, biomarker, prognostic model, nomogram
    Published in Aging on February 21, 2020
    Show abstract

    Functional annotation of primary differentially expressed genes (DEGs). (A) Gene Ontology (GO) functional annotation and (B) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichments for DEGs.



    Feature selection using the Lasso regression model. (A) Lasso regression analysis coefficients. (B) Selection of tuning parameters in the Lasso regression analysis based on 1,000 cross-validations.



    Assessment of the prognostic model. Survival analyses for the training (A), test (B), and overall (C) datasets. Receiver operating curves (ROC) of the prognostic model in the training (D), test (E), and overall (F) datasets. Differences in risk score, survival time, and gene expression between the high- and low-risk groups in the training (G), test (H), and overall (I) datasets.



    Alterations in expression of the five key genes. (A) 73 of 265 samples (28%) had alterations of the five key genes. (B) Frequencies of different alterations. (C) Network of key genes and most frequently altered neighbor genes. (D) Survival analysis for patients with and without alterations in the five key genes.



    Scatter diagram of the relationship between immune cell infiltration, risk scores, and key gene expression. (A) Relationships between immune cell infiltration and risk scores. (B) Relationships between immune cell infiltration and expression of the TSPAN7 (B), MYBL2 (C), FBN2 (D), and DDX39 (E) genes.



    Nomogram for STS. STS: soft tissue sarcoma; LMS: leiomyosarcomas; UPS: undifferentiated pleomorphic sarcoma; MF: myxofibrosarcomas; DL: dedifferentiated liposarcomas; SS: synovial sarcomas; MP: malignant peripheral nerve sheath tumors.



  • Research Paper Volume 12, Issue 2 pp 1725-1746

    Female adipose tissue has improved adaptability and metabolic health compared to males in aged obesity

    Relevance score: 4.379512
    Mita Varghese, Cameron Griffin, Kaitlin McKernan, Leila Eter, Simin Abrishami, Kanakadurga Singer
    Keywords: adipose tissue macrophages, aging, senescence, extracellular matrix remodeling, sex differences
    Published in Aging on January 26, 2020
    Show abstract

    Aging and HFD feeding induced sex differences in total body adiposity and tissue weights. (A) Body weights of C57Bl6/j male and female on ND or 60% HFD starting at 6-week of age (young) or after 10 months of age (old) for 24-week. (B) GWAT percent weight. (C) Relative distribution of GWAT adipocyte cross-sectional area (D) IWAT percent weight. (E) Liver weight. (F) Liver percent weight. (G) H&E staining of liver sections depicting lipid accumulation in young and old obese male and females. Scale bar = 500 μm. N=7-12 /group. Two-way ANOVA with Bonferroni-Dunn’s post-test was performed for (A, B) and (D–F). Statistics from diet and sex interaction are in box. One-way ANOVA with Sidak’s post-test was performed for (C). Statistical significance is indicated by *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Student’s t-test was performed for male and female comparisons between the same diet groups indicated by #p<0.05, ##p<0.01 ###p< 0.001 and ####p<0.0001; error bars are SEM.



    Aging and obesity promote pro-inflammatory ATMs in young and old male mice GWAT. (A) Representative flow cytometry gating strategy for CD64+CD11c+ ATMs in GWAT SVF derived from ND and HFD fed young and old mice. (B) top row- Immunofluorescence images of old male obese GWAT and old female obese GWAT depicting MAC-2 labeling of CLS (magenta) and CAV-1 labeling of adipocytes (green). Scale bar = 500 μm. (B) bottom row- H&E staining of GWAT sections depicting CLS in old obese male and females. Scale bar = 500 μm. Quantitation as a % of SVF of (C) GWAT ATMs (D) GWAT CD11c+ ATMs (E) GWAT CD11c- ATMs. N=7-12/group. Two-way ANOVA with Bonferroni-Dunn’s post-test was performed for (C, E). Statistics from diet and sex interaction are in box. Statistical significance is indicated by *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Student’s t-test was performed for male and female comparisons between the same diet groups indicated by #p<0.05, ##p<0.01 ###p<0.001 and ####p<0.0001; error bars are SEM.



    ADRB3 stimulated lipolysis elevates lipolytic levels in old and obese females but does not affect CD11c ATM numbers in GWAT. (A) Fasting glucose levels and (B) Fasting insulin levels at 10 weeks of HFD. (C) left panel - Glucose tolerance test (GTT) in 18-month-old male and female mice at 12 weeks of HFD; right panel - Area under the curve (AUC) from GTT. (D) Fed serum insulin levels in male and female obese mice after CL-316,243 (CL) treatment. (E) Serum FFA levels. (F) Serum TG levels. (G) Liver percent weight. (H) Immunofluorescence images of PBS or CL treated old male obese GWAT (top row) and old female obese GWAT (bottom row) depicting MAC-2 labeling (magenta) and CAV-1 labeling of adipocytes (green). Scale bar = 500 μm. Flow cytometry analysis and quantitation as a % of SVF of (I) GWAT ATMs (J) GWAT CD11c+ ATMs (K) GWAT CD11c- ATMs (L) GWAT dendritic cells (DC) numbers. N=6-14 /group. One-way ANOVA with Student’s t-test was performed for (A–C). Two-way ANOVA with Bonferroni-Dunn’s post-test was performed for (D–G) and (I–L). Statistics from diet and sex interaction are in box. Statistical significance is indicated by *p <0.05, **p<0.01, ***p<0.001, ****p<0.0001. Student’s t-test was performed for male and female comparisons between the same diet groups indicated by #p<0.05, ##p<0.01 ###p<0.001 and ####p<0.0001; error bars are SEM.



    ADRB3 stimulation promotes inflammatory cytokine and chemokine expression in old and obese female GWAT. Expression of liver inflammation genes - (A) Il6 (B) Mcp1 (C) Arg1 (D) Mgl1 (E) Cx3cr1 (F) Ccr2. Expression of GWAT inflammation genes - (G) Il6 (H) Mcp1 (I) Arg1 (J) Mgl1 (K) Cx3cr1 (L) Ccr2 in lean and obese male and female GWAT with and without ADRB3 stimulation. A.U., arbitrary units normalized to Gapdh, N=5-8. One-way ANOVA with Student’s t-test was performed for (A–L). Statistical significance is indicated by *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; error bars are SEM.



    Oxidative metabolism and ECM remodeling is highly active in older obese female mice. Relative expression of GWAT oxidative genes - (A) Adrb3 (B) Pparγ (C) Pgc1α. Expression of GWAT senescence genes (D) p53 (E) p16 (F) p21. Expression of GWAT fibrosis and ECM remodeling genes - (G) Mmp2 (H) Mmp9 (I) Timp1 (J) Tgfβ1 (K) α-sma (L) Col1a1 in young and old obese male and female GWAT. A.U., arbitrary units normalized to Gapdh. N=5-8. (M) Collagen content in GWAT of young and old obese male and female mice, N=5. (N) Picrosirius red staining of young and old, male and female HFD GWAT positive area as a percentage. N=5. Two-way ANOVA with Bonferroni-Dunn’s post-test was performed for (A–L). Statistics from diet and sex interaction are in box. Statistical significance is indicated by *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. Student’s t-test was performed for male and female comparisons between the same diet groups indicated by #p<0.05, ##p<0.01 ###p<0.001 and ####p<0.0001; error bars are SEM. One-way ANOVA with Student’s t-test was performed for (M–N). Statistical significance is indicated by *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001; error bars are SEM.



  • Research Paper Volume 11, Issue 24 pp 12428-12451

    System level characterization of small molecule drugs and their affected long noncoding RNAs

    Relevance score: 4.1975837
    Haixiu Yang, Yanan Jiang, Yunpeng Zhang, Yanjun Xu, Chunlong Zhang, Junwei Han, Fei Su, Xiaoqi Liu, Kai Mi, Bing Liu, Desi Shang
    Keywords: small molecule drugs, long noncoding RNAs, network, pharmacological analysis, tissue-specificity
    Published in Aging on December 18, 2019
    Show abstract

    Schematic data flowchart of SMLN.



    The SMLN network. The rectangles and circles in the network correspond to small molecules and lncRNAs, respectively. A small molecule and a lncRNA are connected by an edge if the lncRNA differentially expressed when treated with this small molecule. Colors represent different lncRNA and small molecule classes.



    LncRNA expression values and functional characteristics. (A) Fold change value of lncRNAs affected by drugs; colors represent different ATC codes of drugs affected by the specific lncRNA. (B) Sub-network of LINC00667 and the related drugs: LINC00667 was always up-regulated after drug treatment. (C) Functional characteristics of LINC00667 by pathway enrichment with its co-expressed protein-coding genes.



    Pharmacological properties of connected drug pairs in the SSN. (A, left) 417 drug pairs with the same lncRNAs shared the same indications, compared with 1000 permutations. (A, right) Acetohexamide and gliclazide were connected to the same lncRNAs and they were all used for the treatment of diabetes. (B, left) 1066 drug pairs with the same lncRNAs shared the same drug targets, compared with 1000 permutations. (B, right) Minaprine and thioridazine shared the same lncRNA and both target the serotonin receptor 2A (HTR2A). (C, left) The proportion of shared side effects by drug pairs with the same lncRNAs (red), compared with the proportion of shared side effects among the total drug pairs in the SIDER database (blue). (C, right) Atovaquone and galantamine shared the same lncRNAs, although they belong to different categories, and could cause many of the same side effects. (D) Drug pairs with the same lncRNAs had higher TC scores.



    Drug-induced lncRNA modules and enriched KEGG pathways. (A) k=8. (B) k=9. (C) k=10. The K represents the number of the nodes in the modules.



    Tissue-specificity of drug-affected lncRNAs. (A) Jaccard coefficients of lncRNAs between 13 drug classes and tissues of 11 anatomical classes. (B) Jaccard coefficients of lncRNAs between 13 drug classes and 16 tissues. (C) Sub-network of the SMLN with drugs belonging to the (L) code and their affected lncRNAs.



  • Research Paper Volume 11, Issue 23 pp 11084-11110

    α-Mangostin remodels visceral adipose tissue inflammation to ameliorate age-related metabolic disorders in mice

    Relevance score: 4.795168
    Dan Li, Qianyu Liu, Xiuqiang Lu, Zhengqiu Li, Chunming Wang, Chung-Hang Leung, Yitao Wang, Cheng Peng, Ligen Lin
    Keywords: α-mangostin, aging, adiposity, adipose tissue inflammation, macrophage
    Published in Aging on December 6, 2019
    Show abstract

    α-Man ameliorates inflammatory responses in eWAT from LPS-treated mice. (A) The serum levels of IL-6, TNF-α and MCP-1 were determined by ELISA kits. (B) The levels of IL-6, TNF-α and MCP-1 in eWAT were determined by ELISA kits. (C) qRT-PCR analyses for pro-inflammatory cytokines expression in eWAT. (D) qRT-PCR analyses for chemokines in eWAT, including Mcp-1, Mip-1α, Cxcl10, Ccl11, Cx3cl1 and Ccl5. (E) qRT-PCR analyses for macrophage markers in eWAT, including F4/80, Cd68, Cd11c, Cd206 and Arg-1. Data are expressed as means ± SD (n = 5). ##P < 0.01, LPS vs. control, *P < 0.05, **P < 0.01, α-Man + LPS vs. LPS.



    α-Man blocks MAPKs and NF-κB pathways and activates SIRT3 in eWAT from LPS-treated mice. (A) The expression of iNOS and SIRT3 in eWAT were detected by Western blot analyses. (B) The expression of p-ERK, ERK, p-p38 and p38 were detected by Western blot. (C) The expression of p-IKKα/β, IKKα, IKKβ, p-IκBα, IκBα, p-p65 and p65 were detected by Western blot. α-Tubulin was used as an internal control. Data are expressed as means ± SD (n = 5). #P < 0.05 LPS vs. control, *P < 0.05, LPS + α-Man vs. LPS.



    Effects of α-Man in LPS stimulated SIRT3-knockdown RAW264.7 macrophages. (A) The protein expression of SIRT3 was determined by Western blot in LPS-induced RAW264.7 macrophages. α-Tubulin was used as an internal loading control. Data are normalized to the mean value of LPS group. (B) NO production was determined by Griess reagent. (C) iNOS abundance was measured by Western blot. α-Tubulin was used as an internal loading control. Data are normalized to the mean value of scrambled LPS group. The levels of IL-6 (D), TNF-α (E) and MCP-1 (F) were determined by ELISA kit. Data are shown as means ± SD (n = 5). ##P < 0.01, LPS vs. DMSO, **P < 0.01, α-Man + LPS vs. LPS, &P < 0.05, SIRT3KD LPS vs. scrambled LPS, $P < 0.05, $$P < 0.01, SIRT3KD α-Man vs. scrambled α-Man.



    α-Man ameliorates adiposity, insulin resistance, and hyperlipidemia in old mice. (A) The procedure of α-Man treatment in old mice. (B) Effect of α-Man on body weight in old mice. (C) The raw tissue weights and organ indexes for each group of mice. Fasting blood glucose (D), fasting insulin levels (E), and HOMA-IR (F) for each group of mice. (G) The levels of p-AKT and AKT in eWAT were detected by Western blots. β-Actin was used as internal loading control. (H) The levels of serum TC, TG, LDL-C, and HDL-C in serum was detected. Data are expressed as means ± SD (n = 5). #P < 0.05, ##P < 0.01, old mice vs. young mice. *P < 0.05, **P < 0.01, α-Man vs. old mice. Y, young mice; O, old mice; L, old mice administrated with 25 mg/kg α-Man; H, old mice administrated with 50 mg/kg α-Man.



    α-Man mitigates age-related adipose tissue inflammation. (A) H&E staining of eWAT (black scale bar = 50 μm, blue scale bar = 100 μm). (B) Whole-mount immunohistochemistry analysis of the nuclei (blue), perilipin (green), and F4/80 (red), scale bar = 75 μm. The CLSs are indicated by arrows (C) ATM subtypes were quantified as a percentage of the total ATMs population using flow cytometry. (D) qRT-PCR analyses for macrophage markers in eWAT, including F4/80, Cd68, Cd11c, and Cd206. (E) qRT-PCR analyses for chemokines in eWAT, including MCP-1, MIP-1α, Cx3cl1, and Ccl5. Data are normalized to the mean value of old group. Data are expressed as means ± SD (n = 5). #P < 0.05, ##P < 0.01, old mice vs. young mice, *P < 0.05, **P < 0.01, α-Man vs. old mice. Y, young mice; O, old mice; L, old mice administrated with 25 mg/kg α-Man; H, old mice administrated with 50 mg/kg α-Man.



    α-Man mitigates age-related adipose tissue inflammation through NF-κB and MAPKs pathways. (A) Relative mRNA levels of iNos, Il-1β and Tnf-α in eWAT were analyzed by qRT-PCR. (B) The protein levels of iNOS, COX-2 and SIRT3 in eWAT were detected by Western blot analyses and quantified using Image J. (C) The expression of p-IKKα/β, IKKα, IKKβ, p-IκBα, IκBα, p-p65 and p65 was detected by Western blot. (D) The expression of p-ERK, ERK, p-p38, p38, p-JNK and JNK were detected by Western blot. α-Tubulin was used as an internal control. Data are normalized to the mean value of old group. Data are expressed as means ± SD (n = 5). #P < 0.05, ##P < 0.01, old mice vs. young mice, *P < 0.05, **P < 0.01, α-Man vs. old mice. Y, young mice; O, old mice; L, old mice administrated with 25 mg/kg α-Man; H, old mice administrated with 50 mg/kg α-Man.



    α-Man alleviates liver injury in old mice by inhibiting miR155 expression. (A) The levels of TC, TG, LDL-C and HDL-C in livers (n = 5). (B) The levels of ALT and AST in livers (n = 5). (C) H&E staining and Masson’s trichrome staining of liver tissues, and histopathological scores of individual livers on portal inflammation and fibrosis. (n = 5). Black scale bar = 100 μm, red scale bar = 50 μm. Black arrows indicate sites of portal inflammation. 0 = no significant change, 1 = minimal, 2 = mild, 3 = moderate, and 4 = severe pathology. (D) The levels of p-AKT and AKT were detected by Western blot (n = 5). β-Actin was used as an internal loading control. (E) The expression level of miR-155 in the serum and eWAT from mice (n = 5). Data were normalized to level of U6 snRNA. Data are expressed as means ± SD. #P < 0.05, ##P < 0.01, old mice vs. young mice, *P < 0.05, **P < 0.01, α-Man vs. old mice. Y, young mice; O, old mice; L, old mice administrated with 25 mg/kg α-Man; H, old mice administrated with 50 mg/kg α-Man. (F) The expression level of miR-155 in LPS stimulated RAW264.7 macrophages and BMDMs (n = 6). Data were normalized to level of U6 snRNA. Data are expressed as means ± SD. ##P < 0.01, LPS vs. vehicle, **P < 0.01, α-Man + LPS vs. LPS.



    Schematic models of molecular targets of α-Man in attenuating visceral adipose tissue inflammation.



  • Research Paper Volume 11, Issue 22 pp 10116-10143

    The construction and analysis of tumor-infiltrating immune cell and ceRNA networks in recurrent soft tissue sarcoma

    Relevance score: 4.620806
    Runzhi Huang, Tong Meng, Rui Chen, Penghui Yan, Jie Zhang, Peng Hu, Xiaolong Zhu, Huabin Yin, Dianwen Song, Zongqiang Huang
    Keywords: soft tissue sarcoma, bone tumor, recurrence, ceRNA, immune cell, prognosis
    Published in Aging on November 18, 2019
    Show abstract

    The flow chart of the analysis process. Abbreviations: TCGA: The Cancer Genome Atlas; STS: Soft tissue sarcoma; GEO: Gene Expression Omnibus; CCLE: Cancer Cell Line Encyclopedia; GTEx: Genotype-Tissue Expression; UCSC: University of California, Santa Cruz.



    The differentially expressed genes between primary and recurrent STSs. (A) The heatmap and the volcano plot (B) of 178 differentially expressed genes between 259 primary and 3 recurrent STSs; (C) The volcano plot of 148 differentially expressed protein-coding genes between 259 primary and 3 recurrent STSs; The volcano Plot (D) of 21 differentially lncRNAs between 259 primary and 3 recurrent STSs; (E) The composition of differentially expressed genes. The log(fold-change) > 1.0 or < -1.0 and FDR < 0.05. Abbreviations: ceRNAs: competing endogenous RNAs; STSs: soft tissue sarcomas; LncRNA: long non-coding RNA.



    (A) The STS-recurrence related ceRNA network; The Kaplan-Meier survival curves of LPP-AS2 (B), MUC1 (C), hsa-let-7i-5p (D), hsa-let-7f-5p (E), hsa-miR-101-3p (F) and hsa-miR-1226-3p (G). Abbreviations: STSs: soft tissue sarcomas; ceRNAs: competing endogenous RNAs



    The results of the multivariate Cox regression, nomogram (E) and model diagnosis process (B, C, D, F) based on the key members in the ceRNA network. Seven potential prognosis-related ceRNAs were integrated into a new multivariable model. The results of the Lasso regression suggested that all seven genes were essential for modeling (A, B). The nomogram was constructed based on the model (D). The ROC and the calibration curves indicated acceptable accuracy (Area Under Curve (AUC) of 3-year survival: 0.731; AUC of 5-year survival: 0.724) and discrimination of the nomogram (C, E).



    The composition (A) and heatmap (B) of immune cells estimated by CIBERSORT algorithm in sarcomas. (C) The violin plot of immune cells (The blue and red bar stand for recurrent tumor group and primary tumor group, respectively). Abbreviations: CIBERSORT: Cell type identification by estimating relative subsets of RNA transcripts.



    The results of the multivariate Cox regression, Lasso regression (A, B), Kaplan–Meier survival curve of (D), nomogram (E) and model diagnosis process (C, F) based on prognosis related immune cells. All immune cells were integrated into an initial Cox regression model. After the screening process of the Lasso regression, the results suggested that the model was not overfitting (A, B). The nomogram based on the multivariable model (E). The calibration curve and the ROC demonstrated good discrimination and concordance of the nomogram (AUC of 3-year survival: 0.709; AUC of 5-year survival: 0.773) (C, F).



    The co-expression patterns among fractions of immune cells and key members in the ceRNA network. (A) co-expression heatmap of all immune cells; (B) co-expression heatmap of prognostic immune cells and key members of ceRNA network; (C) has-let-7i-5p was significantly associated with dendritic cells resting (R = 0.200, P = 0.003); (D) hsa-miR-1226-3p was significantly associated with dendritic cells resting (R = -0.190, P = 0.004).



    The expressions of MUC1 and CD11c proteins in primary/ recurrent leiomyosarcoma (LMS) (A, B) and liposarcoma (LPS) (C, D) specimens examined by immunohistochemistry (IHC) assay. The upper one is primary STS and under one is recurrent STS.



  • Research Paper Volume 11, Issue 20 pp 9128-9146

    Mesenchymal stem cell senescence alleviates their intrinsic and seno-suppressive paracrine properties contributing to osteoarthritis development

    Relevance score: 5.316716
    Olivier Malaise, Yassin Tachikart, Michael Constantinides, Marcus Mumme, Rosanna Ferreira-Lopez, Sandra Noack, Christian Krettek, Daniele Noël, Jing Wang, Christian Jorgensen, Jean-Marc Brondello
    Keywords: senescence, tissue homeostasis, osteoarthritis, mesenchymal stem cell
    Published in Aging on October 22, 2019
    Show abstract

    p16INK4a is involved in experimental collagen-induced osteoarthritis. Osteoarthritis (OA) was induced by collagenase intra-articular injection in the left knee (NaCl injection in the right knee for control) of 2-month-old C57BL/6JRj male mice. (A) Representative images of OA kinetic development after intra-articular collagenase injection showing synovial inflammation and osteophytosis (top panel) and focus on cartilage degradation (bottom panel). (B) Synovial inflammation quantification (synovitis semi-quantitative score; from 0 to 3) and cartilage degradation score (OA modified score according to van den Berg; from 0 to 30) were analyzed at day 14, 28 and 42 post-injection and compared with NaCl control at day 42. Data are the mean ± SEM (n=8), *=p<0.05, ***=p<0.001, ****=p<0.0001. (C) p16INK4a, IL-1β, IL-6 and MMP-13 mRNA expression levels in the synovial membrane after NaCl or collagenase injection, measured by RT-qPCR. Results were expressed as fold change compared with NaCl control at day 42. Graphs represent the mean ± SEM (n=8); *=p<0.05, **=p<0.01, ***=p<0.001. (D) Experimental design of p16INK4A expression analysis in Cdkn2a+/luc after OA induction. (E) Luminescence analysis in both knees with a CDD camera after intra-peritoneal and intra-articular Cyc-Luc injection. Values for the left knee (collagenase injection) were expressed as fold change relative to the right knee (control). Data are the mean ± SEM (day 14, n=13; day 24, n=6; day 35, n=6; day 42 n=8); *=p<0.05. (F) Representative image of luciferase signal in the left (CIOA) and right (NaCl) knee at day 24. (G) Experimental design of OA induction in Cdkn2a+/luc and Cdkn2aluc/luc mice. (H) Cartilage degradation score at day 42 after NaCl (control) or collagenase (CIOA) injection in 2-month-old Cdkn2a+/luc and Cdkn2aluc/luc mice. Data the mean ± SEM (n=8 and 11 respectively); *=p<0.05, ***=p<0.001.



    Senescence modulates MSCs intrinsic properties. (A) Beta-galactosidase staining in human MSCs at day 14 after DNA damaged-induced senescence (Senescent) or not (Proliferative). Data are the mean ± SEM (n=5); ****=p<0.0001. (B) Representative images of beta-galactosidase staining in proliferative and senescent human MSCs. (C) Proliferation rate (mean ± SEM) in proliferative and senescent human MSCs (n=6); ****=p<0.0001. (D) BrdU incorporation in proliferative and senescent human MSCs. BrdU-positive cells relative to all DAPI-positive cells were counted using an optical microscope (mean ± SEM; n=5). ****=p<0.0001. (E) Colony forming units in proliferative and senescent human MSCs (mean ± SEM; n=3); *=p<0.05. (F) p16INK4a and p21cdkn1a mRNA expression in human MSCs at day 14 after DNA damaged-induced senescence (Senescent) or not (Proliferative) by RT-qPCR. Data are the fold change relative to proliferative cells (mean ± SEM; n=4 for each condition); *=p<0.05. (G) p16INK4a, p21cdkn1a and p27KIP1 protein expression in human MSCs at day 14 after DNA damaged-induced senescence (Senescent) or not (Proliferative) by western blotting. Representative images of MSCs from n=3 independent donors. (H) Representative images of one cartilage pellet after chondrogenesis induction in proliferating and senescent human MSCs (from n=3). (I) Protein expression profiles of total cell extracts from senescent (bottom) and proliferating (top) human MSCs from three different healthy donors. The table showed the 13 proteins that were overexpressed in all three senescent MSC samples.



    Senescence modulates MSCs extrinsic properties in vitro. (A) Experimental design of the without-contact co-culture system to assess the effect of senescent human MSCs on chondrocytes from patients with OA. (B) Expression analysis by RT-qPCR in OA chondrocytes without co-culture (black columns; control), or co-cultured with proliferating MSCs (grey columns), or with senescent MSCs (white columns) for 7 days. Data are expressed as fold change relative to control (mean ± SEM of n=5); *=p<0.05, **=p<0.01.



    SAMP8 mice display a spontaneous OA phenotype. (A) Histo-morphometric analysis by micro-CT of the left knee in SAMR1 and SAMP8 mice. Graphs represent the mean ± SEM (n=8 for SAMR1, n=5 for SAMP8); **=p<0.01, ***=p<0.001. (B) Representative micro-CT images showing higher sub-chondral bone modification and (C) ligament calcifications in SAMP8 mice compared with SAMR1 mice. Knees from SAMR1 and SAMP8 mice were stained with Safranin-O/Fast Green to quantify: (D) spontaneous cartilage degradation (OA modified score according to van den Berg, from 0 to 30), (E) spontaneous synovial membrane inflammation (synovitis semi-quantitative score, from 0 to 3), and (F) osteophytes (osteophyte semi-quantitative score, from 0 to 3). Data are the mean ± SEM (n=5 for each condition). **=p<0.01. (G) Representative images of the spontaneous OA phenotype in SAMP8 mice with cartilage degradation compared with SAMR1 mice.



    Intra-articular injection of senescent MSCs induces OA-like cartilage degradation. (A) p16INK4A, p19ARF, p21cdkn1a, TGF-β, MMP-13, IL-1β and IL-6 mRNA expression in MSCs derived from bone marrow (BM) of 6-month-old SAMP8 or SAMR1 mice by RT-qPCR. Data are the mean ± SEM (n=3 for each conditions); *=p<0.05. (B) Beta-galactosidase staining in MSCs derived from BM of SAMP8 or SAMR1 mice. Data are the mean ± SEM (n=5); ****=p<0.0001. (C) Experimental design of BM-MSC injection in the knee of 2-month-old C57BL/6JRj mice. (D) Cartilage degradation (OA modified score according to van den Berg, from 0 to 30, after Safranin-O/Fast Green staining) at day 42 after SAMP8 or SAMR1 BM-MSC intra-articular injection. Data are the mean ± SEM (n = 5 for both conditions); *=p<0.05. (E) Representative images of cartilage degradation in a C57BL/6JRj mouse after SAMP8 or SAMR-1 BM-MSC injection. (F) Histo-morphometric analyses by micro-CT of the left knee (medial and lateral compartment) at day 42 after injection of SAMR1 or SAMP8 BM-MSCs. Data are the mean ± SEM (n = 5 for each condition).



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