bims-senagi Biomed News
on Senescence and aging
Issue of 2020–11–01
twenty-two papers selected by
Maria Grazia Vizioli, Mayo Clinic
  1. Epigenetics and Vascular Senescence-Potential New Therapeutic Targets?
  2. 6,4'-dihydroxy-7-methoxyflavanone protects against H2O2-induced cellular senescence by inducing SIRT1 and inhibiting phosphatidylinositol 3-kinase/Akt pathway activation.
  3. Mitochondrial Dysfunction Accelerates Ageing.
  4. Treating Senescence like Cancer: Novel Perspectives in Senotherapy of Chronic Diseases.
  5. Mastering organismal aging through the endoplasmic reticulum proteostasis network.
  6. Age-related cerebral small vessel disease and inflammaging.
  7. Herb-Derived Products: Natural Tools to Delay and Counteract Stem Cell Senescence.
  8. Aging, senescence and mitochondria: the PGC-1/ERR axis.
  9. Role of Post-Translational Modifications of cGAS in Innate Immunity.
  10. Systemic overexpression of C-C motif chemokine ligand 2 promotes metabolic dysregulation and premature death in mice with accelerated aging.
  11. γ- and δ-Tocotrienols interfere with senescence leading to decreased viability of cells.
  12. Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma.
  13. Short telomeres increase the risk of severe COVID-19.
  14. Protocol to Generate Senescent Cells from the Mouse Hepatic Cell Line AML12 to Study Hepatic Aging.
  15. ATM-Dependent Recruitment of BRD7 is required for Transcriptional Repression and DNA Repair at DNA Breaks Flanking Transcriptional Active Regions.
  16. Interleukin-6 knockout reverses macrophage differentiation imbalance and alleviates cardiac dysfunction in aging mice.
  17. mTOR-dependent translation amplifies microglia priming in aging mice.
  18. Genetic differences and longevity-related phenotypes influence lifespan and lifespan variation in a sex-specific manner in mice.
  19. Aging Atlas: a multi-omics database for aging biology.
  20. Regulatory coupling between long noncoding RNAs and senescence in irradiated microglia.
  21. Immunesenescence: A Predisposing Risk Factor for the Development of COVID-19?
  22. Histone methyltransferase SET8 is regulated by miR-192/215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells.
  1. Front Pharmacol. 2020 ;11 535395
    Epigenetics and Vascular Senescence-Potential New Therapeutic Targets?
    Qian Ding, Chunhong Shao, Peter Rose, Yi Zhun Zhu.
      Epigenetics is defined as the heritable alterations of gene expression without changes to the coding sequence of DNA. These alterations are mediated by processes including DNA methylation, histone modifications, and non-coding RNAs mechanisms. Vascular aging consists of both structural and functional changes in the vasculature including pathological processes that drive progression such as vascular cell senescence, inflammation, oxidation stress, and calcification. As humans age, these pathological conditions gradually accumulate, driven by epigenetic alterations, and are linked to various aging-related diseases. The development of drugs targeting a spectrum of epigenetic processes therefore offers novel treatment strategies for the targeting of age-related diseases. In our previous studies, we identified HDAC4, JMJD3, Fra-1, and GATA4 as potential pharmacological targets for regulating vascular inflammation, injury, and senescence.
    Keywords:  calcification; cell senescence; epigenetics; inflammation; oxidation stress; vascular aging
    DOI:  https://doi.org/10.3389/fphar.2020.535395
  2. Mol Cell Biochem. 2020 Oct 27.
    6,4'-dihydroxy-7-methoxyflavanone protects against H2O2-induced cellular senescence by inducing SIRT1 and inhibiting phosphatidylinositol 3-kinase/Akt pathway activation.
    Bing Si Li, Ri Zhe Zhu, Byung-Min Choi.
      6, 4'-Dihydroxy-7-methoxyflavanone (DMF) has been shown to possess anti-inflammatory, anti-oxidative, and neuroprotective activities. However, its effect on oxidative stress-induced aging remains undemonstrated. This study aimed at investigating the anti-senescence effect of DMF on hydrogen peroxide (H2O2)-induced premature senescence, and associated molecular mechanisms in human dermal fibroblasts (HDFs). The cells were DMF pretreated with small interfering RNA (siRNAs) of control or sirtuin 1 (SIRT1) before H2O2 exposure, and western blot analysis, senescence-associated β-galactosidase (SA-β-gal) activity, cell counting, gene silencing, and SIRT1 activity assay were performed. Pretreatment with DMF inhibited H2O2-induced senescence phenotypes, which showed decreased SA-β-gal activity and increased cell growth in comparison with H2O2-treated HDFs. Meanwhile, the decreases in ac-p53, p21Cip1/WAF1, and p16Ink4a and the increases in pRb and cyclin D1 were observed. DMF was also found to induce SIRT1 expression and activity level concentration- and time-dependently. Moreover, SIRT1 inhibition abrogated DMF senescence prevention. Additionally, Akt and ERK were activated with different kinetics after H2O2 exposure, and Akt activity inhibition attenuated SA-β-gal activity augmentation. We also found that DMF inhibited H2O2-induced Akt phosphorylation. This study indicates that DMF effectively protects against oxidative stress-induced premature senescence through SIRT1 expression up-regulation and Akt pathway inhibition in HDFs. These results suggest that DMF can be a potential therapeutic molecule for age-related diseases, or a protective agent against the aging process.
    Keywords:  6,4′-dihydroxy-7-methoxyflavanone; Akt; Oxidative stress; Premature senescence; SIRT1
    DOI:  https://doi.org/10.1007/s11010-020-03951-z
  3. Immunometabolism. 2020 Oct 16. 2(4): e200035
    Mitochondrial Dysfunction Accelerates Ageing.
    Johannes Schroth, Sian M Henson.
      We review here the seminal findings of Desdin-Mico et al. showing that T cells with dysfunctional mitochondria induce multimorbity and premature senescence, due to mitochondrial transcription factor A (TFAM). They add further weight to the idea that targeting immunometabolism could be beneficial in combating the detrimental effects of age-related disease.
    Keywords:  T cell; ageing; metabolism; mitochondria; senescence
    DOI:  https://doi.org/10.20900/immunometab20200035
  4. Int J Mol Sci. 2020 Oct 27. pii: E7984. [Epub ahead of print]21(21):
    Treating Senescence like Cancer: Novel Perspectives in Senotherapy of Chronic Diseases.
    Alessia Mongelli, Sandra Atlante, Veronica Barbi, Tiziana Bachetti, Fabio Martelli, Antonella Farsetti, Carlo Gaetano.
      The WHO estimated around 41 million deaths worldwide each year for age-related non-communicable chronic diseases. Hence, developing strategies to control the accumulation of cell senescence in living organisms and the overall aging process is an urgently needed problem of social relevance. During aging, many biological processes are altered, which globally induce the dysfunction of the whole organism. Cell senescence is one of the causes of this modification. Nowadays, several drugs approved for anticancer therapy have been repurposed to treat senescence, and others are under scrutiny in vitro and in vivo to establish their senomorphic or senolytic properties. In some cases, this research led to a significant increase in cell survival or to a prolonged lifespan in animal models, at least. Senomorphics can act to interfere with a specific pathway in order to restore the appropriate cellular function, preserve viability, and to prolong the lifespan. On the other hand, senolytics induce apoptosis in senescent cells allowing the remaining non-senescent population to preserve or restore tissue function. A large number of research articles and reviews recently addressed this topic. Herein, we would like to focus attention on those chemical agents with senomorphic or senolytic properties that perspectively, according to literature, suggest a potential application as senotherapeutics for chronic diseases.
    Keywords:  aging; apoptosis; chronic diseases; clinical trials; senescence; senolytics; senomorphics; senotherapeutics
    DOI:  https://doi.org/10.3390/ijms21217984
  5. Aging Cell. 2020 Oct 31. e13265
    Mastering organismal aging through the endoplasmic reticulum proteostasis network.
    Rebecca C Taylor, Claudio Hetz.
      The aging process is characterized by a progressive decline in the function of most tissues, representing the main risk factor in the development of a variety of human diseases. Studies in multiple animal models have demonstrated that interventions that improve the capacity to maintain endoplasmic reticulum (ER) proteostasis prolong life and healthspan. ER stress is monitored by the unfolded protein response (UPR), a signaling pathway that mediates adaptive processes to restore proteostasis or the elimination of damaged cells by apoptosis. Here, we discuss recent advances in understanding the significance of the UPR to aging and its implications for the maintenance of cell physiology of various cell types and organs. The possible benefits of targeting the UPR to extend healthspan and reduce the risk of developing age-related diseases are also discussed.
    Keywords:  ER stress; aging; autophagy; cell-nonautonomous; protein misfolding; proteostasis
    DOI:  https://doi.org/10.1111/acel.13265
  6. Cell Death Dis. 2020 Oct 30. 11(10): 932
    Age-related cerebral small vessel disease and inflammaging.
    Tiemei Li, Yinong Huang, Wei Cai, Xiaodong Chen, Xuejiao Men, Tingting Lu, Aiming Wu, Zhengqi Lu.
      The continued increase in global life expectancy predicts a rising prevalence of age-related cerebral small vessel diseases (CSVD), which requires a better understanding of the underlying molecular mechanisms. In recent years, the concept of "inflammaging" has attracted increasing attention. It refers to the chronic sterile low-grade inflammation in elderly organisms and is involved in the development of a variety of age-related chronic diseases. Inflammaging is a long-term result of chronic physiological stimulation of the immune system, and various cellular and molecular mechanisms (e.g., cellular senescence, immunosenescence, mitochondrial dysfunction, defective autophagy, metaflammation, gut microbiota dysbiosis) are involved. With the deepening understanding of the etiological basis of age-related CSVD, inflammaging is considered to play an important role in its occurrence and development. One of the most critical pathophysiological mechanisms of CSVD is endothelium dysfunction and subsequent blood-brain barrier (BBB) leakage, which gives a clue in the identification of the disease by detecting circulating biological markers of BBB disruption. The regional analysis showed blood markers of vascular inflammation are often associated with deep perforating arteriopathy (DPA), while blood markers of systemic inflammation appear to be associated with cerebral amyloid angiopathy (CAA). Here, we discuss recent findings in the pathophysiology of inflammaging and their effects on the development of age-related CSVD. Furthermore, we speculate the inflammaging as a potential target for future therapeutic interventions to delay or prevent the progression of the age-related CSVD.
    DOI:  https://doi.org/10.1038/s41419-020-03137-x
  7. Stem Cells Int. 2020 ;2020 8827038
    Herb-Derived Products: Natural Tools to Delay and Counteract Stem Cell Senescence.
    Provvidenza M Abruzzo, Silvia Canaider, Valeria Pizzuti, Luca Pampanella, Raffaella Casadei, Federica Facchin, Carlo Ventura.
      Cellular senescence plays a very important role in organismal aging increasing with age and in age-related diseases (ARDs). This process involves physiological, structural, biochemical, and molecular changes of cells, leading to a characteristic trait referred to "senescence-associated secretory phenotype (SASP)." In particular, with aging, stem cells (SCs) in situ exhibit a diminished capacity of self-renewal and show a decline in their functionality. The identification of interventions able to prevent the accumulation of senescent SCs in the organism or to pretreat cultured multipotent mesenchymal stromal cells (MSCs) prior to employing them for cell therapy is a main purpose of medical research. Many approaches have been investigated and resulted effective to prevent or counteract SC senescence in humans, as well as other animal models. In this work, we have reviewed the chance of using a number of herb-derived products as novel tools in the treatment of cell senescence, highlighting the efficacy of these agents, often still far from being clearly understood.
    DOI:  https://doi.org/10.1155/2020/8827038
  8. J Mol Endocrinol. 2020 Oct 01. pii: JME-20-0196.R1. [Epub ahead of print]
    Aging, senescence and mitochondria: the PGC-1/ERR axis.
    Vincent Giguere, Mathieu Vernier.
      Aging is a degenerative process that results from the accumulation of cellular and tissue lesions, leading progressively to organ dysfunction and death. Although the biological basis of human aging remains unclear, a large amount of data points to deregulated mitochondrial function as a central regulator of this process. Mounting years of research on aging support the notion that the engendered age-related decline of mitochondria is associated with alterations in key pathways that regulate mitochondrial biology. Particularly, several studies in the last decade have emphasized the importance of the estrogen-related receptor (ERR) family of nuclear receptors, master regulators of mitochondrial function, and their transcriptional coactivators PGC-1s in this context. In this review, we summarize key discoveries implicating the PGC-1/ERR axis in age-associated mitochondrial deregulation and tissue dysfunction. Also, we highlight the pharmacological potential of targeting the PGC-1/ERR axis to alleviate the onset of aging and its adverse effects.
    DOI:  https://doi.org/10.1530/JME-20-0196
  9. Int J Mol Sci. 2020 Oct 22. pii: E7842. [Epub ahead of print]21(21):
    Role of Post-Translational Modifications of cGAS in Innate Immunity.
    Yakun Wu, Shitao Li.
      Cyclic GMP-AMP synthase (cGAS) is the synthase that generates the second messenger cyclic GMP-AMP (cGAMP) upon DNA binding. cGAS was first discovered as the cytosolic DNA sensor that detects DNA exposed in the cytoplasm either from pathogens or cellular damage. Activated cGAS instigates the signaling cascades to activate type I interferon (IFN) expression, critical for host defense and autoimmune diseases. In addition, cGAS plays a role in senescence, DNA repair, apoptosis, and tumorigenesis. Recently, various post-translational modifications (PTMs) of cGAS have been reported, such as phosphorylation, ubiquitination, acetylation, glutamylation, and sumoylation. These PTMs profoundly affect cGAS functions. Thus, here we review the recent reported PTMs of cGAS and how these PTMs regulate cGAS enzymatic activity, DNA binding, and protein stability, and discuss the potential future directions.
    Keywords:  acetylation; cGAS; glutamylation; innate immunity; phosphorylation; post-translational modification; sumoylation; ubiquitination
    DOI:  https://doi.org/10.3390/ijms21217842
  10. Aging (Albany NY). 2020 Oct 26. 12
    Systemic overexpression of C-C motif chemokine ligand 2 promotes metabolic dysregulation and premature death in mice with accelerated aging.
    Fedra Luciano-Mateo, Noemí Cabré, Gerard Baiges-Gaya, Salvador Fernández-Arroyo, Anna Hernández-Aguilera, Elisabet Elisabet Rodríguez-Tomàs, Meritxell Arenas, Jordi Camps, Javier A Menéndez, Jorge Joven.
      Injection of tissues with senescent cells induces changes that mimic aging, and this process is delayed in mice engineered to eliminate senescent cells, which secrete proinflammatory cytokines, including C-C motif chemokine ligand 2 (Ccl2). Circulating levels of Ccl2 correlate with age, but the impact of Ccl2 on tissue homeostasis has not been established. We generated an experimental model by crossbreeding mice overexpressing Ccl2 with progeroid mice bearing a mutation in the lamin A (Lmna) gene. Wild-type animals and progeroid mice that do not overexpress Ccl2 were used as controls. Ccl2 overexpression decreased the lifespan of the progeroid mice and induced the dysregulation of glycolysis, the citric acid cycle and one-carbon metabolism in skeletal muscle, driving dynamic changes in energy metabolism and DNA methylation. This impact on cellular bioenergetics was associated with mitochondrial alterations and affected cellular metabolism, autophagy and protein synthesis through AMPK/mTOR pathways. The data revealed the ability of Ccl2 to promote death in mice with accelerated aging, which supports its putative use as a biomarker of an increased senescent cell burden and for the assessment of the efficacy of interventions aimed at extending healthy aging.
    Keywords:  C-C motif chemokine ligand 2; energy metabolism; one-carbon metabolism; progeria
    DOI:  https://doi.org/10.18632/aging.104154
  11. Mol Cell Biochem. 2020 Oct 30.
    γ- and δ-Tocotrienols interfere with senescence leading to decreased viability of cells.
    Maria Janubova, Jozef Hatok, Katarina Konarikova, Ingrid Zitnanova.
      Senescence is an irreversible permanent cell cycle arrest accompanied by changes in cell morphology and physiology. Bioactive compounds including tocotrienols (vitamin E) can affect important biological functions. The aim of this study was to investigate how γ- and δ-tocotrienols can affect stress-induced premature senescence. We established two different models of premature stress senescence by induction of senescence with either hydrogen peroxide or etoposide in human lung fibroblasts MRC-5 (ECACC, England). We observed increased percentage of cells with increased SA-β-galactosidase activity, decreased cell viability/proliferation and increased level of p21 in both models. In addition, γ-tocotrienol or δ-tocotrienol (both at concentrations of 150, 200 and 300 μM) were added to the cells along with the inductor of senescence (cotreatment). We have found that this cotreatment led to the decrease of cell viability/proliferation in both models of premature stress senescence, but did not change the percentage of senescent cells. Moreover, we detected no expression of caspase-3 or apoptotic DNA fragmentation in any models of premature stress senescence after the cotreatment with γ- as well as δ-tocotrienols. However, an increased level of autophagic protein LC-3 II was detected in cells with hydrogen peroxide-induced senescence after the cotreatment with γ-tocotrienol as well as δ-tocotrienol. In case of etoposide-induced senescence only δ-tocotrienol cotreatment led to an increased level of LC-3 II protein in cells. According to our work δ-tocotrienol is more effective compound than γ-tocotrienol.
    Keywords:  Apoptosis; Autophagy; Fibroblasts; MRC-5 cell line; Senescence; Tocotrienols
    DOI:  https://doi.org/10.1007/s11010-020-03954-w
  12. Cell Death Dis. 2020 Oct 28. 11(10): 925
    Metformin as a senostatic drug enhances the anticancer efficacy of CDK4/6 inhibitor in head and neck squamous cell carcinoma.
    Qinchao Hu, Jianmin Peng, Laibo Jiang, Wuguo Li, Qiao Su, Jiayu Zhang, Huan Li, Ming Song, Bin Cheng, Juan Xia, Tong Wu.
      CDK4/6 inhibitors show promising antitumor activity in a variety of solid tumors; however, their role in head and neck squamous cell carcinoma (HNSCC) requires further investigation. The senescence-associated secretory phenotype (SASP) induced by CDK4/6 inhibitors has dual effects on cancer treatment. The need to address the SASP is a serious challenge in the clinical application of CDK4/6 inhibitors. We investigated whether metformin can act as a senostatic drug to modulate the SASP and enhance the anticancer efficacy of CDK4/6 inhibitors in HNSCC. In this study, the efficacy of a combination of the CDK4/6 inhibitor LY2835219 and metformin in HNSCC was investigated in in vitro assays, an HSC6 xenograft model, and a patient-derived xenograft model. Senescence-associated β-galactosidase staining, antibody array, sphere-forming assay, and in vivo tumorigenesis assay were used to detect the impacts of metformin on the senescence and SASP induced by LY2835219. We found that LY2835219 combined with metformin synergistically inhibited HNSCC by inducing cell cycle arrest in vitro and in vivo. Metformin significantly modulated the profiles of the SASP elicited by LY2835219 by inhibiting the mTOR and stat3 pathways. The LY2835219-induced SASP resulted in upregulation of cancer stemness, while this phenomenon can be attenuated when combined with metformin. Furthermore, results showed that the stemness inhibition by metformin was associated with blockade of the IL6-stat3 axis. Survival analysis demonstrated that overexpression of IL6 and stemness markers was associated with poor survival in HNSCC patients, indicating that including metformin to target these proteins might improve patient prognosis. Collectively, our data suggest that metformin can act as a senostatic drug to enhance the anticancer efficacy of CDK4/6 inhibitors by reprogramming the profiles of the SASP.
    DOI:  https://doi.org/10.1038/s41419-020-03126-0
  13. Aging (Albany NY). 2020 Oct 26. 12
    Short telomeres increase the risk of severe COVID-19.
    Antoine Froidure, Manon Mahieu, Delphine Hoton, Pierre-François Laterre, Jean Cyr Yombi, Sandra Koenig, Benoit Ghaye, Jean-Philippe Defour, Anabelle Decottignies.
      Telomeres are non-coding DNA sequences that protect chromosome ends and shorten with age. Short telomere length (TL) is associated with chronic diseases and immunosenescence. The main risk factor for mortality of coronavirus disease 2019 (COVID-19) is older age, but outcome is very heterogeneous among individuals of the same age group. Therefore, we hypothesized that TL influences COVID-19-related outcomes. In a prospective study, we measured TL by Flow-FISH in 70 hospitalized COVID-19 patients and compared TL distribution with our reference cohort of 491 healthy volunteers. We also correlated TL with baseline clinical and biological parameters. We stained autopsy lung tissue from six non-survivor COVID-19 patients to detect senescence-associated β-galactosidase activity, a marker of cellular aging. We found a significantly higher proportion of patients with short telomeres (<10th percentile) in the COVID-19 patients as compared to the reference cohort (P<0.001). Short telomeres were associated with a higher risk of critical disease, defined as admission to intensive care unit (ICU) or death without ICU. TL was negatively correlated with C-reactive protein and neutrophil-to-lymphocyte ratio. Finally, lung tissue from patients with very short telomeres exhibit signs of senescence in structural and immune cells. Our results suggest that TL influences the severity of the disease.
    Keywords:  COVID-19; telomere length
    DOI:  https://doi.org/10.18632/aging.104097
  14. STAR Protoc. 2020 Sep 18. 1(2): 100064
    Protocol to Generate Senescent Cells from the Mouse Hepatic Cell Line AML12 to Study Hepatic Aging.
    Madhulika Tripathi, Paul Michael Yen, Brijesh Kumar Singh.
      Previously developed senescent primary fibroblast models have limited relevance to study age-related changes in metabolically active tissues such as the liver. Here, we describe a protocol to generate senescent cells from the mouse hepatic cell line, AML12. These senescent cells exhibit molecular and metabolic signatures that are similar to those observed in livers from aged mice. These senescent AML12 cells should be a useful in vitro model to study the metabolic effects of aging in the liver. For complete details on the use and execution of this protocol, please refer to Singh et al. (2020).
    DOI:  https://doi.org/10.1016/j.xpro.2020.100064
  15. Adv Sci (Weinh). 2020 Oct;7(20): 2000157
    ATM-Dependent Recruitment of BRD7 is required for Transcriptional Repression and DNA Repair at DNA Breaks Flanking Transcriptional Active Regions.
    Kaishun Hu, Yu Li, Wenjing Wu, Limin Xie, Haiyan Yan, Yuexin Cai, Dong Chen, Qiongchao Jiang, Lehang Lin, Zhen Chen, Jian-You Liao, Yin Zhang, H Phillip Koeffler, Dong Yin, Erwei Song.
      Repair of DNA double-strand breaks (DSBs) is essential for genome integrity, and is accompanied by transcriptional repression at the DSB regions. However, the mechanisms how DNA repair induces transcriptional inhibition remain elusive. Here, it is identified that BRD7 participates in DNA damage response (DDR) and is recruited to the damaged chromatin via ATM signaling. Mechanistically, BRD7 joins the polycomb repressive complex 2 (PRC2), the nucleosome remodeling and histone deacetylation (NuRD) complex at the damaged DNA and recruits E3 ubiquitin ligase RNF168 to the DSBs. Furthermore, ATM-mediated BRD7 phosphorylation is required for recruitment of the PRC2 complex, NuRD complex, DSB sensor complex MRE11-RAD50-NBS1 (MRN), and RNF168 to the active transcription sites at DSBs, resulting in transcriptional repression and DNA repair. Moreover, BRD7 deficiency sensitizes cancer cells to PARP inhibition. Collectively, BRD7 is crucial for DNA repair and DDR-mediated transcription repression, which may serve as a therapeutic target. The findings identify the missing link between DNA repair and transcription regulation that maintains genome integrity.
    Keywords:  ATM; BRD7; NuRD; PRC2; transcriptional repression
    DOI:  https://doi.org/10.1002/advs.202000157
  16. Aging (Albany NY). 2020 Oct 25. 12
    Interleukin-6 knockout reverses macrophage differentiation imbalance and alleviates cardiac dysfunction in aging mice.
    Yuan Wang, Shan Zhu, Wen Wei, Yi Tu, Chuang Chen, Junlong Song, Juanjuan Li, Changhua Wang, Zhiliang Xu, Shengrong Sun.
      Several interleukins (ILs) have been shown to be involved in aging, but the effects of IL-6 on aging-related cardiac dysfunction remain unknown. In this study, the expression and sources of cardiac IL-6 in aging hearts were investigated for the first time. The results showed that cardiac IL-6 expression in mice gradually increased with age, and the expression at 16 months, 20 months and 25 months was higher than that at 3 months. In addition, cardiac macrophages (Møs) were shown to be the main sources of IL-6 in aging mice. IL-6 knockout (KO) significantly alleviated cardiac dysfunction, increased M2 macrophage (Mø2) differentiation, reduced M1 macrophage (Mø1) differentiation and protected against cardiomyocyte apoptosis in aging mice. IL-6 KO also reversed the stimulatory effect of doxorubicin (DOX) treatment on Mø1s and the inhibitory effect of DOX treatment on Mø2s in vitro. Furthermore, the mRNA expression of both aging markers and apoptosis-related markers was markedly inhibited by IL-6 KO. Our results suggest that aging can be significantly reversed by IL-6 KO and that the mechanisms of this effect are related to alleviation of Mø1/Mø2 imbalance and protection against apoptosis in cardiomyocytes.
    Keywords:  aging; cardiac dysfunction; cardiomyocyte apoptosis; interleukin-6; macrophages differentiation
    DOI:  https://doi.org/10.18632/aging.103749
  17. J Clin Invest. 2020 Oct 27. pii: 132727. [Epub ahead of print]
    mTOR-dependent translation amplifies microglia priming in aging mice.
    Lily Keane, Ignazio Antignano, Sean-Patrick Riechers, Raphael Zollinger, Anaelle A Dumas, Nina Offermann, Maria E Bernis, Jenny Russ, Frederike J Graelmann, Patrick N McCormick, Julia Esser, Dario Tejera, Ai Nagano, Jun Wang, Claude Chelala, Yvonne Biederbick, Annett Halle, Paolo Salomoni, Michael Thomas Heneka, Melania Capasso.
      Microglia maintain homeostasis in the brain. However, with age, they become primed and respond more strongly to inflammatory stimuli. We show here that microglia from aged mice upregulated mammalian target of rapamycin (mTOR) complex 1 signaling regulating translation, as well as protein levels of inflammatory mediators. Genetic ablation of mTOR signaling showed a dual, yet contrasting effect on microglia priming: it caused an NF-kB-dependent upregulation of priming genes at mRNA level; however, mice displayed reduced cytokine protein levels, diminished microglia activation and milder sickness behavior. The effect on translation was dependent on reduced phosphorylation of 4EBP1, resulting in decreased binding of eIF4E to eIF4G. Similar changes were present in aged human microglia and in damage-associated microglia, indicating upregulation of mTOR-dependent translation is an essential step licensing microglia priming in aging and neurodegeneration.
    Keywords:  Aging; Cytokines; Inflammation; Macrophages; Translation
    DOI:  https://doi.org/10.1172/JCI132727
  18. Aging Cell. 2020 Oct 26. e13263
    Genetic differences and longevity-related phenotypes influence lifespan and lifespan variation in a sex-specific manner in mice.
    Rong Yuan, C J M Musters, Yun Zhu, Tracy R Evans, Yujie Sun, Elissa J Chesler, Luanne L Peters, David E Harrison, Andrzej Bartke.
      Epidemiological studies of human longevity found two interesting features, robust advantage of female lifespan and consistent reduction of lifespan variation. To help understand the genetic aspects of these phenomena, the current study examined sex differences and variation of longevity using previously published mouse data sets including data on lifespan, age of puberty, and circulating insulin-like growth factor 1 (IGF1) levels in 31 inbred strains, data from colonies of nuclear-receptor-interacting protein 1 (Nrip1) knockout mice, and a congenic strain, B6.C3H-Igf1. Looking at the overall data for all inbred strains, the results show no significant difference in lifespan and lifespan variation between sexes; however, considerable differences were found among and within strains. Across strains, lifespan variations of female and male mice are significantly correlated. Strikingly, between sexes, IGF1 levels correlate with the lifespan variation and maximum lifespan in different directions. Female mice with low IGF1 levels have higher variation and extended maximum lifespan. The opposite is detected in males. Compared to domesticated inbred strains, wild-derived inbred strains have elevated lifespan variation due to increased early deaths in both sexes and extended maximum lifespan in female mice. Intriguingly, the sex differences in survival curves of inbred strains negatively associated with age of female puberty, which is significantly accelerated in domesticated inbred strains compared to wild-derived strains. In conclusion, this study suggests that genetic factors are involved in the regulation of sexual disparities in lifespan and lifespan variation, and dissecting the mouse genome may provide novel insight into the underlying genetic mechanisms.
    DOI:  https://doi.org/10.1111/acel.13263
  19. Nucleic Acids Res. 2020 Oct 29. pii: gkaa894. [Epub ahead of print]
    Aging Atlas: a multi-omics database for aging biology.
    Aging Atlas Consortium
      Organismal aging is driven by interconnected molecular changes encompassing internal and extracellular factors. Combinational analysis of high-throughput 'multi-omics' datasets (gathering information from genomics, epigenomics, transcriptomics, proteomics, metabolomics and pharmacogenomics), at either populational or single-cell levels, can provide a multi-dimensional, integrated profile of the heterogeneous aging process with unprecedented throughput and detail. These new strategies allow for the exploration of the molecular profile and regulatory status of gene expression during aging, and in turn, facilitate the development of new aging interventions. With a continually growing volume of valuable aging-related data, it is necessary to establish an open and integrated database to support a wide spectrum of aging research. The Aging Atlas database aims to provide a wide range of life science researchers with valuable resources that allow access to a large-scale of gene expression and regulation datasets created by various high-throughput omics technologies. The current implementation includes five modules: transcriptomics (RNA-seq), single-cell transcriptomics (scRNA-seq), epigenomics (ChIP-seq), proteomics (protein-protein interaction), and pharmacogenomics (geroprotective compounds). Aging Atlas provides user-friendly functionalities to explore age-related changes in gene expression, as well as raw data download services. Aging Atlas is freely available at https://bigd.big.ac.cn/aging/index.
    DOI:  https://doi.org/10.1093/nar/gkaa894
  20. J Neuroinflammation. 2020 Oct 28. 17(1): 321
    Regulatory coupling between long noncoding RNAs and senescence in irradiated microglia.
    Anan Xu, Rong Li, Anbang Ren, Haifeng Jian, Zhong Huang, Qingxing Zeng, Baiyao Wang, Jieling Zheng, Xiaoyu Chen, Naiying Zheng, Ronghui Zheng, Yunhong Tian, Mengzhong Liu, Zixu Mao, Aimin Ji, Yawei Yuan.
       BACKGROUND: Microglia have been implicated in the pathogenesis of radiation-induced brain injury (RIBI), which severely influences the quality of life during long-term survival. Recently, irradiated microglia were speculated to present an aging-like phenotype. Long noncoding RNAs (lncRNAs) have been recognized to regulate a wide spectrum of biological processes, including senescence; however, their potential role in irradiated microglia remains largely uncharacterized.
    METHODS: We used bioinformatics and experimental methods to identify and analyze the senescence phenotype of irradiated microglia. Western blotting, enzyme-linked immunosorbent assays, immunofluorescence, and quantitative real-time reverse transcription-polymerase chain reaction were performed to clarify the relationship between the radiation-induced differentially expressed lncRNAs (RILs) and the distinctive molecular features of senescence in irradiated microglia.
    RESULTS: We found that the senescence of microglia could be induced using ionizing radiation (IR). A mutual regulation mode existed between RILs and three main features of the senescence phenotype in irradiated microglia: inflammation, the DNA damage response (DDR), and metabolism. Specifically, for inflammation, the expression of two selected RILs (ENSMUST00000190863 and ENSMUST00000130679) was dependent on the major inflammatory signaling pathways of nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK). The two RILs modulated the activation of NF-κB/MAPK signaling and subsequent inflammatory cytokine secretion. For the DDR, differential severity of DNA damage altered the expression profiles of RILs. The selected RIL, ENSMUST00000130679, promoted the DDR. For metabolism, blockade of sterol regulatory element-binding protein-mediated lipogenesis attenuated the fold-change of several RILs induced by IR.
    CONCLUSIONS: Our findings revealed that certain RILs interacted with senescence in irradiated microglia. RILs actively participated in the regulation of senescence features, suggesting that RILs could be promising intervention targets to treat RIBI.
    Keywords:  DNA damage response; Inflammation; LncRNA; Metabolism; Microglia; Radiation; Senescence
    DOI:  https://doi.org/10.1186/s12974-020-02001-1
  21. Front Immunol. 2020 ;11 573662
    Immunesenescence: A Predisposing Risk Factor for the Development of COVID-19?
    Jon Hazeldine, Janet M Lord.
      Bearing a strong resemblance to the phenotypic and functional remodeling of the immune system that occurs during aging (termed immunesenescence), the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease 2019 (COVID-19), is characterized by an expansion of inflammatory monocytes, functional exhaustion of lymphocytes, dysregulated myeloid responses and the presence of highly activated senescent T cells. Alongside advanced age, male gender and pre-existing co-morbidities [e.g., obesity and type 2 diabetes (T2D)] are emerging as significant risk factors for COVID-19. Interestingly, immunesenescence is more profound in males when compared to females, whilst accelerated aging of the immune system, termed premature immunesenescence, has been described in obese subjects and T2D patients. Thus, as three distinct demographic groups with an increased susceptibility to COVID-19 share a common immune profile, could immunesenescence be a generic contributory factor in the development of severe COVID-19? Here, by focussing on three key aspects of an immune response, namely pathogen recognition, elimination and resolution, we address this question by discussing how immunesenescence may weaken or exacerbate the immune response to SARS-CoV-2. We also highlight how aspects of immunesenescence could render potential COVID-19 treatments less effective in older adults and draw attention to certain therapeutic options, which by reversing or circumventing certain features of immunesenescence may prove to be beneficial for the treatment of groups at high risk of severe COVID-19.
    Keywords:  COVID-19; SARS-Cov_2; aging; immune dysfunction; immunesenescence; inflammaging
    DOI:  https://doi.org/10.3389/fimmu.2020.573662
  22. Cell Death Dis. 2020 Oct 30. 11(10): 937
    Histone methyltransferase SET8 is regulated by miR-192/215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells.
    Xiaojing Zhang, Yin Peng, Yuan Yuan, Yuli Gao, Fan Hu, Jian Wang, Xiaohui Zhu, Xianling Feng, Yulan Cheng, Yanjie Wei, Xinmin Fan, Yaohong Xie, Yansi Lv, Hassan Ashktorab, Duane Smoot, Song Li, Stephen J Meltzer, Gangqiang Hou, Zhe Jin.
      Gastric cancer (GC) is the most common cancer throughout the world. Despite advances of the treatments, detailed oncogenic mechanisms are largely unknown. In our previous study, we investigated microRNA (miR) expression profiles in human GC using miR microarrays. We found miR-192/215 were upregulated in GC tissues. Then gene microarray was implemented to discover the targets of miR-192/215. We compared the expression profile of BGC823 cells transfected with miR-192/215 inhibitors, and HFE145 cells transfected with miR-192/-215 mimics, respectively. SET8 was identified as a proposed target based on the expression change of more than twofold. SET8 belongs to the SET domain-containing methyltransferase family and specifically catalyzes monomethylation of H4K20me. It is involved in diverse functions in tumorigenesis and metastasis. Therefore, we focused on the contributions of miR-192/215/SET8 axis to the development of GC. In this study, we observe that functionally, SET8 regulated by miR-192/215 is involved in GC-related biological activities. SET8 is also found to trigger oncogene-induced senescence (OIS) in GC in vivo and in vitro, which is dependent on the DDR (DNA damage response) and p53. Our findings reveal that SET8 functions as a negative regulator of metastasis via the OIS-signaling pathway. Taken together, we investigated the functional significance, molecular mechanisms, and clinical impact of miR-192/215/SET8/p53 in GC.
    DOI:  https://doi.org/10.1038/s41419-020-03130-4
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