bims-senagi Biomed News
on Senescence and aging
Issue of 2020–09–06
27 papers selected by
Maria Grazia Vizioli, Mayo Clinic
  1. Heterochromatin: an epigenetic point of view in aging.
  2. Cellular Senescence: A New Player in Kidney Injury.
  3. The Aged Microenvironment of Melanoma Feeds Escape from Targeted Therapy.
  4. Similar burden of pathogenic coding variants in exceptionally long-lived individuals and individuals without exceptional longevity.
  5. Time-dependent replicative senescence vs. disturbed flow-induced pre-mature aging in atherosclerosis.
  6. COVID-19 and Priorities for Research in Aging.
  7. The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.
  8. The sex chromosomes of the aging epigenome.
  9. Senescence Induction by Combined Ionizing Radiation and DNA Damage Response Inhibitors in Head and Neck Squamous Cell Carcinoma Cells.
  10. AMPK alleviates oxidative stress‑induced premature senescence via inhibition of NF-κB/STAT3 axis-mediated positive feedback loop.
  11. Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice.
  12. Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture.
  13. Senescent hepatic stellate cells caused by deoxycholic acid modulates malignant behavior of hepatocellular carcinoma.
  14. Transcriptional upregulation of proteasome activator Blm10 antagonizes cellular aging.
  15. Alpha-Ketoglutarate, the Metabolite that Regulates Aging in Mice.
  16. Study aging by fibroblasts metabolome.
  17. Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer's Dementia.
  18. Neuron-specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice.
  19. Break-induced replication promotes fragile telomere formation.
  20. Short-term calorie restriction enhances DNA repair by non-homologous end joining in mice.
  21. Aging impairs alveolar epithelial type II cell function in acute lung injury.
  22. Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence.
  23. Circular ANRIL isoforms switch from repressors to activators of p15/CDKN2B expression during RAF1 oncogene-induced senescence.
  24. Is inflammageing influenced by the microbiota in the aged gut? A systematic review.
  25. Mechanisms of NLRP3 priming in inflammaging and age related diseases.
  26. Loss of RAD6B induces degeneration of the cochlea in mice.
  27. A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology.
  1. Exp Mol Med. 2020 Sep 04.
    Heterochromatin: an epigenetic point of view in aging.
    Jong-Hyuk Lee, Edward W Kim, Deborah L Croteau, Vilhelm A Bohr.
      Aging is an inevitable process of life. Defined by progressive physiological and functional loss of tissues and organs, aging increases the risk of mortality for the organism. The aging process is affected by various factors, including genetic and epigenetic ones. Here, we review the chromatin-specific epigenetic changes that occur during normal (chronological) aging and in premature aging diseases. Taking advantage of the reversible nature of epigenetic modifications, we will also discuss possible lifespan expansion strategies through epigenetic modulation, which was considered irreversible until recently.
    DOI:  https://doi.org/10.1038/s12276-020-00497-4
  2. Hypertension. 2020 Aug 31. HYPERTENSIONAHA12014594
    Cellular Senescence: A New Player in Kidney Injury.
    Yongxin Li, Lilach O Lerman.
      Kidney diseases secondary to several pathogeneses affect millions of people worldwide and have become increasingly recognized as a global public health problem. Recent evidence suggests that cellular senescence plays an important role in the pathogenesis of different forms of renal damage, including acute and chronic kidney disease, and renal transplantation. Renal senescence involves cell cycle arrest and affects several cellular pathways, manifesting in downregulation of klotho, elevated expression of cyclin-dependent kinase inhibitors, cellular telomere shortening, and oxidative stress. Furthermore, senescent cells might induce kidney injury by paracrine release of inflammatory factors. Yet, cellular senescence may be renoprotective during development and in some models of renal diseases, reflecting the yin/yang duality of cellular senescence. This review provides an overview of the role of this emerging player in renal injury, with emphasis on new findings of cellular senescence.
    Keywords:  acute kidney injury; aging; kidney; public health; renal insufficiency, chronic
    DOI:  https://doi.org/10.1161/HYPERTENSIONAHA.120.14594
  3. Cancer Discov. 2020 Sep;10(9): 1255-1257
    The Aged Microenvironment of Melanoma Feeds Escape from Targeted Therapy.
    Emily D Montal, Richard M White.
      Alicea and colleagues demonstrate that aged fibroblasts secrete lipids into the tumor microenvironment, allowing for nutrient exchange with melanoma cells. This supportive function of fibroblasts results in increased resistance to BRAF/MEKi therapy in the context of an aged microenvironment, providing crucial mechanistic insight into age-related drug resistance.See related article by Alicea et al., p. 1282.
    DOI:  https://doi.org/10.1158/2159-8290.CD-20-0949
  4. Aging Cell. 2020 Aug 29. e13216
    Similar burden of pathogenic coding variants in exceptionally long-lived individuals and individuals without exceptional longevity.
    Regeneron Genetics Center
      Centenarians (exceptionally long-lived individuals-ELLI) are a unique segment of the population, exhibiting long human lifespan and healthspan, despite generally practicing similar lifestyle habits as their peers. We tested disease-associated mutation burden in ELLI genomes by determining the burden of pathogenic variants reported in the ClinVar and HGMD databases using data from whole exome sequencing (WES) conducted in a cohort of ELLI, their offspring, and control individuals without antecedents of familial longevity (n = 1879), all descendent from the founder population of Ashkenazi Jews. The burden of pathogenic variants did not differ between the three groups. Additional analyses of variants subtypes and variant effect predictor (VEP) biotype frequencies did not reveal a decrease of pathogenic or loss-of-function (LoF) variants in ELLI and offspring compared to the control group. Case-control pathogenic variants enrichment analyses conducted in ELLI and controls also did not identify significant differences in any of the variants between the groups and polygenic risk scores failed to provide a predictive model. Interestingly, cancer and Alzheimer's disease-associated variants were significantly depleted in ELLI compared to controls, suggesting slower accumulation of mutation. That said, polygenic risk score analysis failed to find any predictive variants among the functional variants tested. The high similarity in the burden of pathogenic variation between ELLI and individuals without familial longevity supports the notion that extension of lifespan and healthspan in ELLI is not a consequence of pathogenic variant depletion but rather a result of other genomic, epigenomic, or potentially nongenomic properties.
    DOI:  https://doi.org/10.1111/acel.13216
  5. Redox Biol. 2020 Jun 24. pii: S2213-2317(20)30819-3. [Epub ahead of print] 101614
    Time-dependent replicative senescence vs. disturbed flow-induced pre-mature aging in atherosclerosis.
    Abishai Dominic, Priyanka Banerjee, Dale J Hamilton, Nhat-Tu Le, Jun-Ichi Abe.
      Accumulation of senescent cells has a causative role in the pathology of age-related disorders including atherosclerosis (AS) and cardiovascular diseases (CVDs). However, the concept of senescence is now drastically changing, and the new concept of senescence-associated reprogramming/stemness has emerged, suggesting that senescence is not merely related to "cell cycle arrest" or halting various cellular functions. It is well known that disturbed flow (D-flow) accelerates pre-mature aging and plays a significant role in the development of AS. We will discuss in this review that pre-mature aging induced by D-flow is not comparable to time-dependent aging, particularly with a focus on the possible involvement of senescence-associated secretory phenotype (SASP) in senescence-associated reprogramming/stemness, or increasing cell numbers. We will also present our outlook of nicotinamide adenine dinucleotides (NAD)+ deficiency-induced mitochondrial reactive oxygen species (mtROS) in evoking SASP by activating DNA damage response (DDR). MtROS plays a key role in developing cross-talk between nuclear-mitochondria, SASP, and ultimately atherosclerosis formation. Although senescence induced by time and various stress factors is a classical concept, we wish that the readers will see the undergoing Copernican-like change in this concept, as well as to recognize the significant contrast between pre-mature aging induced by D-flow and time-dependent aging.
    Keywords:  Aging; Atherosclerosis; Oxidative stress; Senescence; Senescent-associated stemness; Telomere shortening
    DOI:  https://doi.org/10.1016/j.redox.2020.101614
  6. Can J Aging. 2020 Sep 02. 1-14
    COVID-19 and Priorities for Research in Aging.
    R Jane Rylett, Flamine Alary, Joanne Goldberg, Susan Rogers, Patricia Versteegh.
      
    DOI:  https://doi.org/10.1017/S0714980820000331
  7. Nature. 2020 Sep 02.
    The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer's disease.
    Ji-Yeun Hur, Georgia R Frost, Xianzhong Wu, Christina Crump, Si Jia Pan, Eitan Wong, Marilia Barros, Thomas Li, Pengju Nie, Yujia Zhai, Jen Chyong Wang, Julia Tcw, Lei Guo, Andrew McKenzie, Chen Ming, Xianxiao Zhou, Minghui Wang, Yotam Sagi, Alan E Renton, Bianca T Esposito, Yong Kim, Katherine R Sadleir, Ivy Trinh, Robert A Rissman, Robert Vassar, Bin Zhang, Douglas S Johnson, Eliezer Masliah, Paul Greengard, Alison Goate, Yue-Ming Li.
      Innate immunity is associated with Alzheimer's disease1, but the influence of immune activation on the production of amyloid-β is unknown2,3. Here we identify interferon-induced transmembrane protein 3 (IFITM3) as a γ-secretase modulatory protein, and establish a mechanism by which inflammation affects the generation of amyloid-β. Inflammatory cytokines induce the expression of IFITM3 in neurons and astrocytes, which binds to γ-secretase and upregulates its activity, thereby increasing the production of amyloid-β. The expression of IFITM3 is increased with ageing and in mouse models that express familial Alzheimer's disease genes. Furthermore, knockout of IFITM3 reduces γ-secretase activity and the formation of amyloid plaques in a transgenic mouse model (5xFAD) of early amyloid deposition. IFITM3 protein is upregulated in tissue samples from a subset of patients with late-onset Alzheimer's disease that exhibit higher γ-secretase activity. The amount of IFITM3 in the γ-secretase complex has a strong and positive correlation with γ-secretase activity in samples from patients with late-onset Alzheimer's disease. These findings reveal a mechanism in which γ-secretase is modulated by neuroinflammation via IFITM3 and the risk of Alzheimer's disease is thereby increased.
    DOI:  https://doi.org/10.1038/s41586-020-2681-2
  8. Aging (Albany NY). 2020 Aug 30.
    The sex chromosomes of the aging epigenome.
    Qihua Tan.
      
    Keywords:  DNA methylation; X-chromosome inactivation; aging; epigenetics; sex chromosomes
    DOI:  https://doi.org/10.18632/aging.104033
  9. Cells. 2020 Sep 01. pii: E2012. [Epub ahead of print]9(9):
    Senescence Induction by Combined Ionizing Radiation and DNA Damage Response Inhibitors in Head and Neck Squamous Cell Carcinoma Cells.
    Clara Dobler, Tina Jost, Markus Hecht, Rainer Fietkau, Luitpold Distel.
      DNA damage response inhibitors (DDRi) may selectively enhance the inactivation of tumor cells in combination with ionizing radiation (IR). The induction of senescence may be the key mechanism of tumor cell inactivation in this combinatorial treatment. In the current study the effect of combined IR with DDRi on the induction of senescence was studied in head and neck squamous cell carcinoma (HNSCC) cells with different human papilloma virus (HPV) status. The integrity of homologous recombination (HR) was assessed in two HPV positive, two HPV negative HNSCC, and two healthy fibroblast cell cultures. Cells were treated with the DDRi CC-115 (DNA-dependent protein kinase, DNA-pK; dual mammalian target of rapamycin, mTor), VE-822 (ATR; ataxia telangiectasia and Rad3-related kinase), and AZD0156 (ATM; ataxia telangiectasia mutated kinase) combined with IR. Effects on senescence, apoptosis, necrosis, and cell cycle were analyzed by flow cytometry. The fibroblast cell lines generally tolerated IR or combined treatment better than the tumor cell lines. The ATM and ATR inhibitors were effectively inducing senescence when combined with IR. The DNA-PK inhibitor was not an important inductor of senescence. HPV status and HR activity had a limited influence on the efficacy of DDRi. Induction of senescence and necrosis varied individually among the cell lines due to molecular heterogeneity and the involvement of DNA damage response pathways in senescence induction.
    Keywords:  ATM; ATR; DNA damage response inhibitor; DNAPK; HNSCC; homologous recombination; ionizing radiation; kinase inhibitor; radiosensitivity; senescence
    DOI:  https://doi.org/10.3390/cells9092012
  10. Mech Ageing Dev. 2020 Aug 31. pii: S0047-6374(20)30143-3. [Epub ahead of print] 111347
    AMPK alleviates oxidative stress‑induced premature senescence via inhibition of NF-κB/STAT3 axis-mediated positive feedback loop.
    Xiaojuan Han, Tianying Zhang, Xiaohua Zhang, Ruisan Zhang, Kejing Lao, Yajing Mi, Xingchun Gou.
      Stress-induced premature senescence (SIPS) is characterized by the secretion of a variety of inflammatory cytokines and chemokines, and proteases, which are defined collectively as the senescence-associated secretory phenotype (SASP). AMP-activated protein kinase (AMPK) activation contributes to SIPS prevention, and the impact of AMPK on SASP may be included, but the mechanisms governing this phenomenon have not elucidated. In this study, we showed that SIPS is accompanied by a dynamic fluctuation of NF-κB activation, which induces SASP production, whilst reinforcing and amplifying local STAT3 signalling and subsequently enhancing downstream senescence. NF-κB and STAT3 inhibitors attenuate oxidative stress-induced senescence in a time-dependent manner. Conditioned medium (CM) from senescent cells rich in SASP factors can induce growth arrest and promote senescence in healthy cells; accordingly, a STAT3 inhibitor blunts the SASP-induced senescence, indicating a positive feedback mechanism via the NF-κB/STAT3 pathway that sustains SASP production and promotes senescence. In addition, we confirmed that AMPK negatively regulates SASP production and senescence development associated with NF-κB/STAT3 inhibition. In summary, our results suggest that AMPK prevents oxidative stress-induced senescence development via inhibiting the NF-κB/SASP/STAT3 signalling mediated positive feedback loop.
    Keywords:  AMPK; NF-κB/STAT3 signalling; Oxidative stress; SASP; Senescence
    DOI:  https://doi.org/10.1016/j.mad.2020.111347
  11. Cell Metab. 2020 Sep 01. pii: S1550-4131(20)30417-4. [Epub ahead of print]32(3): 447-456.e6
    Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice.
    Azar Asadi Shahmirzadi, Daniel Edgar, Chen-Yu Liao, Yueh-Mei Hsu, Mark Lucanic, Arash Asadi Shahmirzadi, Christopher D Wiley, Garbo Gan, Dong Eun Kim, Herbert G Kasler, Chisaka Kuehnemann, Brian Kaplowitz, Dipa Bhaumik, Rebeccah R Riley, Brian K Kennedy, Gordon J Lithgow.
      Metabolism and aging are tightly connected. Alpha-ketoglutarate is a key metabolite in the tricarboxylic acid (TCA) cycle, and its levels change upon fasting, exercise, and aging. Here, we investigate the effect of alpha-ketoglutarate (delivered in the form of a calcium salt, CaAKG) on healthspan and lifespan in C57BL/6 mice. To probe the relationship between healthspan and lifespan extension in mammals, we performed a series of longitudinal, clinically relevant measurements. We find that CaAKG promotes a longer, healthier life associated with a decrease in levels of systemic inflammatory cytokines. We propose that induction of IL-10 by dietary AKG suppresses chronic inflammation, leading to health benefits. By simultaneously reducing frailty and enhancing longevity, AKG, at least in the murine model, results in a compression of morbidity.
    Keywords:  IL-10; SASP; alpha-ketoglutarate; frailty; healthspan; inflammation; lifespan; longevity
    DOI:  https://doi.org/10.1016/j.cmet.2020.08.004
  12. Nat Cell Biol. 2020 Sep;22(9): 1042-1048
    Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture.
    Michelle Riegman, Liran Sagie, Chen Galed, Tom Levin, Noah Steinberg, Scott J Dixon, Ulrich Wiesner, Michelle S Bradbury, Philipp Niethammer, Assaf Zaritsky, Michael Overholtzer.
      Ferroptosis is a regulated form of necrotic cell death that is caused by the accumulation of oxidized phospholipids, leading to membrane damage and cell lysis1,2. Although other types of necrotic death such as pyroptosis and necroptosis are mediated by active mechanisms of execution3-6, ferroptosis is thought to result from the accumulation of unrepaired cell damage1. Previous studies have suggested that ferroptosis has the ability to spread through cell populations in a wave-like manner, resulting in a distinct spatiotemporal pattern of cell death7,8. Here we investigate the mechanism of ferroptosis execution and discover that ferroptotic cell rupture is mediated by plasma membrane pores, similarly to cell lysis in pyroptosis and necroptosis3,4. We further find that intercellular propagation of death occurs following treatment with some ferroptosis-inducing agents, including erastin2,9 and C' dot nanoparticles8, but not upon direct inhibition of the ferroptosis-inhibiting enzyme glutathione peroxidase 4 (GPX4)10. Propagation of a ferroptosis-inducing signal occurs upstream of cell rupture and involves the spreading of a cell swelling effect through cell populations in a lipid peroxide- and iron-dependent manner.
    DOI:  https://doi.org/10.1038/s41556-020-0565-1
  13. J Cancer Res Clin Oncol. 2020 Sep 01.
    Senescent hepatic stellate cells caused by deoxycholic acid modulates malignant behavior of hepatocellular carcinoma.
    Phuong Thao Nguyen, Keishi Kanno, Quoc Thang Pham, Yuka Kikuchi, Masaki Kakimoto, Tomoki Kobayashi, Yuichiro Otani, Nobusuke Kishikawa, Mutsumi Miyauchi, Koji Arihiro, Masanori Ito, Susumu Tazuma.
       PURPOSE: Deoxycholic acid (DCA), a secondary bile acid, is reportedly increased in the serum of patients with nonalcoholic steatohepatitis and animals with experimentally induced hepatocellular carcinoma (HCC), but its contribution to malignant behaviors of HCC has not been precisely clarified. This study aimed to examine the effect of DCA on hepatic stellate cells (HSCs), a major component of nonparenchymal cells in the liver, and its subsequent indirect effect on HCC cells.
    METHODS: LX2 cells, a human HSC line, were treated with DCA in vitro. Then, HuH7 cells, a human hepatoma cell line, were incubated in conditioned media of DCA-treated LX2 to investigate the subsequent effect focusing on malignant behaviors.
    RESULTS: DCA resulted in cellular senescence in LX2 with the decreased cell proliferation via cell cycle arrest at G0/1 phase, together with the induction of senescence-associated secretory phenotype (SASP) factors. To investigate the influence of SASP factors secreted by HSCs in response to DCA, HCC cells were treated with conditioned media that promoted cell migration and invasion via induction of epithelial mesenchymal transition. These changes were attenuated in the presence of neutralizing antibody against IL8 or TGFβ. Pathological analysis of surgical specimens from HCC patients revealed that senescent HSCs were detected in the stroma surrounding HCC.
    CONCLUSION: Our data suggest an important role of HSC senescence caused by DCA for the malignant biological behaviors of HCC via induction of SASP factors, particularly IL8 and TGFβ.
    Keywords:  Cellular senescence; Deoxycholic acid; Epithelial mesenchymal transition; Hepatic stellate cells; Hepatocellular carcinoma; Senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1007/s00432-020-03374-9
  14. Biochem Biophys Res Commun. 2020 Aug 26. pii: S0006-291X(20)31380-2. [Epub ahead of print]
    Transcriptional upregulation of proteasome activator Blm10 antagonizes cellular aging.
    Lian-Bin Chen, Shuang Ma, Tian-Xia Jiang, Xiao-Bo Qiu.
      Cellular aging is associated with the damage to DNA, decline in proteasome activity, loss of histones and alteration of epigenetic marks. The atypical proteasome with the activator PA200 in mammals or its ortholog Blm10 in yeast promotes the acetylation-dependent degradation of the core histones during DNA repair or spermiogenesis. We show here that loss of PA200 or Blm10 is the leading cause of the decline in proteasome activity during aging, the latter of which conversely induces the transcription of Blm10. The transcription factor Crt1 suppressed, but the proteasome subunit Rpn4 promoted, the transcription of Blm10. On the contrary to deletion of Rpn4, deletion of Crt1 elevated Blm10 transcription upon DNA damage, reduced core histone levels during aging, and prolonged replicative lifespan. These results suggest that cells can antagonize aging by up-regulating transcription of Blm10, providing important insights into the mechanisms of aging and the aging-related diseases.
    Keywords:  Aging; Blm10; Histone; Proteasome; Protein degradation; Transcription
    DOI:  https://doi.org/10.1016/j.bbrc.2020.07.003
  15. Cell Metab. 2020 Sep 01. pii: S1550-4131(20)30422-8. [Epub ahead of print]32(3): 323-325
    Alpha-Ketoglutarate, the Metabolite that Regulates Aging in Mice.
    Timothy W Rhoads, Rozalyn M Anderson.
      In this issue of Cell Metabolism, Asadi Shahmirzadi et al. (2020) demonstrate that late-onset dietary supplementation with calcium alpha-ketoglutarate results in increased survival, compressed morbidity, and reduced frailty in mice. The study provides further evidence for critical links between metabolism, inflammation, and aging.
    DOI:  https://doi.org/10.1016/j.cmet.2020.08.009
  16. Curr Mol Med. 2020 Aug 31.
    Study aging by fibroblasts metabolome.
    Ana Rocha, Sandra Magalhães, Alexandra Nunes.
      Aging is a complex multifactorial process that although universal is not fully understood. It is known that the impact of aging on health is influenced by multiple factors, such as sex, race, income, and education, and that age-related dis-eases are strongly associated to the way people get old. The knowledge of biological aging and its comparison to the chronological age is a paramount contributor to predict the metabolic decline and the onset of age-related diseases. As aging processes observed in whole human organism are somehow the reflexion of what happens in each cell type, it is possible to study aging process using cell lines, such as fibroblasts. Metabolomics analysis of cell lines, namely fibroblasts, gives inputs to personalized or integrative medicine; in fact cell metabolomics is an emerging field that addresses fundamental biological and metabolic questions using modern "omic" techniques as FTIR, NMR or MS. This paper revises the relevance of using fibroblasts as cell models to study the metabolome of aging.
    Keywords:  Aging; FTIR; Fibrobalsts; MS; Metabolome; NMR
    DOI:  https://doi.org/10.2174/1566524020999200831120852
  17. Cell Rep. 2020 Sep 01. pii: S2211-1247(20)31080-9. [Epub ahead of print]32(9): 108091
    Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer's Dementia.
    Alzheimer’s Disease Genetics Consortium
      Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer's dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical DLGAP2 expression is observed in AD and is associated with more plaques and tangles at autopsy and faster cognitive decline. Results will inform future studies aimed at investigating the cross-species role of Dlgap2 in regulating cognitive decline and highlight the benefit of using genetically diverse mice to prioritize novel candidates.
    Keywords:  Alzheimer’s; Diversity Outbred; Dlgap2; GWAS; aging; cognition; genetic diversity; resilience; spines; susceptibility; translational
    DOI:  https://doi.org/10.1016/j.celrep.2020.108091
  18. Aging Cell. 2020 Sep 04. e13225
    Neuron-specific deletion of CuZnSOD leads to an advanced sarcopenic phenotype in older mice.
    Shylesh Bhaskaran, Natalie Pollock, Peter C Macpherson, Bumsoo Ahn, Katarzyna M Piekarz, Caroline A Staunton, Jacob L Brown, Rizwan Qaisar, Aphrodite Vasilaki, Arlan Richardson, Anne McArdle, Malcolm J Jackson, Susan V Brooks, Holly Van Remmen.
      Age-associated loss of muscle mass and function (sarcopenia) has a profound effect on the quality of life in the elderly. Our previous studies show that CuZnSOD deletion in mice (Sod1-/- mice) recapitulates sarcopenia phenotypes, including elevated oxidative stress and accelerated muscle atrophy, weakness, and disruption of neuromuscular junctions (NMJs). To determine whether deletion of Sod1 initiated in neurons in adult mice is sufficient to induce muscle atrophy, we treated young (2- to 4-month-old) Sod1flox/SlickHCre mice with tamoxifen to generate i-mn-Sod1KO mice. CuZnSOD protein was 40-50% lower in neuronal tissue in i-mn-Sod1KO mice. Motor neuron number in ventral spinal cord was reduced 28% at 10 months and more than 50% in 18- to 22-month-old i-mn-Sod1KO mice. By 24 months, 22% of NMJs in i-mn-Sod1KO mice displayed a complete lack of innervation and deficits in specific force that are partially reversed by direct muscle stimulation, supporting the loss of NMJ structure and function. Muscle mass was significantly reduced by 16 months of age and further decreased at 24 months of age. Overall, our findings show that neuronal-specific deletion of CuZnSOD is sufficient to cause motor neuron loss in young mice, but that NMJ disruption, muscle atrophy, and weakness are not evident until past middle age. These results suggest that loss of innervation is critical but may not be sufficient until the muscle reaches a threshold beyond which it cannot compensate for neuronal loss or rescue additional fibers past the maximum size of the motor unit.
    Keywords:  CuZnSOD; aging; denervation; motor neuron; sarcopenia
    DOI:  https://doi.org/10.1111/acel.13225
  19. Genes Dev. 2020 Sep 03.
    Break-induced replication promotes fragile telomere formation.
    Zhe Yang, Kaori K Takai, Courtney A Lovejoy, Titia de Lange.
      TRF1 facilitates the replication of telomeric DNA in part by recruiting the BLM helicase, which can resolve G-quadruplexes on the lagging-strand template. Lagging-strand telomeres lacking TRF1 or BLM form fragile telomeres-structures that resemble common fragile sites (CFSs)-but how they are formed is not known. We report that analogous to CFSs, fragile telomeres in BLM-deficient cells involved double-strand break (DSB) formation, in this case by the SLX4/SLX1 nuclease. The DSBs were repaired by POLD3/POLD4-dependent break-induced replication (BIR), resulting in fragile telomeres containing conservatively replicated DNA. BIR also promoted fragile telomere formation in cells with FokI-induced telomeric DSBs and in alternative lengthening of telomeres (ALT) cells, which have spontaneous telomeric damage. BIR of telomeric DSBs competed with PARP1-, LIG3-, and XPF-dependent alternative nonhomologous end joining (alt-NHEJ), which did not generate fragile telomeres. Collectively, these findings indicate that fragile telomeres can arise from BIR-mediated repair of telomeric DSBs.
    Keywords:  BLM; G4; POLD3; POLD4; SLX1; SLX4; TRF1; break-induced replication; fragile telomere; telomere
    DOI:  https://doi.org/10.1101/gad.328575.119
  20. NPJ Aging Mech Dis. 2020 ;6 9
    Short-term calorie restriction enhances DNA repair by non-homologous end joining in mice.
    Zhonghe Ke, Denis Firsanov, Brianna Spencer, Andrei Seluanov, Vera Gorbunova.
      Calorie restriction (CR) improves health, reduces cancer incidence and extends lifespan in multiple organisms including mice. CR was shown to enhance base excision repair and nucleotide excision repair pathways of DNA repair, however, whether CR improves repair of DNA double-strand breaks has not been examined in in vivo system. Here we utilize non-homologous end joining (NHEJ) reporter mice to show that short-term CR strongly enhances DNA repair by NHEJ, which is associated with elevated levels of DNA-PK and SIRT6.
    Keywords:  Medical research; Molecular biology
    DOI:  https://doi.org/10.1038/s41514-020-00047-2
  21. Am J Physiol Lung Cell Mol Physiol. 2020 Sep 02.
    Aging impairs alveolar epithelial type II cell function in acute lung injury.
    Tolga Yazicioglu, Christian Mühlfeld, Chiara Autilio, Cheng-Kai Huang, Christian Bär, Oliver Dittrich-Breiholz, Thomas Thum, Jesus Perez-Gil, Andreas Schmiedl, Christina Brandenberger.
      Morbidity and mortality rates in acute lung injury (ALI) increase with age. Since alveolar epithelial type II cells (AE2) are crucial for lung function and repair, we hypothesized that aging promotes senescence in AE2 and contributes to the severity and impaired regeneration in ALI. ALI was induced with 2.5 μg lipopolysaccharide/g body weight in young (3 months) and old (18 months) mice that were sacrificed 24 h, 72 h and 10 d later. Lung function, pulmonary surfactant activity, stereology, cell senescence and single cell RNA sequencing analyses were performed to investigate AE2 function in aging and ALI. In old mice, surfactant activity was severely impaired. A 60% mortality rate and lung function decline was present in old, but not in young mice with ALI. AE2 of young mice adapted to injury by increasing intracellular surfactant volume and proliferation rate. In old mice, however, this adaptive response was compromised and AE2 of old mice showed signs of cell senescence, increased inflammatory signaling and impaired surfactant metabolism in ALI. These findings provide evidence that ALI promotes a limited proliferation rate, increased inflammatory response and surfactant dysfunction in old, but not young mice, supporting an impaired regenerative capacity and reduced survival rate in ALI with advancing age.
    Keywords:  acute lung injury; alveolar epithelial type II cells; cell senescence; pulmonary aging; surfactant
    DOI:  https://doi.org/10.1152/ajplung.00093.2020
  22. JCI Insight. 2020 Sep 01. pii: 138815. [Epub ahead of print]
    Osteocyte RANKL is required for cortical bone loss with age and is induced by senescence.
    Ha-Neui Kim, Jinhu Xiong, Ryan S MacLeod, Srividhya Iyer, Yuko Fujiwara, Keisha M Cawley, Li Han, Yonghan He, Jeff D Thostenson, Elisabeth Ferreira, Robert L Jilka, Daohong Zhou, Maria Almeida, Charles A O'Brien.
      In aging mice, osteoclast number increases in cortical bone but declines in trabecular bone, suggesting that different mechanisms underlie age-associated bone loss in these two compartments. Osteocytes produce the osteoclastogenic cytokine RANKL, encoded by Tnfsf11. Tnfsf11 mRNA increases in cortical bone of aged mice, suggesting a mechanism underlying the bone loss. To address this possibility, we aged mice lacking RANKL in osteocytes. Whereas 24-month-old control mice had lower cortical bone compared to 8-month-old controls, mice lacking RANKL in osteocytes gained cortical bone from 8 to 24 months of age. Mice of both genotypes lost trabecular bone with age. Osteoclasts increased with age in cortical bone of control mice, but not in RANKL conditional knockout mice. Induction of cellular senescence increased RANKL production in murine and human cell culture models, suggesting an explanation for elevated RANKL levels with age. Over-expression of the senescence-associated transcription factor Gata4 stimulated Tnfsf11 expression in cultured murine osteoblastic cells. Lastly, elimination of senescent cells from aged mice using senolytic compounds reduced Tnfsf11 mRNA in cortical bone. Our results demonstrate the requirement of osteocyte-derived RANKL for age-associated cortical bone loss and suggest that increased Tnfsf11 expression with age results from accumulation of senescent cells in cortical bone.
    Keywords:  Bone Biology; Bone disease
    DOI:  https://doi.org/10.1172/jci.insight.138815
  23. RNA Biol. 2020 Aug 30.
    Circular ANRIL isoforms switch from repressors to activators of p15/CDKN2B expression during RAF1 oncogene-induced senescence.
    Lisa Muniz, Sandra Lazorthes, Maxime Delmas, Julien Ouvrard, Marion Aguirrebengoa, Didier Trouche, Estelle Nicolas.
      Long non-coding RNAs (ncRNAs) are major regulators of gene expression and cell fate. The INK4 locus encodes the tumour suppressor proteins p15INK4b, p16INK4a and p14ARF required for cell cycle arrest and whose expression increases during senescence. ANRIL is a ncRNA antisense to the p15 gene. In proliferative cells, ANRIL prevents senescence by repressing INK4 genes through the recruitment of Polycomb-group proteins. In models of replicative and RASval12 oncogene-induced senescence (OIS), the expression of ANRIL and Polycomb proteins decreases, thus allowing INK4 derepression. Here, we found in a model of RAF1 OIS that ANRIL expression rather increases, due in particular to an increased stability. This led us to search for circular ANRIL isoforms, as circular RNAs are rather stable species. We found that the expression of two circular ANRIL increases in several OIS models (RAF1, MEK1 and BRAF). In proliferative cells, they repress p15 expression, while in RAF1 OIS, they promote full induction of p15, p16 and p14ARF expression. Further analysis of one of these circular ANRIL shows that it interacts with Polycomb proteins and decreases EZH2 Polycomb protein localization and H3K27me3 at the p15 and p16 promoters, respectively. We propose that changes in the ratio between Polycomb proteins and circular ANRIL isoforms allow these isoforms to switch from repressors of p15 gene to activators of all INK4 genes in RAF1 OIS. Our data reveal that regulation of ANRIL expression depends on the senescence inducer and underline the importance of circular ANRIL in the regulation of INK4 gene expression and senescence.
    Keywords:   INK4 locus; Non-coding RNAs; Polycomb proteins; circular RNAs; gene expression regulation; oncogene-induced senescence
    DOI:  https://doi.org/10.1080/15476286.2020.1812910
  24. Exp Gerontol. 2020 Aug 31. pii: S0531-5565(20)30427-7. [Epub ahead of print] 111079
    Is inflammageing influenced by the microbiota in the aged gut? A systematic review.
    Cabirou M Shintouo, Tony Mets, David Beckwee, Ivan Bautmans, Stephen M Ghogomu, Jacob Souopgui, Lynn Leemans, Henry D Meriki, Rose Njemini.
      Ageing is characterized by a low-grade chronic inflammation marked by elevated circulating levels of inflammatory mediators. This chronic inflammation occurring in the absence of obvious infection has been coined as inflammageing and represents a risk factor for morbidity and mortality in the geriatric population. Also, with ageing, important perturbations in the gut microbiota have been underlined and a growing body of literature has implicated age-related gut dysbiosis as contributing to a global inflammatory state in the elderly. Notwithstanding, very little attention has been given to how gut microbiota impact inflammageing. Here, we investigate the available evidence regarding the association between inflammageing and gut microbiota during ageing. PubMed, Web of Science and Scopus were systematically screened, and seven relevant articles in animals or humans were retrieved. The animal studies reported that Parabacteroides, Mucispirillum, Clostridium and Sarcina positively associate with the pro-inflammatory MCP-1 while Akkermansia, Oscillospira, Blautia and Lactobacillus negatively correlate with MCP-1. Furthermore, "aged"-type microbiota were associated with increased levels of IL6, IL-10, Th1, Th2, Treg, TNF-α, TGF-β, p16, SAMHD1, Eotaxin, and RANTES; activation of TLR2, NF-κB and mTOR; and with decreased levels of cyclin E and CDK2. On the other hand, the study on humans demonstrated that bacteria of the phylum Proteobacteria exhibited a positive correlation with IL-6 and IL-8, while Ruminococcus lactaris et rel. portrayed a negative correlation with IL-8. We conclude that changes in "aged"-type gut microbiota are associated with inflammageing.
    Keywords:  Ageing; Cytokines; Gut microbiota; Inflammation
    DOI:  https://doi.org/10.1016/j.exger.2020.111079
  25. Cytokine Growth Factor Rev. 2020 Aug 24. pii: S1359-6101(20)30202-1. [Epub ahead of print]
    Mechanisms of NLRP3 priming in inflammaging and age related diseases.
    Anna Gritsenko, Jack P Green, David Brough, Gloria Lopez-Castejon.
      The NLRP3 inflammasome is a vital part of the innate immune response, whilst its aberrant activation drives the progression of a number of non-communicable diseases. Thus, NLRP3 inflammasome assembly must be tightly controlled at several checkpoints. The priming step of NLRP3 inflammasome activation is associated with increased NLRP3 gene expression, as well as post-translational modifications that control NLRP3 levels and licence the NLRP3 protein for inflammasome assembly. Increasing life expectancy in modern society is accompanied by a growing percentage of elderly individuals. The process of aging is associated with chronic inflammation that drives and/or worsens a range of age related non-communicable conditions. The NLRP3 inflammasome is known to contribute to pathological inflammation in many settings, but the mechanisms that prime NLRP3 for activation throughout aging and related co-morbidities have not been extensively reviewed. Here we dissect the biochemical changes that occur during aging and the pathogenesis of age related diseases and analyse the mechanisms by which they prime the NLRP3 inflammasome, thus exacerbating inflammation.
    Keywords:  Aging; Inflammaging; Inflammasome; NLRP3; Priming; Senescence
    DOI:  https://doi.org/10.1016/j.cytogfr.2020.08.003
  26. Biochem Biophys Res Commun. 2020 Aug 28. pii: S0006-291X(20)31562-X. [Epub ahead of print]
    Loss of RAD6B induces degeneration of the cochlea in mice.
    Yangping Ma, Yanfeng Song, Rong Shen, Panpan Li, Han Ding, Zhao Guo, Xiangwen Liu, Degui Wang.
      Presbycusis is a form of age-related hearing loss (AHL). Many studies have shown that the degeneration of various structures in the cochlea of the inner ear is related to AHL, and DNA damage is an important factor leading to the above process. As an E2 ubiquitin-conjugated enzyme, RAD6B plays an important role in DNA damage repair (DDR) through histone ubiquitination. However, the molecular mechanism is still unclear. In this study, we investigated the role of RAD6B in the morphological changes and DDR mechanisms in aging-related degeneration of the cochlea of mice. We observed that the hair cells, stria vascularis and spiral ganglion in the cochlea of the RAD6B knockout mice showed significant degenerative changes and abnormal expression of proteins associated with DDR mechanisms compared with those of the littermate wild-type mice. In conclusion, our results suggest that the deletion of RAD6B may lead to abnormalities in DDR, thereby accelerating the degeneration of various structures in the cochlea and senescence and apoptosis of cochlea cells.
    Keywords:  Cochlea; DNA damage; Degeneration; RAD6B; Ubiquitin
    DOI:  https://doi.org/10.1016/j.bbrc.2020.08.017
  27. Cells. 2020 Sep 01. pii: E2014. [Epub ahead of print]9(9):
    A Translational Mouse Model for NASH with Advanced Fibrosis and Atherosclerosis Expressing Key Pathways of Human Pathology.
    Anita M van den Hoek, Lars Verschuren, Nicole Worms, Anita van Nieuwkoop, Christa de Ruiter, Joline Attema, Aswin L Menke, Martien P M Caspers, Sridhar Radhakrishnan, Kanita Salic, Robert Kleemann.
      Non-alcoholic steatohepatitis (NASH) is a fast-growing liver disorder that is associated with an increased incidence of cardiovascular disease and type 2 diabetes. Animal models adequately mimicking this condition are scarce. We herein investigate whether Ldlr-/-. Leiden mice on different high-fat diets represent a suitable NASH model. Ldlr-/-. Leiden mice were fed a healthy chow diet or fed a high-fat diet (HFD) containing lard or a fast food diet (FFD) containing milk fat. Additionally, the response to treatment with obeticholic acid (OCA) was evaluated. Both high-fat diets induced obesity, hyperlipidemia, hyperinsulinemia, and increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Mice on both diets developed progressive macro- and microvesicular steatosis, hepatic inflammation, and fibrosis, along with atherosclerosis. HFD induced more severe hyperinsulinemia, while FFD induced more severe hepatic inflammation with advanced (F3) bridging fibrosis, as well as more severe atherosclerosis. OCA treatment significantly reduced hepatic inflammation and fibrosis, and it did not affect atherosclerosis. Hepatic transcriptome analysis was compared with human NASH and illustrated similarity. The present study defines a translational model of NASH with progressive liver fibrosis and simultaneous atherosclerosis development. By adaptation of the fat content of the diet, either insulin resistance (HFD) or hepatic inflammation and fibrosis (FFD) can be aggravated.
    Keywords:  NAFLD; NASH; animal model; atherosclerosis; fibrosis; inflammation; metabolic syndrome
    DOI:  https://doi.org/10.3390/cells9092014
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