EXC 229:  Cellular Stress Responses in Aging-Associated Diseases

• Subject Area: Medicine
• Term: from 2007 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 39010820

• Final Report Year: 2020

Final Report Abstract

Modern societies are facing a dramatic demographic change with an ever-increasing life expectancy that is concomitant with increased risk of age-associated diseases, e.g. diabetes and obesity, as well as skin, kidney, and neurodegenerative disorders, thus posing an enormous challenge for both individuals and their societies. The landmark discovery that modification of specific signaling pathways can extend lifespan and reduce the incidence of age-associated diseases formed the scientific foundation of the Cologne Cluster of Excellence on Cellular Stress Responses in Agingassociated Diseases (CECAD) – to define the molecular and cellular mechanisms underlying the aging process as potential novel targets for prevention, early diagnosis, and treatment of ageassociated diseases. CECAD has actively recruited top basic researchers and clinician scientists who work in concert at the University of Cologne (UoC), the Max Planck Institutes for Biology of Ageing (MPI AGE) and for Metabolism Research (MPI MR), as well as the German Center for Neurodegenerative Diseases (DZNE). Further, CECAD together with the UoC has effected massive infrastructural changes, which have firmly established this Cluster as one of the leading aging research centers worldwide. Moreover, CECAD’s strategic recruitment policy has generated an international and inclusive research environment where female representation is high. In parallel, we have built up educational measures to better train the best global scientific talent at all academic levels. Together, these developments led to a very rapid increase in research momentum, that thereby enabled CECAD scientists through highly collaborative efforts in unravelling novel fundamental principles underlying aging and aging-associated diseases and identifying potential novel targets for intervention. While work initially focused on defining the role of cell autonomous quality control pathways in aging and aging-aging associated diseases, recent studies from the second period have highlighted the importance of interorgan communication and signals originating from the environment that control longevity and health, thereby opening up a new channel for identifying novel therapeutic targets. For the future CECAD will therefore expand its research program and supporting core structures and educational programs in these areas while at the same time enhancing its translational studies through inclusion of unique human cohorts. Collectively, these efforts of CECAD PIs and its participating institutions will not only enable CECAD to continue to be at the forefront of world-class aging research, but also provide a leading training site for aging researchers at all academic levels.

Link to the final report

https://dx.doi.org/10.2314/GBV:1697037887

Publications

• (2011) CDC-48/p97 coordinates CDT-1 degradation with GINS chromatin dissociation to ensure faithful DNA replication. Mol Cell, Volume 44, 1, 7 October 2011: 85-96
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• (2008) C. elegans dauer formation and the molecular basis of plasticity. Genes Dev 22: 2149-65
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• (2008) Endothelial cell-specific NF-kappaB inhibition protects mice from atherosclerosis. Cell Metab 8: 372-83
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• (2008) Epidermal insulin/IGF-1 signalling control interfollicular morphogenesis and proliferative potential through Rac activation. EMBO J 27: 2091-101
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• (2008) Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses. Nat Immunol 9: 1037-46
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• (2008) Prohibitins control cell proliferation and apoptosis by regulating OPA1-dependent cristae morphogenesis in mitochondria. Genes Dev 22: 476-88
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• (2009) Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes. Nat Immunol 10: 761-8
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• (2009) Amino-acid imbalance explains extension of lifespan by dietary restriction in Drosophila. Nature 462: 1061-4
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• (2009) An intersubunit signaling network coordinates ATP hydrolysis by m-AAA proteases. Mol Cell 35: 574-85
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• (2009) Identification of a putative lysosomal cobalamin exporter altered in the cblF defect of vitamin B12 metabolism. Nat Genet 41: 234-9
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• (2009) Nuclear hormone receptor regulation of microRNAs controls developmental progression. Science 324: 95-8
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• (2009) Riboflavin kinase couples TNF receptor 1 to NADPH oxidase. Nature 460: 1159-63
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• (2011) FADD prevents RIP3-mediated epithelial cell necrosis and chronic intestinal inflammation. Nature 477: 330-4
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• (2011) High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nat Neurosci 14: 911-8
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• (2011) MTERF4 regulates translation by targeting the methyltransferase NSUN4 to the mammalian mitochondrial ribosome. Cell Metab 13: 527-39
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  (See online at https://doi.org/10.1016/j.cmet.2011.04.002)
• (2011) Obesity-induced over-expression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabo- lism. Nat Cell Biol 13: 434-46
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• (2011) Role for insulin signaling in catecholaminergic neurons in control of energy homeostasis. Cell Metab 13: 720-8
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  (See online at https://doi.org/10.1016/j.cmet.2011.03.021)
• (2011) The Machado-Joseph disease deubiquitylase ATX-3 couples longevity and proteostasis. Nat Cell Biol 13: 273-81
  Kuhlbrodt K, Janiesch PC, Kevei E, Segref A, Barikbin R, Hoppe T
  (See online at https://doi.org/10.1038/ncb2200)
• (2012) A steroid receptor-microRNA switch regulates life span in response to signals from the gonad. Science 338: 1472-6
  Shen Y, Wollam J, Magner D, Karalay O, Antebi A
  (See online at https://doi.org/10.1126/science.1228967)
• (2012) Intramitochondrial transport of phosphatidic acid in yeast by a lipid transfer protein. Science 338: 815-8
  Connerth M, Tatsuta T, Haag M, Klecker T, Westermann B, Langer T
  (See online at https://doi.org/10.1126/science.1225625)
• (2013) aPKClambda controls epidermal homeostasis and stem cell fate through regulation of division orientation. J Cell Biol 202: 887-900
  Niessen MT, Scott J, Zielinski JG, Vorhagen S, Sotiropoulou PA, Blanpain C, Leitges M, Niessen CM
  (See online at https://doi.org/10.1083/jcb.201307001)
• (2013) DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature 501: 416-20
  Ermolaeva MA, Segref A, Dakhovnik A, Ou HL, Schneider JI, Utermohlen O, Hoppe T, Schumacher B
  (See online at https://doi.org/10.1038/nature12452)
• (2013) Insulin/IGF-1 controls epidermal morphogenesis via regulation of FoxO-mediated p63 inhibition. Dev Cell 26: 176-87
  Günschmann C, Stachelscheid H, Akyuz MD, Schmitz A, Missero C, Brüning JC, Niessen CM
  (See online at https://doi.org/10.1016/j.devcel.2013.05.017)
• (2013) Mitochondrial dynamics controlled by mitofusins regulate Agrp neuronal activity and diet-induced obesity. Cell 155: 188-99
  Dietrich MO, Liu ZW, Horvath TL
  (See online at https://doi.org/10.1016/j.cell.2013.09.004)
• (2013) Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b. Nature 494: 111-5
  Kornfeld JW, Baitzel C, Konner AC, Nicholls HAT, Vogt MC, Herrmanns K, Scheja L, Haumaitre C, Wolf AM, Knippschild U, Seibler J, Cereghini S, Heeren J, Stoffel M, Brüning JC
  (See online at https://doi.org/10.1038/nature11793)
• (2013) The actin cross-linker Filamin/Cheerio mediates tumor malignancy downstream of JNK signaling. J Cell Sci 126: 927-38
  Kulshammer E, Uhlirova M
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• (2013) TRIAP1/PRELI complexes prevent apoptosis by mediating intramitochondrial transport of phosphatidic acid. Cell Metab 18: 287-95
  Potting C, Tatsuta T, Konig T, Haag M, Wai T, Aaltonen MJ, Langer T
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• (2014) CLUH regulates mitochondrial biogenesis by binding mRNAs of nuclear-encoded mitochondrial proteins. J Cell Biol 207: 213-23
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  (See online at https://doi.org/10.1083/jcb.201403129)
• (2014) DAF-16/FOXO and EGL-27/GATA promote developmental growth in response to persistent somatic DNA damage. Nat Cell Biol 16: 1168-1179
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• (2014) Hexosamine pathway metabolites enhance protein quality control and prolong life. Cell 156: 1167-78
  Denzel MS, Storm NJ, Gutschmidt A, Baddi R, Hinze Y, Jarosch E, Sommer T, Hoppe T, Antebi A
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• (2014) Loss of UCP2 attenuates mitochondrial dysfunction without altering ROS production and uncoupling activity. PloS Genet 10: e1004385
  Kukat A, Dogan SA, Edgar D, Mourier A, Jacoby C, Maiti P, Mauer J, Becker C, Senft K, Wibom R, Kudin AP, Hultenby K, Flogel U, Rosenkranz S, Ricquier D, Kunz WS, Trifunovic A
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• (2014) Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding. Cell 156: 495-509
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• (2014) RIPK1 maintains epithelial homeostasis by inhibiting apoptosis and necroptosis. Nature 513: 90-4
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• (2014) Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin. Nat Immunol 15: 423-30
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• (2014) The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission. J Cell Biol 204: 919-29
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• (2014) Tissue-specific loss of DARS2 activates stress responses independently of respiratory chain deficiency in the heart. Cell Metab 19: 458-69
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• (2015) A critical period for experience-dependent remodeling of adult-born neuron connectivity. Neuron 85: 710-7
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• (2015) A synergistic interaction between Chk1- and MK2 inhibitors in KRAS-mutant cancer. Cell Jul 2, 162(1): 146-159
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• (2015) Hypothalamic Agrp neurons drive stereotypic behaviors beyond feeding. Cell 160: 1222-32
  Dietrich MO, Zimmer MR, Bober J, Horvath TL
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• (2015) Hypothalamic POMC neurons promote cannabinoidinduced feeding. Nature 519: 45-50
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• (2015) Hypothalamic UDP Increases in Obesity and Promotes Feeding via P2Y6-Dependent Activation of AgRP Neurons. Cell 162: 1404-17
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• (2015) Imbalanced OPA1 processing and mitochondrial fragmentation cause heart failure in mice. Science 350: aad0116
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• (2015) Interplay among Drosophila transcription factors Ets21c, Fos and Ftz-F1 drives JNK-mediated tumor malignancy. Dis Model Mech 8: 1279-93
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• (2015) The Ras-Erk-ETS signalling pathway is a drug target for longevity. Cell 162: 72-83
  Slack C, Alic N, Foley A, Cabecinha M, Hoddinott MP, Partridge L
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• (2016) AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue. Cell 165: 125-138
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• (2016) Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression. Nat Commun 7: 10612
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• (2016) CLPP coordinates mitoribosomal assembly through the regulation of ERAL1 levels. EMBO J 35: 2566-2583
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• (2016) Dicer1-miR-328-Bace1 signalling controls brown adipose tissue differentiation and function. Nat Cell Biol 18: 328-36
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• (2016) E4 ligase-specific ubiquitination hubs coordinate DNA double-strand-break repair and apoptosis. Nat Struct Mol Biol 23: 995-1002
  Ackermann L, Schell M, Pokrzywa W, Kevei E, Gartner A, Schumacher B, Hoppe T
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• (2016) Hypothalamic feedforward inhibition of thalamocortical network controls arousal and consciousness. Nat Neurosci 19: 290-8
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• (2016) Importance of rare gene copy number alterations for personalized tumor characterization and survival analysis. Genome Biol 17: 204
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• (2016) Insulin and TOR signal in parallel through FOXO and S6K to promote epithelial wound healing. Nat Commun 7: 12972
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• (2016) Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis 16: 828-837
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• (2016) Mechanical regulation of transcription drives Polycomb mediated gene silence during lineage I. Nat Cell Biol 18: 864-75
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• (2016) Mondo complexes regulate TFEB via TOR inhibition to promote longevity in response to gonadal signals. Nat Commun 7: 10944
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• (2016) mTORC1 and mTORC2 regulate skin morphogenesis and epidermal barrier formation. Nat Commun 7: 13226
  Ding X, Bloch W, Iden S, Ruegg MA, Hall MN, Leptin M, Partridge L, Eming SA
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• (2016) Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity. Cell 165: 882-95
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• (2016) On the dependency of cellular protein levels on mRNA abundance. Cell 165: 535-50
  Liu Y, Beyer A, Aebersold R
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