Ageing – basic mechanisms and interventions - Christian Riedel
Ageing and age-related diseases are central to human health; we study the molecular mechanisms that regulate ageing and hope to exploit them for therapeutic purposes.
Our health and longevity is largely determined by the rate at which we age. Fortunately, ageing is a plastic process. In our research group we use the nematode Caenorhabditis Elegans as a model systems to understand the pathways that can accelerate or impair aging. C. Elegans is ideal for ageing-related research, as it is technically well established, short-lived (allowing for lifespan as an easily measurable phenotype), and very responsive to alterations in its ageing-regulatory pathways.
These studies are complemented by efforts in human tissue culture, to verify human conservation and further explore our findings for therapeutic purposes. Our research combines biochemistry (Proteomics, ChIP-Seq, mRNA-Seq,…) with high-throughput genetic screening approaches (RNAi), to understand the regulation of aging at molecular and mechanistic resolution.
Ilke Sen, PhD Student/Postdoc
Lluís Millán Ariño, Postdoc
Andrea Stöhr, Postdoc
Xin Zhou, Postdoc
Lioba Körner, Master Student
Naghmeh Rajaei, Postdoc
Marco Lezzerini, Postdoc
Mengshan Liu, Master Student
Bora Baskaner, Research Assistant
Simone Brandenburg, Research Assistant
Nataly Puerta Cavanzo, Master Student
Marlies Oomen, Master Student
Irem Yücel, Bachelor Student
Tanja Iken, Bachelor Student
Georges Janssens, Postdoc
Daniel Edgar, Postdoc
Poomy Pandey, Research Assistant
Xin-Xuan Lin, PhD Student
Sonja Pikkupeura, Master Student
The role of DAF-16/FOXO and its cofactors in aging regulation
A current focus of ours is the mechanistic exploration of aging regulatory transcription factors, in particular DAF-16/FOXO – a central driver of longevity that integrates many lifespan extending stimuli, i.e. nutrient deprivation, various stresses, or cues of infertility to confer transcription of a wide range of stress resistance and longevity determining genes. We recently identified a variety of co-factors to DAF-16/FOXO, and now we are exploring their mechanistic role.
The role of the chromatin landscape in aging regulation
Transcription is not only controlled by transcription factors but also the chromatin landscape that they interact with. Hence we are complementing our work by studies on the role of chromatin states, chromatin remodellers and the epigenome in the context of aging and age-related disease.
Search for aging-preventive interventions in humans
In addition to the mechanistic studies from above, we also seek pharmacological interventions against aging in mammalian systems, including humans. For this, we validate aging-regulatory mechanisms of particular appeal that were identified in simpler model organisms and test possible targeting strategies. Further, we develop mammalian screening methodologies that allow for the identification of aging-preventive compounds.
Janssens, G.E., Lin, X.X., Millan-Arino, L., Sen, I., Kavsek, A., Seinstra, R.I., Stroustrup, N., Nollen, E.A.A., Riedel, C.G. (2019) Transcriptomics-based screening identifies pharmacological inhibition of Hsp90 as a means to defer aging. Cell Reports 27: 467-480.
Lin, X.X., et al. (2018) DAF-16/FOXO and HLH-30/TFEB function as combinatorial transcription factors to promote stress resistance and longevity. Nature Communications 9(1): 4400.
Riedel, C.G. et al. (2013) DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity. Nature Cell Biology, 15, 491-501.
Kenyon, C. (2010) The genetics of ageing. Nature 464, 504-12.
Calnan, D.R. & Brunet, A. (2008) The FoxO code. Oncogene 27, 2276-88.
Christian Riedel’s group is grateful for support by Vetenskapsrådet, Cancerfonden, Karolinska Institutet, and the pharmaceutical company AstraZeneca.
Chromatin Immunoprecipitation and Sequencing (ChIP-seq) Optimized for Application in Caenorhabditis elegans.
Sen I, Kavšek A, Riedel CG
Curr Protoc 2021 Jul;1(7):e187
Histone Purification Combined with High-Resolution Mass Spectrometry to Examine Histone Post-Translational Modifications and Histone Variants in Caenorhabditis elegans.
Millan-Ariño L, Yuan ZF, Oomen ME, Brandenburg S, Chernobrovkin A, Salignon J, Körner L, Zubarev R A, Garcia B A, Riedel C G. Curr Protoc Protein Sci 2020 12;102(1): e114
DAF-16/FOXO requires Protein Phosphatase 4 to initiate transcription of stress resistance and longevity promoting genes
Sen, I., Zhou, X., Chernobrovkin, A., Puerta-Cavanzo, N., Kanno, T., Salignon, J., Stoehr, A., Lin, X., Baskaner, B., Brandenburg, S., Björkegren, C., Zubarev, R., Riedel, C. (2020). Nature Communications 11(1), 138.
Transcriptomics-Based Screening Identifies Pharmacological Inhibition of Hsp90 as a Means to Defer Aging.
Janssens GE, Lin XX, Millan-Ariño L, Kavšek A, Sen I, Seinstra RI, Stroustrup N, Nollen EAA, Riedel CG
Cell Rep 2019 Apr;27(2):467-480.e6
DAF-16/FOXO and HLH-30/TFEB function as combinatorial transcription factors to promote stress resistance and longevity.
Lin XX, Sen I, Janssens GE, Zhou X, Fonslow BR, Edgar D, Stroustrup N, Swobida P, Yates 3rd JR, Ruvkun G, Riedel CG, Nat Commun 2018 10;9(1):4400
Regulation of Age-related Decline by Transcription Factors and Their Crosstalk with the Epigenome.
Zhou X, Sen I, Lin XX, Riedel CG
Curr. Genomics 2018 Sep;19(6):464-482
ATP-dependent chromatin remodeling: from development to disease.
Lezzerini, M., Riedel, C.G. (2016) Book Chapter in “Chromatin Regulation and Dynamics”, Elsevier, ISBN: 978-0-12-803395-1.
The Deubiquitylase MATH-33 Controls DAF-16 Stability and Function in Metabolism and Longevity.
Heimbucher T, Liu Z, Bossard C, McCloskey R, Carrano AC, Riedel CG, et al
Cell Metab. 2015 Jul;22(1):151-63
DAF-16 employs the chromatin remodeller SWI/SNF to promote stress resistance and longevity.
Riedel CG, Dowen RH, Lourenco GF, Kirienko NV, Heimbucher T, West JA, et al
Nat. Cell Biol. 2013 May;15(5):491-501
The Caenorhabditis elegans RDE-10/RDE-11 complex regulates RNAi by promoting secondary siRNA amplification.
Zhang C, Montgomery TA, Fischer SE, Garcia SM, Riedel CG, Fahlgren N, et al
Curr. Biol. 2012 May;22(10):881-90
The Caenorhabditis elegans SOMI-1 zinc finger protein and SWI/SNF promote regulation of development by the mir-84 microRNA.
Hayes GD, Riedel CG, Ruvkun G
Genes Dev. 2011 Oct;25(19):2079-92
The evolutionarily conserved longevity determinants HCF-1 and SIR-2.1/SIRT1 collaborate to regulate DAF-16/FOXO.
Rizki G, Iwata TN, Li J, Riedel CG, Picard CL, Jan M, et al
PLoS Genet. 2011 Sep;7(9):e1002235
Toward the mechanisms preventing merotelic kinetochore-microtubule attachments.
Cell Cycle 2010 Oct;9(20):4048-9
A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants.
Curran SP, Wu X, Riedel CG, Ruvkun G
Nature 2009 Jun;459(7250):1079-84
The kinetochore proteins Pcs1 and Mde4 and heterochromatin are required to prevent merotelic orientation.
Gregan J, Riedel CG, Pidoux AL, Katou Y, Rumpf C, Schleiffer A, et al
Curr. Biol. 2007 Jul;17(14):1190-200
Tandem affinity purification of functional TAP-tagged proteins from human cells.
Gregan J, Riedel CG, Petronczki M, Cipak L, Rumpf C, Poser I, et al
Nat Protoc 2007 ;2(5):1145-51
Protein phosphatase 2A protects centromeric sister chromatid cohesion during meiosis I.
Riedel CG, Katis VL, Katou Y, Mori S, Itoh T, Helmhart W, et al
Nature 2006 May;441(7089):53-61
Is chromatin remodeling required to build sister-chromatid cohesion?
Riedel CG, Gregan J, Gruber S, Nasmyth K
Trends Biochem. Sci. 2004 Aug;29(8):389-92