Cédric Dray / Armelle Yart
Metabolic interplays and age-related loss of function
During lifespan, environmental fluctuations consistently forced organism and cells to develop metabolic flexibility in order to maintain their energy homeostasis.
In this context, many aspects of cellular/tissue metabolism changes are driven by redox metabolism as well as inter-cellular and inter-organs metabolic interactions that are fundamental to maintain tissue and whole body energetic homeostasis. Altogether, these parameters are in constant adaptation and represent the metabolic resilience of cell (cell capacity to face metabolic alterations).
We hypothesized that metabolic resilience directs the ability of the aging organism to maintain the main metabolic functions (storage, utilization and release of energy) necessary to perform towards healthy-aging or dependence when disrupted.
Our aim is to investigate the role and the regulation of local/systemic metabolic dialogue within a tissue (mesenchyma/parenchyma) and between metabolic tissues (adipose tissues/muscle/liver) by focusing on intracellular changes in metabolic pathways and redox state triggering major modifications of secretion and cell production. This will allow identifying new mechanisms that contribute, when defective, to the onset or aggravation of age-related diseases (sarcopenia, metabolic diseases) that could represent therapeutic targets of interest.
Metabokines and age-related loss of function
Inter-cellular and inter-organs metabolic interactions are fundamental to maintaining tissue and whole body energetic homeostasis. The effectors mediating these metabolic interplays include both hormones/cytokines and metabolites (gathered under the term “metabokines”), the latter being able to act either as nutrients or signaling molecules.
During aging, these changes of “metabokines” profile could interfere with the dialogue between metabolic tissues such as adipose tissues, muscle and liver and consequently support the decline of metabolic flexibility during aging.
Therefore, the impact of aging on the overall distribution of “metabokines” fluxes remains to be fully described. To that aim, we are developing new models of accelerated of early aging (Nothobranchuis Furzeri, genetic diseases, nutritional input) combined to state-of-the-art approaches (fluxomics, organ-on-chip) able to identify and target new pathways and therapeutic candidates.
L'état redox, un nouveau déclencheur du vieillissement
Using up to date experimental animal models and human resources, we are establishing the link between age-related loss of metabolic functions and redox state and are studying the causes and consequences of metabolic flexibility alterations during aging in metabolic tissues.
Many aspects of cellular/tissue metabolism are driven by redox metabolism, which corresponds to a complex network of electron transfer. The maintenance of redox homeostasis is of paramount importance for normal cell and tissue functions and increasing evidences demonstrate that the redox state is the main conductor regulating the metabolic reorganization during stress, which is enabled by functional metabolic flexibility.
In addition to support energy homeostasis, redox state drives many cellular functions including cell proliferation, differentiation, senescence as well as autocrine/paracrine/endocrine activity. While redox stress is well known to be associated with aging, Metabolink aims to understand and to target the network and the dynamics of the metabolic and redox reorganizations associated with aging and age-associated pathologies.
Apelin, sarcopenia, ageing, adipokines, myokines, metabolism
Metabolism, rare diseases, translational research, signalisation, senescence
Ageing, friality, cancer, redox metabolism, hypoxia, metabolic flexibility, lipids, fibroblasts, mesenchymal stem cells
Redox metabolism, Mitochondria, ROS, Adipose tissue, Plasticity, brite and brown adipocytes, Lactate sensing and signaling
Fluxomic, metabolomic HR-MS analysis, data processing
Molecular biology, cell culture ( mouse/human; normoxia/Hypoxia), flux cytometry
Redox metabolism, metabolic challenge, human biological diagnostic, human nutrition, coenzymes
Metabolism, adipocytes, metabolomic, fluxomic, isotopic tracing in vitro/in vivo, cell culture (hypoxia), mitochondrial activity
Metabolism, adipose tissue, apelin, adipokines, obesity, type 2 diabetes
Noonan syndrom, hormones, metabolism and muscle physiology, inter-organ communication
In vivo functional exploration, metabolic phenotyping, surgery
Sophie Le Gonidec
Anesthesia, reanimation, pain
Ageing, sarcopenia, Zebrafish, mitochondrial metabolism
Cognition, obesity, adipose tissue
Apelin/APJ, obesity, adipokines, diabetes, ageing
Mass spectrophometry Fluxomic, Metabolomic
Liver, adipose tissue, macrophages, metabolism, inflammation, ageing
metabolism, metabolic network, metabolomic, fluxomic, metabolic modelisation
Surgery, cognition, obesity, adipose tissue, inflammation
Growth, bone, metabolism, endocrinology, rare diseases, translationnal research
Metabolism, adipocytes, metabolomic, fluxomic, isotopic tracing in vitro/in vivo, cell culture, mitochondria activity
Kemoun P, Ader I, Planat-Benard V, Dray C, Fazilleau N, Monsarrat P, Cousin B, Paupert J, Ousset M, Lorsignol A, Raymond-Letron I, Vellas B, Valet P, Kirkwood T, Beard J, Pénicaud L, Casteilla L. A gerophysiology perspective on healthy ageing. Ageing Res Rev. 2022, 73:101537. Review
Personnaz J, Dortignac A, Piccolo E, Iacovini JS, Mariette J, Pollizi A, Batut A, Deleruyelle S, Paccoud R, Moreau E, Martins F, Clouaire T, Rayah F, Montagner A, Wahli W, Schwabe RF, Yart A, Castan-Laurell I, Postic C, Moro C, Legube G, Guillou H, Valet P, Dray C, Pradère JP. Nuclear HMGB1 regulates liver lipogenesis through negative regulation of liver X receptor. Sci Adv. 2022,8(12):eabg9055.
Bullich S, De Souto Barreto P, Dortignac A, He L, Dray C, Valet P, Guiard BP. Apelin controls emotional behavior in age- and metabolic state-dependent manner Psychoneuroendocrinology. 2022,140:105711.
Ader I, Pénicaud L, Andrieu S, Beard JR, Davezac N, Dray C, Fazilleau N, Gourdy P, Guyonnet S, Liblau R, Parini A, Payoux P, Rampon C, Raymond-Letron I, Rolland Y, De Souto Barreto P, Valet P, Vergnolle N, Sierra F, Vellas B, Casteilla L. Healthy Aging Biomarkers: The INSPIRE’s Contribution. J Frailty Aging. 2021,10(4):313-319
Paccoud R, Saint-Laurent C, Piccolo E, Tajan M, Dortignac A, Pereira O, Le Gonidec S, Baba I, Gélineau A, Askia H, Branchereau M, Charpentier J, Personnaz J, Branka S, Auriau J, Deleruyelle S, Canouil M, Beton N, Salles JP, Tauber M, Weill J, Froguel P, Neel BG, Araki T, Heymes C, Burcelin R, Castan I, Valet P, Dray C, Gautier EL, Edouard T, Pradère JP, Yart A. SHP2 drives inflammation-triggered insulin resistance by reshaping tissue macrophage populations. Sci Transl Med. 2021;13(591):eabe2587
Lagarde D, Jeanson Y, Portais JC, Galinier A, Ader I, Casteilla L, Carrière A. Lactate Fluxes and Plasticity of Adipose Tissues: A Redox Perspective. Front Physiol. 2021,12:689747. Review
Lagarde D, Jeanson Y, Barreau C, Moro C, Peyriga L, Cahoreau E, Guissard C, Arnaud E, Galinier A, Bouzier-Sore AK, Pellerin L, Chouchani ET, Pénicaud L, Ader I, Portais JC, Casteilla L, Carrière A. Lactate fluxes mediated by the monocarboxylate transporter-1 are key determinants of the metabolic activity of beige adipocytes. J Biol Chem. 2021, 296:100137
Stuani L, Sabatier M, Saland E, Cognet G, Poupin N, Bosc C, Castelli FA, Gales L, Turtoi E, Montersino C, Farge T, Boet E, Broin N, Larrue C, Baran N, Cissé MY, Conti M, Loric S, Kaoma T, Hucteau A, Zavoriti A, Sahal A, Mouchel PL, Gotanègre M, Cassan C, Fernando L, Wang F, Hosseini M, Chu-Van E, Le Cam L, Carroll M, Selak MA, Vey N, Castellano R, Fenaille F, Turtoi A, Cazals G, Bories P, Gibon Y, Nicolay B, Ronseaux S, Marszalek JR, Takahashi K, DiNardo CD, Konopleva M, Pancaldi V, Collette Y, Bellvert F, Jourdan F, Linares LK, Récher C, Portais JC, Sarry JE. Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia. J.Exp Med. 2021, 218(5):e2020092
Tajan M, Hennequart M, Cheung EC, Zani F, Hock AK, Legrave N, Maddocks ODK, Ridgway RA, Athineos D, Suárez-Bonnet A, Ludwig RL, Novellasdemunt L, Angelis N, Li VSW, Vlachogiannis G, Valeri N, Mainolfi N, Suri V, Friedman A, Manfredi M, Blyth K, Sansom OJ, Vousden KH. Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy Nat Commun. 2021,12(1):366
Quillien A, Gilbert G, Boulet M, Ethuin S, Waltzer L, Vandel L. Prmt5 promotes vascular morphogenesis independently of its methyltransferase activity. PLoS Genet. 2021,17(6):e1009641.
Millard, Schmitt U, Kiefer P, Vorholt JA, Heux S, Portais JC. ScalaFlux: A scalable approach to quantify fluxes in metabolic subnetworks. PLoS Comput Biol. 2020,16(4):e1007799.
- Vinel C, Lukjanenko I, Batut A, Deleyruelle S, Pradere JP, Le Gonidec S, Dortignac A, Geoffre N, Pereira O, Karaz S, Lee U, Camus M, Chaoui K, Mouisel E, Bigot A, Mouly V, Vigneau M, Pagano A, Chopard A, Pillard F, Guyonnet S, Cesari M, Schiltz O, Pahor M, Feige J,Vellas B, Valet P, Dray C. The exerkine apelin reverses age-associated sarcopenia. 2018, Nat. Med. 24: 1360-1371.
- Gourdy P, Cazals L, Thalamas C, Sommet A, Calvas F, Galitzy M,Vinel C, Dray C,Hanaire H, Castan-Laurell I, Valet P. Apelin administration improves insulin sensitivity in overweight men: a randomised trial. 2018, Diabetes Obes. Metab. 20: 157-164.