Integrative cellular ageing and inflammation

Cellular ageing and cell plasticity : from fundamentals to pharmacological interventions

The continuous increase of the elderly population is causing a socio-economic challenge to societies, revealing the need of new interventions for the prevention of age-associated processes and related diseases. The research activities of the ICAI team are aimed at deciphering ageing processes at the multiscale level, molecular, cellular, tissue and integrative, and to propose preventive and regenerative strategies to counteract these processes. Specific hallmarks of ageing have been established that altogether represent the ageing phenotype. Among these hallmarks, our projects are particularly focused on cell senescence, impaired regenerative capacity, mitochondrial dysfunction, loss of proteostasis and inflammageing. Our projects aim to better understand cell plasticity/adaptation and how to fine-tune cell fate in the context of ageing and age-related diseases in a pluridisciplinary manner by focusing on redox states, proteolytic modulators and inflammation components. The research we propose is related to basic understanding of cellular ageing processes as well as clinical data to derive new ageing biomarkers and/or therapeutical strategies.s

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Our projects are based on different ageing or age-associated diseases models (mice: geriatric vs young, Alzheimer disease, MS, Atherosclerosis, Cancer...) using cells from primary cultures or from human donors. Developmentof anti-ageing compounds is performed using rational design in collaboration with medicinal chemistry teams or in vitro phenotypic screenings using librairies of compounds.

Highlights

Using the skin model, we have recently shown the contribution of the p27 pathway to the establishment of keratinocyte senescence in response to glyoxal treatment. Furthermore, characterization of the senescent keratinocyte secretome has led to the identification of specific cytokines expressed at different steps of the senescence process,

The ICAI team is involved in the INSERM transversal program AGEMED on ageing aimed at deciphering the time-dependent mechanisms or clocks driving cellular senescence using several in vitro models of cellular senescence and inducers.The major aim of this on-going ambitious and large-scale collaborative project is to identify new biomarkers and pathways of SCs, 

Using a bank of human plasma samples, we recently characterized thioredoxin-80 (Trx-80) as a potential ageing biomarker, a truncated version of the well-known antioxidant and anti-inflammatory protein thioredoxin-1 (Trx-1). Trx-80 was shown to activate NLRP3 inflammasome and promote the pro-inflammatory phenotype of Macrophage (M1). Loss of Trx-1 over Trx-80 with age appears as molecular switch from an anti-inflammatory to a proinflammatory phenotype and may largely contribute to oxidative stress, and inflammation that is associated with ageing,

ICAI team is involved in a Leducq Foundation consortium, the long-term objective of which is to boost the cardiac regenerative potential through identifying the basis of cardiomyocyte cell cycle arrest and its regulation. 

ICAI is a lead team in Kallikrein-related peptidase’s field and contributed/contributes to the identification of innovative series of pharmacological modulators at the interface with medicinal chemistry, in the context of inflammatory and age-related disease’s.

Future directions

Axis 1- Cellular senescence and innovative anti-ageing agents.

Cellular senescence is defined as a terminal growth arrest triggered by different stress signals. Although senescent cells (SCs) can no longer proliferate, they remain metabolically active and adopt the so-called senescence-associated secretory phenotype (SASP). Accumulation of SCs in tissues of older organisms is known to trigger or exacerbate ageing-associated inflammation and its related-diseases. SCs differ depending on the cell type, how senescence was triggered, and how long senescence persisted, however molecular clocks driving cell senescence during ageing are still poorly understood. One of our objectives is to better characterize senescent cells of interest, macrophages, skeletal muscle, microgial cells, neurons, cancer cells to dissect out disrupted processes (metabolism, antioxidant systems, proteolytic components) by developing robust in vitro models. The ultimate goal is to derived specific senescence signatures that can either serve as ageing biomarkers or be exploited as therapeutical targets. We particularly propose to study the impact of intermittent hypoxia during sleep apnea on the triggering of neural senescence and role in AD physiopathology. Moreover, we also examine the interplay between neuronal senescence, iron homeostasis and the deregulation of the KLK8 serine protease to potentially derive from these findings a new class of multifunctional neuroprotectors that simultaneously impact several pathways involved in AD physiopathology. Thanks to our pluridisciplinarity, ranging from chemical biology to in vivo analysis, our ambition is also to identify innovative and first-in-class rejuvenating molecules, including senomodulators, anti-oxidants and anti-inflammatory agents. Pharmacological depletion or regulation of senescent cells using respectively senolytics or senomorphics represents a promising approach.However, their translational potential to the clinic remains limited due to their lack of specificity, leading to adverse off-target effects. We propose a pluridisciplinary approach to derive senomodulators that will selectively eliminate senescent cells while sparing other cell populations through: (1) the targeting of surfaceome of SCs by identifying specific markers, (2) the design of new class of multifunctional compounds sensitive to a giving senescence microenvironment. 

Axis 2- Loss of proteostasis and pathological proteolysis.

Deregulated proteolysis is a characteristics of many pathological and ageing-related processes. The team is particularly expert on the enzymology of proteases particularly kallikreins (KLK) and on their role on age-related diseases. The team is particularly invested in the development of pharmaco-modulators that counteract unopposed activity of CNS kallikreins. Beyond KLK6 inhibitors as regenerative strategy in demyelinating diseases, we also study other lead neurodegenerative diseases such as Lewy Body Dementias and identified original candidates that will be subjected to a preclinical study in close collaboration with ND-Bioscience (EPFL, Lausanne). We propose to decipher the role of extracellular serine proteases on the cell plasticity and senescence of cancer cells, particularly we will address their impact in the aggressiveness of colon cancer. In elderly, circulating levels of Trx-80 increase and was shown to drive macrophages switch to pro-inflammatory phenotype contributing to enhance inflammatory environment. Hence identifying the proteolytic machinery that leads to Trx-80 is of a great interest to better understand molecular basis of its genesis and identify potential therapeutical targets in inflammageing and related pathologies. Namely, the intra or extra proteolytic networks involved in the age-related and pathological cleavage of Trx-1 will be depicted by using both in vitroenzymology and integrated degradomics approaches. 

Axis 3- Inflammation, tissue plasticity and regeneration.

Heart failure (HF) and atherosclerosis are major age-related CVDs, and notably loss of cardiac regeneration after ischemia and in response to inflammageing belongs to the major causes of ageing.A major blockade to this regeneration is the low capacity of cardiomyocytes to self-renew. Recent studies have shown that exposure to atmospheric oxygen at birth is responsible for cardiomyocytes proliferation arrest through an increase of ROS production. Thus, the central hypothesis of our project was that cardiomyocytes redox state regulates the endogenous regenerative capacity of the mammalian heart. To test this hypothesis, we are currently using two parallel strategies, ie (1) the modulation of mitochondrial ROS production through regulation of Uncoupling Protein 2 (Ucp2) expression and (2) the decrease of ROS levels using Thioredoxin (Trx-1 and 2) upregulation strategies and mimetic peptides. 

In another hand, macrophages have high phenotypic plasticity, are key inflammatory players in aged organisms contributing to the installation of inflammageing. In ageing, tissue microenvironment largely program macrophages for pro-inflammatory and senescent phenotypes. Moreover, individual macrophages hold the potential for a dynamic phenotype switch and are a meaningful target for therapeutic intervention. Hence, we aim in better understanding the mechanisms that triggers macrophage senescence and its role in the development of age-related diseases.

Collaborations

Dr Brahim Nait Oumesmar, Brain Institute, Sorbonne Université, Paris 

Dr Nicolas Masurier, Max Mousseron Institute (IBMM), Montpellier University

Dr Han Li, Pasteur Institute, Paris

Dr Jean-Pierre Vartanian, Pasteur Institute, Paris

Dr Sakina Mhaouty-Kodja, - Neuroscience Paris-Seine – IBPS, Paris

Dr Marie Clotilde Alves-Guerra, Institut Cochin, Paris

Dr Carine Nizard and Dr Anne-Laure Bulteau, LVMH Recherche, Saint-Jean de Braye

Dr Christophe Capallere, Ashland, Sophia Antipolis

Dr Anne Salvayre : INSERM / Université Paul Sabatier UMR 1048, I2MC, Toulouse

Dr Luke Szweda and Dr Hesham Sadek, UT Southwestern Medical Center, Dallas, USA

Dr Miguel Torres, CNIC, Madrid, Spain

Dr Yasmine Aguib and Dr Magdi Yacoub, Magdi Yacoub Institute, Harefield, UK

Dr Renato Feirrera Freitas, Federal University of ABC, Brazil

Dr Bernard Pirotte, Faculty of Pharmacy, University of Liège, Belgium

Dr Natalia Ignatenko, University of Arizona, Tuscon, USA

Dr Viktor Magdolen, Technical University de Munich, Germany

Dr Morley Hollenberg, University of Calgary, Canada

Dr Maria Brattsand, Umeå University, Sweden

Dr Eleftherios Diamandis, Mount Sinai Hospital, Toronto, Canada

Dr Hilal Lashuel, EPFL, Lausanne, Switzerland