The objective is to study the relationship between nutrition and intrinsic capacities and understand the impact of Reactive Oxygen Species (ROS) metabolism in this context. For this, different approaches will be carried out within the framework of the INSPIRE platform to promote healthy aging. First, the epidemiological component will be made from data from human cohorts, aged 70 and over, randomized with multi-domain interventions in order to analyze the link between the nutrition and intrinsic abilities. Existing cohorts (MAPT, NOLAN, COGFRAIL) will be analyzed as well as the ongoing cohort of the INSPIRE project. We developed a mathematical model centred on the mitochondrial dysfunctions and more precisely on the dysfunction of mitochondrial respiratory chain (MRC) as it was shown to be a major point in ROS production (80% of total ROS production).

The maintenance of healthy mitochondria is critical for brain functions throughout adult life. Aging is associated with a decrease in mitochondrial quality, the decline of biological functions and the development of several diseases. 

Biological ageing is a complex process, influenced by genetic and environmental
factors. Factors influencing the ageing of the mouth are in part genetic, but are mainly related to lifestyles habits, and hence often depend on socio-economic status. Numerous diseases of the oral cavity share common risk factors with other non-communicable diseases like diabetes or cancer. There is a bidirectional relationship between oral health and biological ageing. On one hand, age-related diseases, like dementia, cancer or geriatric depression, are frequent in elderly persons, and might have a direct impact on oral health. For example, oral health status may be jeopardised by frailty, disability, care dependency or limited access to professional oral health care. Another example is the side effect of several medications in causing xerostomia and hyposalivation. On the other hand, oral health problems such as periodontitis, unstable removable dentures, insufficient chewing or dysphagia are related to low Oral Health Reported Quality of Life scores, and nutritional state in geriatric individuals.

Deep convolutional neural networks (CNN) have been tackling, with impressive results, most of the pattern recognition challenges of the past few decades. With the advent of efficient digitization techniques for microscopy slides (Whole slide images, WSI), the use of deep learning models on histopathology images has been widely explored as it may save time and reduce errors in the diagnosis, prognosis or response to therapy predictions.

The objective is to study the relationship between nutrition and intrinsic capacities and understand the impact of Reactive Oxygen Species (ROS) metabolism in this context. For this, different approaches will be carried out within the framework of the INSPIRE platform to promote healthy aging. First, the epidemiological component will be made from data from human cohorts, aged 70 and over, randomized with multi-domain interventions in order to analyze the link between the nutrition and intrinsic abilities. Existing cohorts (MAPT, NOLAN, COGFRAIL) will be analyzed as well as the ongoing cohort of the INSPIRE project. We developed a mathematical model centred on the mitochondrial dysfunctions and more precisely on the dysfunction of mitochondrial respiratory chain (MRC) as it was shown to be a major point in ROS production (80% of total ROS production).

The general aim of the thesis project is to better understand the pathophysiology of Noonan syndrome (NS), a relatively frequent (1/2000 live births) genetic disorder associating cranio-facial features, cardiopathies, short stature and learning disability. Beside these congenital involvements, patients with NS also display a wide range of clinical traits that are reminiscent of early ageing, the pathophysiology of which is misunderstood: bone defects (e.g. decreased bone mass), muscle weakness, predisposition to myeloproliferative disorders (e.g. juvenile myelomonocytic leukaemia, JMML) and metabolic imbalance (e.g. insulin resistance). Interestingly, we and other obtained striking evidences that many of NS impairments are related to the dysfunction of cells from the myelomonocytic lineage : myeloid precursors in JMML, osteoclast in bone defects, monocytes/macrophages in insulin resistance. As a result, our project now aims

1. to understand the cellular and molecular mechanisms that confer on these cells their pathophysiological potential with a particular focus on the pro-senescent potential of RAS/MAPK hyperactivation,
2. to assess the relative contribution of myelomonocytic cells to the development of the different traits of the disease, and
3. to translate the obtained observations to the clinics.

Cutaneous melanoma is a very aggressive and immunogenic skin cancer that can be treated by immunotherapy based on the administration of antibodies neutralizing CTLA-4 and PD-1, two immune checkpoints expressed on the surface of activated T lymphocytes, acting as a real brake on lymphocyte activation. To date, the best clinical responses in patients with advanced melanoma have been obtained with the combination of ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). However, almost half of patients with metastatic melanoma do not respond to this treatment and there are no biomarkers predictive of resistance. In this context, cellular senescence, a process of genetic, epigenetic and metabolic reprogramming as well as morphological modifications of the cell during aging, seems to play a dual role in resistance to immunotherapy.

The thrombotic risk, mainly due to blood platelet dysfunctions, has a considerable impact in the cardiovascular complications in elderly. However, the mechanisms involved in the increased thrombotic risk and platelet dysfunctions associated to aging are still poorly characterized and therapeutic strategies are very limited. In this context, it seems urgent (i) to better understand the mechanisms involved in the dysfunction of platelet production and activation in an aging context and (ii) to find new pharmacological platelet targets or biomarkers in order to prevent and limit thrombotic complications. The research PhD project aims to finely study the processes of production and activation of blood platelets, from molecular mechanisms to pathophysiology, in an aging context. This project will use transgenic mouse models and a panel of in vivo experimental procedures in mice as well as in vitro and ex vivo imaging and biochemical techniques.