The Metabolism, Aging and Disease Thematic Strand integrates CNC.IBILI expertise of 54 Ph.D members in cell-, animal- and patient-based models relevant for the study of metabolic and chronic diseases and aging-related cell and tissue dysfunction, in line with Horizon2020, with emphasis on an integrative approach from molecule to man. The strand has internationally competitive expertise that focuses on the loss of cell function brought about by mitochondrial (dys)function, pro-inflammatory cytokine and reactive oxygen species (ROS) production and actions, and disruption of intracellular protein quality control mechanisms. At a systemic level these processes are associated with alterations in both tissue and whole-body metabolic fluxes and a chronic excess of pro- over anti-inflammatory cytokines.
These studies are highly timely and relevant given the changes in lifestyle and demographics of the Portuguese population. Due to ongoing urbanization, Portuguese society is increasingly exposed to a lifestyle characterized by overconsumption of saturated fats and sugars and a reduction of daily physical activity. This change is implicated in the increasing prevalence of obesity-based metabolic disorders, including type 2 diabetes (T2D) and related complications that include cardiovascular disease, Alzheimer’s disease (AD) and certain types of cancer. This lifestyle change is coupled with a demographic shift towards an elderly population. This impending “perfect storm” of aging and lifestyle risk factors will not only generate a surge in metabolic and degenerative diseases incidence, but also confound our understanding of lifestyle, nutrition and aging contributions to the aetiology and epidemiology of these diseases.
The groups that support the Thematic Strand have established expertise in nutrient metabolism, mitochondrial physiology, inflammation and intracellular protein quality control. This expertise provides a framework for a more holistic understanding of how disease and aging are linked to changes in nutritional state, cellular organelle function, energy generation, and turnover of proteins and other cellular building blocks. Importantly, these themes connect with approaches and objectives proposed for the other Thematic Strands, thus focusing the expertise gathered in a few strategically competitive areas of disease management that progress from cellular dysfunction, to the use of metabolic-based tracers for diagnostics, and to the proposal and testing of novel clinically-relevant targets.
Metab 1: Cell Metabolism and Quality Control
Metab 2: Mitochondria, Metabolism and Disease
Metab 3: Metabolic Control
Metab 4: ImmunoMetabolic Pharmacology
Neuro 7: Aging and Brain diseases: advanced diagnosis and biomarkers
Taking advantage of the expertise of the constituent groups, and heeding the Horizon2020 emphasis on understanding effects of demographic changes on wellbeing, we will focus on improving our understanding of chronic diseases that are anticipated to become more frequent in the population. These include Alzheimers disease per se, Type 2 diabetes, nonalcoholic fatty liver disease and sarcopenia. Our flagships represent pathophysiological nodes that we hypothesize to be common themes of these disorders, namely mitochondrial function, protein quality control, ROS management, intermediary metabolic fluxes and inflammation. Integrating these flagships will provide a more effective paradigm for understanding and management of these diseases.
1. Cell Quality control disruption in aging and disease
We will investigate mitochondrial function as a continuum of events resulting from constant input of nutrients and signals, as well as pre-determined genetic and epigenetic backgrounds. Studies will focus on whether mitochondrial capacity can be programmed in utero (by diet, exercise or exposure to xenobiotics), and transmitted transgenerationally via epigenetically-modified gametes, resulting in pre-disposition to disease or accelerated aging.
Failures in mitochondrial quality control and redox status, impaired management of misfolded/aggregated proteins and altered intercellular communication all conspire to potentiate cell degeneration. Thus, an overarching goal is to clarify the precise sequence and mechanisms by which each of these events propagates and/or reinforces the others and whether such a model better informs or predicts neurodegenerative and metabolic diseases, as well as the effects of aging per se. Since mitochondrial abnormalities and impaired protein processing appear to be defining events in the molecular pathologies of the diseases noted, we will focus on therapeutic strategies that restore these functions.
2. Immune system deregulation
Since immune system over-activation is a key trigger for cell degeneration, we will seek to further understand the underlying molecular mechanisms of this process and to develop novel approaches for reducing unintended effects of immune system activation without disabling its protective role. These include: 1) modulating the cytotoxic potential of autoreactive CD8+T lymphocytes; 2) defining autoantibody contribution to degeneration of the brain; 3) controlling ROS production to correct imbalances between their immune-regulatory and their pro-inflammatory functions.
3. Substrate availability and metabolic pathways
A functional cell requires that its metabolic demands be met by efficient utilization of preferred substrates. This process may be disrupted externally by changes in substrate availability; for example abnormal blood glucose and lipid excursions in diabetes, or by cellular events that disrupt metabolic flow, for example the inhibition of glycolytic enzymes by ROS or impaired electron transport in mitochondria. Quantification of substrate selection and utilization in this setting has two fundamental outcomes. First, it informs the consequences of intracellular damage and malfunction on specific metabolic fluxes. Second, it guides interventions of nutrient control and/or modification for restoring intracellular energy and metabolite homeostasis. Assessment of hepatic glucose and glycogen fluxes in diabetes have been successfully translated to the clinical setting via stable isotope tracers and noninvasive chemical biopsy methods. Future targets will include measurement of amino acid fluxes to inform sarcopenia in the elderly and identifying nutrient fluxes that promote triglyceride accumulation in fatty liver disease. The reasons are 1) our tracer methodologies have sufficiently progressed for translation to humans and 2), these conditions involve interplay of nutritional, inflammatory and intracellular signaling/trafficking factors that can be effectively addressed by this Strand.