BJRP 011001

Impact Of Lifestyle And Ageing On Brain Function Via Their Effects On Neuroenergetics: Role Of Brain Monocarboxylate Transporters

Abstract

There is an ever increasing scientific interest for the interplay between cell’s environment, lifestyle and ageing. Lifestyle, which includes regular exercise and diet, can have profound impact on our brain health. The precise mechanisms by which these conditions can improve brain activities and the nature of the specific molecular targets affected in the brain are not entirely clear. One aspect that has not been thoroughly explored is the potential effect of regular exercise and diet on neuroenergetics, i.e. the capacity of the brain to generate and use the energy necessary to support its activity. Additionally, although it is known that caloric restriction and regular exercise affect longevity, the exact molecular mechanisms through which they influence various cell signaling/modulators of lifespan remain a largely unresolved issue. Thus, it could be envisaged that decreased neuroenergetics capacity during ageing could also be involved in the loss of neural cell viability and impaired cognitive performance.

The classical view of glial cells as simple supportive cells for neurons is being replaced by a new vision in which astrocytes, a subtype of glial cells in the CNS, could regulate synaptic efficacy and plasticity notably via energetics (Pellerin, 2008). Ca2+ signaling participates in the cooperation between astrocytes and neurons by modulating several functions including neuroenergetics. Among nutrients, glucose constitutes an evolutionarily stable, precious metabolic fuel which is catabolized through glycolytic and oxidative pathways. However, astrocytes play a central role in supplying neurons with the alternative energy substrate lactate (obtained from glucose) in register with changes in synaptic activity (Pellerin, 2008). This new concept termed the astrocyte-neuron lactate shuttle (ANLS) hypothesis suggested that the presence of a metabolic cooperation between astrocytes and neurons is essential for several brain functions as well as for brain energetics in general. Recent findings have highlighted the importance of monocarboxylate transporters (MCTs), able to transport lactate, pyruvate and ketone bodies, in the regulation of cooperative energy substrate utilization by neurons and astrocytes (Maekawa et al., 2008; Pierre et al., 2009). 

The main objectives of the present project are the followings: 1) Unravel the alterations in neuron/astrocyte metabolic interactions, emphasizing on MCT expression occurring in specific brain regions following exercise training and/or caloric restriction, and in correlation with ageing. 2) Describe the signalling mechanisms that might be responsible for these changes in MCT expression observed in both astrocytes and neurons. 3) Investigate the importance of MCTs for the improvement in brain functions observed following exercise training and/or caloric restriction, searching for their beneficial effects during ageing. 4) Evaluate the effects of in vivo administration of guanosine, aiming to reveal the involvement of neuroenergetics in the neuroprotective effects of guanosine. 5) Evaluate the effects of in vivo administration of lactate on LPS-induced neuroinflammation, aiming to demonstrate a neuroprotective effect via an improvement in energetics. 

In order to fulfill these objectives, it is proposed to conduct a series of experiments in vitro and in vivo, taking advantage of materials, technical skills and experience provided in a complementary manner by the Swiss and the Brazilian partners. Thus, in parallel, Brazilian and Swiss partner labs will investigate the impact of exercise and caloric restriction respectively on neuron/astrocyte metabolic interactions, with emphasis on expression of MCTs in various brain regions of mice at various ages. A first meeting between the main investigators of the partners in the two countries will take place to share and exchange both materials and technical skills.

It is expected that such a project will provide some invaluable information about whether and how ageing/lifestyle interaction can benefit brain activity through the modulation of energetics parameters. In addition to promote our understanding about mechanisms underlying brain plasticity and energetics, such knowledge could eventually benefit to governmental agencies in order to establish new guidelines to improve general public health.

 

Prof. Luc PELLERIN
Dr Diogo Onofre Gomes DE SOUZA