How does physical exercise translate into better brains?

Age-related brain diseases (eg, mild cognitive impairment "MCI", Alzheimer, Parkinson) will increase dramatically with the aging population, representing the single most threatening burden of human suffering and social and economic cost in Western societies and eventually worldwide. Evidence from basic as well as clinical research indicates that physical exercise is an efficient intervention measure of low cost, and low risk. An important aspect is that it may serve to maximize the proportion of the life-time that an individual remains autonomous, before institutionalization becomes necessary. However, the biological basis is only partly understood. In particular, evidence is incomplete on which signals mediate the effects of exercise into the brain. We hypothesised that the change in the balance of lactate versus glucose as energy substrate during intense aerobic exercise may carry an important part of the exercise induced signalling from body to brain. For physical performance, training parameters have been optimized and genetically based variation in responsiveness deciphered. Corresponding data are lacking for effects on the brain. During the project period, we discovered that the lactate receptor, HCAR1 (also known as HCA1 or GPR81), is active in brain, implying that lactate released from skeletal muscles during intense exercise could act through HCAR1 as a body-brain signal. Work was therefore focused on clarifying this novel aspect of our hypothesis. Mice exposed to high intensity interval exercise on a treadmill 5 days a week for 7 weeks showed increased levels of the growth factor VEGF (which is known to stimulate the growth of nerve cells as well as thin blood vessels) and increased density of capillary blood vessels (ie, the site of exchange of oxygen and other materials) in brain. This effect was reproduced by injecting lactate subcutaneously in sedentary mice to achieve bouts of high blood lactate concentrations similar to those in exercised mice. In knockout mice lacking HCAR1, exercise or lactate did not change VEGF or blood vessel density. This is the first demonstration that a substance produced in large amounts by exercising muscle exerts a supportive effect in brain. Impaired blood supply is believed to contribute to the development of Alzheimer's disease, as well as to other age-related dementias. The findings suggest that HCAR1 is a potential target for prevention and therapy and that an 'exercise pill' may be developed as a supplement to physical exercise. This may be particularly useful in persons at high risk of developing Alzheimer's disease, who are typically unable to attain adequate levels of exercise. Genetically based variation in the ability to exercise was addressed in rat strains selected during 28 generations for high and low capacity for running (HCR and LCR). After high intensity interval training on a treadmill for 36 weeks (5 days a week for 12 weeks, 2 days a week for 24 weeks), mitochondrial volume as percent of total cytoplasm volume in hippocampus increased significantly in LCR rats. This change did not occur in HCR rats, perhaps reflecting the fact HCR rats are already in a state adapted to performing a high level of exercise. Similarly, the amounts of proteins protecting against damage caused by the formation of or damage by oxygen radicals in mitochondria (UCP2 and SOD2) were concomitantly increased or maintained, respectively, after training in LCR rats. No significant changes in UCP2 or SOD2 were observed after training in HCR rats. These findings indicate that a prolonged regime of bouts of high intensity interval exercise increases mitochondrial capacity in a brain region associated with memory, notably in individuals with low intrinsic aerobic fitness. The results have provided new biological understanding and are expected to lead to innovation on how to maintain brain health and handle the impending problem of the aging population.

Age-related brain diseases (eg cognitive impairment, Alzheimer, Parkinson) will increase dramatically with the aging population, representing the single most threatening burden of human suffering and social and economic cost in western societies and event ually worldwide. Evidence from basic as well as clinical research indicates that physical exercise is an efficient intervention measure of low cost, and low risk. An important aspect is that it may serve to maximize the proportion of the life-time that an individual remains autonomous, before institutionalization becomes necessary. However, the biological basis is only partly understood. In particular, evidence is incomplete on which signals mediate the effects of exercise into the brain. We hypothesise t hat the change in the balance of lactate versus glucose as energy substrate may carry an important part of the exercise induced signalling from body to brain. For physical performance, training parameters have been optimized and genetically based variatio n in responsiveness deciphered. Corresponding data are lacking for effects on the brain. The proposed research project will address these fundamental and practically important questions experimentally, bringing together top Norwegian expertise on neurosci ence (University of Oslo) with top expertise on exercise research (NTNU, Trondheim) and molecular biology (Rikshospitalet, Oslo University Hospital). We utilize recently available knock-out mice (generated by our groups), and draw on novel technology and knowledge from outstanding collaborating groups in the UK (Wellcome Trust Sanger Institute, Cambridge) and the USA (Salk Institute for Biological Studies, La Jolla CA). The results are expected to provide new biological understanding and to lead to innova tion on how to handle the impending problem of the aging population.