Chronicles

The incidence and prevalence of age-related neurodegenerative diseases such as Alzheimer’s Disease, Parkinson’s Disease and others, tends to increase as the average life expectancy of developed societies lengthens. In 2014, the European Union (EU) presented an aging index of 119.8% - the Portuguese index being 138.6%. These values rendered Portugal at the expectancy of an accelerated increase in the number of cases of age-related neurodegenerative diseases, conditions with devastating consequences at a social, economic and mental health levels. These disorders have a chronic and progressive nature and are characterized by the death of neurons in selected brain areas, a process for which there are not any neuroprotective treatments or cures currently available. Given this situation, the discovery that regular physical activity can constitute a preventive or therapeutic tool together with healthy dietary habits and, in certain situations, as an adjuvant to pharmacological agents, brings a window of hope to our aged society.

During the practice of physical activity, in which exercise is included, our organism suffers alterations that can be either acute or chronic (adaptations) depending on the type, intensity, duration and regularity of the physical activity at hand. The increase in heart frequency, ventilation and sweating are part of the acute effects of exercise practice. In what regards adaptations, these include muscular hypertrophy, the reduction of fat mass, decreased cardiorespiratory frequency and blood pressure, a more efficient distribution of the blood flow and an increase in oxygen consumption, namely in metabolically active organs such as the brain.

At the level of the brain, exercise practice stimulates the formation of new blood vessels (angiogenesis), improving the brain’s blood flow, as well as the supply of oxygen and glucose (energetic substrate) to the neurons. These adaptations facilitate the synthesis and secretion of neurotrophines, namely the Brain-Derived Neurotrophic Factor (BDNF). It also exists a modulation of the levels of some neurotransmitters, an increase in cerebral plasticity (structural and functional changes that the brain undergoes in response to different stimuli) and of neurogenesis (formation of new neurons), that can result from epigenetic modifications that alter the expression of certain genes. In addition, during the practice of exercise, the muscles liberate molecules that stimulate an increase in BDNF levels in the brain. All these phenomena improve the function of the brain, namely learning and memory, attention and concentration. In fact, many studies suggest that the volume of the brain areas that control reasoning and memory (the prefrontal cortex and the medial temporal cortex) are higher in people that practice exercise compared to those that do not. In addition, exercise practice lowers stress and anxiety levels and improves mood and sleep which, indirectly contributes to a good function of the brain, postponing brain-aging, cognitive decline and reducing the risk of developing neurodegenerative diseases. Most studies conclude that aerobic training (such as running, walking, biking or swimming), which stimulates oxygen consumption for energy production, is what benefits the brain the most, since these activities help the heart pump more blood, promoting in turn a good oxygenation and glucose supply to the neurons.

With exercise practice several cellular and molecular mechanisms are activated. One of the most relevant molecules is the AMP-activated Protein Kinase (AMPK), whose function increases when ATP levels (cellular energy) decrease. Since exercise practice induces ATP consumption in our cells, the enzyme AMPK becomes active and signals a wide range of events in these cells. Amongst these, we can remark the formation of new mitochondria, the energy factories of our cells. AMPK also leads to the expression of more glucose transporters, facilitating the entry of glucose into the cells.

It was recently verified that, via AMPK, the practice of exercise also promotes the activation of the autophagy pathway. Autophagy is a cellular mechanism that allows for the degradation of toxic proteins and/or of dysfunctional organelles, like mitochondria subject to cellular aging. This way, autophagy allows for non-dividing cells, such as neurons, to destroy toxic protein aggregates, a typical phenomenon of neurodegenerative diseases. Making an analogy with our daily life, it is as if the neurons would be the streets of our city and the toxic protein aggregates were an obstacle that prevents the cars to circulate within them, resulting in a traffic jam. In a simple way, this is what happens in the brain: an accumulation in toxic residues (protein aggregates) causes the alteration of neural communication and, consequently, leads towards neuronal death. On the other hand, the degradation of damaged mitochondria warrants that the cells will not become metabolically compromised. In fact, it has been verified that a moderate exercise activates the autophagy pathway, especially the mitophagy (degradation of mitochondria by autophagy), preventing the neurodegenerative process. Several studies have proved that the activation of AMPK as a result of energetic expenditure (ATP) during exercise practice leads to the inhibition of molecules that induce inflammation, one of the processes involved in neuronal lesions.

Alzheimer’s disease is one of the most known neurodegenerative diseases and represents the main cause of dementia worldwide. This disease is characterized by the formation of senile plaques and neurofibrillary tangles at a neuronal level, that result in the aggregation of proteins with an abnormal conformation. The hippocampus, the brain structure associated to our memories, is the main damaged area in this disease, and therefore, alterations in memory are the most characteristic symptoms. Several studies have highlighted that daily exercise practice does not only reduce the risk of incidence of Alzheimer’s Disease in aging adults, but also reduces the cognitive decline in these patients and helps with the maintenance of autonomy in daily routines. Activities such as walking, running, swimming, tennis or going to the gym (elliptic, treadmill, static bike,…) seem to be the most adequate. Relaxing activities can also be interesting, since as the disease advances the mental confusion, and with that some mood changes and aggresivity signs, increase. One study went even further by concluding that aerobic physical activity leads to an increase in the volume of different brain regions in aged individuals as a result of the acquired cardiovascular capacity in response to physical activity.

The control of our movements is due to a complex and extensive network of neurons that allows for the communication between different brain regions. The liberation of the neurotransmitter dopamine by the neurons in the substantia nigra is responsible for the control of our voluntary movements. In Parkinson’s Disease, there is a loss of the control of these movements secondary to the progressive loss of the neurons liberating dopamine. As a result, the typical symptoms of this disease emerge:  stiffness, body tremors and posture changes. The practice of exercise seems to reduce the incidence and postpone the progression of Parkinson’s Disease. A study in adults on an initial stage of the disease revealed that treadmill running induces an increase in the affinity that dopamine has to its receptor, which reverses the effect of a decrease on its levels. Furthermore, these patients displayed an improved body posture when compared to patients that did not practice this kind of activity. Another study demonstrated that if, in order to stimulate the cognitive capacity and safe locomotion, a training with virtual reality is added to the treadmill running, it is also possible to reduce the high number of falls of these patients.

Recent studies clearly show that the lifelong regular practice of moderate intensity exercise improves intellectual performance, reducing the risk of appearance of age-related neurodegenerative diseases such as Alzheimer’s Disease and Parkinson’s Disease. To sum up, exercise practice seems to be a worthy ally since it results in an improved quality of life and promotes an active and cognitively healthy aging. The health of your brain depends on your choices!

Author:  Cláudia Pereira, Paula I.Moreira, Sandra M.Cardoso and Ana Cristina Rego are Researchers at the Center for Neuroscience and Cell Biology (CNC), University of Coimbra (UC). Fábio Sousa is junior researcher and Ana Catarina Pereira is MSc student, both at the Center for Neuroscience and Cell Biology (CNC), University of Coimbra (UC).

The project: This chronicle results from the collaboration between the Center for Neuroscience and Cell Biology (CNC) of the University of Coimbra, the European Advanced Training Network FOIE GRAS (http://www.projectfoiegras.eu), the Erasmus+ Program and the Academic Sports Federation University (FADU) in the scope of the European University Games Coimbra 2018.

Coordination: Anabela Marisa Azul, João Ramalho-Santos, Mireia Alemany i Pagès, Paulo Oliveira and Sara Varela Amaral

Illustration: Rui Tavares