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Proof of resistance

Team from USP details the mechanisms by which adepts of moderate physical activity beat sedentary people in the fight against infections and tumors

As in the finals of a championship, it is impossible to please both teams. The sedentary are going to feel uncomfortable, maybe to the point of rethinking their justifications for not moving their bodies more than the minimum necessary, while those who practice regular and moderate physical activity will certainly have their pride boosted when they get to know the results reached by researcher Luis Fernando Costa Rosa. His work, carried out at the Biomedical Sciences Institute (ICB) of the University of São Paulo (USP), reveals the mechanisms by which sportsmen are better prepared than those who are adepts of immobility to face infections caused by viruses or bacteria. The lovers of movement also come out ahead in resistance to cancer, as is indicated by one of this group’s experiments: rats that did one hour of treadmill a day – equivalent to two or three hours for humans – survived for twice the time expected a Walker tumor, one of the most lethal, which leads to death in a couple of weeks.

Analyses of the blood taken both from laboratory animals and from professional sportsmen indicate that different kinds of sports, such as swimming or running, determine different responses from the immune system. Depending on the intensity and on the muscle that are activated, there may be a greater or lesser mobilization of blood cells or of substances called cytokines, which bring about an integrated action of the immune system. The conclusions open up the possibility of indicating the most suitable exercises for specific diseases, something until now done only on the basis of intuition, without any experimental evidence.

The team from USP concluded, for example, that swimming helps to control rheumatoid arthritis, a kind of chronic and incurable inflammation that develops in the joints, with progressive pain and deformation. It is estimated that there are in Brazil some 2 million sufferers from rheumatoid arthritis, which is more common in women, above all those over the age of 50. With the caution that typical of researchers, Rosa warns, though, that the conclusions emerged from experiments with rats, and that is still early to think of immediate applications in human beings.

But there is one part of this research whose results can already be adopted. The team from USP examined the energy supplements based on amino acids (the units of proteins) sold in stores that are often in the neighborhood of fitness centers – and the conclusion is that they do not always do all that one imagines them to do. To the displeasure of those who dream of quickly acquiring a body like Arnold Schwarzenegger’s, the bad news is that amino acids in general do not increase muscle mass – the supposed effect of anabolic steroids. On the other hand, at least one of them, glutamine, really does work like an extra source of energy for cells that proliferate rapidly – both those of the immune system and those of the wall of the intestines – during physical exercise. Accordingly, glutamine satisfies the immediate needs of the organism, in a process that exhausts itself with the end of the exercise, without anything being left over to make the arms or legs more presentable.

Rosa began to study the role of glutamine in the alterations of the immune response of professional athletes – more subject to physical stress and to infections than sedentary individuals – in 1996. He had just got back from postgraduate studies at Eric Newsholme’s laboratory, in Oxford, England – it was Newsholme who discovered that glutamine is the main source of energy for the cells of the immune system. Rosa detailed this process and proved that the action of glutamine is complementary to that of the principal molecule that provides the organism with energy, glucose, even though they both follow different biochemical paths, as published in an article published in May 2002 in the Nutrition magazine. “With this metabolic adaptation”, says the researcher, “the cells acquire versatility and produce energy using an abundant raw material, glutamine, while they use the glucose to synthesize proteins that are essential to the process of duplicating cells.”

This is not the only way by which the immune system helps the organism to produce energy more quickly. Only two years ago, Bente Pedersen, from the University of Copenhagen, in Denmark, discovered that interleukin-6 – a protein that activates the cells of the immune system in response to inflammations – helps to convert the reserves of glucose stored in the liver into glucose ready to be burnt by the cells. This work established another strategic function for the immune system – a set of 2 trillion white cells grouped under the generic name of leukocytes. Dispersed in the bloodstream and in the tissues, the leukocytes are equivalent to 2% of the body weight – if they could be gathered together, they would correspond, in mass, to the liver or the brain.

They used to be regarded just as cleaners of the organism, fit only to destroy viruses, bacteria and old or diseased cells, until Pedersen’s work came to light and attract other scientists. “There must be other proteins of the immune system that regulate the production of energy”, Rosa believes. At the head of one of the only Brazilian research centers for exercise and immunity, the researcher from USP is getting his wind back to follow along the trail opened up by the Danish researcher, ready to assess the importance of these mechanisms in human beings.

Gains in immunity
Those who do gymnastics, who swim, run or cycle at least three times a week – with an intensity equivalent to 60% or 70% of the maximum capacity for the consumption of oxygen, according to the classic definition of moderate physical activity – have quicker access than the couch potatoes to these alternative means of energy. But those who envy the now proven vigor of sportsmen have a consolation: ten minutes of going upstairs are enough to enjoy a now proven benefit of physical activity and to begin to muster the leukocytes. Half an hour after starting exercise, the blood that is running through the body contains a number of white cells that is two or even four times more than normal – the proportion depends on the intensity of the exercise, doing justice to those who do not think twice before stepping onto the treadmill or getting onto the bicycle.

But where did these leukocytes entering the circulation come from? They were released more intensely by the bone marrow, where they are produced, and taken from the depths of organs like the lungs, liver and spleen. It is only two days later, on average, that these cells come out of the arteries and veins and spread through the muscles and other tissues in the body – that they begin to cleanse the body of viruses, bacteria, toxins or even sick cells, thus fulfilling their best known mission.

This group’s work has also proved that moderate physical effort augments the response to vaccines. In an experiment carried out at the ICB with sedentary rats, the vaccine used against tuberculosis, BCG (standing for Bacille Calmette-Guerin), increased by 69% the quantity of a kind of antibody called immunoglobulin g (IgG), while the trained rats gained almost double (135%) the quantity of these antibodies. Physical activity may also recover the losses from the immune system caused by malnutrition, as is indicated by a work whose detailed conclusions should come out shortly in the Clinical Nutrition magazine.

Exploring these lines of study, the two with doctor’s degrees, eight studying for a doctorate, two for their master’s degree, and eight trainees in Rosa’s team – they all swim, run or cycle, although the coordinator of the laboratory denies that an affinity for sport is a curricular requirement – are giving scientific support to the trite saying that physical activity does you good. But the search for explanations for the gains in immunity calls for as much stamina as the marathon. In March 2001, Reury Frank Pereira Bacurau, one of Rosa’s students, concluded his doctorate showing the action of physical effort against Walker’s tumor, which attacks such vital organs as the lungs, the liver and the intestines.

Normally, moderate exercise does the organism good, and intense exercise tends to be harmful, for consuming too much energy. Bacurau, though, demonstrated successfully that, in the case of cancer, both one kind and the other may be benefic. Left hanging in the air, though, was the doubt over how the organism gets this benefit. Only now, two years later, has it been possible to explain the results in a more consistent manner. Physical activity seems to act as a marker of time – the rats in the experiment would go to the treadmill always at 8 o’clock in the morning, five times a week.

The running may work just like melatonin, the hormone produced by the pituitary gland at the base of the brain. For being released in a larger quantity at night, melatonin lowers the temperature of the body and induces sleep. Accordingly, it acts like a regulator of the biological clock, governed by the alternation between light and dark. The regularity with which it is released – just as the exercised carried out at the same time – determines the pattern for the functioning of the other processes of the organism, like digestion, heartbeats and breathing.

The growth of a tumor, in any part of the body, disrupts the production of melatonin and disorganizes the rhythm at which the organism was accustomed to function – this is part of the organic disorder known as cachexia. “When cachexia begins, the organism gets lost, but exercise may partly replace the nightly peak of melatonin”, Rosa says. “The organism seems to swap the signal from the melatonin for the exercise, recovering, at least in part, the previous organization.” During exercise, there is intense communication between the nervous, hormonal and immune systems, which are mobilized in order to generate energy as quickly as possible (see the illustration on the previous age). The experiments carried out at the ICB’s laboratory reinforced the idea that the hours on the treadmill the rats were submitted to may have reestablished the connections lost with the advance of the tumor.

Relief for arthritis
Little by little, the hypothesis is gaining strength that different exercises may help to resolve different diseases. To reduce the pains in the joints caused by rheumatoid arthritis, for example, it is now known that swimming is an effective activity, as shown by Francisco Navarro, another of Rosa’s students, in work with female rats – this problem is more common with the female ones. In comparison with the animals that kept far away from the water, a decrease of up to 40% was to be seen in the symptoms of rheumatoid arthritis, by means of markers of pain, such as prostaglandin, in rats that swam one hour a day, five times a week. It is also clearer why exercise does the heart good.

Generally speaking, it is because it stimulates the production of the so-called pro-inflammatory cytokines – like the Tumor Necrosis Factor alpha – in a process that leads to the recovery of the heart of infarcted rats, according to the preliminary results of a study to be presented this month in Copenhagen, at the International Society of Immunology and Exercise Symposium. At this scientific meeting in the Danish capital, Rosa will subject himself to cross-examination by other specialists also with the most recent results on malnutrition and physical activity.

It has been known for at least 30 years that the lack of food reduces the production of cells in the immune system – as, indeed, it affects the whole organism. As the team from the ICB demonstrated, though, moderate exercise turns this loss around and increases the production of cytokines and the proliferation of lymphocytes, a kind of leukocyte, in a process managed by glutamine. Produced mainly by the muscle cells, this amino acid also puts back into equilibrium the two kinds of immune responses: the cellular, activated in the fight against tumors and infections, and the humoral, driven by antibodies and adopted against parasites and in allergic reactions.

Besides the novelties on the processes that go on in the inside of the leukocytes, the researchers discovered a phenomenon they called the Paradox of the African Runner: undernourished rats run better than well nourished ones. “It may be that they run faster for having half the weight of the well nourished ones, or for managing to store more energy, since they have spent 23 hours resting and one hour in activity”, says Rosa. “In the hour they use up energy, they have more reserves than the other group.” The team from USP reinforces the results by accompanying professional athletes, like Rodrigo Tadei and Edmundo Caetano, two stars of the Brazilian triathlon who have been taking part in the researches for five years.

The study, which showed, for example, the importance of glutamine for the athletes’ immune response as an extra source of energy, was carried out on 12 triathletes who swam 1.5 kilometers, cycled 40 kilometers and ran for another 10, as well as on 24 marathon runners, who covered a 30-kilometer course in two hours – one month before the competition, they stretched their arms out for the first blood sample, the analysis of which was to set the foundations for the study. Rosa himself gave his blood for science, literally.

It was in January last year, when he got on his bicycle, his student for a doctorate Reinaldo Bassit got onto another, and the two set pedaling off en route to Uberaba, in the state of Minas Gerais, 500 kilometers from São Paulo. They would stop every 12 hours, after having covered 250 kilometers, and would give a little blood to a support team that followed them in a van. “We intended to do the 1,000 kilometers there and back, but we only did 700, because on the way back it began to rain and get very windy, near Ribeirão Preto, and we had to quit “, says the researcher-sportsman, who was an rower for 18 years. He swapped the boat for a racing bike, but he still wakes up at half past four in the morning to pedal from 80 to 120 kilometers. He arrives at the laboratory at eight, and whenever he manages to free himself from his family duties, ends the day running the 12 to 15 kilometers back home. He is, by the way, the runner who appears in the illustration and the swimmer above.

The project
Influence of Immune Exercise on the Immune Response of Undernourished Rats (nº 01/06655-1); Modality Regular line of research grants; Coordinator Luis Fernando Bicudo Pereira Costa Rosa – Biomedical Sciences Institute at USP; Investment R$ 383,047.25