Study elucidates at the cellular level how exercise preserves physical fitness in aging – 01/17/2023 – Equilíbrio e Saúde

Experts agree that regular physical exercise is essential to ensure quality of life and longevity. However, little is known about how this habit influences the functioning of muscle cells. A new study conducted at the Institute of Biomedical Sciences at the University of São Paulo (ICB-USP) helps to understand, at a cellular level, how physical activity contributes to maintaining physical fitness even during aging.

According to the work, supported by FAPESP and published in the journal The Proceedings of the National Academy of Sciences (PNAS), the answer lies in the mitochondria. This important cellular component, responsible for providing energy to cells, is constantly remodeling thanks to a phenomenon called mitochondrial dynamics.

This organelle can split in two or join a similar one through processes called mitochondrial fission and fusion. Based on this dynamic, the distribution and function of hundreds or thousands of mitochondria present in muscle cells are coordinated.

Through experiments with a very simple model organism, the soil worm Caenorhabditis elegans, the researchers observed that, during aging, fragmented mitochondria accumulate in muscle cells [que são disfuncionais]. But when physical exercise is practiced regularly throughout life, the frequency of fused mitochondria increases, which benefits both mitochondrial metabolism and cellular functioning, thus contributing to the maintenance of muscle physiology during aging.

“In the work, we demonstrated that, in the muscle, a single session of physical exercise rapidly induces mitochondrial fission. And soon afterwards, after a recovery period, mitochondrial fusion occurs. Already daily sessions throughout life favor the appearance of mitochondria connected, thus delaying the mitochondrial fragmentation and the decline in physical conditioning observed during aging. In this way, physical exercise and mitochondrial dynamics showed an important association with the maintenance of muscle function in senescence. It was the proof of concept that was missing”, he says Julio Cesar Batista Ferreira, professor at ICB-USP and research coordinator.

In previous studies, the group had already shown that physical exercise acts in the treatment of cardiovascular diseases by promoting the appearance of fused mitochondria in the heart (read more here).

But it was still necessary to understand how physical activity impacts the aging of healthy organisms. And for that, the researchers chose to use the nematode C. elegans, considered an excellent experimental model for studying aging (read more here).

“It is very laborious and expensive to carry out a study on aging by following individuals or rodents for years, throughout their entire lives. The advantage of C. elegans is that it has a number of similarities with humans, but it has a life cycle of just 25 days. Thus, it was possible to show, for the first time, what happens to an organism that exercises throughout life and what are the critical cellular events involved in the process”, says Ferreira.

According to the researcher, the mitochondrial dynamics is important to maintain the quantity and quality of the mitochondria in the cell and, consequently, the proper functioning of the muscles. Through proteins called GTPases that “cut” and “glue” the mitochondria, the fusion or fission of these organelles occurs. “In this way, under stressful conditions, the proteins remove the part of the mitochondria that is not working to be destroyed and join the functional part with another mitochondrion. “

The results of the study indicate that both connectivity and the mitochondrial cycle of fission and fusion are essential for maintaining physical fitness and responsiveness to exercise during aging.

training protocol

One of the first steps of the study was to develop an exercise protocol for the worms. “Usually, these organisms live in a solid medium [na natureza eles vivem na terra e, nos laboratórios de pesquisa, em gelatina]. When we transfer them to a liquid medium, we observe that they increase the wave frequency associated with greater energy expenditure, similar to what happens to us humans when we exercise”, says Ferreira.

In this way, the researchers demonstrated that the daily exposure of the worms to the liquid environment results in a series of physiological and biochemical adaptations similar to those observed in humans and exercised rodents.

“We found that, when they exercise throughout their lives, the process of mitochondrial fusion and fission remains intact during senescence, unlike sedentary worms that accumulate fragmented and dysfunctional mitochondria already at ten days of life, when they are considered senile. regular exercise makes the worm have a better quality of life, which we measure by different indicators such as muscle function, mobility, food intake and resistance to different types of stress throughout life. exercised,” he points out.

According to Ferreira, worms that swam regularly until adulthood, but became sedentary during old age, also showed better indicators compared to those that were always sedentary. “This happens because there is a cellular memory created by the daily stimuli of physical activity, which is dependent on the process of mitochondrial fission and fusion and protects these organisms during aging”, she explains.

accelerated aging

Using genetic engineering techniques, the researchers turned off the main genes involved in the process of “cutting” and “gluing” mitochondria in the worms. This genetic modification caused an accelerated aging and, for these organisms, exercise started to have a toxic effect, since the remodeling, segregation and removal of dysfunctional mitochondria does not occur.

“This confirms the importance of mitochondrial dynamics both for senescence and for the practice of physical activity”, says Ferreira.

In a second part of the study, the researchers investigated whether increased longevity is accompanied by improved physical fitness in the worms. For this, experiments were carried out with strains of worms capable of living up to 40 days thanks to punctual alterations in the genome. Surprisingly, physical exercise had a toxic effect on four of the five long-lived worm strains tested in the study.

“We wanted to understand if increased longevity is associated with the same mechanism of improvement in physical fitness and responsiveness to exercise throughout life. This is a crucial question, given that the world’s population is living longer. However, the study showed that longevity is not necessarily related to quality of life. It is worth remembering that there is no equivalent in humans for these genetically modified worms and that they live almost twice as long as wild worms”, says Ferreira to Agência Fapesp.

metabolic sensor

Only one strain of long-lived worms (among the five studied) showed improvement in physical fitness throughout life. This strain expresses an enzyme called AMPK [sigla em inglês para proteína quinase ativada por monofosfato de adenosina] constitutively active, which acts as a metabolic sensor in cells, regulating energy and mitochondrial metabolism. In general, the production of this protein tends to decrease with aging.

“In this experiment, only worms that had active AMPK throughout their lives [graças a mutações feitas em laboratório] lived and swam better longer. However, when we genetically turned off the proteins that regulate mitochondrial dynamics, the effects of AMPK were abolished. In this case, the worms showed reduced physical fitness and, consequently, a decline in muscle function in old age”, says Ferreira.

Experiments with AMPK suggest that activation of this enzyme may mimic some benefits of exercise by regulating mitochondrial dynamics.

“The targeting mechanisms to optimize mitochondrial fission and fusion, as well as the activation of AMPK, may represent promising strategies for healthy aging, through improvement in the biochemical and contractile functions of the muscle”, says the researcher.

Ferreira explains that regular physical exercise contributes to healthy aging, as it regulates the main systems that support proper cell functioning, including mitochondrial dynamics.

“However, we know that the regular practice of physical activity is still extremely low in the population. Certainly, public policies that use scientific information to encourage this habit are necessary. Furthermore, we cannot forget that pharmacological interventions capable of controlling such processes have the potential to treat several diseases associated with aging”, he evaluates.

The group coordinated by Ferreira at ICB-USP has, in recent years, developed a molecule called SAMBA capable of facilitating mitochondrial fusion and, consequently, improving the quality of life of animals with heart failure (read more here). The compound is currently in preclinical testing for safety and efficacy.

The article Exercise preserves physical fitness during aging through AMPK and mitochondrial dynamics can be read here.