Can We Keep Our Brain from Getting Old? Cellular Physiology’s Perspective on Ageing

Galen, around the year 200, thought that “Ageing is an intermediate state between health and disease: it is not a pathological state, but biological functions are reduced and weakened.” And so it seems because we observe that all people forget things as age advances, although much less than people with Alzheimer’s disease, for example. All elders lose elasticity and shiver a little, but people with Parkinson’s disease lose control of their movements. In other words, neurodegenerative characteristics manifest themselves with aging, but to a lesser degree. Since aging happens to everyone, it is not considered a disease itself, but it is the main risk factor for developing chronic diseases associated with old age.

Interestingly, not everyone ages to the same degree. A very small proportion of people reach the age of 80 without suffering from a single chronic disease and retaining their mental abilities, while many people suffer from several chronic diseases simultaneously even from the age of 50. So, aging is malleable. Understanding its biological basis will allow us to develop strategies for most people to live eighty years to the fullest.

In collaboration with national and international specialists, we do research on why we age. We seek to understand the biological changes in the body over time, which increase the probability of developing chronic diseases and dying. Among chronic diseases, neurodegeneration is the most devastating, because mental abilities distinguish us.

The biological changes that occur with aging are similar in several species, such as worms, flies, mice, and humans. Among these changes, autophagy, one of the most important intracellular repair processes, stops working. Special vesicles inside cells called lysosomes contain digestive enzymes capable of degrading all types of macromolecules that people, animals and plants are made of. There is a molecular machinery that detects a damaged part of the cell or something that, for any reason, must be digested and introduces it to the lysosomes. If autophagy doesn’t work, aggregates of damaged proteins, mitochondria, or other organelles accumulate inside the cells, which erode the cells’ functionality. After the cellular material introduced into the lysosomes has been digested, the different components that were produced by digestion—amino acids, glucose, proteins, fatty acids, iron, etc.—which are essential for metabolism, can be released into the cytoplasm. Therefore, if autophagy fails, it interferes with the entire metabolism: the amount of glucose used by the cell or the amount of adenosine triphosphate (ATP molecule, a source of energy for the cell) that it generates; amino acids for protein synthesis, iron availability, etc., all these processes may fail. Autophagy also protects the genome, facilitates the repair of damaged DNA, and keeps parts of the nucleus renewed. If autophagy doesn’t work, damaged genetic material builds up.

In neurons in particular, correct autophagy is essential because these are cells that we have since birth, which must be maintained over the years through the renewal of their parts so that they continue to work. In neurons, autophagy also stops working with aging. In the brains of people who died of Alzheimer’s or Parkinson’s diseases, it has been observed that autophagy work has been interrupted, preventing the cleaning of damaged parts and regeneration. It has been experimentally demonstrated in mice that inhibiting autophagy only in neurons develops characteristics of neurodegeneration. On the other hand, in studies carried out in flies and worms, it was found that the failure of autophagy causes the aging of the body and, on the contrary, increasing autophagy only in neurons extends longevity.

These observations indicate that the brain affects the longevity of the organism, perhaps because it acts as a primary sensor of physiological and environmental stressors. It is worth protecting our brain by stimulating autophagy in neurons.

In collaboration with doctor Bulmaro Cisneros, researcher at CINVESTAV, and doctor Felipe Court, researcher at Universidad Mayor in Chile, we study why autophagy fails with aging and look for interventions that may prevent it. We have discovered that in the brains of old mice a protein called CRM₁ increases, which transports proteins from the nucleus to the cytoplasm and, as a result of changing the location of proteins that carry out autophagy, they can no longer function. Figure 1 shows the hippocampus, which carries out memory and learning functions, in which the increase in the CRM₁ protein can be observed in an old mouse brain compared to that of a young mouse.

In brain sections of young or old mice, the MAP₂ protein, which identifies neurons, is shown in purple and the CRM₁ protein is shown in green

Various pharmacological or genetic interventions that induce autophagy can delay aging. Intermittent fasting is one way to induce autophagy. However, particularly in Mexican population, a high percentage of people have metabolic syndrome, prediabetes, or diabetes, so it is not advisable to fast without medical supervision, as it can be counterproductive. At present, better than the use of drugs, exercising and eating without being satiated are the ideal interventions to induce autophagy even in the brain.

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