María Mittelbrunn: "With age, the immune system becomes more primitive."

Dossier Inflammation, the epidemic that accelerates cancer or Alzheimer's 1 article

• "With age, the immune system becomes more primitive."

Internationally recognized as one of the leading experts in inflammaging, María Mittelbrunn (Madrid, 1977) is a principal investigator at the Immunometabolism and Inflammation Laboratory at the Severo Ochoa Center for Molecular Biology (CISC-UAM), located in Madrid. For decades, she has been studying the immune system to determine its role in aging and find the elixir that will delay this process and all the diseases associated with it. Her research has shown that immune cells, specifically T lymphocytes, are the philosopher's stone of the body's resilience to the passage of time.

What is theinflammaging?

— It's a term first proposed by Italian immunologist Claudio Franceschi in 2000 to refer to the sustained chronic inflammation associated with aging. For a long time, it was thought that the passage of time caused us to become inflamed and this was a risk factor for many diseases such as cancer, neurodegenerative diseases, and metabolic diseases. But we now know this isn't the case, and recent studies show that this relationship between inflammation and aging doesn't occur in Amazonian communities; nor do people living in rural or less industrialized environments exhibit the same level of inflammation as Western societies. We have also now learned that inflammation can be blocked, thus delaying aging and the onset of health problems.

Why does this chronic inflammation occur?

— Two types of factors contribute to it: on the one hand, external factors, such as lifestyle; the pollutants we're exposed to; our diet, which increasingly contains ultra-processed foods; and even the viruses and infections we suffer. And we also see factors that come from within the body itself and affect aging.

What are they?

— They have to do with the same biology. Cells usually undergo programmed death to avoid triggering an inflammatory process. However, sometimes a more abrupt cell death occurs, releasing components that activate inflammation. With aging, dying cells, or zombies, also accumulate, the so-called senescent cells, which are also inflammatory. And the microbiota also plays a role, of course.

What role does it play?

— When we're young, the gut, with its diverse array of bacteria, is in balance. As we age, this changes, contributing to inflammation. In our lab, we hypothesize that all these factors, both internal and external, ultimately deregulate the immune system and, consequently, increase chronic inflammation.

So, does the immune system somehow control the rate at which we age?

— In 2020, we demonstrated that a type of immune cell, T lymphocytes, are capable of accelerating or slowing aging. When we prematurely aged mouse T lymphocytes in the laboratory, the animals began to age extensively, developing chronic inflammation and prematurely developing associated diseases, such as neurodegenerative and cardiovascular diseases.

Because?

— The body's cells that age most rapidly are the immune cells, which are constantly fighting threats and wear out more quickly. An aging T cell is no longer able to do its job properly, distinguishing between a healthy cell and a damaged one, and begins to make mistakes, making errors, and damaging the same tissues. We are now conducting experiments to try to do just the opposite: slow the aging of T cells or rejuvenate them.

Why are these aging lymphocytes not replaced by walnuts?

— Lymphocytes are the only cells in the body trained in the thymus, an organ located in the chest, between the sternum and the heart, which degenerates and practically disappears with age. In fact, its activity peaks when we are babies; by puberty, its activity has already greatly reduced, and by my age, nothing remains, having been replaced by adipose tissue. It makes sense that this is so, because the thymus trains lymphocytes to distinguish healthy from infected or tumorous things. If it continued to do so into adulthood, it could be mistraining immune cells to recognize a cancerous cell as healthy. Furthermore, with age, the immune system becomes more primitive.

What does it refer to?

— Immunity is composed, on the one hand, of innate immunity, which is the body's first barrier, quite nonspecific, and reacts the same to a virus as it does to a bacteria. And, on the other, adaptive immunity, more specific and with memory to remember a pathogen. When we are young, both arms of the immune system are in balance and function very well. As we age and lose the thymus, we also begin to lose the adaptive system and rely more on the innate system. It's therefore as if the immune system becomes more primitive and orchestrates more nonspecific responses. In our laboratory, we are studying ways to reverse this imbalance. Because rejuvenating the immune system is a predictor of longevity.

Through drugs?

— Yes, also cell therapies that allow us to replace aging lymphocytes with young lymphocytes. But above all, we are exploring strategies to rejuvenate the immune system through lifestyle and diet. We have seen that in obese and overweight people with impaired immune systems, if they follow a nutritional intervention and lose weight, some signs of inflammation and aging become reversible.

What can be done to stop chronic inflammation?

— Exercise, exercise, exercise. It's proven to slow you down. And diet is essential, especially if it's low in carbohydrates; in this sense, the Mediterranean diet is an excellent option. And also, social relationships. They studied a small town in the United States, Roseto, where its inhabitants, who were of Italian origin, lived much longer than the rest of the Americans. And they saw that their secret was that... they took care of each other.

Dossier Inflammation, the epidemic that accelerates cancer or Alzheimer's 1 article

• "With age, the immune system becomes more primitive."