As soon as they started dealing with healthy elderly people over 100 years old, researchers from the Federal University of Minas Gerais (UFMG) realized that they have to act quickly to schedule appointments, collect blood and perform tests. Of the 50 centenarians being followed, two have died in the last two months. One of the causes may be a deregulation of the activities of the immune system, with an increase or decrease in antibodies and cells that participate in the elimination of disease-causing agents, as indicated by another study with the elderly, also at UFMG.
“In addition to the senescence that settles in the muscles, heart, other organs and cells, aging is associated with mild chronic inflammation, with an intense production of proteins called pro-inflammatory cytokines”, observes immunologist Ana Maria Caetano Faria, from the Institute of Biological Sciences at UFMG. “Those who stay healthy, mainly because of genetics, diet and good habits, are able to compensate for this mechanism and keep the production of anti-inflammatory cytokines such as interleukin-10 stable, so that inflammation is activated only when necessary. , without harming the organism. Proteins that activate inflammation, which are generally indispensable in the fight against microbes and tumors, can favor the emergence of diseases such as Alzheimer’s, bipolar disorder, multiple sclerosis, arthritis or muscle degeneration.
If the amount of anti-inflammatory cytokines circulating in the blood does not remain stable, chronic inflammation sets in and the body begins to deteriorate sharply from the age of 70 onwards. In a study published in July in the scientific journal Experimental Gerontology, the group from Fiocruz and UFMG examined the levels of 27 proteins known as mediators of the immune system, responsible for the activation of defense cells and other immune system control mechanisms, in blood samples collected from 541 healthy people aged 3 more than 70 years, all without apparent infection. In septuagenarians, the number of mediators was half of the highest level, verified in the range between 60 and 70 years old (see charts).
Also called cytokines, mediators perform many functions in the body: in addition to activating or deactivating inflammatory processes, they stimulate the production of antibodies and cells capable of destroying pathogens or recruit them to sites of infection. Likewise, the immune system has other roles besides fighting infections, such as maintaining tolerance to the body’s tissues, thus preventing so-called autoimmune diseases, and eliminating old or dead cells.
The number of mediators varies according to what Martins-Filho, Faria and their colleagues call waves. There is a large increase in mediators between 6 and 10 years and a decline between 11 and 20 years and 21 and 30 years. It increases again between 31 and 40 years old and grows even more between 51 and 60 years old. After age 70, there is a sharp decline in the levels of these proteins in blood serum, especially in women. In the group of septuagenarians, the levels of 12 cytokines, including interferon-gamma, a powerful antiviral and antitumor, dropped, while only two of this set of proteins showed a drop among men of the same age.
“The first peak of cytokines, at age 6, indicates a maturing of the immune response, after the children have had contact with viruses and other pathogens, as a result of living in day care centers and schools”, comments immunologist pediatrician Magda Carneiro-Sampaio, from the Instituto da Criança, Hospital das Clínicas, University of São Paulo (ICr-HC-USP), which did not participate in the study. “In this phase they develop the memory response against viruses and bacteria.”
According to her, the outpatient clinics of pediatric hospitals in several cities in Brazil and in other countries were crowded with the reopening of schools and day care centers earlier this year precisely because the seclusion of children during the pandemic prevented contact between them and slowed the development of the so-called cells. memory, which become able to face infections in response to the gradual exchange of pathogenic agents in daily life. Upon meeting again, the children were given a high dose of a variety of viruses, usually transmitted through the air.
Cytokine waves differ between men and women. “Probably because of hormonal fluctuations throughout life, women tend to have changes in the levels of immune system mediators before men do,” says biochemist-pharmaceutical Olindo Assis Martins-Filho, from the René Rachou Institute of the Oswaldo Cruz Foundation ( Fiocruz) in Belo Horizonte, co-author of the work in Experimental Gerontology. “In women these levels drop after the age of 30, while in men only after the age of 50.”
It is not yet known why cytokine levels fluctuate throughout life. “This variation is a curious phenomenon, since cytokines are generally produced in response to infections; it would be expected that they would not vary so much with age”, comments biologist Dario Simões Zamboni, from the Faculty of Medicine of Ribeirão Preto (FMRP) at USP, who was also not part of this research. “One possibility is that some of the people who participated in this study are naturally inflamed or have some latent infection, but either way these observations open doors for future studies.” In 2020, Zamboni was part of a group that elucidated one of the triggering mechanisms of the so-called cytokine storm, which results in intense inflammation in people with Covid-19.
Highs and lows also occur with the levels of two types of defense cells, T lymphocytes, produced in the thymus, and B lymphocytes, which leave the bone marrow. A study by the UFMG and Fiocruz team with 232 healthy participants with no apparent infection (80 children and 152 adults), aged between 0 and 86 years, recorded the greatest drops in the amount of B lymphocytes circulating in the blood between 11 and 40 years and after 61 years, while with B lymphocytes the greatest reduction was after 75 years. The results are detailed in an article published in November 2008 in the scientific journal neuroimmunomodulation.
“In this work from 2008, we saw what we call the drop-of-water effect”, says Faria. “An elderly person over 75 years of age is in excellent health, but suddenly suffers a fall or some minor accident, which causes the body to lose its delicate balance and a decline in health and even sudden death ensues.”
Minas Gerais experts identified connections between the mediators. “They talk to each other”, summarizes Martins-Filho. They can act alone, increasing or reducing the action of another, or together. Faria exemplifies: when produced at the same time by dendritic cells, two cytokines – transforming growth factor-beta (TGF-β) and interleukin-6 (Il-6) – stimulate the differentiation of T lymphocytes into an inflammatory cell type , while TGF-β alone has an anti-inflammatory effect.
In the study by Fiocruz and UFMG, connectivity was shown to be greater between 3 and 5 years of age, with different rates of decline and reconstruction in men and women. Martins-Filho notes that a very intense immune response, as seen in Covid-19 and sepsis (generalized infections), can lead to disconnection between cytokines.
As in septuagenarians the production of T lymphocytes decreases, due to the continuous atrophy of the thymus, there is a slower replacement of cells and loss of cellular diversity. “To make a good response to vaccines, cellular diversity is very important”, comments Zamboni. The predominance of memory cells favors the response against pathogens already known to the body, but not against new ones, such as the one that causes Covid-19.
It is not yet known whether it is possible to restore defenses among the elderly, but it is already known that alcoholic beverages can weaken them. The UFMG group showed in 2006 at the Clinical and Experimental Immunology that excessive alcohol consumption for four days in mice triggered an intense inflammatory reaction. “Thirty days after the experiment, the functions of the animals’ immune cells were still altered”, reports Faria.
ANDRADE, MC et al. Alcohol-induced gastritis prevents oral tolerance induction in mice. Clinical and Experimental Immunology. v. 146, no. 2, p. 312-22. Nov. 2006.
BRITO-DE-SOUSA, JP et al. Serum soluble mediator waves and networks along healthy aging. Experimental Gerontology. v. 164, 111771. 22 Mar. 2022
FARIA, AMC et al. Variation rhythms of lymphocyte subsets during healthy aging. neuroimmunomodulation. v. 15, no. 4-6, p. 365-79. 26 nov. 2008
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