Klotho protein prevents neuron death, says study

The cellular aging process is multifactorial and encompasses several fields of knowledge. Finding mechanisms to protect cells from damage is one of the fronts, and a group of researchers has just taken another step in that direction. An article published in the journal Scientific Reports, from the Nature group, pointed out that the klotho protein had a protective role against inflammation in cells of the central nervous system that interact with neurons —the so-called glial cells.

The study, in vitro, used a lipopolysaccharide (LPS) —a membrane molecule of some bacteria for the tests—, inducing inflammation in the cells. The action takes place because the presence of LPS increases the secretion of pro-inflammatory cytokines which, when produced in excess or chronically, can lead to neuronal death. As the use of LPS in glial cells generates an increase in pro-inflammatory mediators, the group analyzed whether pre-treatment with klotho would make any difference in the cellular response.

“The work demonstrated for the first time in neuronal culture the anti-inflammatory and neuroprotective effect of the klotho protein”, point out the researchers. The data suggest that it may act not only on the metabolism of neurons and astrocytes, but is also an important component in the modulation of glial neuroinflammation. Thus, the therapeutic potential of klotho may be beneficial for pathological processes with neuroinflammatory factors.

The findings complement previous evidence found by the group, which showed that klotho is involved in the action of astrocytes, nerve cells whose function is to provide nutrients to support neurons. The study was supported by FAPESP through aid to research in the line of aging and neuroprotection, which also includes Elisa Mitiko Kawamoto, one of the scientists who signed the publication.

promising studies

Discovered in 1997, klotho is an anti-aging protein whose concentration increases significantly after birth and in adulthood, decreasing as age advances, when there is a chronic inflammation known as “inflammaging”. This unregulated, systemic, low-grade inflammation in the brain is associated with cognitive deficits and the progression of neurodegenerative diseases.

“Throughout my career, I became interested not only in studying the molecular bases associated with neurodegenerative diseases, but in trying to understand why these diseases occur in aging and why some people manage to age in a healthy way”, points out Cristoforo Scavone, professor from the Department of Pharmacology at the Institute of Biomedical Sciences at the University of São Paulo (ICB-USP) and co-author of the article.

Professors have long dedicated themselves to investigating these processes, outlining promising research paths. “I was previously in a study on chronic kidney disease associated with neuroinflammation and we found that this klotho protein was reduced and this correlated with the appearance of cognitive deficits”, he reports.

The protective and anti-inflammatory activity of the molecule had already been observed in the renal, vascular and pulmonary systems, but it was, until then, little studied in cases of neuroinflammation, a point in which the recent publication stands out. “Now, in this study, we had strong evidence that the protein also has a neuroprotective effect. Pre-treatment with klotho was able to decrease the secretion of pro-inflammatory cytokines and reversed the increase in secretion induced by inflammation”, emphasize the researchers .

Neuroinflammation is an intrinsic feature of the aging process. It is already known that neurodegenerative diseases and injuries that affect the central nervous system act on glia, including astrocytes. Depending on the nature of their activation, they can lead to the production of pro- or anti-inflammatory mediators and have beneficial or harmful effects on neurons. Thus, studies that map these mechanisms are important to outline therapeutic possibilities.

Despite the good results, the authors caution that it is not clear whether klotho is the only mediator involved in the observed neuroprotective effect. However, the accumulated evidence justifies that its potential is better elucidated.

The work is also signed by Vinicius Nakao, Larissa de Sá Lima, Paloma Segura de Mello, Natacha de Souza Port’s, Paula Fernanda Kinoshita and Caio Henrique Yokoyama Mazucanti and involved the Institute of Biomedical Sciences of the Federal University of Goiás (UFG) and the Laboratory of Clinical Research at the National Institute on Aging (NIA), in the United States, where Mazucanti is carrying out doctoral studies with support from FAPESP.