Excess nutrients and aging

Aging is accelerated and life is shortened in animals whose cells “believe” they have too many nutrients, despite eating a normal diet.

In this situation, the cells receive the wrong signal that they have an excess of nutrients, and this causes organs such as the pancreas, liver and kidneys to function poorly and become inflamed.

This has been determined in a recent study, led by a team made up of, among others, Alejo Efeyan, head of the Metabolism and Cellular Signaling Group at the National Cancer Research Center (CNIO), Ana Ortega-Molina, who currently directs its Laboratory of Metabolism in Cancer and Aging at the Severo Ochoa Molecular Biology Center (CBM), Consuelo Borrás and Daniel Monleón, from the University of Valencia, María Casanova-Acebes, head of the Cancer Immunity group at the CNIO, from Spain all these institutions, as well as Rafael de Cabo, from the National Institute on Aging (NIA) in Bethesda, United States.

Faced with a population that ages at an accelerated rate, it is essential to understand what happens in the body over time, on a molecular scale. It is known that the mTOR protein complex is involved in many processes, a key agent in multiple functions of the body and especially in metabolism.

In the new study, it has been proven, in animal models, that when mTOR activity increases, although only moderately, aging is advanced, and the life span of animals can be shortened by up to 20%.

Given the central role of mTOR in metabolism, this research provides clues to understand why aging-related diseases appear or worsen in people with high body mass index, an indicator related to obesity and inflammation. It also provides information on why caloric restriction (a type of diet associated with greater longevity in animals) can promote healthy aging, since certain genes that are activated when restricting nutrient intake interact with mTOR.

The activity of the mTOR protein complex is regulated depending on the amount of nutrients available in the cell. The authors of this study devised a system to trick mTOR, and thus be able to regulate its activity at will in animal models.

Ana Ortega-Molina, first author of the study and currently a researcher at the Severo Ochoa Molecular Biology Center, and Alejo Efeyan, senior author, from the Metabolism and Cellular Signaling Group of the CNIO. (Photo: CNIO)

The interior of cells is a continuous coming and going of chemical signals, which are transmitted thanks to proteins (of course cells also communicate with each other, with intercellular signals). The mTOR protein complex is a key agent in the great highway of cellular communication involved in the use of energy, the metabolism of the cell. mTOR is also known to influence longevity, although how is not yet well understood.

To manipulate the activity of mTOR at will, the CNIO team focused not on mTOR itself, but on the protein that must send it the signal indicating the amount of nutrients available in the cell. The researchers genetically modified this protein to make it lie, sending the signal to mTOR that there are more nutrients in the cell than there really are.

Thus, the mTOR chemical signaling pathway is activated as if the animals were eating more, although in reality their diet does not change.

When animals with this protein, which deceives mTOR, reach maturity, the functioning of the cells begins to fail and characteristic symptoms of aging are detected: the skin becomes thinner and damage appears in the pancreas, liver, kidneys and other organs. The cells of the immune system come to repair them, but they are overwhelmed by the amount of damage, they accumulate and, instead of repairing, they trigger inflammation that further increases the problems in these organs.

The result of this vicious circle is that the lifespan of these animals in which mTOR works more than normal is shortened by 20%, which on the human scale would be equivalent to about 16 years.

The study sought to cut that circle by blocking the immune response that causes inflammation. The organ damage then improved enough to gain what in humans would be a few years of life.

Therefore, the authors of the study affirm that acting against chronic inflammation is a potential therapeutic measure to mitigate the deterioration of health.

What happens when acting on the information that mTOR receives, simulating an excess of nutrients, is reminiscent of a change typical of natural aging. The CNIO group compared their model with colonies of naturally aging mice, both their own and those from the National Institute on Aging (NIA).

For example, the activity of lysosomes, which are the organelles with which the cell eliminates and recycles its waste, is reduced in both naturally old animals and genetically modified ones. “When there is an excess of nutrients, it is logical that the cell turns off the recycling activity of the lysosomes, because this recycling starts especially when there are no nutrients,” clarifies Efeyan.

This decrease in lysosome activity also occurs in human aging, as verified by the group from the University of Valencia when comparing blood samples from young people and septuagenarians.

Beyond this work, Efeyan considers that this new animal model offers “ample fertile ground to ask more questions about how the increase in nutrients, or their signaling, facilitates processes in different organs that allow us to understand their aging in particular. Or, for example, investigate the relationship with neurodegenerative diseases, because there is some inflammation in the central nervous system. It is a tool that many more people can use.”

The study is titled “A mild increase in nutrient signaling to mTORC1 in mice leads to parenchymal damage, myeloid inflammation and shortened lifespan.” And it has been published in the academic journal Nature Aging. (Source: CNIO)