Aging and cells that “believe” they have too many nutrients
New work now finds in animal models that When mTOR activity increases, but only moderately, aging occurs earlier and the life expectancy of animals can be reduced by up to 20%.
Given the central role of mTOR in metabolism, this study provides a clue understand why age-related diseases appear or worsen in people with a high body mass index, indicator associated with obesity and inflammation. It also provides information about Why calorie restriction—a type of diet linked to longer lifespan in animals—may promote healthy agingbecause certain genes that are activated by nutrient restriction interact with mTOR.
In addition, a new research tool is being created “to study the relationship between increased nutrient intake and aging in various organs,” says lead author. Alejo EfeyanHead of the Metabolism and Cell Signaling Group at the National Center for Cancer Research (CNIO).
The study was published in Natural aging. Its first author is Ana Ortega-Molinawho currently directs and collaborates in his Cancer Metabolism and Aging Laboratory at the Severo Ochoa Center for Molecular Biology (CBM). Rafael de Cabo, from the National Institute on Aging (NIA) in Bethesda, USA, Consuelo Borras And Daniel Monleonfrom the University of Valencia, and Maria Casanova-AcebesHead of the Cancer Immunity Group at CNIO.
Premature aging in animals that “believe” they eat more
The activity of the mTOR protein complex is regulated depending on the amount of nutrients available in the cell. The authors of this study developed system for change in MTORand thus be able to regulate its activity at will in animal models.
Inside cells, there is a constant coming and going of chemical signals, which are transmitted thanks to proteins (of course, cells also communicate with each other through intercellular signals). The mTOR protein complex is a key agent in the great highway of cellular communication involved in energy use and cell metabolism. mTOR is also known to influence lifespan, although how this is not yet entirely clear.
To manipulate mTOR activity at will, the CNIO team focused not on mTOR itself, but on a protein that would send it a signal indicating the amount of nutrients available in the cell. Researchers have genetically modified this protein to make it liedand sends a signal to mTOR that there are more nutrients in the cell than there actually are.
Thus, the mTOR chemical signaling pathway is activated as if the animals were eating more, although in fact their diet does not change.
Cell functioning begins to deteriorate
When animals with this protein, which deceives before mTOR, they reach maturityCell functioning begins to deteriorate and characteristic symptoms of aging appear: The skin becomes thinner, damage to the pancreas, liver, kidneys and other organs appears. Cells of the immune system come to repair them, but they are overloaded with the amount of damage, accumulate and, instead of repairing, cause inflammation, which further increases the problems in these organs.
The result of this vicious cycle is that the lifespan of these animals, in which mTOR is working more than usual, is reduced by 20%, which on a human scale would be equivalent to about 16 years.
In the study we aimed cut this circle by blocking the immune response that causes inflammation.. The organ damage then improved enough to extend a person’s life by several years.
For this reason, the authors argue that targeting chronic inflammation is “a potential therapeutic intervention to control health decline,” Ortega-Molina says.
Results extrapolated to humans
What happens when the information that mTOR receives is influenced by simulating nutrient excess, This resembles changes typical of natural aging. The CNIO team compared their model to colonies of naturally aging mice, both their own and those of the National Institute on Aging (NIA).
For example, the activity of lysosomes—the organelles through which a cell removes and processes its waste—is reduced in both naturally aged animals and genetically modified ones. “When there is an excess of nutrients, it is logical that the cell turns off the recycling activity of lysosomes, because this recycling begins especially when there are no nutrients,” Efeyan clarifies.
This decline in lysosome activity also occurs as humans age, as confirmed by a team from the University of Valencia when comparing blood samples from young people and people over seventy years of age.
New tool
Beyond this work, Efeyan believes this new animal model offers “ample fertile ground to ask more questions about how increasing nutrient supply or nutrient signaling facilitates processes in various organs that allow us, in particular, to understand their aging.” Or, for example, explore the connection with neurodegenerative diseases, because there is some kind of inflammation in the central nervous system. It’s a tool that a lot more people can use.”
This work has received funding, inter alia, from the Ministry of Science, Innovation and Universities, the Spanish Research Agency, the European Research Agency, the European Regional Development Funds, the Scientific Foundation of the Spanish Association Against Cancer, the La Caixa Foundation, the Olivia Maternity Grant for Cancer Research and Institute for Aging Research (NIA) Intramural Research Program. Jurena Vivas, one of the authors, is a beneficiary of the Friends of the CNIO contract funded by the Domingo Martinez Foundation.
Help article:
Ana Ortega-Molina, Cristina Lebrero-Fernandez, Alba Sanz, Miguel Calvo-Rubio, Nerea Deleito-Seldas, Lucia de Prado-Rivas, Ana Belen Plata-Gomez, Elena Fernandez-Florido, Patricia Gonzalez-Garcia, Jurena Vivas-Garcia, Elena Sánchez García, Osvaldo Graña-Castro, Nathan L. Price, Alejandra Arroca-Crevillen, Eduardo Calheiras, Daniel Monleon, Consuelo Borrás, Maria Casanova-Acebes, Rafael de Cabo, Alejo Efeyan. “Moderate increases in nutrient signaling to mTORC1 in mice lead to parenchymal damage, myeloid inflammation, and shortened lifespan.”. The nature of aging 2024.
DOI: https://doi.org/10.1038/s43587-024-00635-x
Fountain: CNIO