CNIO researchers have found that cells signaling that they contain excess nutrients can lead to organ malfunction and inflammation, potentially accelerating aging. Using animal models and comparisons with human blood samples, they have shown that targeting inflammation can alleviate the symptoms of aging and extend life, with implications for understanding diseases associated with aging and obesity.
Researchers find that excess nutrients in cells cause inflammation and organ dysfunction, accelerating aging. Their research suggests that interventions for inflammation can improve lifespan.
The accelerated aging of our population underlines the urgency of understanding the molecular changes that occur in the body over time. The mTOR protein complex plays a crucial role in many bodily functions, especially metabolism. A new study by researchers at Spain’s National Cancer Research Center (CNIO) shows that even a small increase in mTOR activity can cause premature aging in animal models, shortening their lifespan by as much as 20%.
This study, published in Nature aging, provides insight into why diseases associated with aging worsen in individuals with a high body mass index, an indicator of obesity and inflammation. It also explains why calorie restriction, known to extend lifespan in animals, promotes healthy aging by activating specific genes that interact with mTOR.
In addition, the study introduces a new research tool designed “to study the relationship between nutrient increase and the aging of various organs,” said lead author Alejo Efeyan, head of the Metabolism and Cell Signaling Group at the National Cancer Research Center (CNIO). ). .
Manipulation of mTOR in animal models
The activity of the mTOR protein complex is regulated depending on the amount of nutrients available in the cell. The authors developed a method to manipulate mTOR activity in animal models by targeting the protein that signals dietary levels of mTOR. By genetically modifying this protein to simulate higher nutrient levels, they triggered mTOR to activate its pathway as if the animals were consuming more food, even though their actual diet remained unchanged.
Ana Ortega-Molina, lead author and current researcher at the Severo Ochoa Molecular Biology Center, and Alejo Efeyan, senior author, from the CNIO Metabolism and Cell Signaling Group. Credit: Antonio Tabernero/CNIO
Consequences of enhanced mTOR activity
When animals with the modified protein mature, their cellular functions begin to deteriorate, leading to aging symptoms such as thinning skin and damage to organs such as the pancreas, liver and kidneys. Immune system cells arrive to repair them, but are overwhelmed by the amount of damage. They build up and, instead of repairing, cause inflammation that further increases problems in those organs.
This cycle of damage and ineffective repair shortens the animals’ lifespan by 20%, equivalent to about 16 years in humans.
Potential therapeutic measures
The researchers tried to disrupt this cycle by inhibiting the immune response that causes inflammation. As a result, organ damage improved enough to provide what would be a few years of life in humans.
First author Ana Ortega-Molina, head of the Metabolism in Cancer and Aging Laboratory at CBM, notes that targeting chronic inflammation “is a potential therapeutic measure that controls health deterioration.”
Potential human implications
When the CNIO group manipulated mTOR to simulate nutrient excess, the resulting changes mirrored the changes we see in natural aging. They compared their model to colonies of naturally aging mice, including both their own and those from the National Institute on Aging (NIA).
For example, the activity of lysosomes, the organelles through which the cell removes and recycles its waste, is reduced in both naturally aged and genetically modified animals. “When there is an excess of nutrients, it is logical that the cell stops the recycling activity of lysosomes, because this recycling mainly takes place when there are no nutrients,” says Efeyan.
This decrease in lysosomal activity also occurs with human aging, as verified by the University of Valencia group when comparing blood samples from young people and people over 70.
A new tool
In addition to this article, Efeyan believes that this new animal model “provides sufficient fertile ground to ask more questions about how the increase in nutrients, or their signaling, facilitates processes in the different organs that allow us to understand, above all, their aging. 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.”
Other co-authors are Rafael de Cabo from the National Institute on Aging (NIA) in Bethesda, USA, Consuelo Borrás and Daniel Monleón, from the University of Valencia, and María Casanova-Acebes, head of the Cancer Immunity group at CNIO.
Reference: “A Mild Increase in Nutrient Signaling to mTORC1 in Mice Leads to Parenchymal Damage, Myeloid Inflammation, and Shortened Lifespan” by Ana Ortega-Molina, Cristina Lebrero-Fernández, Alba Sanz, Miguel Calvo-Rubio, Nerea Deleyto-Seldas , Lucía de Prado-Rivas, Ana Belén Plata-Gómez, Elena Fernández-Florido, Patricia González-García, Yurena Vivas-García, Elena Sánchez García, Osvaldo Graña-Castro, Nathan L. Price, Alejandra Aroca-Crevillén, Eduardo Caleiras, Daniel Monleón, Consuelo Borrás, María Casanova-Acebes, Rafael de Cabo and Alejo Efeyan, June 7, 2024, Nature aging.
DOI: 10.1038/s43587-024-00635-x
This work has been funded, among others, by the Spanish Ministry of Science, Innovation and Universities, the Spanish Research Agency, the European Regional Development Fund, the Spanish Association against Cancer Research Scientific Foundation, “la Caixa” Banking Foundation, Olivia Roddom Oncology Research Grant, intramural research program at the NIA, National Institutes of Health. Yurena Vivas, one of the authors, is a beneficiary of a CNIO Friends contract funded by the Domingo Martinez Foundation.