CNIO researchers found that cells signaling excess nutrients can lead to organ failure and inflammation, potentially accelerating aging. Using animal models and comparisons with human blood samples, they demonstrated that targeting inflammation could alleviate the symptoms of aging and extend life, with implications for understanding diseases related to aging and obesity.
Scientists have discovered that an excess of nutrients in cells triggers inflammation and organ dysfunction, which accelerates aging. Their study suggests that interventions in inflammation may improve lifespan.
The accelerated aging of our population underscores the urgency to understand the molecular changes that occur in the body over time. The mTOR protein complex plays a critical role in many body functions, especially metabolism. A new study by researchers at Spain’s National Center for Cancer Research (CNIO) shows that even a modest increase in mTOR activity can induce premature aging in animal models, shortening their lifespan by up to 20%.
This study, published in Nature Aging, provides insight into why diseases associated with aging are exacerbated 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 the increase of nutrients and the aging of different organs,” said lead author Alejo Efeyan, who leads 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 by the amount of nutrients available in the cell. The authors developed a method to manipulate mTOR activity in animal models by targeting a protein that signals nutrient levels for mTOR. They genetically modified this protein to simulate higher nutrient levels, triggering 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 Center for Molecular Biology, and Alejo Efeyan, lead author, from the CNIO Metabolism and Cell Signaling Group. Credit: Antonio Tabernero /CNIO
Consequences of enhanced mTOR activity
When animals with the modified protein reach maturity, their cellular functions begin to deteriorate, leading to signs of aging such as thinner skin and damage to organs such as the pancreas, liver and kidneys. Immune system cells come to repair them, but are overwhelmed by the amount of damage. They build up and instead of repairing themselves, they trigger inflammation that further increases the problems in these organs.
This cycle of damage and ineffective repair shortens the lifespan of animals by 20%, equivalent to about 16 years in humans.
Potential therapeutic measures
The researchers aimed to disrupt this cycle by inhibiting the immune response that causes inflammation. As a result, organ damage has improved enough to add several years to life in humans.
First author Ana Ortega-Molina, who heads the Laboratory of Cancer Metabolism and Aging at CBM, notes that targeting chronic inflammation is “a potential therapeutic measure that controls health deterioration.”
Potential human consequences
When the CNIO group manipulated mTOR to simulate nutrient excess, the resulting changes mirrored those seen in natural aging. They compared their model to colonies of naturally aging mice, including their own and those maintained by the National Institute on Aging (NIA).
For example, the activity of lysosomes, which are the organelles through which the cell removes and recycles its waste, is reduced in both naturally aging and genetically modified animals. “When there is an excess of nutrients, it makes sense that the cell shuts down the recycling activity of the lysosomes, because this recycling works especially well when there are no nutrients,” says Efeyan.
This decrease in lysosomal activity also occurs during human aging, as verified by a group from the University of Valencia comparing blood samples from young people and people in their seventies.
A new tool
In addition to this paper, Efeyan believes that this new animal model offers “extensive fertile ground for asking more questions about how increasing nutrients or their signaling facilitates processes in various organs that allow us to understand especially their aging.” Or perhaps to investigate the connection with neurodegenerative diseases, because there is some inflammation in the central nervous system. It’s a tool that can be used by many more people.”
Other co-authors include Rafael de Cabo from the National Institute on Aging (NIA) in Bethesda, USA, Consuelo Borrás and Daniel Monleón from the University of Valencia, and MarÃa Casanova-Acebes, head of the Cancer Immunity group at the CNIO.
Reference: “Moderate 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, LucÃa de Prado- Rivas, Ana Belén Plata-Gómez, Elena Fernández-Florido, Patricia González-GarcÃa, Yurena Vivas-GarcÃa, Elena Sánchez GarcÃa, Osvaldo Graña-Castro, Nathan L. Price, Alejandra Aroca-Crevillén, Eduardo Caleiras, Daniel Monleón, Daniel Monleón , Daniel Consuelo Borrás, MarÃa Casanova-Acebes, Rafael de Cabo and Alejo Efeyan, 7 June 2024, Nature Aging.
DOI: 10.1038/s43587-024-00635-x
This work was funded, among others, by the Spanish Ministry of Science, Innovation and Universities, the Spanish Research Agency, the European Regional Development Fund, the Scientific Foundation of the Spanish Association Against Cancer Research, the “la Caixa” Banking Foundation, the Oncology Olivia Roddom Research Grant, the Intramural Research Program in NIA, National Institute of Health. Yurena Vivas, one of the authors, is a recipient of a CNIO Friends contract funded by the Domingo Martinez Foundation.