Healthy aging impact: New study reveals excessive nutrient signaling limits longevity

14 Jun 2024 --- Researchers at the Spanish National Cancer Research Center (CNIO) discovered that when cells are signaled to have excess nutrients independent from increased nutrient intake, it speeds up aging. This leads to malfunction and inflammation of critical organs, including the pancreas, liver and kidneys. The research team spotlights that intervening in this inflammation may relieve symptoms and increase survival.

In the animal model study, the CNIO team found that when the mTOR protein complex (a central regulator of cell metabolism and physiology) is slightly increased, aging starts earlier and can shorten animals’ lifetimes by up to 30%. 

The researchers explain that the activity of the mTOR protein complex is regulated according to the amount of nutrients available in the cell. 

Nutrition Insight discusses the study’s findings and implications with two CNIO researchers, senior author Dr. Alejo Efeyan and primary author Dr. Ana Ortega-Molina. 

“We have shown for the first time in mammals that active nutrient signaling limits longevity,” says Efeyan. “This shows that excessive nutrients may have pro-aging properties, but it also has an optimistic angle. While we have known for many decades that we can restrict nutrient intake for extending longevity, now we know one molecular component (the Rag GTPase – mTOR axis) that is very likely to be responsible for these effects.” 

Ortega-Molina adds: “We still have to dissect what organs are more relevant, which cell types age better or slower than others, and the precise cellular and molecular effects downstream of nutrients and mTORC1 that precipitate health decline in each organ.”

Nutrient signaling
The mTOR protein complex is crucial in cell communication and metabolism. The process influences longevity, although this process was not fully understood. 

By developing a system to “trick” the mTOR protein complex, the CNIO researchers could regulate its activity at will in animal models. They genetically modified the protein that should send the signal indicating the amount of nutrients available in the cell — signaling there are more nutrients than in reality.

The kidneys from RagC-mutant mice have increased damaged cells (in blue) that attract inflammatory cells (Image credit: CNIO).When animals with this modified protein reach maturity, their cell functioning begins to fail. The researchers detected characteristic symptoms of aging: thinner skin and damage in the pancreas, liver, kidneys and other organs. 

Arriving immune cells are “overwhelmed by the amount of damage” they accumulate instead of repairing and thus trigger inflammation that further increases organ problems.

As a result, the lifespan of these animals with the overactive mTOR complex is shortened by 30%. Compared to humans, that would be “equivalent to about 16 years.” 

Next, the researchers blocked the immune response that causes inflammation in an attempt to break this vicious circle. Damage in the organics improved — equivalent to “a few years of life” in humans. 

Expanding research base 
Ortega-Molina explains that the research, published in Nature Aging, adds to existing science on cell aging in two main ways. 

The mTOR axis is likely responsible for the healthy aging benefit associated with nutrient intake restriction.“First, work in model organisms such as yeast and worms has previously established a connection between nutrients, the activation of the master regulator of metabolism mTOR, and aging.” 

“But previous attempts to show this in mammals have failed because the genetic tools engineered before (genetically engineered mice) were pushing the signaling to levels typically associated with the malignant behavior of cancer cells, but not suited to understand the health decline that occurs over time.”

“Second, we have dissected how this occurs,” she continues. “Cellular damage in cells from multiple tissues by increased nutrient signaling is further accelerated by inflammatory damage (inflammatory cells causing additional damage to tissues), and was possible because of the study of a mammalian system closely similar to human aging.”

Beyond the current research, Efeyan adds that the new animal model also offers a basis for asking more questions about how nutrient increase, or their signaling, facilitates processes in the different organs to understand their aging. 

“For example, investigate the relationship with neurodegenerative diseases because of some inflammation in the central nervous system. It’s a tool that many more people can use.” 

“Potential therapeutic measure”  
Although the research has been conducted on mice, the scientists also compared their molecular processes with blood samples from people in their 70s. This indicates that the study can be extrapolated to human aging. 

The authors suggest that acting on chronic inflammation is a potential therapeutic measure that controls health deterioration. 

Acting on chronic inflammation is a potential therapeutic measure that controls health deterioration.“Our study shows that damage caused by nutrient signaling may be too profuse late in life to control or revert, but even in such a scenario, controlling the associated inflammation may suffice to alleviate the symptoms and to extend survival,” says Efeyan. “This suggests the control of myeloid inflammatory cells may be a reasonable avenue to explore against aging and the effects of aged organs.”  

He underscores that controlling inflammation is not straightforward. “These immune cells also fight pathogens, and the ability to fight pathogens is compromised in the elderly population.” 

“Mice are kept under pathogen-free conditions, but such manipulation in people must be taken cautiously. A reasonable approach to this would be to specifically control the inflammation of certain organs, and only in specific immune populations so that inflammatory damage can be harnessed without affecting immune responses to pathogens.”

Calorie restriction 
The authors add that many aging-related diseases are associated with body mass index, also linked to mild chronic inflammation. 

They note there is “some degree” of the relationship between dietary restriction and the mTOR process, speculating that limiting food intake acts at least partially through the modulation of this signaling axis. 

“Conversely, dietary restriction is an extremely efficacious intervention to extend healthy aging and longevity in mammals,” concludes the research. Restricting calorie intake may promote healthy aging as genes activated by limiting nutrient intake interact with the mTOR process. 

By Jolanda van Hal