Scientists identify how dietary restrictions slow brain aging and increase lifespan

Calorie restriction is known to improve health and increase lifespan, but how it does this remains a mystery, especially how it protects the brain. Scientists at the Buck Institute for Research on Aging have discovered the role of a gene called OXR1, which is necessary for the lifespan extension seen with dietary restrictions and essential for healthy brain aging.

“When people limit the amount of food they eat, they usually think it might affect their digestive tract or fat accumulation, but not necessarily how it affects the brain,” said Kenneth Wilson, Ph. D., Buck postdoctoral fellow and first author. of the study, published in Natural communications. “It turns out it’s an important gene in the brain.”

The team further demonstrated a detailed cellular mechanism explaining how dietary restrictions can delay aging and slow the progression of neurodegenerative diseases. The work, carried out on fruit flies and human cells, also identifies potential therapeutic targets to slow aging and age-related neurodegenerative diseases.

“We discovered a neuron-specific response that mediates neuroprotection from dietary restriction,” said Professor Buck, Ph.D., co-senior author of the study. “Strategies such as intermittent fasting or calorie restriction, which limit nutrients, may increase levels of this gene to attenuate its protective effects.”

“The gene is an important brain resilience factor that protects against aging and neurological diseases,” said Professor Lisa Ellerby, Ph.D., co-senior author of the study.

Understanding variability in response to dietary restriction

Team members have previously shown mechanisms that improve lifespan and lifespan with dietary restrictions, but there is such variability in response to reduced calories between individuals and different tissues that it It is clear that there are many processes at play yet to be discovered. This project was started to understand why different people respond differently to diets.

The team began by analyzing around 200 strains of flies with different genetic backgrounds. The flies were raised on two different diets, either a normal diet or a food restriction, which was only 10% of normal nutrition. The researchers identified five genes with specific variants that significantly affect longevity under dietary restriction. Of these, two had homologs in human genetics.

The team chose a gene to explore in depth, called “mustard” (mtd) in fruit flies and “oxidation resistance 1” (OXR1) in humans and mice. The gene protects cells from oxidative damage, but the mechanism of how this gene works was unclear. Loss of OXR1 in humans results in severe neurological abnormalities and premature death. In mice, additional OXR1 improves survival in a model of amyotrophic lateral sclerosis (ALS).

The link between brain aging, neurodegeneration and lifespan

To understand how an active gene in neurons affects overall lifespan, the team performed a series of extensive tests. They discovered that OXR1 affects a complex called retromer, which is a set of proteins necessary for recycling cellular proteins and lipids.

“The retromer is an important mechanism in neurons because it determines the fate of all proteins introduced into the cell,” Wilson said. Retromer dysfunction has been associated with age-related neurodegenerative diseases that are protected by dietary restrictions, particularly Alzheimer’s and Parkinson’s diseases.

Overall, their results tell the story of how dietary restriction slows brain aging through the action of mtd/OXR1 in retromere maintenance.

“This work shows that the retromer pathway, involved in cellular protein reuse, plays a key role in protecting neurons when nutrients are limited,” Kapahi said. The team discovered that mtd/OXR1 preserves retromer function and is necessary for neuronal function, healthy brain aging, and the increased lifespan observed with dietary restriction.

“Diet influences this gene. By eating less, you actually improve this mechanism of sorting proteins correctly in your cells, because your cells improve the expression of OXR1,” Wilson said.

The team also found that increasing mtd in flies allowed them to live longer, leading the researchers to speculate that in humans, excessive expression of OXR1 could help extend lifespan . “Our next step is to identify specific compounds that increase OXR1 levels during aging to delay brain aging,” Ellerby said.

“I hope this will give us a better idea of ​​why our brains degenerate in the first place,” Wilson said.

“Diet impacts every process in your body,” he said. “I think this work supports efforts to follow a healthy diet, because what you eat will have a bigger impact than you think.”