How Dietary Restriction Slows Brain Aging And Increases Longevity

"When people restrict the amount of food that they eat, they typically think it might affect their digestive tract or fat buildup, but not necessarily about how it affects the brain," said Kenneth Wilson, Ph.D., Buck postdoc and first author of the study, published online on January 11, 2024, in Nature Communications. "As it turns out, this is a gene that is important in the brain."

Their anti-aging research, done in fruit flies and human cells identified potential therapeutic targets to slow aging and age-related neurodegenerative diseases. Additionally, the team demonstrated a detailed cellular mechanism of how dietary restriction can delay aging and slow the progression of neurodegenerative diseases.

"We found a neuron-specific response that mediates the neuroprotection of dietary restriction," said Buck Professor Pankaj Kapahi, Ph.D., co-senior author of the study. "Strategies such as intermittent fasting or caloric restriction, which limit nutrients, may enhance levels of this gene to mediate its protective effects."

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

The team began by scanning around 200 strains of flies with different genetic backgrounds that were raised on two different diets: either a normal diet or with dietary restriction that was only 10% of normal nutrition. The analysis identified five genes that had specific variants that were found to significantly affect longevity under dietary restriction, and of these two had counterparts in human genetics. 

The gene called mustard (mtd) was chosen to explore in fruit flies and oxidation resistance 1 (OXR1) was chosen to explore in both mice and humans. The gene protects cells from oxidative damage, the loss of OXR1 in humans results in severe neurological defects as well as premature death. In mice, extra OXRI improves the survival of models of amyotrophic lateral sclerosis (ALS). 

A series of in-depth tests were conducted that revealed that OXR1 affects a complex called the retomer which is a set of proteins that are necessary for recycling cellular protein and lipids (autophagy). Retromer dysfunction is associated with age-related neurodegenerative diseases that are protected by dietary restriction, specifically Parkinson’s and Alzheimer’s diseases.

Their work tells the story of how dietary restriction slows brain aging by the action of mtd/OXR1 in maintaining the retromer. The team found that mtd/OXR1 helps to preserve retromer function and is necessary for neuronal function, healthy brain again, and lifespan extension which is seen with dietary restriction. They also found that boosting mtd in flies caused them to live longer, which is speculated that, in humans, the excess expression of OXR1 might also extend longevity. 

"The retromer is an important mechanism in neurons because it determines the fate of all proteins that are brought into the cell," said Wilson. "Diet is influencing this gene. By eating less, you are actually enhancing this mechanism of proteins being sorted properly in your cells, because your cells are enhancing the expression of OXR1.”

"This work shows that the retromer pathway, which is involved in reusing cellular proteins, has a key role in protecting neurons when nutrients are limited," said Kapahi.

"Our next step is to identify specific compounds that increase the levels of OXR1 during aging to delay brain aging," said Ellerby.

"Hopefully from this, we can get more of an idea of why our brains degenerate in the first place," said Wilson. "Diet impacts all the processes in your body," he said. "I think this work supports efforts to follow a healthy diet because what you eat is going to affect more than you know."