Calorie restriction is known to improve health and increase lifespan, but much of how it does so remains a mystery, especially how it protects the brain. Buck’s scientists discovered the role of a gene called OXR1 which is necessary for the lifespan extension seen with dietary restriction and is essential for healthy brain aging.
“When people restrict the amount of food they eat, they usually think it might affect their digestive system or fat storage, but not necessarily how it affects the brain,” said Kenneth Wilson, Ph.D., Buck postdoc and first author. of the study, published online Jan. 11, 2024 at Nature communications. “As it turns out, this is a gene that is important in the brain.”
The team further showed a detailed cellular mechanism for how dietary restriction can delay aging and slow the progression of neurodegenerative diseases. The work, done in fruit flies and human cells, also identifies potential therapeutic targets for slowing aging and age-related neurodegenerative diseases.
“We found a specific neuronal 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 the levels of this gene to mediate its protective effects.”
“The gene is an important brain resilience factor that protects against aging and neurological disease,” said Buck Professor Lisa Ellerby, Ph.D., co-senior author of the study.
Understanding variability in response to dietary restriction
Members of the team have previously shown mechanisms that improve lifespan and health with dietary restriction, but there is so much variation in the response to reduced calories in individuals and different tissues that it is clear that there are many processes that have yet to be discovered. This project was started to understand why different people respond to diets in different ways.
The team started by scanning about 200 strains of flies with different genetic backgrounds. Flies were reared on two different diets, either normal diet or dietary restriction, which was only 10% of normal diet. The researchers identified five genes that had specific variants that significantly affected longevity under dietary restriction. Of these, two had counterparts in human genetics.
The team chose one gene to explore in depth, called “mustard“(mtd) in flies and “Resistance to oxidation 1“(OXR1) in humans and mice. The gene protects cells from oxidative damage, but the mechanism of how this gene works has been unclear. His loss OXR1 in humans it results in severe neurological defects and premature death. In mice, moreover OXR1 improves survival in a model of amyotrophic lateral sclerosis (ALS).
The relationship between brain aging, neurodegeneration and lifespan
To understand how a gene that is active in neurons affects overall lifespan, the team did a series of in-depth tests. They found it OXR1 it affects a complex called a retromer, which is a set of proteins necessary for the recycling of cellular proteins and lipids. “The retromer is an important mechanism in neurons because it determines the fate of all proteins that enter the cell,” Wilson said. Retromer dysfunction has been associated with age-related neurodegenerative diseases that are protected by dietary restriction, especially Alzheimer’s and Parkinson’s diseases.
Taken together, their results told the story of how dietary restriction slows brain aging by acting on mtd/OXR1 in maintaining the retromer. “This work shows that the retromer pathway, which is involved in recycling cellular proteins, has a key role in protecting neurons when nutrients are limited,” Kapahi said. The team found it mtd/OXR1 it maintains retromer function and is essential for neuronal function, healthy brain aging, and lifespan extension seen with dietary restriction.
“Diet affects this gene. By eating less, you actually enhance this mechanism of proteins being sorted correctly in your cells, because your cells enhance the expression OXR1,” Wilson said.
The team also found this boost mtd in flies it made them live longer, leading researchers to hypothesize that in humans its overexpression OXR1 can help extend lifespan. “Our next step is to identify specific compounds that increase levels OXR1 during aging to delay brain aging,” Ellerby said.
“Hopefully from this we can get more insight into why our brains degenerate in the first place,” Wilson said.
“Diet affects all the processes in your body,” he said. “I think this work supports efforts to follow a healthy diet, because what you eat will affect more than you know.”
Kapahi is a founder and member of the scientific advisory board of Juvify Bio. The other authors have no conflict of interest.