Buck scientists have found a role for a gene called OXR1 that is crucial for the lifespan extension seen with dietary restriction and is essential for proper brain aging.

Calorie restriction has been shown to promote longevity and enhance health, but its exact mechanism of action is still unknown, particularly its protective effects on the brain.

“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.”

Scientists Demonstrate How Dietary Restriction Delays Aging

The group also provided a thorough biological mechanism illustrating how dietary restriction might halt the onset of neurodegenerative disorders and delay aging.

In addition to identifying possible therapeutic targets to delay aging and age-related neurodegenerative disorders, the study is being done in human cells and fruit flies.

“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.

Understanding Variability in Response to Dietary Restriction

Team members have previously demonstrated how dietary restriction extends longevity and health span, but given the wide range of responses to calorie restriction in various tissues and people, it is obvious that several unidentified pathways are at work. The purpose of this study is to investigate the reasons behind the varying responses that people have to diets.

Approximately 200 strains of flies with various genetic origins were initially scanned by the scientists.

Either a regular diet or a diet restricted to 10% of the recommended daily intake was given to the flies during their upbringing.

Five genes were found to have particular variations that had a substantial impact on lifespan when subjected to food restriction. Two of those have an equivalent in human genetics.

The team chose one gene to explore thoroughly, called “mustard” (mtd) in fruit flies and “Oxidation Resistance 1” (OXR1) in humans and mice.

Though its exact mode of action is unknown, the gene shields cells against oxidative damage. In humans, the OXR1 deletion causes severe neurological abnormalities and early mortality. In a mouse model of amyotrophic lateral sclerosis (ALS), more OXR1 increases survival.

Connection Between Brain Aging, Neurodegeneration And Lifespan

The researchers conducted a number of comprehensive studies to determine the impact of a neuronally active gene on overall longevity.

They discovered that OXR1 has an impact on the retromer complex, a group of proteins required for recycling lipids and proteins in cells.

“The retromer is an important mechanism in neurons because it determines the fate of all proteins that are brought into the cell,” said Wilson.

Age-related neurodegenerative illnesses, such as Alzheimer’s and Parkinson’s disease, that are prevented from progressing by dietary restriction have been linked to retromer malfunction.

Overall, their findings demonstrated how dietary restriction inhibits the aging of the brain by preserving the retromer through the action of mtd/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.

The researchers discovered that mtd/OXR1 is essential for neuronal function, healthy brain aging, and the lifespan extension observed with dietary restriction. It also maintains retromer activity.

“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,” said Wilson.

Researchers hypothesized that overexpression of OXR1 in humans may contribute to longer lifespans after discovering that raising mtd in flies extended their lifespan.

“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.”

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