How dietary restriction protects the brain and delays ageing

Researchers at the Buck Institute have revealed a link between dietary restriction, a gene called OXR1, and the preservation of brain health

The positive effects of calorie restrictions on health and lifespan are well known. However, Professor Pankaj Kapahi and postdoc Kenneth Wilson from Buck Institute have emphasised the importance of the OXR1 gene in regulating the protective effects of dietary restriction on the brain.

It’s previously been known that restricting calories mainly affects the digestive tract or fat buildup. The researchers discovered that OXR1, active in the brain, plays a role in the lifespan extension observed with dietary restriction.

Healthy ageing in the brain

This gene, known as “mustard” (mtd) in fruit flies and “Oxidation Resistance 1” (OXR1) in humans and mice, has been identified as a key factor in healthy brain ageing.

The team investigated the cellular mechanisms underlying ageing delay and the slowing of neurodegenerative diseases, using fruit flies and human cells as models.

They pinpointed a neuron-specific response responsible for the neuroprotection associated with dietary restriction, revealing a potential route for therapeutic intervention in ageing and age-related neurodegenerative diseases.

The research study

To understand the variability in individuals’ responses to dietary restriction, the researchers examined approximately 200 strains of flies with different genetic backgrounds.

Two genes, including OXR1, were identified as having significant variants affecting longevity under dietary restriction. The loss of OXR1 in humans has been linked to severe neurological defects and premature death, while mice with extra OXR1 showed improved survival in a model of amyotrophic lateral sclerosis (ALS).

The workings of OXR1

The team uncovered the complicated workings of OXR1 and its impact on a cellular complex known as the retromer, essential for recycling cellular proteins and lipids.

Retromer dysfunction has been associated with age-related neurodegenerative diseases such as Alzheimer’s and Parkinson’s, conditions that are mitigated by dietary restriction.

The study emphasises how dietary restriction slows brain ageing through the action of OXR1 in preserving retromer function. “Diet is influencing this gene. By eating less, you are enhancing this mechanism of proteins being sorted properly in your cells because your cells are enhancing the expression of OXR1,” explained Kenneth Wilson.

“By eating less, you are enhancing this mechanism of proteins being sorted properly in your cells”

Dietary restrictions increasing lifespan

The researchers found that increasing mtd/OXR1 in flies resulted in a longer lifespan, suggesting potentially similar effects in humans. The next step for the team involves identifying specific compounds that can elevate OXR1 levels during ageing, with the aim of delaying brain ageing.

This groundbreaking research emphasises the impact of diet on brain health and longevity. Professor Kenneth Wilson said, “Diet impacts all the processes in your body. I think this work supports efforts to follow a healthy diet because what you eat will affect more than you know.”

With potential therapeutic targets identified, the study opens new areas for understanding the complexities of brain ageing and neuroprotection.