Researchers in the US have uncovered a role for a gene called OXR1 that is necessary for the lifespan extension seen with dietary restriction and is essential for healthy brain ageing.
The research is published in the journal Nature Communications.
Kenneth Wilson, Ph.D., a Buck Institute postdoc and first author of the study, said: “When people restrict the amount of food that they eat, they typically think it might affect their digestive tract or fat build-up, but not necessarily about how it affects the brain.
“As it turns out, this is a gene that is important in the brain.”
The team also demonstrated a detailed cellular mechanism of how dietary restriction can delay ageing and slow the progression of neurodegenerative diseases.
Their work, done in fruit flies and human cells, also identifies potential therapeutic targets to slow aging and age-related neurodegenerative diseases.
Professor Pankaj Kapahi , Ph.D., co-senior author of the study, said: “We found a neuron-specific response that mediates the neuroprotection of dietary restriction.
“Strategies such as intermittent fasting or caloric restriction, which limit nutrients, may enhance levels of this gene to mediate its protective effects.”
Professor Lisa Ellerby, Ph.D., co-senior author of the study, added: “The gene is an important brain resilience factor protecting against ageing and neurological diseases.”
Buck researchers have previously shown mechanisms that improve lifespan and healthspan with dietary restriction, but there is so much variability in response to reduced calories across individuals and different tissues that it is clear there are many yet to be discovered processes in play.
The new project was started to understand why different people respond to diets in different ways.
The team began by scanning about 200 strains of flies with different genetic backgrounds.
The flies were raised with two different diets, either with a normal diet or with dietary restriction, which was only 10 per cent of normal nutrition.
Researchers identified five genes which had specific variants that significantly affected longevity under dietary restriction. Of those, two had counterparts in human genetics.
The researchers chose one gene to explore thoroughly, 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 for how this gene functions was unknown.
The loss of OXR1 in humans results in severe neurological defects and premature death while in mice, extra OXR1 improves survival in a model of amyotrophic lateral sclerosis (ALS).
To figure out how a gene that is active in neurons affects overall lifespan, the researchers did a series of in-depth tests.
They learned that OXR1 affects a complex called the retromer, which is a set of proteins necessary for recycling cellular proteins and lipids.
Wilson said: “The retromer is an important mechanism in neurons because it determines the fate of all proteins that are brought into the cell.”
Retromer dysfunction has been associated with age-related neurodegenerative diseases that are protected by dietary restriction, specifically Parkinson’s and Alzheimer’s diseases.
Overall, their results told the story of how dietary restriction slows brain ageing by the action of mtd/OXR1 in maintaining the retromer.
Kapahi said: “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.
The team found that mtd/OXR1 preserves retromer function and is necessary for neuronal function, healthy brain ageing and lifespan extension seen with dietary restriction.
Wilson said: “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.”
The researchers also found that boosting mtd in flies caused them to live longer, leading researchers to speculate that in humans excess expression of OXR1 might help extend lifespan.
Ellerby said: “Our next step is to identify specific compounds that increase the levels of OXR1 during aging to delay brain ageing.”
Wilson added:
“Hopefully from this we can get more of an idea of why our brains degenerate in the first place.
“Diet impacts all the processes in your body.
“I think this work supports efforts to follow a healthy diet, because what you eat is going to affect more than you know.”
