Buck Institute researchers identify how dietary restriction slows brain aging and increases lifespan

Discovered mechanism provides potential therapeutic targets to slow aging and age-related neurodegenerative diseases.
Caloric restriction is a well-documented way of improving both healthspan and lifespan; however, aspects of the the actual mechanism have been shrouded in mystery, particularly in how CR protects the brain. Now researchers at the Buck Institute for Research on Aging have uncovered a role for OXR1, a gene that is necessary for the lifespan extension seen with dietary restriction and is essential for healthy brain aging [1].

Buck Institute researchers identify how dietary restriction slows brain aging and increases lifespan
Buck postdoc Kenneth Wilson, PhD, is first author of the study
“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, PhD, Buck postdoc and first author of the study, published in Nature Communications. “As it turns out, this is a gene that is important in the brain.”

Longevity.Technology: In addition, the Buck team were able to demonstrate a detailed cellular mechanism of 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 to slow aging and age-related neurodegenerative diseases.

“We found a neuron-specific response that mediates the neuroprotection of dietary restriction,” said Buck Professor, Pankaj Kapahi PhD, 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, PhD, co-senior author of the study.

Apples and oranges
Members of the team 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, there are clearly many yet-to-be-discovered processes in play. This 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 meant they only received 10% of normal nutrition. Researchers identified five genes which had specific variants that significantly affected longevity under dietary restriction, and of those, two had counterparts in human genetics.

Time to cut the mustard
The team 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 unclear.

The loss of OXR1 in humans results in severe neurological defects and premature death, and inn mice, extra OXR1 improves survival in a model of amyotrophic lateral sclerosis (ALS).

The link between brain aging, neurodegeneration and lifespan
To figure out how a gene that is active in neurons affects overall lifespan, the team did a series of in-depth tests, and discovered that that OXR1 affects a complex called the retromer, which is a set of proteins necessary for recycling cellular proteins and lipids.

“The retromer is an important mechanism in neurons because it determines the fate of all proteins that are brought into the cell,” said Wilson. Retromer dysfunction has been associated with age-related neurodegenerative diseases that are protected by dietary restriction, specifically Alzheimer’s and Parkinson’s diseases.

Buck Institute researchers identify how dietary restriction slows brain aging and increases lifespan