Researchers at Buck has discovered the role of a gene called OXR1, which is essential to both healthy brain aging and the lifespan extension found with dietary restriction.
Restricting calories is known to improve health and increase lifespan, but much of how it does so remains a mystery, especially in regard to how it protects 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. As it turns out, this is a gene that is important in the brain,” said Mr. Kenneth Wilson, Ph.D., Buck postdoc and first author of the study, published in Nature Communications.
The team additionally demonstrated 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.
Buck Professor Pankaj Kapahi, Ph.D., co-senior author of the study, stated that, “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.”
“The gene is an important brain resilience factor protecting against aging and neurological diseases,” stressed Buck Professor Lisa Ellerby, Ph.D., co-senior author of the study.
The Research
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 that it is clear there are 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 was only 10 percent of normal nutrition. Researchers identified five genes that had specific variants that significantly affected longevity under dietary restriction. Of those, two had counterparts 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. 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. In mice, extra OXR1 improves survival in a model of amyotrophic lateral sclerosis (ALS).
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