Summary – Caloric restriction is recognized for its health benefits and life-extending properties, yet the specifics of its effects, particularly on brain protection, are not fully understood. Researchers have recently identified the significant role of a gene named OXR1, essential in extending lifespan through dietary restriction and crucial for the maintenance of brain health during aging.
Kenneth Wilson, Ph.D., a Buck postdoc and the study’s first author, emphasizes the unexpected impact of dietary choices on brain health. “When people restrict food intake, they might think about effects on digestion or fat, but not the brain,” he said. The study, published in Nature Communications on January 11, 2024, reveals that OXR1 is vital in the brain, hinting at deeper connections between diet and neural well-being.
Neuroprotection and Aging: The Role of Diet
The Buck team’s research, using fruit flies and human cells, demonstrates how dietary restriction can delay aging and slow neurodegenerative disease progression. This work pinpoints potential therapeutic targets to combat aging and related neurological disorders.
Buck Professor Pankaj Kapahi, Ph.D., co-senior author, highlights a neuron-specific response underpinning dietary restriction’s neuroprotective effects. “Limiting nutrients through intermittent fasting or caloric restriction may enhance OXR1 levels, mediating protection,” he explains. Buck Professor Lisa Ellerby, Ph.D., adds that OXR1 serves as a crucial factor in brain resilience against aging and neurological diseases.
The study began by examining around 200 strains of fruit flies on normal and restricted diets. This led to the identification of five genes, including “mustard” (mtd) in flies and “Oxidation Resistance 1” (OXR1) in humans and mice, influencing longevity under dietary restriction. The loss of OXR1 in humans results in severe neurological issues and early death, while its abundance in mice enhances survival in amyotrophic lateral sclerosis (ALS) models.
The link between brain aging, neurodegeneration, and lifespan is further explored through the role of OXR1 in the retromer complex, crucial for recycling cellular proteins and lipids. Wilson notes, “The retromer is significant in neurons, as it decides the fate of proteins entering the cell.” Dysfunctions in this complex are linked to Alzheimer’s and Parkinson’s, diseases mitigated by dietary restriction.
The team’s findings reveal how dietary restriction slows brain aging via mtd/OXR1’s role in maintaining retromer function. “Eating less enhances the sorting of proteins in cells by boosting OXR1 expression,” Wilson concludes.
The study opens new avenues, with researchers now aiming to find compounds that elevate OXR1 levels, potentially delaying brain aging and extending lifespan.