It is well known that restricting calorie intake improves health and increases life expectancy, but how this happens remains a mystery, especially in terms of protecting the brain. Buck scientists led by Kenneth Wilson, Ph.D., Buck postdoctoral fellow and first author of the study, have uncovered a role for a gene called OXR1, which is necessary for extending lifespan on a restricted diet, and is essential for healthy brain aging. The research results were published in Nature Communications.
Why Different People React Differently to a Diet
In addition, the team has revealed a detailed cellular mechanism of how dietary restriction can delay ageing and slow the progression of neurodegenerative diseases. The work, conducted on fruit flies and human cells, also identifies potential therapeutic targets for slowing aging and age-related neurodegenerative diseases. The researchers have found a neuron-specific response that mediates the neuroprotective effect of a restricted diet. Strategies such as intermittent fasting or calorie restriction that limit nutrient intake may increase levels of this gene to mediate its protective effect, according to Buck Professor Pankaj Kapahi , Ph.D., co-author of the study. The gene is an important factor in brain resilience, which protects against aging and neurological diseases.
Team members have already shown mechanisms that improve life expectancy and healthspan through dietary restriction, but the response to reduced calorie intake is so variable from person to person and in different tissues that there are many as yet undiscovered processes at play. This project was set up to understand why different people respond differently to diet.
The team began by studying around 200 strains of flies with different genetic backgrounds. The flies were raised on two different diets, either a normal diet or a restricted diet that was only 10% of the normal diet. The researchers identified five genes that had specific variants that significantly affected longevity on a restricted diet. Two of these genes had counterparts in human genetics. The team selected one gene to study in depth:mustard(mtd) in fruit flies and oxidative resistance 1(OXR1) in humans and mice. The gene protects cells from oxidative damage, but the mechanism of how this gene works was unclear. Loss of OXR1 in humans leads to severe neurological defects and premature death. In mice, additional OXR1 improves survival in a model of amyotrophic lateral sclerosis (ALS).
Link Between Brain Ageing, Neurodegeneration and Life Expectancy
To find out how a gene active in neurons affects overall lifespan, the team conducted a series of in-depth tests. The scientists found that OXR1 affects a complex called retromer, a group of proteins necessary for the recycling of cellular proteins and lipids. According to the researchers, the retromer is an important mechanism in neurons because it determines the fate of all proteins that are introduced into the cell. A malfunction of the retromer has been linked to age-related neurodegenerative diseases that are protected by a restricted diet, in particular Alzheimer’s and Parkinson’s disease.
Overall, their results show how dietary restriction slows brain aging through the action of mtd/OXR1 on retromere maintenance. This work shows that the retromer pathway, which is involved in the recycling of cell proteins, plays 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 aging and lifespan extension when nutrition is limited. Diet influences this gene. According to the researchers, eating less actually promotes this mechanism of proteins being properly sorted in the cells because the cells increase the expression of OXR1.
The team also found that increasing mtd expression in flies leads to a longer life, leading the researchers to speculate that overexpression of OXR1 in humans could contribute to a longer lifespan. The next step is to identify specific substances that increase OXR1 levels during aging to delay brain aging.