Scientists at the Buck Institute for Research on Aging have identified a gene called OXR1 that plays a crucial role in the lifespan extension and healthy brain aging observed with dietary restriction. This finding sheds light on the mechanisms behind the benefits of calorie restriction, which is known to improve health and increase lifespan.
The team of researchers, led by postdoctoral fellow Kenneth Wilson, explored the effects of dietary restriction on the brain, an area that has remained largely unexplored. Their study, published in Nature Communications, reveals that the gene OXR1 is vital for the protective effects of dietary restriction on brain health.
"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 Wilson. "As it turns out, this is a gene that is important in the brain."
Using fruit flies and human cells, the scientists also uncovered a detailed cellular mechanism that explains how dietary restriction can delay aging and slow the progression of neurodegenerative diseases. Furthermore, the study identified potential therapeutic targets that could be utilized to slow aging and age-related neurodegenerative conditions.
"We found a neuron-specific response that mediates the neuroprotection of dietary restriction," explained Professor Pankaj Kapahi, 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 OXR1 is a crucial factor in maintaining brain resilience and protecting against aging and neurological diseases, according to Professor Lisa Ellerby, another co-senior author of the study.
The researchers also aimed to understand the variability in individuals' responses to dietary restriction. By scanning different genetic backgrounds of approximately 200 strains of fruit flies, they identified five genes that significantly affected longevity under dietary restriction. One gene, called "mustard" (mtd) in fruit flies and "Oxidation Resistance 1" (OXR1) in humans and mice, stood out as a promising candidate for further investigation.
OXR1 plays a critical role in protecting cells from oxidative damage, but its precise mechanism of action remained unclear. Loss of OXR1 in humans leads to severe neurological defects and premature death, while in mice, increased OXR1 expression improves survival in a model of amyotrophic lateral sclerosis (ALS).
To understand how OXR1 affects overall lifespan, the researchers conducted extensive tests and discovered its involvement in the retromer complex. This complex consists of proteins necessary for recycling cellular proteins and lipids and has been linked to age-related neurodegenerative diseases like Alzheimer's and Parkinson's.
"The retromer is an important mechanism in neurons because it determines the fate of all proteins that are brought into the cell," explained Wilson.
By preserving retromer function, OXR1 slows brain aging and contributes to the lifespan extension observed with dietary restriction. Interestingly, the team also found that boosting mtd, the fruit fly counterpart of OXR1, increased the flies' lifespan. This suggests that excess expression of OXR1 in humans may have the potential to extend lifespan.
"Our next step is to identify specific compounds that increase the levels of OXR1 during aging to delay brain aging," said Professor Ellerby. "Hopefully, from this, we can get more of an idea of why our brains degenerate in the first place."
The implications of this research are profound, highlighting the impact of diet on overall health. Wilson emphasized the importance of following a healthy diet, stating, "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."
