Beyond Calories: Study Reveals Genes Responsible for Dietary Restrictions’ Lifespan Extending Effects
Akshay Naik 12 January 2024
Scientists have now pinpointed how dietary restrictions not only influence the digestive system, but also significantly impact brain ageing, offering potential therapeutic targets for age-related neuro-degenerative diseases. 
Restricting calories is known to improve health and increase lifespan, but much of how it does so remains a mystery, especially with regard to how it protects the brain. Scientists from the Buck Institute for Research on Aging have now uncovered a role for a gene called OXR1 that is necessary for the lifespan extension seen with dietary restrictions and for healthy brain ageing. 
Published in the journal Nature Communications, this study was led by Dr Kenneth Wilson from the Buck Institute for Research on Aging.
“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,” explained Dr Wilson. 
The study, conducted in fruit flies and human cells, demonstrated a detailed cellular mechanism showcasing how dietary restriction could potentially delay ageing and mitigate neuro-degenerative diseases.
Dr Pankaj  Kapahi, a co-author of the study, emphasised the discovery saying, “We found a neuron-specific response that mediates the neuro-protection through 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 and neurological diseases,” added Dr Lisa Ellerby, another senior researcher and co-author of the study. 
In earlier research, members of this team had shown mechanisms that improve lifespan and health-span 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. Therefore, this project started with the aim to understand why different people respond to diets in different ways. 
By examining around 200 fly strains with different genetic backgrounds, the research identified five genes, two of which had counterparts in human genetics. The flies were raised with two different diets, either with a normal diet or with dietary restriction, which was only 10% of normal nutrition. The chosen gene,' ‘mustard’ (mtd) in fruit flies and ‘Oxidation Resistance 1’ (OXR1) in humans and mice was found to play a critical role in protecting cells from oxidative damage.
As it turned out, the gene protects cells from oxidative damage but the mechanism for how this gene functions remained 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).
In order to identify how a gene that is active in neurons affects overall lifespan, the team did a series of in-depth tests. They found that ORX1 affects a complex called retromer, which is a set of proteins essential for recycling cellular proteins and lipids, and, thus, is a key player in brain ageing and neuro-degeneration. Retromer dysfunction has been associated with age-related neuro-degenerative diseases that are protected by dietary restriction, specifically Alzheimer’s and Parkinson’s diseases. 
The team's in-depth tests revealed that mtd/OXR1 preserves retromer function, influencing neuronal health, brain ageing and the extended lifespan observed with dietary restriction. By eating less, individuals may enhance the expression of OXR1, maintaining proper protein sorting within cells.
“Diet is influencing this gene. By eating less, you are actually enhancing this mechanism of proteins being sorted properly in your cells, because your cells are enhancing the expression of OXR1,” explained Dr Wilson.  
The researchers further observed that boosting mtd in flies led to an extended lifespan, prompting speculation about a potential link in humans. The next phase of this research involves identifying specific compounds that increase OXR1 levels to delay brain ageing, offering insights into the degeneration of the human brain.
"Hopefully from this we can get more of an idea of why our brain’s degenerate in the first place. 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,” emphasised Dr Wilson. 
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