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Scientists unlock the secrets of brain health and longevity through caloric restriction

[Jan. 21, 2024: JD Shavit, The Brighter Side of News]


A recent study has shed light on a lesser-known but critical aspect of caloric restriction: its profound influence on brain health and longevity. (CREDIT: Shutterstock)


When we think about restricting our calorie intake, we often focus on its impact on our waistlines and overall health. However, a recent study conducted by scientists at the Buck Institute for Research on Aging has shed light on a lesser-known but critical aspect of caloric restriction: its profound influence on brain health and longevity.


In the quest to uncover the intricate mechanisms behind the benefits of caloric restriction, the Buck Institute research team stumbled upon a crucial player in the puzzle: a gene called OXR1.


 
 

Dr. Kenneth Wilson, a postdoctoral researcher at the Buck Institute and the study's first author, emphasized the significance of this discovery: "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."


Published in Nature Communications, the study not only pinpointed the role of OXR1 in extending lifespan through dietary restriction but also unraveled the cellular mechanisms underlying this phenomenon. The researchers conducted experiments on fruit flies and human cells, revealing potential therapeutic targets for delaying aging and combating age-related neurodegenerative diseases.


 

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The team's findings revealed a neuron-specific response responsible for the neuroprotection offered by dietary restriction. Dr. Kapahi, a co-senior author of the study, highlighted the implications: "Strategies such as intermittent fasting or caloric restriction, which limit nutrients, may enhance levels of this gene to mediate its protective effects."


Dr. Lisa Ellerby, another co-senior author, emphasized the gene's role in safeguarding the brain against aging and neurological diseases, affirming, "The gene is an important brain resilience factor protecting against aging and neurological diseases."


 
 

The Variability of Dietary Restriction Response


While the benefits of caloric restriction on health and lifespan are well-established, there is significant variability in how individuals and different tissues respond to reduced calorie intake. To delve deeper into this variability, the Buck Institute researchers initiated a project aimed at unraveling the reasons behind these differing responses.


mtd is upregulated allele-specifically by Traffic Jam (TJ) to extend lifespan under DR. (CREDIT: Nature Communications)


Their research began by examining approximately 200 strains of fruit flies with distinct genetic backgrounds. These flies were raised on two distinct diets: a regular diet and a diet with dietary restriction, providing only 10% of normal nutrition. The scientists identified five genes with specific variants that significantly influenced longevity under dietary restriction, and two of these genes had human counterparts.


 
 

The chosen gene for further exploration was dubbed "mustard" (mtd) in fruit flies and "Oxidation Resistance 1" (OXR1) in humans and mice. OXR1 plays a pivotal role in protecting cells from oxidative damage, but its mechanism of action remained elusive. Loss of OXR1 in humans results in severe neurological defects and premature death, while in mice, increased OXR1 enhances survival in an amyotrophic lateral sclerosis (ALS) model.



The Brain-Aging Connection


To understand how a gene primarily active in neurons can impact overall lifespan, the research team conducted a series of intricate experiments. They discovered that OXR1 exerts its effects on a complex known as the retromer, which comprises proteins essential for recycling cellular proteins and lipids.


Dr. Wilson explained, "The retromer is an important mechanism in neurons because it determines the fate of all proteins that are brought into the cell." Dysfunctional retromers have been associated with age-related neurodegenerative diseases, such as Alzheimer's and Parkinson's, both of which are mitigated by dietary restriction.


 
 

The study unveiled the narrative of how dietary restriction counteracts brain aging through the actions of mtd/OXR1, preserving retromer function and supporting neuronal health, healthy brain aging, and extended lifespan.


mtd interacts with the retromer complex and is required for retromer maintenance. GO terms for the top 50 genes co-expressed with OXR1 show enrichment for endolysosomal network. Arranged by organelle and function. (CREDIT: Nature Communications)


Remarkably, the researchers also found that increasing mtd levels in flies led to longer lifespans, sparking speculation that boosting OXR1 expression in humans might similarly extend lifespan. Dr. Ellerby revealed their next steps: "Our next step is to identify specific compounds that increase the levels of OXR1 during aging to delay brain aging."


 
 

Dr. Wilson emphasized the broader implications of their research: "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."


Immunohistochemistry of brains from flies under constitutively active pan-neuronal mtdRNAi (bottom) show reduced Vps35 signal. Blue = DAPI, red = Vps35, green = Mtd. (CREDIT: Nature Communications)


The Buck Institute's groundbreaking study not only enriches our understanding of the profound effects of caloric restriction but also offers a glimpse into the intricate web of mechanisms that govern brain health and longevity.


 
 

As the scientific community continues to explore these mechanisms, the quest for a longer, healthier life takes on new dimensions, with diet emerging as a powerful tool in the quest for optimal well-being.





For more science news stories check out our New Discoveries section at The Brighter Side of News.


 

Note: Materials provided above by The Brighter Side of News. Content may be edited for style and length.


 
 

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