The mechanism provides potential therapeutic targets to slow aging and age-related neurodegenerative diseases.
Restricting calories is known to improve health and increase lifespan, but much of how it does so remains a mystery, especially in regard to how it protects the brain. Buck scientists have uncovered a role for a gene called OXR1 that is necessary for the lifespan extension seen with dietary restriction and is essential for healthy brain 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,” said Kenneth Wilson, Ph.D., Buck postdoc and first author of the study, published online on January 11, 2024, in mechanisms that improve lifespan and healthspan 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. This project was started to understand why different people respond to diets in different ways.
The team began by scanning about 200 strains of flies with different genetic backgrounds. The flies were raised with two different diets, either with a normal diet or with dietary restriction, which was only 10% of normal nutrition. Researchers identified five genes which had specific variants that significantly affected longevity under dietary restriction. Of those, two had counterparts in human genetics.
The team chose one gene to explore thoroughly, called “mustard” (mtd) in fruit flies and “Oxidation Resistance 1” (OXR1) in humans and mice. The gene protects cells from oxidative damage, but the mechanism for how this gene functions was 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).
Linking Brain Aging, Neurodegeneration, and Lifespan
To figure out how a gene that is active in neurons affects overall lifespan, the team did a series of in-depth tests. They found that OXR1 affects a complex called the retromer, which is a set of proteins necessary for recycling cellular proteins and lipids. “The retromer is an important mechanism in neurons because it determines the fate of all proteins that are brought into the cell,” said Wilson. Retromer dysfunction has been associated with age-related neurodegenerative diseases that are protected by dietary restriction, specifically DOI: 10.1038/s41467-023-44343-3
Other Buck researchers involved in the study are: Sudipta Bar, Enrique Carrera, Brian Hodge, Tyler Hilsabeck, Joanna Bons, George Brownridge III, Jennifer Beck, Jacob Rose, Melia Granath-Panelo, Christopher Nelson, Grace Qi, Akos Gerencser, Jianfeng Lan, Rachel Brem, and Birgit Schilling.
This work was supported in part by funds from the