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, PhD, Buck postdoc and first author of the study, published online on
January 11, 2024 in Nature
Communications. “As it turns out,
this is a gene that is important in the brain.”
The team additionally demonstrated a
detailed cellular mechanism of how dietary restriction can delay aging and slow
the progression of neurodegenerative diseases. The work, done in fruit flies
and human cells, also identifies potential therapeutic targets to slow aging
and age-related neurodegenerative diseases.
“We
found a neuron-specific response that mediates the neuroprotection of dietary
restriction,” said Buck Professor Pankaj Kapahi, PhD, 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 is an important brain resilience factor protecting against aging and
neurological diseases,” said Buck Professor Lisa Ellerby, PhD, co-senior author of the
study.
Understanding variability in response
to dietary restriction
Members
of the team have previously shown 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).
The link between 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 Alzheimer’s and Parkinson’s diseases.
Overall,
their results told the story of how dietary restriction slows brain aging by
the action of mtd/OXR1 in maintaining the retromer. “This work shows that the
retromer pathway, which is involved in reusing cellular proteins, has a key
role in protecting neurons when nutrients are limited,” said Kapahi. The team
found that mtd/OXR1 preserves retromer function and is necessary for neuronal
function, healthy brain aging, and lifespan extension seen with dietary
restriction.
“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,” said Wilson.
The
team also found that boosting mtd in flies
caused them to live longer, leading researchers to speculate that in humans
excess expression of OXR1 might
help extend lifespan. “Our next step is to identify specific compounds that
increase the levels of OXR1 during
aging to delay brain aging,” said Ellerby.
“Hopefully
from this we can get more of an idea of why our brains degenerate in the first
place,” said Wilson.
“Diet
impacts all the processes in your body,” he said. “I think this work supports
efforts to follow a healthy diet, because what you eat is going to affect more
than you know.”
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