Summary: A new study reveals how a ketogenic diet,
high in fat and low in carbohydrates, improves memory in aging mice.
Researchers found that the diet triggers a molecular signaling pathway
that enhances synapse function, leading to improved memory. This
discovery could pave the way for new therapies targeting memory without
the need for dietary changes.
Key Facts:
- Ketogenic diet improves memory in aging mice by modifying the synaptic proteome.
- The protein kinase A signaling pathway is activated by the ketogenic diet, enhancing synapse function.
- This research offers a potential new approach to improving memory through molecular targeting, independent of dietary changes.
Source: Buck Institute
The ketogenic diet has its fanatics and detractors among
dieters, but either way, the diet has a scientifically documented impact
on memory in mice.
While uncovering how the high fat,
low carbohydrate diet boosts memory in older mice, Buck scientists and a
team from the University of Chile identified a new molecular signaling
pathway that improves synapse function and helps explain the diet’s
benefit on brain health and aging.
Published in the June 5, 2024 issue of Cell Reports Medicine,
the findings provide new directions for targeting the memory effects on
a molecular level, without requiring a ketogenic diet or even the
byproducts of it.
testing indicated that in synapses, a particular signaling pathway
(protein kinase A, which is critical to synapse activity) was activated
by the ketogenic diet. Credit: Neuroscience News
The
paper is titled “Ketogenic diet administration later in life improves
memory by modifying the synaptic cortical proteome via the PKA signaling
pathway in aging mice.”
“Our work indicates that the effects of the ketogenic diet benefit
brain function broadly, and we provide a mechanism of action that offers
a strategy for the maintenance and improvement of this function during
aging,” said the study’s senior author, Christian González-Billault,
Ph.D., who is a professor at the Universidad de Chile and director of
their Geroscience Center for Brain Health and Metabolism, and adjunct
professor at the Buck Institute.
“Building off our previous work
showing that a ketogenic diet improves healthspan and memory in aging
mice, this new work indicates that we can start with older animals and
still improve the health of the aging brain, and that the changes begin
to happen relatively quickly,” said John Newman, MD, Ph.D., whose
laboratory at Buck collaborated with Dr. González-Billault on the study.
Newman
is both an assistant professor at the Buck Institute, and a
geriatrician at University of California, San Francisco. “It is the most
detailed study to date of the ketogenic diet and aging brain in mice.”
More than a century ago, researchers observed that rats that consumed less food lived longer.
“We
now know that being able to manipulate lifespan is not about
specifically eating less,” said Newman, but actually is related to
signals inside cells that turn on and off specific pathways in response
to available nutrients.
Many of those pathways are related to aging, such as controlling protein turnover and metabolism.
Some of those signals are the ketone bodies, which consist of
acetoacetate (AcAc), β-hydroxybutyrate (BHB) and to a much lesser
extent, acetone. These molecules are routinely produced in the liver.
They
ramp up when glucose is in short supply, whether due to caloric
restriction, intense exercise or low carbohydrate intake, such as with a
ketogenic diet.
Seven years ago, Newman led a team that published
the first proof of the concept that if a ketogenic diet exposes mice to
increased levels of ketone bodies over much of their adult life, it
helps them to live longer and age in a more healthy way.
“The most
striking effect on their health as they aged was that their memory was
preserved; it was possibly even better than when they were younger,” he
said.
The current study, designed to answer what part of the
ketogenic diet was having the effect and how it was affecting the brain
on a molecular level to improve memory, was led by González-Billault in a
collaboration with scientists at the Buck. Mice on a ketogenic diet are
fed a ratio of 90% calories from fat and 10% from protein, while mice
on a control diet received the same amount of protein but only 13% fat.
The
test mice, of “advanced age” of more than two years old, received one
week of the ketogenic diet, cycled with one week of the control diet, to
keep the mice from overeating and becoming obese.
The benefits of the ketogenic diet, said, González-Billault, were
demonstrated through neurophysiological and behavioral experiments with
the mice that test how well the mechanisms involved in memory
generation, storage, and retrieval function in aged animals.
When
these showed that the ketogenic diet appeared to benefit how well the
synapses responsible for memory worked, they took a deep dive into the
protein composition at these synapses in the hippocampus, in a
collaboration with Buck professor Birgit Schilling, Ph.D., who directs
the Proteomics and Mass Spectrometry Center.
“Surprisingly, we saw
that the ketogenic diet caused dramatic changes in the proteins of the
synapse,” said Schilling. Even more surprising, she said, was that the
changes started after a relatively brief exposure to the diet (tested
after only one week on the diet) and only became more pronounced over
time (tested again after six weeks and a year).
Further testing
indicated that in synapses, a particular signaling pathway (protein
kinase A, which is critical to synapse activity) was activated by the
ketogenic diet. In isolated cells, the team then showed that it appears
that BHB, the main ketone body produced in a ketogenic diet, is
activating this pathway.
This leads to the idea, said
González-Billault, that ketone bodies (specifically BHB) play a crucial
role not only as an energy source, but also as a signaling molecule.
“BHB
is almost certainly not the only molecule in play, but we think this is
an important part of understanding how the ketogenic diet and ketone
bodies work,” said Newman.
“This is the first study to really connect deep molecular mechanisms
of ketone bodies all the way through to improving the aging brain.”
Looking
forward, he said, the next step would be to see if the same memory
protection could be achieved by using BHB alone, or possibly going even
more targeted than that by manipulating the protein kinase A signaling
pathway directly.
“If we could recreate some of the big-picture
effects on synapse function and memory just by manipulating that
signaling pathway in the right cells,” he said, “we wouldn’t even need
to eat a ketogenic diet in the end.”
About this diet, aging, and memory research news
Author: Christian González-Billault
Source: Buck Institute
Contact: Christian González-Billault – Buck Institute
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Ketogenic
diet administration later in life improves memory by modifying the
synaptic cortical proteome via the PKA signaling pathway in aging mice” by Christian González-Billault et al. Cell Reports Medicine
