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NOVATO, Calif. — As we age, our brains often struggle to keep up. Memories fade, and cognition slows. But what if a simple change in diet could help keep our minds sharp, even in our twilight years? A new study suggests that a high-fat, low-carb ketogenic diet (KD), even when someone starts it later in life, may do just that — enhancing memory and cognitive performance in aging mice.
The research, led by Dr. Diego Acuña-Catalán at the University of Chile and published in Cell Reports Medicine, adds to a growing body of evidence that KDs can have neuroprotective effects. Ketogenic diets prompt the body to burn fat for fuel, producing compounds called ketone bodies that can stand in for glucose as the brain's energy source. Previous animal studies have shown that long-term KDs started in midlife can improve memory in old age. But whether starting this diet later in life, when age-related cognitive decline has already begun to set in, could still be beneficial was an open question.
To find out, Acuña-Catalán and his colleagues put a group of 20 to 23-month-old mice — the rough equivalent of 60 to 70-year-old humans — on a cyclic KD, alternating weekly between the high-fat chow and regular food. After just four months, the KD mice outperformed their regularly fed counterparts on tests of working memory and long-term memory. They also showed improved motor coordination on a rotarod test, which measures balance and physical performance.
Digging deeper, the researchers found that the memory-boosting effects of the KD were accompanied by striking changes in the brain. Neurons in the prefrontal cortex, a region crucial for working memory, had more complex dendrite branches - the treelike structures that receive signals from other neurons. This increased complexity suggests that KD mice may have enhanced neural connectivity and plasticity, making their brains more adaptable and resilient.
“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,” says Dr. John Newman from the Buck Institute in a media release.
Methodology
To connect these brain changes to behavioral improvements, the researchers turned to a range of sophisticated techniques. They started with electrophysiology, measuring the electrical activity in brain slices from the hippocampus, a key memory center. Neurons from KD mice showed enhanced long-term potentiation (LTP), a strengthening of the connections between neurons that are thought to underlie learning and memory.
Next, they used a classic neuroanatomy technique called Golgi staining to visualize the intricate geometry of individual neurons. This revealed the increased dendritic complexity in the prefrontal cortex of KD mice. Interestingly, they also found that dendritic spines, the tiny protrusions where neurons form synaptic connections, were more abundant and more likely to be of the “stubby” variety in KD brains. Stubby spines are thought to be particularly stable and mature, possibly reflecting enhanced synaptic strength.
Finally, to get a handle on the molecular mechanisms at play, the team turned to proteomics — the study of proteins, their functions, and their structure. By analyzing the protein composition of synapses (the sites of communication between neurons) in the cerebral cortex, they identified key signaling pathways that were ramped up by the KD. Notably, the cAMP/PKA pathway, known to be involved in memory formation, was strongly activated. This was accompanied by increased production of the neurotrophin BDNF, a protein that supports the growth and survival of neurons and synapses.
Promising Results, With Caveats
The findings offer compelling evidence that a KD started even late in life can enhance memory and cognition, possibly by rewiring neural circuits to be more plastic and efficient. The activation of the cAMP/PKA pathway and BDNF production provide tantalizing clues to the underlying molecular mechanisms.
“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,” Newman says.
However, the study does have some limitations. Mice, of course, are not tiny humans, and it remains to be seen if the results will translate to people. The researchers also only studied male mice, so potential sex differences in response to the diet are unknown. Additionally, while the four-month timeframe is significant in mouse lifespan, longer studies would be needed to assess the durability of the cognitive benefits.
From Mice to Mind: Looking Ahead
Despite these caveats, the work represents an exciting advance. It suggests that dietary interventions, even starting at an advanced age, could be a powerful way to support brain health. With an aging population and rising rates of age-related cognitive decline and dementia, novel strategies to preserve and enhance cognition are sorely needed.
The detailed circuit and molecular analyses also provide valuable road maps for future research. Understanding exactly how KDs reshape neural connectivity and signaling could lead to more targeted therapies, dietary or pharmacological, that mimic these beneficial effects. The activation of BDNF signaling is particularly intriguing, as this pathway is known to be impaired in various neurodegenerative conditions.
Of course, much more work is needed before doctors start prescribing KDs for grandma's forgetfulness. The safety and tolerability of the diet in older adults need rigorous testing, as do the optimal timing, duration, and composition of the diet. Interactions with common age-related health conditions and medications will also be critical to examine.
But if the benefits seen in mice do indeed translate to humans, KDs could represent a relatively simple, non-invasive way to preserve memory and potentially stave off cognitive decline. Unlike many proposed anti-aging therapies, diet is readily modifiable by most individuals. And while the idea of giving up carbs may not sound appealing to everyone, cycling between a KD and regular food, as done in this study, could offer a more palatable approach.
Ultimately, this provocative mouse study serves up plenty of food for thought. For humans hoping to maintain their mental faculties well into old age, a ketogenic boost may one day be just what the doctor ordered. For now, as we await further research, perhaps the best prescription is a balanced diet, regular exercise, and a healthy dose of scientific curiosity about how we might all keep our minds sharp throughout our lifespan.
