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Researchers at Johns Hopkins Medicine and the National Institutes of Health’s National Institute on Aging have uncovered promising findings regarding the effects of intermittent fasting and a standard healthy diet on brain health in older adults with obesity and insulin resistance. Their study, published in Cell Metabolism, found that both diets led to improvements in cognition, with intermittent fasting showing slightly stronger benefits.
As people live longer, the prevalence of conditions like Alzheimer’s and related dementias is expected to rise, posing significant challenges for individuals, families, and healthcare systems. Cognitive decline not only impacts quality of life but also leads to increased disability and loss of independence, creating a pressing demand for effective preventive strategies.
One key factor implicated in brain aging and the development of Alzheimer’s disease is insulin resistance. Insulin resistance, which is more common with advancing age and obesity, affects the body’s ability to regulate glucose and has been linked to cognitive impairment and neurodegenerative diseases. Given this connection, interventions that improve insulin sensitivity could potentially mitigate cognitive decline and promote brain health in older adults.
“There is a widespread impression both among scientists and in the general public that diets in general and intermittent fasting in particular are good for cognitive function and brain health and may mitigate the risk for Alzheimer’s disease; however, there has been very little data from clinical studies to support this notion. We sought to close this evidence gap by comprehensively assessing cognition and multiple brain health biomarkers in response to a 5:2 intermittent fasting and a healthy living diet,” said study author Dimitrios Kapogiannis, a senior investigator and chief of the Human Neuroscience Section at the National Institute on Aging.
The researchers recruited 40 participants who were older adults with obesity and insulin resistance, a group at higher risk for accelerated brain aging and cognitive decline. These participants were randomly assigned to one of two dietary plans: the 5:2 intermittent fasting diet or the USDA-approved healthy living diet.
The intermittent fasting group followed a regimen where they restricted their calorie intake to one-quarter of the recommended daily intake for two consecutive days each week, consuming only two shakes providing 480 calories each day. On the remaining five days, they followed the healthy living diet. The healthy living group, on the other hand, adhered to the healthy living diet every day, which emphasized balanced meals including fruits, vegetables, whole grains, lean proteins, and low-fat dairy, while limiting added sugars, saturated fats, and sodium.
To monitor adherence and reinforce the dietary plans, participants attended in-person visits at weeks 2, 4, and 6 for anthropometric measurements and blood draws, and were contacted by phone or email on weeks 1, 3, 5, and 7. The final visit took place at week 8, with assessments conducted at the start and end of the study period.
The assessments included brain health measures, cognition tests, and systemic and peripheral metabolism measures. Neuron-derived extracellular vesicles were collected from the participants’ blood to analyze biomarkers related to brain cell activity and insulin signaling. Additionally, brain imaging and cognitive performance tests were conducted to gauge the impact of the diets on brain aging and function.
The findings of the study revealed that both the intermittent fasting and healthy living diets led to improvements in insulin resistance and cognitive function. Participants in both groups exhibited decreased insulin resistance, but the improvements were more pronounced in the intermittent fasting group. This was evidenced by significant reductions in specific biomarkers of insulin resistance found in the neuron-derived extracellular vesicles.
In terms of brain health, the study found that both diets contributed to slowing the pace of brain aging, particularly in brain regions critical for executive function, such as the anterior cingulate and prefrontal cortex. This was measured using brain-age-gap estimates derived from MRI scans, which indicate how much older or younger an individual’s brain appears relative to their chronological age. Both diets resulted in similar reductions in the brain-age-gap, suggesting beneficial effects on brain aging.
“Both diets were good for overall health and brain health, but 5:2 intermittent fasting showed stronger effects for reversing insulin resistance, improving executive function, and optimizing brain metabolism than the healthy living diet,” Kapogiannis told PsyPost. “However, we did not find any evidence that these two diets change any Alzheimer’s-related biomarkers in the short term. Finally, sex and genetic factors, such as APOE, may modify responses to the diets. Therefore, which diet is best should be an individualized choice.”
Specifically, the intermittent fasting group showed significant improvements in tasks related to strategic planning and cognitive flexibility. They also exhibited greater enhancements in memory, particularly in long delay cued recall, compared to the healthy living group. Physical activity levels increased in the intermittent fasting group, with a decrease in sedentary behavior, whereas the healthy living group did not show significant changes in physical activity.
Interestingly, despite the overall positive outcomes, the study did not find significant changes in cerebrospinal fluid biomarkers associated with Alzheimer’s disease, such as amyloid-beta and tau proteins. This suggests that while the dietary interventions had clear benefits for insulin resistance and cognitive function, their impact on Alzheimer’s disease-specific biomarkers was limited.
“A couple things surprised us: The fact that a low intensity conventional intervention, such as the healthy living diet, was effective in improving brain health; almost as effective as a higher-intensity intervention such as 5:2 intermittent fasting for many outcomes,” Kapogiannis explained. “Also, the fact that cerebrospinal fluid biomarkers of Alzheimer’s disease did not show any improvements – however, the intervention lasted only 8 weeks, so the biomarkers might have improved with a longer intervention.”
While the study’s findings are promising, some limitations should be considered. The study duration was relatively short. Therefore, the long-term effects of the diets remain unknown. Additionally, the sample size was small, with only 20 participants in each diet group, which limits the ability to draw definitive conclusions about sub-groups based on sex or genetic factors.
“We can reasonably speculate about but not really know what the long-term effects of the diets are,” Kapogiannis noted. “Studying intermittent fasting for longer periods of time is essential. Also, combining diet with ketogenic supplements to see whether there are added benefits from driving brain ketones higher. Long-term, I think that the choice of diet for an individual should be decided along the principles of Precision Medicine, based on sex, genetic factors and biomarkers.”
By employing a comprehensive and multimodal approach to assess the effects of dietary interventions on brain health, the study sets a methodological standard that future research can build upon. It highlights the potential of neuron-derived extracellular vesicles, magnetic resonance imaging, and magnetic resonance spectroscopy to offer detailed insights into how diets impact cognitive function and insulin resistance in older adults.
“I hope that this study offers a blueprint for future research to vigorously assess long-term effects of diet on brain health,” Kapogiannis said.
The study, “Brain responses to intermittent fasting and the healthy living diet in older adults,” was authored by Dimitrios Kapogiannis, Apostolos Manolopoulos, Roger Mullins, Konstantinos Avgerinos, Francheska Delgado-Peraza, Maja Mustapic, Carlos Nogueras-Ortiz, Pamela J. Yao, Krishna A. Pucha, Janet Brooks, Qinghua Chen, Shalaila S. Haas, Ruiyang Ge, Lisa M. Hartnell, Mark R. Cookson, Josephine M. Egan, Sophia Frangou, and Mark P. Mattson.
