Scientists from Singapore have found that intermittent fasting alleviates damage incurred by chronic cerebral hypoperfusion, the impaired blood flow to the brain that is thought to be a cause of age-related dementia [1].
Why intermittent fasting?
Back in the early days of geroscience, caloric restriction was the first intervention to substantially increase lifespan in lab animals, and now, many decades later, it remains one of the most powerful anti-aging interventions available. However, it is hard to maintain the required level of caloric restriction (35-40%) in humans. Recently, intermittent fasting has emerged as another version of dietary restriction, with one influential study suggesting that it promotes longevity in mice [2]. Another one found that intermittent fasting improves long-term memory and neurogenesis [3].
Many intermittent fasting regimens have been proposed, such as “day in, day out” and one meal a day, but the most popular is probably 16/8, in which daily food intake is restricted to an eight-hour window. This regimen is relatively easy to maintain, and one thorough review found it to be beneficial, including for humans [4].
Robust protection
In this new study, the researchers investigated whether intermittent fasting (IF) can help with chronic cerebral hypoperfusion (CCH), which is basically impaired blood flow to the brain. CCH is thought to contribute to age-related cognitive decline and dementia by increasing oxidative stress, inflammation, and matrix metalloproteinases.
The researchers developed a mouse model of CCH by artificially occluding the carotid artery. Two-month-old mice were put on a 16/8 IF diet, while the control group ate throughout the day. It is important to note that the mice’s diet was relatively healthy, with 58% carbohydrate, 24% protein, and 18% fat. After another four months, CCH was induced by carotid artery stenosis for either 15 or 30 days.
The IF group exhibited lower body weight and a significant increase in blood ketones, which supports the claim that 16/8 IF induces ketosis. The researchers then tested how IF affected various types of CCH-induced damage. One of the hallmarks of CCH is increased microvascular leakage, which was attenuated by IF very significantly, almost to the level of healthy controls.
The researchers then measured the permeability of the blood-brain barrier (BBB), which safeguards the brain from various pathogens. BBB permeability increased significantly in the non-IF CCH group, but intermittent fasting prevented this increase almost completely. IF also partially rescued levels of tight junction proteins reduced by CCH. Tight junctions are protein structures that “glue” cells together to decrease permeability.
Results were highly promising in neuronal pathologies as well. IF attenuated CCH-induced decreases in white matter integrity and almost completely protected hippocampal neurons from death. Cleaved caspase-3, a marker of cellular death, was significantly increased by the 30-day perturbation in non-IF animals but not in the IF group.
Matrix metalloproteinases (MMPs) are enzymes that degrade the cellular matrix, an important component of the blood-brain barrier. They are indispensable for healthy remodeling of the matrix, but their overexpression can be harmful, and in the brain, this has been linked to both vascular and neuronal pathologies. In this study, IF robustly protected against the increase in MMP levels induced by CCH.
IF helps the healthy brain
One of the mechanisms by which CCH damages the brain is oxidative stress. The levels of two major antioxidants, glutathione and superoxide dismutase, were not significantly changed by CCH in non-IF animals. However, they were greatly increased by IF in all groups, including healthy controls. In other words, even though antioxidant levels were not negatively affected by the injury, they were positively affected by IF, which might have helped to alleviate CCH-induced damage.
Interestingly, a similar tendency was evident in some other measurements, where IF led to beneficial changes even in non-injured controls. This included vascular leakage, BBB permeability, white matter integrity, and cortex levels of tight junction proteins. These results suggest that IF benefits even a healthy brain.
Conclusion
This study investigated some interesting aspects of the effect intermittent fasting has on the brain. Like many previous studies, it showed that IF, and its popular 16/8 form in particular, confer health benefits. IF robustly protected from damage induced to the brain by chronic cerebral hypoperfusion, a condition that might cause age-related dementia. However, this study would be hard to recreate in humans, because it involved long-term IF prior to CCH onset, which cannot be predicted in humans. On the other hand, IF is probably not popular enough yet to allow for an epidemiological study, so we will have to do with mouse data for now.
Literature
[1] Rajeev, V., Fann, D. Y., Dinh, Q. N., Kim, H. A., De Silva, T. M., Jo, D. G., … & Arumugam, T. V. (2022). Intermittent Fasting Attenuates Hallmark Vascular and Neuronal Pathologies in a Mouse Model of Vascular Cognitive Impairment. International Journal of Biological Sciences, 18(16), 6052-6067.
[2] Mitchell, S. J., Bernier, M., Mattison, J. A., Aon, M. A., Kaiser, T. A., Anson, R. M., … & de Cabo, R. (2019). Daily fasting improves health and survival in male mice independent of diet composition and calories. Cell Metabolism, 29(1), 221-228.
[3] Dias, G. P., Murphy, T., Stangl, D., Ahmet, S., Morisse, B., Nix, A., … & Thuret, S. (2021). Intermittent fasting enhances long-term memory consolidation, adult hippocampal neurogenesis, and expression of longevity gene Klotho. Molecular psychiatry, 26(11), 6365-6379.
[4] De Cabo, R., & Mattson, M. P. (2019). Effects of intermittent fasting on health, aging, and disease. New England Journal of Medicine, 381(26), 2541-2551.
