Scientists have found that intermittent fasting can ameliorate Alzheimer’s in mice by improving sleep patterns [1].
Time to eat, time to fast
Time-restricted eating, also referred to as intermittent fasting (IF), can take different shapes, such as the one-meal-a-day regimen, alternate-day fasting, or 16/8, in which a person fasts for 16 hours and eats during the remainder of the day. However, the debate around IF is ongoing. While it has been credited with providing benefits in obesity, diabetes, cardiovascular disease, cancers, and neurological disorders [2], some experts doubt that IF is doing anything beyond helping people consume fewer calories.
There is evidence that IF might improve sleep quality [3], which is known to deteriorate in Alzheimer’s disease. Up to 80% of Alzheimer’s patients experience sleep-related problems, such as difficulty falling or staying asleep [4]. The relationship between Alzheimer’s and poor sleep quality might be bi-directional, with one exacerbating the other. Some studies suggest that alterations of circadian rhythms emerge early during Alzheimer’s progression and directly contribute to pathology [5].
TRF rescues sleep patterns impaired by Alzheimer’s
In this new study published in Cell Metabolism, the researchers used a mouse model of Alzheimer’s disease and an 18/6 regimen of time-restricted feeding (TRF) to understand the interplay between them. The treatment group was put on TRF at three months old, prior to the appearance of Alzheimer’s symptoms. By six months, the mice developed progressive pathology, including formation of amyloid plaques, the foremost Alzheimer’s hallmark. At 11 months, the control group showed various signs of sleep problems, such as decreased total sleep duration and altered activity rhythms.
The researchers detected some well-known effects of TRF in the treated mice, such as reduced levels of blood glucose and higher levels of ketone bodies. Importantly, both groups consumed the same amount of food and maintained the same body weight, so any impact that TRF had was not due to caloric restriction.
TRF significantly improved sleep quality, albeit in a sex-specific manner. Females seemed to benefit more, with improvements in total sleep time that put them on par with non-Alzheimer’s controls. Males showed no changes in total sleep duration but benefited from improved mid-day wakefulness and faster onset of sleep. The treated mice’s activity patterns, according to the researchers, “became indistinguishable from those observed in non-transgenic mice.”
Markers of Alzheimer’s reduced
The researchers then performed RNA sequencing to identify the impact of TRF on gene expression. Between the treated and non-treated mice, dozens of Alzheimer’s- and inflammation-related genes were differentially expressed in the brain, including those associated with autophagy, myelination, and immune response. The researchers report TRF having “a profound impact on the brain transcriptome” in Alzheimer’s mice. Amazingly, 40% of the genes aberrantly expressed in the hippocampi of these mice were restored to levels approaching those of non-transgenic controls.
Several markers of Alzheimer’s pathology were reduced by TRF, including loss of neurons in the hippocampus, the total area of amyloid plaques, and their number. Via a series of experiments, the researchers determined that TRF both helped in clearing pre-existing plaques and reduced the rate of new amyloid deposition. While there is considerable doubt that amyloid-ß accumulation is a cause of Alzheimer’s, it does show a strong correlation with its progression. The researchers then validated their findings in a second, more aggressive model of Alzheimer’s, where TRF began much closer to the appearance of symptoms, suggesting that it might be beneficial even if started after the diagnosis.
Improved cognition
Finally, the researchers evaluated changes in cognitive function in this model. Treated mice demonstrated improvements in short- and long-term memory in the radial arm test and performed better in the novel object recognition test.
However, murine Alzheimer’s trials have an abysmally low rate of translation to humans. Moreover, due to differences in metabolism, intermittent fasting in mice might not recapitulate this intervention in humans very well. More rigorous studies are needed to support these intriguing findings.
Here, we demonstrate the efficacy of a circadian intervention based on TRF in rescuing pathology and behavior in two mouse models of AD. We provide ample evidence of the pleiotropic effects of TRF treatment in modulating behavior and sleep, normalizing hippocampal gene expression in specific pathways associated with AD and neuroinflammation, and improving memory deficits. Importantly, our results show that TRF can alter disease trajectory by slowing the progression of amyloid pathology, as evidenced by reduced plaque load, slower rate of amyloid deposition, and increased Aß42 clearance.
Literature
[1] Whittaker, D. S., Akhmetova, L., Carlin, D., Romero, H., Welsh, D. K., Colwell, C. S., & Desplats, P. (2023). Circadian modulation by time-restricted feeding rescues brain pathology and improves memory in mouse models of Alzheimer’s disease. Cell Metabolism, 35(10), 1704-1721.
[2] McStay, M., Gabel, K., Cienfuegos, S., Ezpeleta, M., Lin, S., & Varady, K. A. (2021). Intermittent fasting and sleep: A review of human trials. Nutrients, 13(10), 3489.
[3] Queiroz, J. D. N., Macedo, R. C. O., Tinsley, G. M., & Reischak-Oliveira, A. (2021). Time-restricted eating and circadian rhythms: the biological clock is ticking. Critical reviews in food science and nutrition, 61(17), 2863-2875.
[4] Colwell, C. S. (2021). Defining circadian disruption in neurodegenerative disorders. The Journal of clinical investigation, 131(19).
[5] Cronin, P., McCarthy, M. J., Lim, A. S., Salmon, D. P., Galasko, D., Masliah, E., … & Desplats, P. (2017). Circadian alterations during early stages of Alzheimer’s disease are associated with aberrant cycles of DNA methylation in BMAL1. Alzheimer’s & Dementia, 13(6), 689-700.Chicago
