Summary: Two short cycles of a fasting-like low-calorie diet reduce inflammation and delay cognitive decline in mouse models of Alzheimer’s disease. Researchers say the diet is safe for humans and may help reduce Alzheimer’s symptoms.
Dietary cycles similar to fasting appear to reduce Alzheimer’s symptoms in mice genetically engineered to develop the disease, according to a study led by the USC Leonard Davis School of Gerontology.
The study appeared in Cell reports On September 27.
The researchers, led by Professor Valter Longo in collaboration with Professors Christian Pike and Pinchas Cohen, found that mice that spent several cycles in a simulated fasting diet had less Alzheimer’s pathology.
The researchers also found lower levels of two of the disease’s main markers: amyloid beta — a primary driver of plaque buildup in the brain — and hyperphosphorylated tau protein, which causes tangles in the brain.
They found that compared to mice fed a normal diet, there was less brain inflammation and better performance on cognitive tests.
A fasting-mimicking diet (FMD) is high in unsaturated fat and generally low in calories, protein, and carbohydrates, while still providing essential nutrients designed to mimic the effects of a water-only fast.
Previous research led by Longo has shown that short, periodic FMD cycles are associated with a variety of beneficial effects, including boosting stem cell regeneration, reducing the side effects of chemotherapy, and reducing the risk of cancer, diabetes, heart disease, and other diseases. – Related diseases in humans and rodents.
Promising results in mouse models of Alzheimer’s
Alongside healthy mice, the team investigated two mouse models of Alzheimer’s, E4FAD and 3xTg. During the study, mice were fed twice a month to simulate fasting for 4 or 5 days and were allowed to eat normally between FMD cycles.
In a long-term experiment to see the effect on older mice, 3xTg mice were placed on the diet for 30 cycles over 15 months. Short-term trials in both 3xTg and E4FAD mice ranged from one FMD cycle to 12 cycles over 6 months.
In both models, mice that underwent FMD cycles showed promising reductions in amyloid beta-adherent, disruptive plaques in the brain, and tau pathology compared to mice fed a normal diet.
FMD mice also showed lower levels of brain inflammation, including reduced numbers of activated microglia, immune cells that seek out and destroy pathogens and damaged cells in the brain.
In addition, the mice on the diet showed lower levels of oxidative stress, which contributes to damage to neurons and the accumulation of amyloid in the brain in Alzheimer’s pathology.
The study specifically pointed to the free radical “superoxide” as the central culprit for the damage in these Alzheimer’s mouse models, Longo explained.
Externally, the mice of both Alzheimer’s models that received FMD showed less cognitive decline than their normal diet counterparts. Cognitive behavior, including exploration and performance in the maze, was tested in young rats before and several months after the introduction of a regular diet or twice-monthly FMD cycles.
Alzheimer’s mice given FMD significantly outperformed Alzheimer’s mice fed a normal diet and in some cases performed similarly to non-Alzheimer’s control mice, indicating a significant slowing of cognitive decline.
FMD cycles have been shown to be effective in reversing various markers of pathology but also cognitive deficits in two major mouse models of Alzheimer’s disease. Longo said the results are promising.
A small clinical study examines its feasibility in humans
In addition to the study in mice, Longo and his colleagues included a fasting-mimicking diet from a small Phase 1 clinical trial that diagnosed mild cognitive impairment or mild Alzheimer’s disease.
40 such healthy, family-supported patients were randomized to a once-a-month, 5-day fast or a 5-day period of either pasta- or rice-based lunch or dinner.
Preliminary data suggest that FMD is safe and effective in patients with mild impairment or early Alzheimer’s disease. Additional tests in the ongoing clinical trial will measure cognitive performance, inflammation and more, Longo said.
Other dietary trials published by Longo and colleagues indicated other benefits of the menstrual cycle, such as loss of fat mass without loss of muscle mass and improved cardiometabolic risks, especially in overweight or obese individuals.
In particular, in a recently published clinical trial, Longo was a co-author, FMD cycles were associated with disease recurrence in diabetic patients. According to the Alzheimer’s Association, diabetes doubles the risk of developing Alzheimer’s disease.
Other authors include Priya Rangan, Fleur Lobo, and USCA’s Edoardo Parella. Terry-Leigh Stephenson, Christian J. Pike, Pinchas Cohen, Kyle Xia, Katelyn Tran, Brandon Ann, and Dolly Chowdhury of USC; Anna Laura Crimonini, Luca Tagliafico, Angelica Farce, Irene Caffa, Fiametta Monacelli, Patrizio Odetti, Tommaso Bonfilio, and Alessio Nencioni University of Genoa, Italy; Nicolas Rochette, Marco Morselli and Matteo Pellegrini of UCLA; Mary Jo Ladue of the University of Illinois at Chicago; and Martina Pigliautile, Virginia Bocardi, and Patrizia Meccocchi of the University of Perugia, Italy.
Financial support The study was funded in part by National Institutes of Health/National Institute on Aging grants AG20642, AG025135, and P01 AG034906 to Longo; AG058068 to Pike; NIA T32 training grant AG052374 to Rangan; and grants PE-2016-02362694 and PE-2016-02363073 of the Italian Ministry of Health to Odetti, Meccocchi, Monacelli, and Longo. Ladue’s laboratory is supported by NIH (NIA) R01 AG056472, R01 AG057008, UH2/3 NS10012, R56 AG058655, 1R44 AG060826, from the Institutional Fund of the University of Illinois, Chicago, Charity College of Medicine.
Longo is the founder and has an ownership interest in L-Nutra; The company’s food products are used in studies related to fasting. Longo’s interest in El-Nutra is disclosed and governed by USC’s conflict-of-interest policies. USC has an ownership interest in L-Nutra and the ability to receive royalty payments from L-Nutra. USC’s financial interest in the Company is disclosed and governed by USC’s institutional conflict-of-interest policies.
About nutrition and Alzheimer’s disease research news
Author: Leigh Hopper
Contact: Leigh Hopper – USC
Image: The image is in the public domain.
Preliminary study: Open Access.
“Fasting-Mimicking Dietary Cycles Reduce Neuroinflammation to Reduce Cognitive Decline in Alzheimer’s Models” by Walter Longo et al Cell reports
Fasting-Mimicking Dietary Cycles Reduce Neuroinflammation to Reduce Cognitive Decline in Alzheimer’s Models
- FMD cycles reduce cognitive decline and AD pathology in preclinical mouse models
- FMD cycles reduce the number of hippocampal microglia and neuroinflammation
- 3xTg mice lacking Nox2 show enhanced cognition and microglia activation
- Clinical evidence suggests that FMD cycles are safe and effective in reducing the risk of AD. Patients are likely to be in groups.
Several aging and disease risk factors suggest that the effect of fasting-mimicking diet (FMD) cycles may influence Alzheimer’s disease (AD).
Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with superior effects induced by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aβ load and hyperphosphorylated tau, increase neural stem cell gene expression, decrease microglia number, and decrease expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2). 3xTg Nox2-deficient mice or mice treated with the NADPH oxidase inhibitor apocynin show enhanced cognition and reduced microglia activity compared to controls.
Clinical evidence suggests that FMD cycles are feasible and generally safe in a small group of AD patients.
These results suggest that FMD cycles delay cognitive decline in AD models by reducing neuroinflammation and/or superoxide production in the brain.