Summary: Two short cycles of a low-calorie diet that mimics fasting reduced inflammation and delayed cognitive decline in mouse models of Alzheimer’s disease. Researchers report the diet is safe for humans and could help reduce signs of Alzheimer’s.
Cycles of a diet that mimics fasting appears to reduce signs of Alzheimer’s in mice genetically engineered to develop the illness, according to a new USC Leonard Davis School of Gerontology-led study.
The study appeared in Cell Reports on Sept. 27.
The researchers, led by Professor Valter Longo in collaboration with Professors Christian Pike and Pinchas Cohen, found that mice that had undergone several cycles of the fasting-mimicking diet showed less Alzheimer’s pathology.
The researchers found lower levels of two major hallmarks of the disease: amyloid beta – the primary driver of plaque buildup in the brain – and hyperphosphorylated tau protein, which forms tangles in the brain.
They also found that brain inflammation lessened and better performance on cognitive tests compared to the mice that were fed a standard diet.
The fasting-mimicking diet (FMD) is high in unsaturated fats and low in overall calories, protein, and carbohydrates and is designed to mimic the effects of a water-only fast while still providing necessary nutrients.
Previous research led by Longo has indicated that brief, periodic FMD cycles are associated with a range of beneficial effects, including the promotion of stem cell regeneration, lessening of chemotherapy side effects, and lowering risk factors for cancer, diabetes, heart disease and other age-related diseases in mice and humans.
Alongside healthy mice, the team investigated two mouse models of Alzheimer’s, E4FAD and 3xTg. During the study, mice were fed the fasting-mimicking diet for 4 or 5 days twice per month and were allowed to eat normally between FMD cycles.
In a long-term experiment to see the effects in aged mice, 3xTg mice were placed on the diet for 30 cycles in 15 months. Shorter-term experiments in both 3xTg and E4FAD mice ranged from a single FMD cycle to 12 cycles in 6 months.
In both models, mice who underwent FMD cycles showed promising reductions in amyloid beta – which form the sticky, disruptive plaques in the brain – and tau pathology compared to mice eating a standard diet.
The FMD mice also showed lower levels of brain inflammation, including a reduction in the number of active microglia, the immune cells that seek and destroy pathogens and damaged cells in the brain.
In addition, mice on the diet demonstrated a lower level of oxidative stress, which plays a role in Alzheimer’s pathology by damaging neurons and contributing to the accumulation of amyloid in the brain.
The study specifically pointed to the free radical “superoxide” as a central culprit in the damage occurring in these Alzheimer’s mouse models, Longo explained.
Outwardly, mice of both Alzheimer’s models who underwent the FMD showed less cognitive decline than their standard diet counterparts. Cognitive behavior, including exploration and performance within mazes, was tested in young mice before the dietary regimen began and again after several months of either a standard diet or twice-monthly FMD cycles.
The Alzheimer’s mice given the FMD significantly outperformed the Alzheimer’s mice given standard diets and in some instances performed similarly to the non-Alzheimer’s-prone control mice, indicating that cognitive decline had been significantly slowed.
The FMD cycles appeared effective in reversing a range of pathology markers but also cognitive defects in two of the major mouse models for Alzheimer’s disease. Longo said that the results are promising.
In addition to the study in mice, Longo and colleagues also included data from a small Phase 1 clinical trial of the fasting-mimicking diet in human patients diagnosed with mild cognitive impairment or mild Alzheimer’s disease.
The fasting-mimicking diet (FMD) is high in unsaturated fats and low in overall calories, protein, and carbohydrates and is designed to mimic the effects of a water-only fast while still providing necessary nutrients. Image is in the public domain
Forty such patients who were otherwise healthy and had family support were randomized to either a once-monthly, 5-day fasting-mimicking diet or a 5-day period in which lunch or dinner was replaced with a meal based on pasta or rice.
Initial data indicates that the FMD is safe and feasible for patients with mild impairment or early Alzheimer’s disease. Further tests in the ongoing clinical trial will measure cognitive performance, inflammation and more, Longo said.
Other early trials of the diet published by Longo and colleagues have indicated other benefits of a monthly cycle, such as a loss of fat mass without loss of muscle mass and improved cardiometabolic risk factors, especially in overweight or obese people.
Notably, in a recently published clinical trial in which Longo was a co-author, FMD cycles were associated with disease regression in diabetes patients. Diabetes nearly doubles the risk of developing Alzheimer’s disease, per the Alzheimer’s Association.
Other authors included co-first authors Priya Rangan, Fleur Lobo and Edoardo Parrella of USC; Terri-Leigh Stephen, Christian J. Pike, Pinchas Cohen, Kyle Xia, Katelynn Tran, Brandon Ann, and Dolly Chowdhury of USC; Anna Laura Cremonini, Luca Tagliafico, Angelica Persia, Irene Caffa, Fiammetta Monacelli, Patrizio Odetti, Tommaso Bonfiglio, and Alessio Nencioni of the University of Genoa, Italy; Nicolas Rochette, Marco Morselli, and Matteo Pellegrini of UCLA; Mary Jo LaDu of the University of Illinois at Chicago; and Martina Pigliautile, Virginia Boccardi, and Patrizia Mecocci of the University of Perugia, Italy.
Funding: 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; the NIA T32 training grant AG052374 to Rangan; and the PE-2016-02362694 and PE-2016-02363073 grants by the Italian Ministry of Health to Odetti, Mecocci, Monacelli, and Longo. The LaDu lab is funded by NIH (NIA) R01 AG056472, R01 AG057008, UH2/3 NS10012, R56 AG058655, 1R44 AG060826, institutional funds from the College of Medicine at the University of Illinois, Chicago, and generous philanthropic contributions.
Longo is the founder of and has an ownership interest in L-Nutra; the company’s food products are used in studies of the fasting-mimicking diet. Longo’s interest in L-Nutra was disclosed and managed per USC’s conflict-of-interest policies. USC has an ownership interest in L-Nutra and the potential to receive royalty payments from L-Nutra. USC’s financial interest in the company has been disclosed and managed under USC’s institutional conflict-of-interest policies.
Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer’s models
- FMD cycles reduce cognitive decline and AD pathology in preclinical mouse models
- FMD cycles decrease hippocampal microglia number and neuroinflammation
- 3xTg mice lacking Nox2 show improved cognition and microglia activation
- Clinical data suggest FMD cycles are safe and feasible in a small group of AD patients
The effects of fasting-mimicking diet (FMD) cycles in reducing many aging and disease risk factors indicate it could affect Alzheimer’s disease (AD).
Here, we show that FMD cycles reduce cognitive decline and AD pathology in E4FAD and 3xTg AD mouse models, with effects superior to those caused by protein restriction cycles. In 3xTg mice, long-term FMD cycles reduce hippocampal Aβ load and hyperphosphorylated tau, enhance genesis of neural stem cells, decrease microglia number, and reduce expression of neuroinflammatory genes, including superoxide-generating NADPH oxidase (Nox2). 3xTg mice lacking Nox2 or mice treated with the NADPH oxidase inhibitor apocynin also display improved cognition and reduced microglia activation compared with controls.
Clinical data indicate that FMD cycles are feasible and generally safe in a small group of AD patients.
These results indicate that FMD cycles delay cognitive decline in AD models in part by reducing neuroinflammation and/or superoxide production in the brain.