Cycles of a diet that mimics fasting appear to reduce signs of Alzheimer’s in mice genetically engineered to develop the disease, according to a new study led by the USC Leonard Davis School of Geronology.
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 had undergone several cycles of the fasting-mimicking diet showed less Alzheimer’s disease.
The researchers found lower levels of two key features of the disease: amyloid beta, the main driver of plaque build-up in the brain, and the hyperphosphorylated tau protein, which forms tangles in the brain.
They also found that brain inflammation decreased and they performed better on cognitive tests compared to mice that were fed a standard diet.
The fasting-mimicking diet (FMD) is high in unsaturated fat and low in calories, protein, and overall carbohydrates and is designed to mimic the effects of a water-only fast while providing necessary nutrients.
Previous research led by Longo has indicated that short, periodic cycles of FMD are associated with a number of beneficial effects, including promoting stem cell regeneration, decreasing the side effects of chemotherapy, and reduction of risk factors for cancer, diabetes, heart disease and other age. -related diseases in mice and humans.
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 the fasting-mimicking diet for 4 or 5 days twice a month and were allowed to eat normally between FMD cycles.
In a long-term experiment to see the effects in old mice, 3xTg mice were placed on the diet for 30 cycles over 15 months. Short-term experiments in both 3xTg and E4FAD mice ranged from a single cycle of FMD to 12 cycles over 6 months.
In both models, mice undergoing cycles of FMD showed promising reductions in amyloid beta, which forms 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 out 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 disease by damaging neurons and contributing to the accumulation of amyloid in the brain.
The study specifically pointed to free radical “superoxide” as a central culprit in the damage produced in these mouse models of Alzheimer’s, Longo explained.
Outwardly, the mice in the two Alzheimer’s models that suffered from FMD showed less cognitive impairment than their counterparts on the standard diet. Cognitive behavior, including exploration and performance within the mazes, was tested in young mice before the dietary regimen began and again after several months of a standard diet or bimonthly FMD cycles.
Alzheimer’s mice given FMD significantly outperformed Alzheimer’s mice on standard diets and, in some cases, performed similarly to non-Alzheimer-prone control mice, indicating that cognitive decline s ‘had slowed down significantly.
FMD cycles appeared to be effective in reversing a number of markers of pathology, but also cognitive defects in two of the leading mouse models for Alzheimer’s disease. Longo said the results are promising.
A small clinical study explores feasibility for humans
In addition to the mouse study, 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 dementia. mild Alzheimer’s
Forty of these otherwise healthy patients with family support were randomized to either a 5-day fasting-mock diet once a month or a 5-day period in which lunch or dinner was replaced for a meal based on pasta or rice.
Initial data indicate that FMD is safe and feasible for patients with mild disability 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 loss of fat mass without loss of muscle mass and improvement in cardiometabolic risk factors, particularly in people who are overweight or obesity
Notably, in a recently published clinical trial that Longo co-authored, FMD cycles were associated with disease regression in patients with diabetes. Diabetes nearly doubles your risk of developing Alzheimer’s disease, according to the Alzheimer’s Association.
Other authors included co-first authors Priya Rangan, Fleur Lobo, and Edoardo Parrella of USC; USC’s Terri-Leigh Stephen, Christian J. Pike, Pinchas Cohen, Kyle Xia, Katelynn Tran, Brandon Ann and Dolly Chowdhury; Anna Laura Cremonini, Luca Tagliafico, Angelica Persia, Irene Caffa, Fiammetta Monacelli, Patrizio Odetti, Tommaso Bonfiglio and Alessio Nencioni from the University of Genoa, Italy; Nicolas Rochette, Marco Morselli and Matteo Pellegrini from UCLA; Mary Jo LaDu of the University of Illinois at Chicago; and Martina Pigliautile, Virginia Boccardi and Patrizia Mecocci from 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 in Pike; the NIA training grant T32 AG052374 to Rangan; and grants PE-2016-02362694 and PE-2016-02363073 from the Italian Ministry of Health to Odetti, Mecocci, Monacelli, and Longo. The LaDu laboratory is funded by NIH (NIA) R01 AG056472, R01 AG057008, UH2/3 NS10012, R56 AG058655, 1R44 AG060826, institutional funds from the University of Illinois at Chicago School of Medicine, and generous tropical contributions.
Longo is the founder and has an ownership interest in L-Nutra; the company’s food products are used in fasting-mimicking diet studies. Longo’s interest in L-Nutra was disclosed and managed according to USC’s conflict of interest policies. USC has an 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.
About this diet and Alzheimer’s disease research news
Author: Leigh Hopper
Contact: Leigh Hopper – USC
Image: The image is in the public domain
Original Research: Open access
“Fasting-Mimetic Diet Cycles Reduce Neuroinflammation to Attenuate Cognitive Decline in Alzheimer’s Models” by Valter Longo et al. Cell reports
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
- Foot-and-mouth disease cycles decrease hippocampal microglia and neuroinflammation
- 3xTg mice lacking Nox2 show improved cognition and microglial activation
- Clinical data suggest that 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 that it may 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 burden and hyperphosphorylated tau, enhance neural stem cell genesis, decrease microglia numbers, and reduce neuroinflammatory gene expression, including the superoxide-generating NADPH oxidase (Nox2). 3xTg mice lacking Nox2 or mice treated with the NADPH oxidase inhibitor apocynin also show enhanced cognition and reduced microglial activation compared to 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.