Fasting-mimicking diet reduces signs of dementia in mice

Cycles of a diet that mimics fasting appear to reduce signs of Alzheimer’s disease in mice genetically engineered to develop the disease, according to a new study conducted by the USC Leonard Davis School of Gerontology.

The study appeared in Cell reports September 27.

The researchers, led by Professor Valter Longo in collaboration with Professors Christian Pike and Pinchas Cohen, found that mice that underwent multiple cycles of fasting-mimicking diets showed less Alzheimer’s disease. The researchers found lower levels of two major hallmarks of the disease: beta-amyloid – the main driver of plaque buildup in the brain – and hyperphosphorylated tau protein, which forms tangles in the brain. They also found that brain inflammation decreased and performed better on cognitive tests compared to mice fed a standard diet.

The Fasting-Mimicking Diet (FMD) is high in unsaturated fat and low in calories, protein, and carbohydrates and is designed to mimic the effects of a water-based fast while providing necessary nutrients. Previous research by Longo has indicated that periodic brief cycles of foot-and-mouth disease are associated with a range of beneficial effects, including promoting stem cell regeneration, decreasing chemotherapy side effects, and reducing risk factors. risk of cancer, diabetes, heart disease and other ages. related diseases in mice and man.

Promising results in mouse models of Alzheimer’s disease

Alongside healthy mice, the team studied two mouse models of Alzheimer’s disease, E4FAD and 3xTg. During the study, mice were fed the fasting-mimicking diet for 4 or 5 days twice a month and allowed to eat normally between FMD cycles. In a long-term experiment to see the effects on aged mice, 3xTg mice were dieted for 30 cycles over 15 months. Shorter-term experiences in 3xTg and E4FAD mice ranged from a single cycle of FMD to 12 cycles in 6 months.

In both models, mice that underwent cycles of foot-and-mouth disease showed promising reductions in beta-amyloid — which forms the sticky, disruptive plaques in the brain — and tau pathology compared to mice on a diet. standard. 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. Additionally, dieting mice demonstrated lower levels of oxidative stress, which plays a role in Alzheimer’s disease by damaging neurons and contributing to amyloid buildup in the brain. The study specifically pointed to the “superoxide” free radical as a central culprit for the damage that occurred in these Alzheimer’s mouse models, Longo explained.

Externally, mice from both Alzheimer’s models that suffered foot-and-mouth disease showed less cognitive decline than their standard-diet counterparts. Cognitive behavior, including exploration and performance in mazes, was tested in young mice before starting the diet and again after several months of a standard diet or fortnightly FMD cycles. Alzheimer’s mice given foot-and-mouth disease significantly outperformed Alzheimer’s mice given a standard diet and in some cases performed similarly to control mice not prone to Alzheimer’s disease, indicating that the decline cognitive had been considerably slowed down.

Foot-and-mouth disease cycles have been shown to be effective in reversing a range of pathological markers as well as cognitive defects in two of the main mouse models of Alzheimer’s disease. Longo said the results are promising.

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 Alzheimer’s disease. light. Forty of these patients who were otherwise healthy and had family support were randomized to receive either a monthly diet mimicking the 5-day fast or a 5-day period during which lunch or dinner was replaced by a pasta or rice meal.

Initial data indicate that FMD is safe and feasible for patients with mild impairment or early-stage Alzheimer’s disease. Other 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 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 overweight or obese people.

Notably, in a recently published clinical trial in which Longo was a co-author, foot-and-mouth disease cycles were associated with disease regression in diabetic patients. Diabetes nearly doubles the 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; 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 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.

The study was supported in part by grants AG20642, AG025135, and P01 AG034906 from the National Institutes of Health/National Institute on Aging in Longo; AG058068 to Pike; NIA T32 AG052374 training grant 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 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 at Chicago, and generous philanthropic contributions .

Longo is the founder and has a stake in L-Nutra; the company’s food products are used in fasting-mimicking diet studies. Longo’s interest in L-Nutra has been disclosed and managed in accordance with 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 in accordance with USC’s institutional policies on conflicts of interest.

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