Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer's models

Priya Rangan; Fleur Lobo; Edoardo Parrella; Nicolas Rochette; Marco Morselli; Terri-Leigh Stephen; Anna Laura Cremonini; Luca Tagliafico; Angelica Persia; Irene Caffa; Fiammetta Monacelli; Patrizio Odetti; Tommaso Bonfiglio; Alessio Nencioni; Martina Pigliautile; Virginia Boccardi; Patrizia Mecocci; Christian J Pike; Pinchas Cohen; Mary Jo LaDu; Matteo Pellegrini; Kyle Xia; Katelynn Tran; Brandon Ann; Dolly Chowdhury; Valter D Longo

doi:10.1016/j.celrep.2022.111417

Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer's models

Cell Rep. 2022 Sep 27;40(13):111417. doi: 10.1016/j.celrep.2022.111417.

Authors

Priya Rangan¹, Fleur Lobo¹, Edoardo Parrella², Nicolas Rochette³, Marco Morselli⁴, Terri-Leigh Stephen¹, Anna Laura Cremonini⁵, Luca Tagliafico⁶, Angelica Persia⁶, Irene Caffa⁶, Fiammetta Monacelli⁵, Patrizio Odetti⁵, Tommaso Bonfiglio⁶, Alessio Nencioni⁵, Martina Pigliautile⁷, Virginia Boccardi⁷, Patrizia Mecocci⁷, Christian J Pike¹, Pinchas Cohen⁸, Mary Jo LaDu⁹, Matteo Pellegrini⁴, Kyle Xia¹, Katelynn Tran¹, Brandon Ann¹, Dolly Chowdhury¹, Valter D Longo¹⁰

Affiliations

¹ Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA.
² Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA; Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, Brescia, BS 25123, Italy.
³ Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, 611 Charles E. Young Dr. E., Los Angeles, CA 90095, USA; Department of Ecology and Evolutionary Biology, University of California, Los Angeles, 612 Charles E. Young Dr. E., Los Angeles, CA 90095, USA.
⁴ Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, 610 Charles E. Young Dr. S., Los Angeles, CA 90095, USA; Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, 611 Charles E. Young Dr. E., Los Angeles, CA 90095, USA.
⁵ Department of Internal Medicine and Medical Specialties, University of Genoa, Viale Benedetto XV 6, Genova, GE 16132, Italy; IRCCS Ospedale Policlinico San Martino, Largo Rosanna Benzi 10, 16132 Genoa, Italy.
⁶ Department of Internal Medicine and Medical Specialties, University of Genoa, Viale Benedetto XV 6, Genova, GE 16132, Italy.
⁷ Santa Maria della Misericordia Hospital, Section of Gerontology and Geriatrics, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
⁸ Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA; USC Dornsife College of Letters, Arts & Sciences, Department of Biological Sciences, University of Southern California, 3551 Trousdale Pkwy., Los Angeles, CA 90089-0191, USA.
⁹ Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA.
¹⁰ Longevity Institute, School of Gerontology, Department of Biological Sciences, University of Southern California, 3715 McClintock Avenue, Los Angeles, CA 90089-0191, USA; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, 1425 San Pablo St., Los Angeles, CA 90033, USA; IFOM FIRC Institute of Molecular Oncology, Via Adamello 16, Milano, MI 20139, Italy. Electronic address: vlongo@usc.edu.

Abstract

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.

Trial registration: ClinicalTrials.gov NCT05480358.

Keywords: Alzheimer’s disease; CP: Metabolism; CP: Neuroscience; NADPH oxidase; amyloid beta; fasting; fasting-mimicking diet; hyperphosphorylated tau; microglia; neuroinflammation; protein restriction; superoxide.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Animals
Cognitive Dysfunction*
Disease Models, Animal
Fasting
Mice
Mice, Transgenic
NADPH Oxidases
Neuroinflammatory Diseases
Superoxides
tau Proteins / metabolism

Fasting-mimicking diet cycles reduce neuroinflammation to attenuate cognitive decline in Alzheimer's models

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