Protein restriction cycles reduce IGF-1 and phosphorylated Tau and improve behavior in Alzheimer’s mice

A recent University of Southern California study showed great benefit in cycling intake of dietary protein — well, not all protein, but essential amino acids — in mice with Alzheimer’s disease.

The protein restriction cycles improved memory and reduced brain levels of phosphorylated tau in the mice, but did not affect brain levels of β amyloid (Aβ) plaques.

The protein cycles lasted four months and consisted of alternating weeks of a normal diet and a protein-restricted (PR) diet.

The normal diet contained 25% protein, 17% fat, and 58% carbohydrate.

The PR diet lacked nine essential amino acids (EAA) – that is, amino acids the body cannot make: isoleucine, leucine, lysine, methionine, phenyalanine, threonine, tryptophan, valine, and arginine. Fat and carbohydrate contents were presumably the same as in the normal diet.

Interestingly, the researchers supplemented the PR diet by adding more of the remaining 11 amino acids, mainly the nonessential amino acids (NEAA), to make the diet’s nitrogen content the same as in the normal control diet. As a result, the PR diet contained about twice the amount of NEAA as did the normal diet.

The mice in this study were triple transgenic Alzheimer’s (3xTg-AD) mice, which overexpress two human genes (presenilin-1 and amyloid precursor protein (APP)) having mutations linked to Alzheimer’s disease, and one (tau) linked to frontotemporal dementia. These mutations result in development of both Aβ plaques and phosphorylated tau tangles in the brain, as well as age-dependent Alzheimer-like cognitive impairment.

Here is the article’s abstract:

In laboratory animals, calorie restriction (CR) protects against aging, oxidative stress, and neurodegenerative pathologies. Reduced levels of growth hormone and IGF-1, which mediate some of the protective effects of CR, can also extend longevity and/or protect against age-related diseases in rodents and humans. However, severely restricted diets are difficult to maintain and are associated with chronically low weight and other major side effects. Here we show that 4 months of periodic protein restriction cycles (PRCs) with supplementation of nonessential amino acids in mice already displaying significant cognitive impairment and Alzheimer’s disease (AD)-like pathology reduced circulating IGF-1 levels by 30-70% and caused an 8-fold increase in IGFBP-1. Whereas PRCs did not affect the levels of β amyloid (Aβ), they decreased tau phosphorylation in the hippocampus and alleviated the age-dependent impairment in cognitive performance. These results indicate that periodic protein restriction cycles without CR can promote changes in circulating growth factors and tau phosphorylation associated with protection against age-related neuropathologies.

Study authors included USC’s Valter Longo and Pinchas Cohen, and Luigi Fontana of Washington University in St. Louis.


Parrella E, et al. Protein restriction cycles reduce IGF-1 and phosphorylated Tau, and improve behavioral performance in an Alzheimer’s disease mouse model.
Aging Cell. 2013 Apr;12(2):257-68. doi: 10.1111/acel.12049.

4 thoughts on “Protein restriction cycles reduce IGF-1 and phosphorylated Tau and improve behavior in Alzheimer’s mice

  1. Hello Mac,

    At first glance, it seems this intervention could have worked in part due to autophagy, because restriction of leucine, an essential amino acid, inhibits mTOR (mammalian target of rapamycin), an autophagy blocker.

    However, although inhibiting mTOR can lead to autophagy, this response can be suppressed by glutamine, a nonessential amino acid, which inhibits autophagy at least in part by cell swelling.

    Therefore, I think results in these mice would have been even better if the nonessential amino acids were restricted, along with the essential ones, during periods of protein restriction. This would have enhanced autophagy. Further, the mice’s high carbohydrate intake should activate TFEB during protein restriction, enhancing lysosomal biogenesis. When combined with autophagy, this could lead to a decrease in β amyloid (Aβ) plaques.

  2. When resuming protein consumption following a 2 – 4 day abstention, is it critical to eat a diet of essential plus nonessential amino acids? Or is the balance of amino acids not very important. Here, I am assuming the amount of protein per day conforms to current recommendations for adults.

  3. Hi Eric,

    On resuming protein consumption, only the essential amino acids are critical to obtain. One doesn’t need to eat the nonessential amino acids, as cells can make them from carbon precursors, like oxaloacetate and pyruvate, derived from, e.g., burning carbohydrate by glycolysis.

    Of course, both the essential and nonessential amino acids are found together in food, and there’s no reason to restrict the nonessentials during periods of regular protein consumption.

    Yes, the amount of protein eaten during regular (nonrestrictive) periods could conform to current recommendations, like the RDA of 0.8 grams per kilogram of bodyweight per day. Most people can do fine on less than this amount of protein, however.

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