Why take protein breaks?

This blog (and this) presents an idea that, based on current research, appears likely true and may save your life:

Taking intermittent "protein breaks," when you eat very little or no protein for 2-4 consecutive days while eating plenty of carbohydrate, can slow aging and prevent, delay, or reverse many diseases including obesity, type 2 diabetes, autoimmune disorders, and brain diseases such as Alzheimer's and Parkinson's.

If you take protein breaks, you must follow each by a period of eating adequate amounts of protein.

This hypothesis awaits confirmation by randomized human clinical trials, but it appears consistent with prior studies in humans, other animals, and living cells.

Because no clinical trial has yet been done to establish the efficacy of protein breaks in humans, I cannot recommend them.  But I recommend you consider them with your doctor.

Alzheimer’s at EMBO 2013: dietary treatment and prevention through autophagy

Here's a PDF of my poster presented at the EMBO autophagy conference in May 2013.  And here's the abstract.

The poster's text:

An autophagic role in Alzheimer's disease for intermittent dietary periods of very low-protein, high-carbohydrate intake

Hypothesis: Intermittent periods of very low-protein, high-carbohydrate dietary intake may enhance autolysosomal proteolysis in Alzheimer's disease (AD) by increasing activity of transcription factor EB (TFEB).

Background: AD is characterized by 1) activation of neuronal autophagy with defective autolysosomal degradation,^[1] and 2) neuronal insulin resistance, characterized by increased amyloid-β (Aβ) production in autophagosomes and reduced neuronal internalization of extracellular Aβ oligomers.^[2] 

Translocation of transcription factor EB (TFEB) from cytosol to nucleus increases transcription of 291 genes and thereby induces autophagy,^[3] lysosomal biogenesis, acidification, and proteolysis.^[4]

Phosphorylation of TFEB by mammalian target of rapamycin complex 1 (mTORC1) and by glycogen synthase kinase 3 (GSK3)^[5] inhibits TFEB nuclear translocation.

GSK3 inhibition in transgenic AD mice increases acidification of lysosomes, reduces Aβ deposits, and ameliorates cognitive deficits.^[6]

Why very low protein intake?  mTORC1 phosphorylation of TFEB is inhibited by amino acid starvation, even in the presence of strong insulin signaling.^[7]  Very low protein intake, combined with GSK3 inhibition, is therefore expected to promote TFEB nuclear translocation.

Why high carbohydrate intake?  High carbohydrate intake stimulates secretion of insulin, which inhibits GSK3^[8] and presumably therefore reduces GSK3's phosphorylation of TFEB.  Combined with mTORC1 inhibition, enhanced insulin signaling should thereby promote TFEB nuclear translocation.

This hypothesis awaits testing, e.g., in a transgenic AD mouse model.

---

^[1] Nixon RA, Yang DS. Autophagy failure in Alzheimer's disease—locating the primary defect. Neurobiology of Disease (2011) 43(1): 38-45.

^[2] Talbot K, et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. (2012) 122(4): 1316–1338.

^[3] Settembre C, et al. TFEB Links Autophagy to Lysosomal Biogenesis. Science (2011) 332(6036): 1429-1433.

^[4] Sardiello M, et al. A Gene Network Regulating Lysosomal Biogenesis and Function. Science (2009) 325(5939): 473-477.

^[5] Parr C, et al. GSK3 inhibition promotes lysosomal biogenesis and the autophagic degradation of the Amyloid-β Precursor Protein. Mol. Cell. Biol. (2012) 32(21): 4410-4418.

^[6] Avrahami L, et al. Inhibition of GSK-3 Ameliorates beta-Amyloid(A-beta) Pathology and Restores Lysosomal Acidification and mTOR Activity in the Alzheimer's Disease Mouse Model. In vivo and In vitro Studies.  J Biol Chem (2012) Nov 15.

^[7] Settembre C, et al.  A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB. The EMBO Journal (2012) 31, 1095-1108.

^[8] Collino M, et al. Insulin Reduces Cerebral Ischemia/Reperfusion Injury in the Hippocampus of Diabetic Rats. A Role for Glycogen Synthase Kinase-3β.  Diabetes (2009) 58(1): 235-242.

Protein restriction cycles improve behavior and reduce IGF-1 and phosphorylated Tau 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.