Here’s a photo of the scientist attendees at the EMBO 2013 autophagy meeting in Norway on the cruise ship MS Trollfjord.
There were many autophagy luminaries there, including a number of rumored candidates for Nobel prizes.
Reader Arash raised the interesting question whether the intermittent dietary protein restriction used in protein breaks could cause excessive autophagy. This is important because too much autophagy can kill cells in certain settings, like oxygen deprivation in the brain (cerebral ischemia).
Excess autophagy apparently does not occur with intermittent protein restriction, because autophagy is self-limiting in this circumstance. Restricting dietary protein, which is made of amino acids, deactivates mammalian target of rapamycin complex 1 (mTORC1), leading to protein degradation in cells by autophagy, which frees up amino acids, leading to reactivation of mTORC1 and consequent inhibition of autophagy again.
[I]ncreased intracellular free amino acids produced during autophagic degradation can reactivate the mTORC1 signaling and thus downregulate autophagy, serving as a self-limiting feedback loop in autophagy regulation. …
Here’s 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, and 2) neuronal insulin resistance, characterized by increased amyloid-β (Aβ) production in autophagosomes and reduced neuronal internalization of extracellular Aβ oligomers.
Translocation of transcription factor EB (TFEB) from cytosol to nucleus increases transcription of 291 genes and thereby induces autophagy, lysosomal biogenesis, acidification, and proteolysis.
Phosphorylation of TFEB by mammalian target of rapamycin complex 1 (mTORC1) and by glycogen synthase kinase 3 (GSK3) inhibits TFEB nuclear translocation.
GSK3 inhibition in transgenic AD mice increases acidification of lysosomes, reduces Aβ deposits, and ameliorates cognitive deficits.
Why very low protein intake? mTORC1 phosphorylation of TFEB is inhibited by amino acid starvation, even in the presence of strong insulin signaling. 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 and presumably therefore reduces GSK3’s phosphorylation of TFEB. Combined with mTORC1 inhibition, enhanced insulin signaling should thereby promote TFEB nuclear translocation.
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.
Here’s the text of an abstract I’ll be presenting at the European Molecular Biology Organization (EMBO) autophagy conference in Norway in May 2013:
Occasional periods of very low-protein, high-carbohydrate dietary intake may enhance lysosomal proteolysis in Alzheimer’s disease (AD) by increasing activity of transcription factor EB (TFEB) via inhibition of glycogen synthase kinase 3 (GSK3).
AD is characterized by 1) activation of neuronal autophagy with defective autolysosomal degradation, and 2) neuronal insulin resistance, characterized by increased amyloid-β (Aβ) production in autophagosomes and reduced neuronal internalization of extracellular Aβ oligomers.
Suitable AD therapies may therefore aim to reduce neuronal insulin resistance and increase activity of TFEB, a master gene regulator of lysosomal biogenesis. Upon cellular starvation and in response to inhibition of mammalian target of rapamycin (mTOR), TFEB translocates from the cytosol to the nucleus, whereupon it increases transcription of 291 genes, including many involved in autophagy. At least 20 of these genes participate in lysosomal biogenesis, acidification, and proteolysis.