Imagine that you are the owner of a small factory that makes replacement windows.

Normally, your ordering department does a pretty good job of things and the supply of the constituent parts necessary to make a decent replacement window (one assumes these to be things like glass, vinyl, aluminum, hardware, etc.) arrive punctually and in sufficient amounts to allow you to make the maximum number of windows with the minimum amount of wastage.

However, over time changes in personnel lead to problems of supply and demand. Tired, jaded people in the ordering department forget a decimal point and you wind up with an excess of window locks; poorly-trained workers on the assembly line make a variety of newbie-type errors that result in windows that are unsellable. Over time this pile of unsellable windows begins to accumulate to the point where it begins to clog up the aisles, creating an unhealthy workplace. Soon the corporate bank account is drained due to excessive purchasing and the assembly area is choked with unusable, unsellable, windows. Workers begin to grumble about the unsafe working conditions and a few threaten to strike unless conditions improve. An investigation seems to indicate that your factory supervisor, Mr. Mtor, has a grudge against you due to his being passed up for a promotion at his last salary review and has been going around sabotaging things by telling the workers to not bother about quality control and cleaning up after themselves.

Concerned about the future of the family enterprise, you fire Mr. Mtor and hire a sharp graduate of Wharton School of Business and soon things begin to right themselves. A special work team is put together to go through the piles of unsellable windows, cannibalizing parts that can be reused to create properly constructed, sell-able windows. All new orders are now reviewed to insure that no duplication or excess inventory is allowed to siphon off precious capital and storage space. Soon conditions begin to improve, your workers seem much more happier, and productivity and profitability skyrocket.

Welcome to the wonderful world of cellular autophagy.

Autophagy (‘self-eating’) is a catabolic (breakdown) process used by cells to degrade and remove some of their internal components deemed to be unnecessary or undesirable. Like our window company, cells are little factories of a sort, and as such they function under many of the same dynamic considerations: Things accumulate; byproducts are produced that can’t do anything, etc.

In cells these byproducts are usually some sort of misshapen protein that folded in some manner incomprehensible to the cell and hence not usable. This is not all that uncommon and many common chronic diseases are characterized by the production of proteins that did not fold properly. Much like having a rock in your shoe, having misfolded proteins in the synthetic/secretory parts of the cell factory (an organelle called the endoplasmic reticulum) results in what is known as the unfolded protein response, a stress reaction to these weird proteins.

Eat them up yum yum.

This phenomenon is called ‘ER Stress’ and can result in either of two outcomes.

Try to fix things or at least spit it out: The response to the misfolded proteins can trigger molecules called chaperones that can attempt to fix/refold the proteins into something usable. Lacking this response, the cell can attempt to encapsulate the offending stuff, digest it, and then spit the capsule out. This is autophagy.

Failing that, call it quits: If things are so bad, sometimes the cell just calls it a day and commits at type of cellular hari-kari suicide called apoptosis.

In addition to acting as a type of cell cleansing mechanism, autophagy is a very old survival tool. Like a factory deprived of raw materials because of a transit site, cells deprived of nutrients will scrounge around the workplace looking under tables and behind cabinets for surplus parts. In the cell’s case, when deprived of nutrients like the amino acids tyrosine and methionine, the cell will begin to breakdown parts of itself to keep going. Much of the time, this breakdown is a good thing, and perhaps explains why things like calorie restriction seem to increase lifespan: under those conditions the cell is munching away at itself, and since it is no fool, a lot of what it munches away at is junk best gotten rid of anyway.

Autophagy is normally kept under control by a protein called MTOR that acts as a sensor for conditions that might require autophagy. Normally MTOR blocks autophagy, so when it is inhibited, autophagy strikes up the band. MTOR can get screwed up in cancer, which is not a great thing since autophagy tends to block the apoptosis suicide mechanism (why kill yourself when things are working this great?) This has led some to posit that enhancing autophagy might not be a great thing. However it is probably not this simple as other genes that act as tumor suppressors appear to enhance autophagy by blocking MTOR, so we still don’t know the complete answer on that one.

Two things for sure: autophagy looks like a winning strategy when it comes to neurodegenerative disease and aging. Slower aging associated with decreased MTOR activity, while disease like Parkinsons and Alzheimers are linked to blockages in autophagy.

Some natural products, including epigallocatechin gallate (EGCG), caffeine, curcumin, and resveratrol, have also been reported to inhibit MTOR when applied to isolated cells in culture. More work is needed to see if these work at the level of dietary supplementation.

There are sugars,and then there are sugars.

One interesting agent with well-recognized effects on autophagy is the natural disaccharide sugar trehalose, a sugar produced by bonding two glucose molecules together in a way that differs significantly from the sugar on top of a jelly donut. Trehalose is found in many organisms, including bacteria, yeast, fungi, insects, invertebrates, and plants. It functions to protect the integrity of the cell against various environmental stresses like heat, cold, desiccation, dehydration, and oxidation by preventing the screwing-up of the cell’s protein insides.

Extracting trehalose used to be a difficult and costly process, but recently an inexpensive extraction technology has allowed for its use in a broad spectrum of applications. Trehalose prevents cells from dehydrating, a phenomena that disrupts much of the cell’s insides in way that are not reparable. Trehalose-treated cells seem to resist this because the trehalose ‘splints’ their guts in place, so that when the cells get a chance to rehydrate they come back good-as-new. Dehydrated cells are common with aging, as the aging process tends to thin out the cell membrane, making it harder and harder for the cell to maintain its internal water balance.

Trehalose has been accepted as a novel food ingredient under the GRAS terms in the U.S. and the EU. Trehalose has also found commercial application as a food ingredient. It is available in dietary supplement form.

Maybe the most interesting property of trehalose is its ability to enhance autophagy. Neurofibrillary tangle (NFT) is a characteristic hallmark of Alzheimer’s disease. The accumulation of a protein called tau in the NFTs is one of the characteristic features of several diseases known as tauopathies. In cell culture studies trehalose treatment exhibited significantly decreased level of tau in all tau species.

What is especially interesting about trehalose is that it works in ways that are independent of the MTOR protein, leaving it free to do its work as a sensor of changing environmental conditions.

Turns out we didn’t have to fire Mr. Mtor after all.

The more technically inclined, with an up-to-date modern browser, may want to check out the autophagy network map in Quodlibet.

1. Kim SI, Lee WK, Kang SS, Lee SY, Jeong MJ, Lee HJ, Kim SS, Johnson GV, Chun W. Suppression of autophagy and activation of glycogen synthase kinase 3beta facilitate the aggregate formation of tau. Korean J Physiol Pharmacol. 2011 Apr;15(2):107-14. Epub 2011 Apr 30. PUBMED
2. Rodríguez-Navarro JA, Rodríguez L, Casarejos MJ, Solano RM, Gómez A, Perucho J, Cuervo AM, García de Yébenes J, Mena MA.Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressing mice through autophagy activation. Neurobiol Dis. 2010 Sep;39(3):423-38. Epub 2010 May 28. PUBMED
3. Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein.J Biol Chem. 2007 Feb 23;282(8):5641-52. Epub 2006 Dec 20. PUBMED
4. Krüger U, Wang Y, Kumar S, Mandelkow EM. Autophagic degradation of tau in primary neurons and its enhancement by trehalose. Neurobiol Aging. 2011 Dec 12. [Epub ahead of print] PUBMED

Tags: autophagy | mtor | Trehalose