Discusses available over-the-counter promoters of autophagy and their potential role in the diet.
Chemical Autophagy Promoters
Autophagy is a complex and vital cell process and just about any substance one tests turns out to have an affect on it. Whether or not that affect is significant in the real world is another question. A number of substances have been found that promote autophagy and clear the protein aggregates associated with neurodegenerative diseases32. Most are either prescription drugs or are unsuited to human medical use. A few, however, are freely available as supplements.
Curcumin is a chemical found in the spice turmeric used throughout Asia as a food additive and a traditional herbal medicine as well. In Japan, turmeric is fermented to diminish its bitterness and sold as a tea powder to cure hangovers. Cultures that consume curcumin regularly (as turmeric in yellow curries) have about a fourth the age-adjusted incidence of AD as those that do not33. There are research results that curcumin can break up the plaques associated with that disease34.
Curcumin has recently attracted the attention of cancer researchers where it has been shown to kill cancer cells by promoting autophagy35,36. Cancer cells are fragile broken cells. Autophagy is often a cell process they cannot pull off and one explanation is that they end up killing themselves in the effort.
There are, however, some cancer types that can perform autophagy successfully. If such a cancer were being treated with a method that starved cells, inducing autophagy could then end up rescuing the cells and diminishing the effectiveness of the treatment.
Curcumin induces autophagy by the same pathway as calorie restriction, via the signal proteins mTor (mammalian target of rapamycin) and insulin37. Autophagy induced by protein restriction uses a different mechanism that does not involve these proteins. Curcumin may not, therefore, be additive to the protein restriction effect though it should be additive to the calorie restriction effect.
The principal argument against the effectiveness of curcumin as an autophagy enhancer is that very little is normally seen in studies to get past the digestion and reach the blood stream. Piperine, the active ingredient in black pepper, is usually added to curcumin in small amounts to enhance absorption by as much as 2000%38 (with 20 mg). The amount usually added in commercial capsules, about 3mg, is only about 1/6 the average American dietary consumption39. The usual explanation for piperine’s effects is that it inhibits the cytochrome systems in the intestine and liver cells that normally degrade the the wide array of small chemicals (including curcumin and resveratrol) that plants produce. The observed increase in absorption seems to me far too large for the observed inhibition of the cytochromes and I suspect that it really acts by stimulating some form of endocytosis.
Nutrients generally move from the gut to the bloodstream by selective transport across the cell membranes of the cells lining the small intestine. They are then deposited in the hepatic portal vein and sent directly to the liver. If they make it past the liver they then enter the general circulation. If they can then make it past the blood-brain barrier, they can finally reach the nerve cells.
It is unlikely that the liver would let either curcumin or resveratrol pass intact. There is however a back-door to the general circulation through the lymphatic system. Fats are normally digested down to fatty acids and selectively transported into the cells that line the intestine. Short-chain fatty acids then proceed to the hepatic portal vein. Long-chain fatty acids, however, are transported across the cell and, after some mysterious processing, deposited in the lacteals, the capillaries of the lymphatic system, as so-called chylomicrons. The chylomicrons then move through the lymphatic system and deposit in the general circulation in the subclavian vein far beyond the reach of the ever-vigilant liver40. Fat soluble substances such as curcumin and resveratrol can then perhaps hitch a ride in the fat and reach the general circulation.
In the lower reaches of the small intestine there are so-called M cells in the lining of the intestine that engulf particles as large as whole bacteria in a form of endocytosis called phagocytosis. Again fat globules and the substances dissolved in them could be engulfed as well and end up in the lymphatic system. Piperine may stimulate endocytosis and this is possibly why it enhances absorption.
There is another form of endocytosis called pinocytosis that is practiced by all cells to take in certain materials from the bloodstream. Though the amount of extracellular fluid enveloped is too small to contain something as large as a bacterium, a fat globule could conceivably enter a cell by this route. This process has yet to be demonstrated by the cells that line the intestine but remains a possibility. If it exists, it could allow viruses to enter the body and this may be sufficient reason to disallow it to cells in contact with the outside world.
In fact there are organisms that exploit M cell phagocytosis to enter the body. The M cells pass what they envelop to phagocytes that normally digest them with their lysosomes. These invaders, however, may produce a substance that prevents the lysosomes from merging with the vesicles enclosing them and are thus saved from destruction. Or (as in the case of prion disease protein) the invader can survive the digestive process of the lysosome.
The kidneys filter blood at a constant rate (GFR) that, apart from actual dehydration, is independent of water consumption. In the kidney, blood cells are mechanically filtered from the stream and returned to the general circulation. Water and solutes are then retrieved from the stream as needed and what is in excess flows to the bladder.
When a substance enters the blood stream, it is immediately subject to removal by the kidneys. The kidneys divert 20% to 25% of the blood flow from the heart and normally filter from 50 to 150 milliliters of blood per minute. For a typical adult blood volume of 5000 milliliters, this represents 1-3 percent per minute. So in 20 to 60 minutes, about half the blood is filtered. For an inert substance that spends no time attached to blood vessel walls or other blood components and that is not reabsorbed by the kidneys, the blood half-life would then be 20 to 60 minutes. (This is near to curcumin’s half-life value.) In that time, its concentration would drop by half from its original concentration. In the next 20 to 60 minutes it would drop to one-fourth of its initial concentration, and so on.
A substance that spends some time adhering to vessel walls or blood cells or diffuses into and out of cells and intercellular spaces would have a longer half-life. Likewise for a substance that the kidneys reabsorb from the urine stream.
Conversely, substances that are actively removed from the bloodstream would have shorter half-lives. The liver does this for some substances, depositing them in the bile. The kidneys do some of it as well, actively depositing some wastes in the urine. Phagocytes in the spleen actively remove even solids from the bloodstream and perhaps deposit the remains in the hepatic portal vein that goes to the liver. There liver phagocytes may then possibly deposit some of it in the bile. There may even be some active (energy expended) and passive transport of wastes from the linings of the intestines.
In a sense, substances may also be removed from the bloodstream by being converted into something else, usually by the liver. Resveratrol, for instance, is converted to resveratrol-glucuronide by the liver. In consequence, the half-life of resveratrol is only minutes but the half-life of the glucuronide derivative is about 9 hours. In the tissue, however, resveratrol-glucuronide can be converted back to resveratrol, and you can see that the half-life alone does not fully describe resveratrol’s bioavailability41.
And, of course, a substance can be removed from the bloodstream beacause it is being consumed in the tissues.
Resveratrol is a chemical found in grape skins and other plant sources that likewise seems to promote autophagy and produces results in cancer research similar to curcumin.
Since both curcumin and resveratrol seemingly promote autophagy and are safe, inexpensive and readily available without prescription, it is suggested that they be used in periods of protein restriction to enhance its effects.
At this point in time, their association with autophagy is circumstantial and their usage cannot be quantified so they cannot reliably substitute for protein or calorie restriction in inducing autophagy. They still may help by perhaps lowering the autophagy threshold, and they appear beneficial apart from any autophagy-inducing effects.
Spermidine is a poly-amine found in grapefruit and seminal fluid that promotes autophagy by a different pathway than resveratrol80. It has been found to reduce the amount of aging in yeast, flies, worms, and human immune cells by inducing autophagy81. Currently it is not available as a supplement and one would presumably eat grapefruit or whatever to obtain it. As grapefruit disrupts the normal metabolism of many drugs such as statins, its chronic use may be contraindicated for some. Mature cheeses, fermented soybeans, fermented tea, Japanese Sake, domestic mushrooms, potatoes and fresh bread are also sources of spermidine. Note that grapefruit seed extract contains no spermidine.
Trehalose is a disaccharide, a complex sugar composed of two simple sugars bonded to each other. Sucrose and lactose are other common examples of disaccharides. In sucrose, a molecule of glucose is bound to a molecule of fructose. In lactose, a molecule of glucose is bound to a molecule of galactose. In trehalose, a molecule of glucose is bound to another molecule of glucose. It differs from maltose, another disaccharide composed of two glucoses, only in the orientation of the two glucoses in the disaccharide.
It is common in insects and crustaceans like crab and lobster and in some mushrooms. Similar as for lactose, the human body has a specific intestinal enzyme to split it into its simple sugar constituents. And, likewise, some people lack the enzyme and cannot digest it.
Since trehalose is usually digested down to glucose, it is somewhat of a mystery how any of it get into the bloodstream intact. Trehalose is known to interact with proteins and prevent their mis-folding. To get to the center of a protein, it must be somewhat hydrophobic and perhaps it travels with fat and is thus protected from degradation.
Trehalose has long been known to help with protein folding and has found use in free cell cultures for it protective affects. Recently it has been demonstrated to induce autophagy by a means independent of calorie restriction’s mechanism. This autophagy induction has been shown to clear protein aggregates in models of HD, PD42 and oculopharyngeal muscular dystrophy (OPMD)43.
Currently, trehalose I can be purchased over the internet. If used in place of sucrose (at twice the amount since it is only half as sweet) in breakfast coffee or tea, it might help induce the autophagy that should ensue from the overnight fast when a low protein breakfast is consumed.
Lipids and Lecithin
Since curcumin, resveratrol and possibly trehalose likely travel with fat, you should take fat in some form when taking them, whether in food or in capsule. Lecithin also aids fat absorption and could be taken as well. (Mayonnaise is oil emulsified with egg lecithin and could handily serve this purpose.) As for timing, both curcumin and resveratrol peak about one hour after ingestion44. They should probably be taken (in capsule form or in the foodstuff that contain them) at midpoint in the protein free part of protein cycling or the calorie free part of ADCR so that their autophagy stimulation is in sync with the autophagy stimulation from the protein or calorie restriction. It may be, however, that they are more effective earlier or later in the restriction period if at all. We just do not know at this time.
Because so much is not known about absorption and timing issues for curcumin and resveratrol, it would be premature to depend solely on them to induce autophagy and not use protein or calorie restriction for that purpose. However, there is evidence for both that they may help with cancer and cardiovascular diseases as well, and, as we have seen, those are statistically far more life-threatening than the neurodegenerative diseases.
The element lithium is also a known autophagy inducer and is available over the counter as lithium orotate in low dose form (5mg/capsule). Two capsule per day, the suggested dose, or 10 mg/day is somewhat less than the 30 mg/day dosage in the studies where it has shown benefits to neurodegenerative diseases and it might not have the same effect.
Lithium is also used at much higher doses (90-180 mg/day) as a mood stabilizer. It is then a prescription drug since the therapeutic level is close to the lethal level.
There is substantial confusion with lithium dosage because it is usable only as a salt. That means the lithium atom enters solution by giving up an electron. It must therefore be paired with something that can receive the electron. Just as sodium is paired with chloride in table salt, lithium is paired with another entity, usually carbonate or orotate. Because lithium is such a light atom, it is only a small portion of the total mass of the pair. 10 mg of lithium carbonate, for example, represents only 1 mg of lithium. The numbers I have given are for the mass of the lithium only. If you use lithium salts, you need to watch out for this distinction.
Regardless of how autophagy is induced, it needs to be done cyclically so that the cytoplasm consumed by the autophagy can be replaced. For this the inducer needs to be out of the system by time the autophagy induction time ends and the recovery period begins. Curcumin levels drop by half every hour whereas resveratrol drops by half every 9 hours. Using these numbers, resveratrol should probably be taken early in the protein restriction period and curcumin late. Lithium, on the other hand, drops by half in about 32 hours with much variation45. This is too long to be useful for alternate day protein cycling, and I would not recommend its use for this purpose (though it may still be useful to lower the trigger threshold of another autophagy inducer). In most therapeutic uses of lithium, the level is always held high. From the point of autophagy induction, this is like always inhaling without exhaling. Or like pulling the trigger of a gun and holding it. The trigger must be released and pulled again to fire another shot. This absence of cycling may in fact be responsible for much of the contradictory data seen in research with chemical autophagy inducers. In protein cycling, the high protein portion of the diet is as important as the low and we use the term ‘cycling’ just to emphasize that point.
What often happens with a substance that induces autophagy is that a starvation condition is created where some essential substance is inadequately supplied by the body and must then be salvaged from the cell to permit continued synthesis. Lithium, for instance, creates a shortage of the lipid inositol required for membrane synthesis46. The cell then initiates autophagy to recover inositol from existing surplus membranes.
The cell also begins to produce more of the proteins involved in inositol synthesis in response to the shortage. This so-called ‘up regulated’ inositol synthesis machinery then compensates for the shortage created by lithium and further autophagy does not occur. This is a general response to any shortage. Enzyme protein production is regulated by negative feedback mechanisms. The end product of the enzyme pathway feeds back a signal to the enzyme-production factory that inhibits further production. A balance between end product and the enzymes that produce it is then achieved. Autophagy happens because the need for nutrients cannot wait for the relatively slow process of ‘up regulating’ the synthesis machinery. Cycling then allows the ‘up regulation’ to be reversed by the same feedback mechanism (down regulated) so that the autophagy inducer can work again.
When autophagy is induced by protein or calorie restriction, however, there is a true shortage that cannot be corrected by simply up regulating synthesis machinery. Of course eventually the restriction must end to prevent starvation, but, for the entire restriction period, autophagy will be happening since, in order to function, human cells must constantly make new proteins regardless of conditions.
Exercise and Alcohol
Exercise has recently been shown to initiate autophagy in response to the stress arising from the consequent production of ROS (reactive oxygen species)83. Alcohol consumption likewise induces autophagy84 presumably by the same mechanism. Apparently autophagy induction is so common that there seems to be little need to go out of one’s way for it. All you need is some stress on the cells. So is everything bad you do to yourself then good? Indeed the accumulation of autophagosomes is a hallmark of neurodegenerative diseases. Taking a substance to accumulate even more hardly seems beneficial. What needs to be promoted is the completion of autophagy rather than its initiation, a topic discussed in more detail in the next chapter.