Discusses how statins are promoter of autophagy.
Statins and the Blood-Brain Barrier
Statins are drugs that inhibit the body’s production of cholesterol. They include simvastatin (marketed as Zocor), atorvastatin (marketed as Lipitor) and lovastatin (marketed as Mevacor) among others. Their effectiveness against cardiovascular diseases and relative safety have made them by far the most widely-prescribed class of drugs ever.
Statin use is becoming about as common as aspirin use. A majority of people over 50 in the United States now have statin prescriptions. In most countries, including even the medically cautious UK, statins are now available over the counter without prescription. And, as their patents have expired, their costs continue to plummet and they will soon sell for pennies a pill. Since statin use is so widespread and growing rapidly, we must consider its interactions with protein cycling.
All commercial statins are given names in the form prefix + ‘vastatin’. Hence simvastatin, atorvastatin, lovastatin, cerivastatin , fluvastatin , mevastatin , pitavastatin , pravastatin , rosuvastatin , etc. They all work by direct inhibition of a specific enzyme in the cholesterol-synthesis pathway. They differ primarily in their degree of oil solubility. The more oil-soluble (lipophilic) is the statin, the more easily it can cross the blood-brain-barrier and directly affect neurons and their support tissues.
The blood-brain-barrier prevents cholesterol and other fats in the bloodstream from reaching the neurons. In consequence the neurons or their support tissues (glia, astrocytes) must synthesize the cholesterol required for neuron structures. If this synthesis is inhibited by statin use, the neurons might be impaired thereby in some vital function. This is in fact the argument advanced by some against statin use. It may be behind the rare memory-loss side-effects reported in statin use.
Besides cholesterol, the metabolic pathway inhibited by statins is also used to make the chemical Co-enzyme Q10 (CoQ10). CoQ10 is one of the few entirely-hydrophobic molecules of the cell. As such it resides entirely within the lipid phase in the interior of cell membranes where it serves a vital role as an electron transporter. It is especially important in the mitochondrion. When mitochondria fail, they release their acid interiors into the cytoplasm leading to death and dissolution of the entire cell. It is speculated by some that the depletion of mitochondrial CoQ10 by statins may thus be behind the cell death phenomenon rhabdomyolysis ( discussed in a previous chapter) seen in a small percentage of statin users.
Since protein cycling or ADCR may stress cells already made fragile by statin use, you may choose to supplement CoQ10 when using statins. In pill form, CoQ10 supplements are expensive so I suggest you use the powder form instead. It should be added to the fat component of your meals at about 50 mg/day and should cost no more than 8 cents per day.
Certainly statin use should not be stopped just because you are protein cycling. The evidence of its benefits to cardiovascular profiles is just too strong. Unsurprisingly, cardiovascular diseases aggravate dementia and parkinsonism, the very things protein cycling seeks to avoid. There is even a remarkable statistical study where the incidence of dementia and parkinsonism was seen to be reduced by half with simvastatin and much less with atorvastatin or lovastatin. Simvastatin, unlike atorvastatin, can cross the blood-brain-barrier. This suggests that lipophilic statins like simvastatin could prevent dementia and parkinsonism by direct action on the brain rather than just indirectly by cardiovascular benefits72. If the patents on simvastatin had not run out, you would probably be hearing a lot more about these results.
In fact cholesterol depletion by lipophilic statins is a known inducer of autophagy73 and this may be the mechanism by which it reduces dementia and parkinsonism, clearing the mis-folded protein aggregates associated with these conditions. In the near future statins may be prescribed for AD and PD even where cholesterol levels are normal.
Alternate day statin dosing has been shown to be as nearly effective as daily dosing74. Perhaps statins could be cycled concurrently with protein or calorie cycling to synergize eachother’s benefits.
It is not too surprising that blocking cholesterol synthesis seems to promote autophagy. When cell membranes are recycled, the cholesterol they contain is made available for new membrane synthesis in the same way as amino acids are made available for new protein synthesis. Perhaps cycling statins could be as effective as cycling proteins in promoting autophagy. We may never know since statins are coming off their patents and there is little incentive to do the necessary studies. Further statins have some problems in crossing the blood-brain barrier and would likely promote autophagy less in the CNS than in the rest of the body, the exact opposite of what is desired to restrain the development of neurodegenerative diseases.
The ideal autophagy inducer would freely cross the blood-brain barrier, or better yet, act just on the barrier itself. There may in fact be such a drug, 2-aminobicyclo-(2.2,1)-heptane-2-carboxylic acid (BCH), a leucine analogue also known as 2-Amino-2-norbornanecarboxylic acid. It selectively inhibits a protein complex, LAT1, that is required for the essential aromatic and branch-chained amino acids to cross the barrier75. When this enzyme is inhibited, essential amino acids, especially aromatics (phenylalanine, tyrosine, tryptophan) are no longer available to the cells of the CNS and autophagy must ensue. This drug, or one that behaved the same, in a cycling regime would induce continual rounds of autophagy in exactly the same way as protein cycling but without the hassle of a restrictive diet and without affecting uninvolved parts of the body. The vast financial potential of such a drug should justify the studies necessary to engineer it into a pharmaceutical product.