Chapter 34
Leucine Restriction
It stands to reason that protein intake activates mTOR. Energy (calories) alone is not enough; the workers need building material. True, calorie deficiency can turn off mTOR, because it ramps up AMPK, but it is not primarily calories that trigger mTOR activity—it is amino acids, the building blocks of protein. This is good news. Protein restriction is much easier to maintain and safer than dietary restriction and could even be more powerful, because it suppresses both mTOR and IGF-1, the two pathways thought to be responsible for the life extension and health benefits of calorie restriction.
A small handful of amino acids is especially important: methionine and the three branched-chain amino acids (BCAAs) isoleucine, leucine, and valine (so called because fatty side chains branch off their central structure). If you reduce intake of these particular amino acids, you get many of the beneficial effects of protein restriction, which itself is the linchpin of calorie restriction, and in the lab it is enough to restrict methionine to prolong a life. So reducing calories to suppress mTOR and extend lifespan is like fasting to keep your peanut allergy in check. It works, but it overshoots the mark.
Where are these amino acids that speed up mTOR concentrated? In animal proteins. Whey protein contains more mTOR-stimulating leucine than the comparable amount of wheat protein. Even those who eat strictly plant-based usually exceed the total required amount of protein, but still consume about 30 percent fewer BCAAs (including leucine) and 47 percent less methionine than omnivores. This is reflected in significantly lower levels in the blood, which may explain the higher life expectancy and lower cancer rates of plant eaters. (Tryptophan is the only other amino acid whose restriction alone can extend life expectancy in rats, delay tumor formation, and increase average and maximum lifespan. It is found in lower amounts in the diet and in the blood of people who eat plant-based.)
This could explain the life expectancy of long-lived populations such as that on the Japanese island of Okinawa, whose death rate from the major diseases of aging is about half that of Americans. In Okinawa’s traditional diet, plants are clearly central. Protein makes up only about 10 percent, less than one percent is of animal origin—so roughly one serving of meat per month and an egg every two months. Longevity here is surpassed only by that of those who do not eat any meat at all, the vegetarian Adventists in California, who probably have the highest life expectancy of any formally described population in history.
Those who eat plant-based have the additional benefit of being able to avoid palmitic acid more easily, the saturated fat found mainly in meat and dairy products that has also been proven to activate mTOR. One warning, though: Those who eat vegetarian and do not ensure a regular, reliable source of vitamin B12, either through supplements or B12-fortified foods, could develop an elevated level of the methionine breakdown product homocysteine. Homocysteine also activates mTOR, but it can be detoxified by B vitamins.
Leucine Restriction
To prevent mTOR from ramping up when eating, some researchers suggested that medications could be developed to prevent part of the absorption of the harmful amino acids in the intestine. I find it more reasonable to simply eat less of them. Leucine is probably the most potent mTOR activator and is found concentrated where it is needed most for promoting growth: in milk. Whey proteins contain the highest amount of leucine, 75 percent more than beef. A whey drink can considerably activate mTOR within an hour of consumption.
Cow’s milk contains more than three times as much leucine as breast milk, which makes sense because calves grow about 40 times faster than babies. (Rat pups double their weight in five days, so it is understandable that rat milk has ten times more leucine than human milk.) In animals, milk contains different amounts of leucine tailored to the growth and developmental needs of the respective offspring. No animal—except humans—drinks milk after it has been weaned.
Milk is not simply a beverage. It is a highly complex system that sends hormone signals to activate mTOR. When we drink the milk of a faster-growing species, especially later in our lives, there is concern that we “overstimulate” the signals to mTOR. An early, visible manifestation of excessive mTOR stimulation could be acne.
Acne is considered a Western disease of civilization, since it rarely occurred or did not occur at all in places like Okinawa. That drinking milk worsens acne was first noted more than 100 years ago. Those who consume the most dairy products are twice as likely to get acne as those who eat the least. 75 to 90 percent of dairy products on the market come from pregnant cows, so this could have to do with the hormone content of the milk, but regardless, mTOR increases risk, also because it promotes the production of sebum, the oily secretion of the sebaceous glands.
Acne is seen as the prototypical mTOR-driven skin disease. The fact that in Western countries up to 85 percent of all teenagers get acne argues for overactivated mTOR signals and provides an explanation for why acne is associated with breast and prostate cancer. mTOR is upregulated in almost 100 percent of cases of advanced prostate cancer in men, which is why milk consumption is a considerable dietary risk factor for both the development and spread of prostate cancer.
Milk drinkers also seem to live shorter lives, unless they drink fermented milk (soured milk). During fermentation, lactic acid bacteria break down some of the galactose, the branched-chain amino acids, and the bovine microRNA, which may explain why yogurt consumption is less risky.
A Cup of Tea and Broccoli
Can we eat anything specific to dampen mTOR activity? Tomato powder reduces activation of mTOR in older rats, and a tomato extract slowed mTOR in human breast cancer cells in the Petri dish, but this still has to be evaluated clinically. Components of broccoli, on the other hand, have already been studied.
One of these components is DIM. It is formed when the component indole-3-carbinol from cruciferous vegetables encounters human stomach acid, and it suppresses activation of mTOR. Sulforaphane, another product of eating vegetables from the broccoli family, also calms mTOR; therefore, people who eat their greens can live longer and healthier on average.
Because hyperactive mTOR signals could play a role in autism, a team from Johns Hopkins and Harvard Universities conducted a randomized placebo-controlled double-blind trial in which young men with autism were given sulforaphane equivalent to a few cups of broccoli daily. The scientists observed improvements such as had never previously been achieved by a medication (for details see see.nf/autism).
Can we drink something to slow mTOR activity? Exposing yeast cells to the amount of caffeine that circulates in human blood after a cup of coffee leads to an inhibition of mTOR activity sufficient to extend life. In mice, both caffeinated and decaffeinated coffee were able to downregulate mTOR similarly, suggesting that it is not caffeine helping here but something else in coffee. Green tea, in turn, contains the flavonoid EGCG, which suppresses mTOR activity at physiologically relevant concentration. This could explain why a topically applied lotion with 2 percent green tea halves the number of pimples and why consumption of green tea is associated with a longer life.
And How Do You Maintain Your Muscles While Doing This?
If we can suppress mTOR so well with dietary changes, do we need to worry about side effects like with rapamycin? The enzyme belongs to two different protein complexes—the mTOR complex 1 (mTORC1) and the mTOR complex 2 (mTORC2). mTORC1 accelerates aging, whereas mTORC2 actually seems to be protective. Unfortunately, rapamycin interferes with both, and mTORC2 deficiency brings many negative effects with it. Protein restriction, however, targets only mTORC1, so you get the benefit without the downsides. Is there a downside to suppressing mTOR through diet?