MicroRNAs

Only about 2 percent of our DNA actually codes for proteins. So what do the other 98 percent do? When I was studying, the more than one billion gene sequences of seemingly functionless DNA were dismissed as “noise,” “waste sequences,” or “junk DNA”—they were considered accumulated genetic trash from our evolution. But that would probably be a bit wasteful. A parallel from astrophysics was drawn for this mystery: dark matter—the supposed fact that we have no explanation for about 85 percent of the matter in the universe. The mystery of the dark matter of our genome was solved in 2001: Most DNA breaks with the Central Dogma and is actively transcribed into non-coding RNA—that is, RNA that does not code for proteins. But what does it do, then?

Today we know that there are over 100 types of non-coding RNA, but now we want to focus on the true ones, the actual ones: microRNA. To encode an average messenger RNA, it takes a DNA sequence with thousands of letters. By contrast, microRNAs are only about 20 letters long. For example, the first microRNA ever discovered was 22 letters long, drawn from the four-letter RNA alphabet: UUCCCUGAGACCUCAAGUGUGA. And what do microRNAs do? As a rule, they are produced in order to attach to messenger RNAs and prevent them from being translated into proteins.

So if DNA is the blueprint and messenger RNAs are the construction workers who turn those instructions into parts of a house, then microRNAs are, so to speak, officials who step in and prevent certain workers from doing their job. That is a good thing, too, because without building oversight, the simplest safety standards would be ignored. And the various elements must be built in the right order—you shouldn’t call in the roofers when the foundation has not yet been poured.

It is especially instructive to understand how microRNA regulation works, because a single microRNA can block over 1000 different messenger RNAs. That means a microRNA can silence over 1000 different genes. To stick with my house-building analogy: With a simple instruction, all workers on the first floor can be told to wait until the workers on the ground floor are finished. Then there are also regulators that regulate the regulators—other non-coding RNAs that prevent the microRNAs from stopping the messenger RNAs—but that would take us too far afield.

Just as the complexity threatened to become overwhelming, because a trillion microRNA combinations of 20 letters are possible from the four letters of the RNA alphabet, researchers realized that only a few thousand microRNAs appear to be active in the human body. And in each cell, the five most common microRNAs make up, on average, half of the cell’s entire microRNA pool. But in 2007 it got even more interesting.

It was discovered that microRNAs circulate in at least twelve different bodily fluids. (When I read that, I couldn’t help thinking: Wait a minute—do I even know a dozen bodily fluids?) Before that, it was not considered possible, because we have enzymes that break down any RNA outside of cells (as a precaution against viruses, which often bring RNA with them). It then turned out that the microRNAs are transported in exosomes—tiny vesicles that bud off from cells. In the past, these budding vesicles were thought to be the cells’ waste-disposal containers. (Why do scientists always immediately think of waste when they don’t understand something?) But in 2007 it was discovered that these vesicles were full of microRNA. Our cells communicate with one another! For example, a liver cell can send out microRNAs to regulate genes in a lung cell, which in turn can regulate a brain cell, or vice versa. They can even speak to the next generation by depositing their microRNA cargo in a sperm cell or an egg cell.

And the bottom line? We can now say with certainty that microRNAs likely regulate virtually every biological process and play a decisive role in practically every aspect of health. Genetically engineered mice that cannot form microRNAs do not even survive the embryonic stage. Diseases of every form and size have been linked to faulty regulation of microRNAs. But the good news is that we can do something. microRNA expression can be changed through diet.

MicroRNAs and aging

What does that have to do with aging? Since microRNAs are an important regulator for all cellular signaling pathways, it would not be surprising if they also played a role in aging, but this connection has a special significance. The very first microRNA was discovered in the simple roundworm C. elegans. Now guess what it did there? It regulated its life span. Reducing the activity of this simple microRNA shortens its life span and accelerates tissue aging, whereas overexpression of the microRNA significantly extends the worm’s life. It turned out that the target of the microRNA was a DAF-16 suppressor gene. The worm’s DAF-16 gene is the equivalent of the FOXO gene, which can make certain primitive animals immortal and, in humans, is one of the most important genetic determinants of extreme longevity. By blocking the suppression of this longevity gene, the microRNA brought about the extension of life span. If you know the expression patterns of just a few microRNAs in C. elegans, you can predict the longevity of individual worms.

To investigate the effect of microRNAs on the life span of mammals, a series of intervention studies was conducted in mice. One group was fed a high-fat diet and lived 101 weeks. A second group was fed a high-fat diet and was additionally given the opportunity to exercise voluntarily, and it lived for 114 weeks. The third group was fed a low-fat diet and lived up to 127 weeks. A fourth group received low-fat food plus exercise and lived 131 weeks. The fifth group received calorie-reduced, high-fat food and lived 137 weeks. And the last mice ate calorie-reduced and low-fat and lived 153 weeks—over 50 percent longer than the mice in the group with regular high-fat feeding. Using this strategy, the researchers found that 92 microRNAs correlated with life span, 84 of them in an inverse relationship. In other words, the microRNAs generally seemed to suppress longevity genes, so that certain microRNA levels in the longest-lived group were up to 90 percent lower. However, there are also exceptions.