JUMPING GENES / AGING
Are waking viruses the time bomb that causes aging?
A new study found that human age is closely correlated with chemical tags on DNA, scars left by a lifelong fight between our cells and dormant viruses. But I think this study also hints at a path to life extension and even immortality — potentially using tools that we already have.
Our genomes are riddled with jumping genes, also called retrotransposons — pieces of DNA that can copy and paste themselves into new locations. These parasitic DNA sequences are descended from ancient viruses that had at some point in our evolutionary history infected our ancestors’ sex cells and worked their way into our lineages. It’s not just some accidental insertion here or there — about a half of our genome is made out of those mobile elements, and most of them are probably descended from ancient viruses.
We have been fighting an invisible war against them for billions of years. A mobile genetic element in the genome is like a bull in a china shop. It does not care about other genes and, when awaken, can copy and paste itself into a middle of another one, making it useless. Different copies of those mobile elements sticking to each other can cause chromosomes to twist and break up. Pieces of DNA resulting from the chaotic copying and pasting leak into the cytoplasm, where they trigger inflammation designed to counteract invading viruses (normally there should be no DNA outside the nucleus). All this chaos damages the genome, drains energy resources, and eventually causes the cell to either die, trigger an immune attack, or become cancerous.
So our bodies go to great lengths to keep retrotransposons asleep — our lives depend on it. If all the retrotransposons in our body were suddenly allowed to wake up, we would be consumed in a frenzy of uncontrollable cancer, inflammation and necrosis, and would probably perish as quickly as Dorian Gray after destroying his portrait.
When we are born, our cells have “tight” genomes — physically and figuratively. Physically speaking, DNA is densely coiled and only loosened in specific locations where genes are being read. Figuratively, these young genomes are like a clear radio transmission from the distant past: mostly silent, with only specific, useful genes playing their notes. But as we age, the genomes get “looser”. The dense wrapping melts away. The radio transmission gathers static. It gets hard to hear the useful genes behind other sounds. These other sounds are the retrotransposons waking up and commencing their chaotic activity, which exacerbates the loosening of the genome even further. Cells fight back by sticking chemical tags on retrotransposon DNA that say “keep out”, like marking a landmine. This suppressive tagging of DNA is called methylation. As the genome loosens up with age, cells put more and more of these tags onto retrotransposons. This is what the paper mentioned above, by Michael Corley’s lab at Weill Cornell, is about: methylation of retrotransposons apparently predicts age better than anything else.
But there’s more to the study that caught my attention. It also shows that this methylation is accelerated in HIV-positive people (this was known before), and partially slowed down by antiretroviral therapy (this, to my knowledge, is news.)
The thing is, HIV is a retrovirus — the same kind of virus, broadly speaking, that litters our genome. HIV also pastes itself into random locations within DNA and uses similar enzymes to do that. So it’s not a total surprise that the very drugs we use against HIV are also effective against our own internal viruses. And the fact that antiretroviral therapy can turn back the biological clock in HIV-positive people might mean that it can extend lives of HIV-negative people too. So, however weird it might sound, there is a real chance that we will all soon be taking ART as a life extension therapy.
Now, at this point you should accuse me of conflating correlation and causation. The newly discovered “biological clock” of methylation, you might say, is simply a correlate of many other things deteriorating in the body, not their cause. Less methylation after ART does not necessarily mean that aging had been slowed down — it probably just means that the clock is now off.
You would probably be right. It is of course inherently unlikely that any one drug will significantly prolong the lives of healthy humans better than the things we already know about — diet, lifestyle, relationships. But the idea is not as wacky as it might sound.
There is, in fact, a reason to believe that the Dorian Gray-style awakening of retrotransposons, only in slow motion, is what aging really is — that we all eventually die from losing our bodies to ancient viruses.
If aging was a result of simple cellular damage accumulating over time — mutations caused by environmental toxins, for example — then we would age evenly, at the same rate throughout our lives. But aging is an exponential curve — once it starts, it gets worse and worse faster and faster. The behavior of retrotransposons, say some scientists, fits these dynamics much better. As the genome loosens up with age, retrotransposons become more active, causing genomic damage, and so further loosening the DNA. It is as if the retrotransposons thaw from a genetic permafrost and cause the rest of the genome to rot. Another reason to believe that viruses may cause aging is the fact that HIV causes it. It doesn’t just increase DNA methylation — it actually does cause a range of aging-like symptoms that can’t be directly explained by its effects on the immune system. So although DNA methylation of retrotransposons is a symptom, not a cause (in fact, the role of methylation is to fight retrotransposons), targeting retrotransposons in a way that reduces this methylation might actually slow down aging. And now we know that this can be done, at least to some extent, with drugs that already exist and are used by millions of people.
To be clear, there is no consensus on whether this would work — slow down aging, let alone in people who are HIV-negative. HIV-targeting drugs may not be the most effective solution, they may need to be modified and optimized, and might have long-term side effects that would negate any life extension. Most experts would argue that retrotransposons are only one part of the aging puzzle. For example, there is no conclusive answer to what causes the genomes to start loosening up in the first place — it could be retrotransposons, but it could also be other factors that set aging in motion.
But at the very least, it seems pretty clear that retrotransposons play an important role in, well, killing us.
This fact is especially striking if you consider another puzzling, even creepy fact about retrotransposons: it appears that it is, in fact, possible to effectively suppress them, but for some bizarre reason, most of our cells are choosing not to do that.
There is one time when the genome doesn’t just loosen but “opens up” entirely: this happens during the production of sex cells, when all the tags such as methylation (there are others) are stripped clean from the genome. This is precisely the situation that I said above would rapidly kill us, like Dorian Gray. So why don’t our sex cells all rot away? The reason is — they activate what appears to be a specifically designed molecular system to totally suppress the activity of retrotransposons, called piwi RNA. Retrotransposons all wake up and begin their chaotic activity, but the activity is immediately blocked by piwi RNA, and no one gets a chance to complete the copy/paste process. So this piwi RNA successfully maintains the immortality of our genetic lineage, and has apparently been doing so for billions of years.
Why in the world, then, can’t the rest of the cells in our body do the same? There is some precedent. For example, cnidarians — jellyfish and polyps — use piwi RNA in all cells of their body. These organisms are famously long-lived and some may even be immortal. Flatworms and axolotls employ the same system for their remarkable regenerative abilities. But by and large, piwi RNA is limited to its use in reproduction.
This seems like a scam — just like the fact that our bodies can produce beneficial hormones, but only deploy them if we prudently exercise. And in both cases, the answer is: evolution doesn’t care about our well-being. It is not interested in making everyone healthy or long-lived. It is interested in furthering the lineage, and selecting the best torchbearers to carry it. So it might, in fact, not mind the retrotransposons slowly rotting our genomes. Maybe, aging is not a bug but a feature: a time bomb that is placed by evolution in our bodies to prevent old people from weighing down on younger generations.
But maybe, that is actually good news. If aging were a result of slow deterioration, then it would seem impossible to stop, like fighting against time itself. But if aging is a time bomb, doesn’t it make it possible to defuse it?