Zombie Cells and How to Get Rid of Them
In the tombs of ancient Greece, skeletons are often weighed down with stones and other heavy objects, as though to prevent the dead from resurrecting. And even further back, in ancient Mesopotamia, there are stories like the one about the goddess Ishtar, who threatens, ‘I will let the dead rise and eat the living.’ Today, we still have these kinds of horror stories about the living dead – zombies – and they have made it into this book as well. The zombies we’re going to encounter, though, are different from the Hollywood ones. Our zombies are zombie cells.
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Normally, cells anxiously monitor their own condition. If they sense something is wrong, they will kill themselves in cellular suicide – what’s called apoptosis. This is why human cells are hard to grow in the laboratory. When the cells are removed from the body, they notice that something is off and promptly kill themselves. This level of paranoia might seem drastic, but as always, there’s an evolutionary reason your cells behave like this. Cellular suicide is a mechanism to prevent cancer and fight infections. If one of your cells suspects it’s turning cancerous or has been infected with a virus, it selflessly sacrifices itself to save the rest of your body. That might sound heroic, but it is actually a completely normal part of how your body works. In fact, while you’ve been reading this paragraph alone, a few million of your cells have killed themselves. Yes, millions. You lose between 50 and 70 billion cells to apoptosis every day. That is a mindbogglingly large number, but it’s actually just a tiny fraction of your cells, and your body can easily replace them.
In some cases, damaged cells don’t outright kill themselves, but instead enter a state called cellular senescence. This is what we call zombie cells. Senescence was first described by Leonard Hayflick as the result of reaching Hayflick’s limit. That is, cells can end up as zombie cells when they run out of telomeres. But there are plenty of other ways, too. In general, all the types of damage that can lead a cell to cellular suicide can also make it become a zombie cell instead.
When a cell turns into a zombie cell, it stops most of its normal activity, including ceasing to divide. But instead of dying, which would be an obvious next step, the cell sticks around. And on top of that, it starts spewing out a cocktail of damaging molecules into its surroundings. It’s not a long stretch to imagine cells like that could promote ageing. So scientists from the Mayo Clinic in Minnesota set out to investigate how zombie cells affect the lifespan of biological organisms. In one study, the scientist isolated zombie cells from old mice and transplanted them into young, healthy mice. The young mice started out full of vigour but it took just a single dose of zombie cells to slow them down. Curiously, the mice remained weak, even six months after the transplantation, when the original zombie cells were long gone. The reason turns out to be that zombie cells – in true zombie fashion – spread their condition to other cells. The molecules they spew out in their surroundings can make normal, healthy cells become zombie cells as well – even cells that are located in totally different areas of the body. As a result, the mice of the experiment never recovered from the zombie cell transplantation. They ended up dying earlier than normal mice, and the more zombie cells were transplanted, the worse they fared.
What happened to these poor mice is actually somewhat similar to what happens during normal ageing. We’re not suddenly injected with zombie cells, but as we grow old, zombie cells tend to accumulate in the body. An old person has many more zombie cells than a young person. And given that zombie cells clearly have a negative effect, perhaps it would be beneficial to get rid of them outright? Researchers – again from the Mayo Clinic – have tested this using some ingenious genetic engineering. In short, the researchers made mice with cells containing a special genetic construct. You can imagine the construct as a little bomb that would only be active in zombie cells, and which the researchers could trigger on command using a special trigger molecule. Upon administering this molecule to the mice, the ‘cellular bomb’ would go off in zombie cells and kill them.
The researchers divided their genetically engineered mice into two groups to test the effect of removing zombie cells. The first group was left alone while the researchers triggered the cellular bomb twice-weekly in the other group. It was necessary to kill the zombie cells continuously like this because zombie cells appear throughout life. By targeting them again and again, the scientists made sure their mice remained zombie-free. As expected, getting rid of the zombie cells proved a boon for the mice. The scientists noted that the zombie-free mice looked significantly healthier and more energetic than their zombie-plagued peers. And ultimately, the zombie-free mice also lived around twenty-five per cent longer than the control mice.
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So, should you and I be looking for a way to get rid of our own zombie cells? It is important to note that cellular senescence is not always a damaging phenomenon. Zombie cells actually play an important role in both our development and in wound healing, which should not be disrupted. However, the mice studies from above pretty clearly implicate zombie cells in ageing, and there’s even signs zombie cells help promote several age-related diseases. It seems cellular senescence is a helpful mechanism in youth but gets derailed over time.
The immune system somehow plays a role here. Normally, immune cells can eat and remove the zombie cells. In fact, the damaging molecules spewed out by zombie cells are partly used to attract immune cells. But in old age, the zombie cells call in vain. Ageing robs us of immune cells, and those that are still around are often occupied elsewhere.
That means we will have to find another way to rid ourselves of the zombie cells. You and I don’t have any ‘cellular bomb’ encoded in our genes, so we will have to come up with something else. There are two options. We could try to ‘rescue’ the zombie cells, turning them back into normal, healthy cells. Or we could try to kill the zombies.
Option two sounds more fun, and it seems cellular senescence researchers agree. At least, zombie killing is by far the most researched option. Unfortunately, however, killing zombie cells is not as easy as killing zombies in the movies. The main obstacle is that zombie cells don’t all hang out together. They’re spread out throughout the body and are always in the minority, even in old age. As a result, you have to be very accurate when targeting zombie cells. Even slight inaccuracy would mean you end up killing many more normal cells than zombie cells. That would be a net negative.
Despite the difficulty, scientists have managed to find drug candidates that target zombie cells specifically. These drugs are called ‘senolytics’, and most of them kill by forcing the zombie cells into cellular suicide. As we’ve discussed, this is the fate most zombie cells were destined for anyway before they became zombie cells instead. The zombie cells inhibit the cellular suicide response, but senolytic compounds can force their hands.
The senolytics found so far include many compounds derived from plants. So, once again, I’m reminding you to eat your fruit and vegetables. One example of a senolytic molecule is a flavonoid called fisetin, which is found in strawberries and apples. Adding extra fisetin to the chow of old mice improves their lifespan, even when started late in life. The study in question used much higher concentrations of fisetin than you’d realistically get from your food, though. If you wanted an equivalent amount, you’d have to eat a few kilos of strawberries. Now you have the excuse.
Other examples of zombie-killing compounds that can extend the life of mice include the flavonoid procyanidin C1, which is found in grapes and also fisetin’s close cousin, quercetin, which is found in onions and cabbage. Quercetin is especially well-researched in combination with the drug dasatinib. This combination is much more powerful than quercetin alone. Now, dasatinib is a leukaemia drug, so not something you’d eat on a normal day. But the combination of dasatinib and quercetin is currently being investigated in humans in several clinical trials. They’re a good candidate for a future pharmaceutical solution to zombie cells, but a leukaemia drug is obviously not something to play around with. In general, even though some of the zombie-killing compounds can be found as supplements, caution is warranted. At high concentrations, these molecules are toxic to normal cells too. Anyone experimenting with them should really know what they are doing.
The best approach to fighting our zombie cells is to cross our fingers and watch the clinical trials. There’s actually already been a success story: an experimental senolytic drug has been used to safely improve two age-related eye conditions. Given the tons of money involved and many different trials, it’s possible a senolytic will be the first real anti-ageing drug approved by medical authorities. In the meantime, there’s a bunch of – admittedly less effective – ways of combating zombie cells.
First, viral infections can turn cells into zombie cells. And interestingly, some viruses, like influenza type A, can be fought using senolytic compounds like quercetin.
Second, there’s the immune angle. A healthy immune system would probably be able to take care of the zombie cell problem all on its own.
Third, it is interesting to note that most zombie-killing compounds are flavonoids from plants. Sure, to get the amounts used in these studies, you’d have to eat like an elephant. But there are lots of plant compounds similar to these. Who knows if they have a synergistic effect together.
And finally, while we’ve established it’s more fun to kill the zombie cells, there’s also exciting research taking place that aims to reverse the condition. Several studies have shown that the circadian rhythm hormone melatonin can help bring zombie cells back to a healthy state. Melatonin is not the ‘sleep hormone’ as it is sometimes described, but optimising sleep and having a consistent wake/sleep schedule is a good idea.