Flossing for Longevity
Alzheimer’s disease is one of the worst fates that can befall an old person. The neurodegenerative disease slowly erases a lifetime of memories until patients cannot even remember the people they love. It’s a devastating way to end a long life.
The disease is characterised by the appearance of protein plaques in the brain. These plaques consist of a peptide called amyloid beta, and you can think of them as little clumps. We don’t know why the amyloid beta clumps form, but we do know they can lead to inflammation in the brain and that they eventually kill brain cells.
This gives us an obvious solution: remove the clumps, or even better, prevent them from occurring in the first place. That’s easier said than done, of course, because the brain is protected by the blood–brain barrier. As we’ve discussed, this makes it notoriously hard to develop drugs for the brain. A drug doesn’t just have to work – say be able to remove the amyloid beta clumps – it also has to be able to actually get into the brain. And that can only be achieved by scaling what’s essentially a biological version of the Berlin Wall.
Despite all the difficulties, pharmaceutical companies have in fact succeeded in developing drugs that can prevent amyloid beta clumps from forming in the brain. They have even developed drugs that can remove them. But unfortunately, it doesn’t help. Nothing does, really. The fight against Alzheimer’s has cost billions of dollars, and thousands of our most talented scientists have dedicated their lives to it. Hundreds of potential drugs have been tested in clinical trials, but despite the gargantuan effort, we have nothing to show for it. Every single promising drug has failed. There’s no cure – not even a little hope for spontaneous remission. The best we can do is to slightly delay the inevitable.
What could we possibly be missing? There must be something fundamental about Alzheimer’s that we don’t yet understand. How else can everything fail? It doesn’t help our efforts that Alzheimer’s disease – unlike virtually all other diseases – is unique to humans. Mice, for example, often get cancer, but they simply don’t get Alzheimer’s. In order to research Alzheimer’s, scientists have had to artificially design mice reminiscent of human Alzheimer’s patients. And then try to cure these mice in the hopes that the lessons can be transferred back to humans.
Are we perhaps wrong about the involvement of amyloid beta clumps in Alzheimer’s? That’s very unlikely. You see, we know that people with Down’s syndrome have a much higher risk of getting Alzheimer’s disease. They also tend to get it very early. Down’s syndrome is caused by having an extra copy of chromosome 21, and on that chromosome sits the amyloid beta gene. This suggests that an increased amount of amyloid beta coincides with Alzheimer’s. Scientists believe other people with Alzheimer’s experience something similar. Either they produce more amyloid beta than normal, or perhaps they are worse at clearing it up. In both cases, amyloid beta is seen as a sort of waste product. We don’t really know what its intended function is – we only know it from Alzheimer’s disease. So essentially, the story goes: we have a protein with no purpose, and in old age, it makes clumps in the brain and kills us.
That’s a little hard to believe. Especially because we’re far from the only animal that has the amyloid beta protein. In fact, it’s extremely well-preserved throughout the course of evolution. Monkeys have it, mice have it – even fish have it. And all of these animals have versions of the protein that are nearly identical to our own. That’s usually a clue that a protein has an important function. If an animal is born with a mutation in an important gene, they tend to fare worse than others, meaning they will not contribute as much to the next generation. This means proteins tend to change only slowly if they are important and will often be similar across species.
So, if amyloid beta is important, what is its function? Most likely, it is to be a weapon against microbes. You see, scientists have discovered that amyloid beta kills microbes if you add it to microbial cultures in the laboratory. It does so by clumping around the microbe to neutralise and kill it while subsequently keeping it under lock just in case. It’s a fascinating mechanism and not just something that happens in laboratory cultures. If scientists inject bacteria into the brains of mice, amyloid beta springs into action and forms clumps around the bacteria. As a result, mice lacking amyloid beta are killed by these bacterial injections, while mice that can use amyloid beta tend to survive. At the same time, we know from the genetics of Alzheimer’s that the immune system plays some kind of role in disease development.
So we certainly have a smoking gun suggesting that Alzheimer’s could have microbial involvement. Now all we need to know is who pulled the trigger.
A study from Taiwan provides the main suspect. The Taiwanese researchers discovered that people infected with the herpes virus are two-and-a-half times more likely to get Alzheimer’s than those who aren’t – that is, unless they are taking anti-herpes medication. This medication suppresses the virus, and interestingly, it also brings the risk of Alzheimer’s back to normal. The case strengthens as several research groups have found traces of the herpes virus in brain tissue samples from deceased Alzheimer’s patients (while being absent from controls). In one study, the virus was even found inside the amyloid beta clumps in Alzheimer’s brains. Researchers can also duplicate the effect in the laboratory. If brain cells in culture are infected with herpes virus, amyloid beta clumps appear – unless anti-herpes medicine is also added. The connection could also explain a puzzling finding about the grandfather of the Alzheimer’s risk genes. We have previously encountered the APOE gene in which a specific genetic variant increases the risk of Alzheimer’s disease. It turns out the same genetic variant increases the risk of getting cold sores for people infected with the herpes virus. It could be that this particular genetic variant simply makes people worse at fighting herpes infections.
Critics of the microbial theory of Alzheimer’s point to the fact that some people are infected with herpes virus but don’t develop Alzheimer’s. But, as we’ve learned, this is quite normal. Some people are infected with Helicobacter pylori and don’t get peptic ulcers. Some people are infected with Epstein-Barr virus and don’t develop multiple sclerosis. In both cases, the disease happens as a by-product of infection – the pathogen is not trying to directly induce it. That’s probably the reason why pathogens can cause disease in some people while sparing others. That, and the influence of genetics, different sub-strains, severity of infection and also randomness or luck.
The next critique point is more valid, though. As it turns out, the herpes virus is not the only pathogen that has been associated with the development of Alzheimer’s disease. Suspect number two is the bacterium Porphyromonas gingivalis
(P. gingivalis), which normally lives in the mouth. Again,
P. gingivalis has been found in brain tissue from deceased Alzheimer’s patients. In some cases, the bacterium can cause a severe inflammatory condition of the mouth called periodontitis. This condition is associated with an increased risk of Alzheimer’s (and also of cardiovascular disease). In fact, there is even one study that gave dental examinations to 8,000 people in their sixties and found those with gum disease had a greater risk of developing dementia two decades down the line. Whether or not there is causation here, remember to floss.
Further down the list of suspects are the bacterium Chlamydophila pneumoniae (not to be confused with the sexually transmitted infection) and fungi such as Candida albicans. Again, both have been discovered in the brains of deceased Alzheimer’s patients but not in controls. At this point, the best evidence is for the herpes virus, but as we’ve discussed already, one-two combinations from microbes are not uncommon. The culprit could be a single microbe with the rest being simple followers, it could be a combination, or microbes could turn out not to be the culprit after all. We don’t yet know, but given that Alzheimer’s is currently untreatable, it won’t hurt to take the microbial theory seriously.
Infections messing up the brain
We already know other cases where infections cause Alzheimer’s-like symptoms. One of these is syphilis, also known as the French, Italian or Spanish disease, depending on whether you ask the Italians, the French or the Portuguese. Syphilis is caused by a sexually transmitted bacterium that originated in the Americas but spread to the rest of the world after European contact. The bacterium found itself right at home, and before the invention of antibiotics, it was the leading provider of customers for European psychiatric hospitals. After many years of infection, the syphilis bacterium can enter the nervous system and cause symptoms such as dementia and ‘personality changes’. People go raving mad. There are plenty of famous examples of syphilis causing havoc in the brain, most notably, Prohibition-era gangster Al Capone, who was eventually brought down by his love of brothels. Capone was released from prison on compassionate grounds after beginning to display completely delusional behaviour. He died not long after, at the age of forty-eight.
In 1911, pathologist Peyton Rous made a strange discovery during his studies of chickens with cancer. Rous found that he could transmit the cancer to other chickens using an extract from the cancerous nodule. The cause wasn’t cancer cells – or bacteria, for that matter – because it still worked if all cells and bacteria were first filtered out. Instead, the cause turned out to be a virus. It was the first time humans had directly observed a cancer-causing virus.
Rous’s attempt didn’t attract much interest initially, and it took many years before anyone tried to repeat it. In 1933, other scientists found cancer-causing viruses in rabbits; nine years later, they were found in mice, and then in cats nine years after that. At this point, you can probably guess how the whole thing unfolded. Throughout the period where all these cancer-causing viruses were discovered, there was fierce opposition to the idea that viruses could cause cancer. Especially when some scientists cautiously suggested that there might also be viruses of this kind in humans. As a result, Peyton Rous didn’t receive his Nobel Prize until 1966 – fifty-five years after his discovery. This made him the oldest ever Nobel laureate in medicine. Despite the opposition, though, German scientist Harald zur Hausen finally discovered a cancer-causing virus in humans in the 1970s. The virus in question was Human Papillomavirus (HPV), which causes cervical cancer, and which we have previously encountered in the story about Henrietta Lacks. Since then, we have discovered many other cancer-causing viruses in humans. Among them are the Epstein-Barr virus and herpes virus 8, which we have already met, as well as hepatitis B and C, which can cause liver cancer.
Today, we know that about twenty per cent of all cancer cases in humans are caused by microbes. In addition to the many viruses, there are also carcinogenic bacteria, such as our old acquaintance Helicobacter pylori, which can cause cancer in the stomach, and Chlamydia trachomatis (yes, this time the sexually transmitted disease), which can contribute to cervical cancer alongside HPV. Of all of these, though, HPV is the worst. To be clear, not all HPV viruses are dangerous. There are more than 170 kinds, and most problems arise from the ones called HPV16 and HPV18, which are cancer-causing. The two alone account for about five per cent of all cancers in the entire world. The majority of these cases are cervical cancers in women, but we are also seeing an increasing number of men with HPV-caused cancer, including in the oral cavity. This will hopefully be a thing of the past someday, as we have vaccines that can prevent HPV infection (although conspiracy theorists are currently working hard to do the virus’s bidding).
Okay, so we know that about twenty per cent of all cancers are caused by microbes. That still leaves the other eighty per cent to have other causes. Maybe. There’s still a lot we don’t know. In recent years, more and more microorganisms have been found in tumours. It turns out that virtually all tumours in humans are infected by bacteria. That might just be because the cancer suppresses the immune system, making the bacteria take shelter there. But it could also be because the bacteria are helping to form the tumour to begin with. An interesting example is the bacterium Fusobacterium nucleatum, which usually lives in the mouth, where it can contribute to cavities in the teeth (again, floss). However, researchers have also found this bacterium in cancers of the colon – and if the tumour spreads, the bacterium follows. Meanwhile, antibiotic treatment to kill the bacterium inhibits growth of the tumour. Similarly, scientists have also found fungi that are 3,000 times more common in tissue samples from pancreases with cancers compared to healthy pancreases.
Exactly how this all ties together is still unclear. Do microbes cause cancer? Do they just promote the growth of cancer? Do microbes help cancer by fighting the immune system? Which are just followers, and which are the culprits? One thing I can say for sure, though, is that the list of cancer-causing microbes is not yet complete.
I think you get the point now. We could continue this chapter with all sorts of other age-related diseases: bacteria from the mouth being found in arterial plaque (floss); influenza increasing the risk of having a heart attack; viruses implicated in the development of Parkinson’s disease; and so on and so on. The point is that microbes influence the development of every single age-related disease that plagues us. If we ever want to eradicate these diseases, it will involve fighting against the small critters that prey on us.
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Imagine for a moment that you’re a virus. You’re a bit of genetic information in a tiny shell, swimming around in what must feel like an infinite ocean. In reality, it’s some poor guy’s salivary gland. Your comrades have succeeded in infecting him, and now you’re spreading from cell to cell. As with all other biological beings, your ultimate goal is to make a lot of copies of yourself. And for that, you need the molecular apparatus that exists in a cell.
Fortune smiles upon you and you run into a victim. You attach to the surface of the hapless cell and trick it into bringing you inside. Then, your DNA fuses with the cell’s own. At that point, it’s too late for the cell. If it detects what’s happened, it promptly carries out cellular suicide to at least protect the rest of the body. But if this happens, your mission is ruined. You’ll lose the opportunity to force the cell to make viral particles. So what do you do? You may remember that one of the triggers for cellular suicide sits on the mitochondria. There are other proteins that can be used to fight viruses here, too, so it’s an obvious place for you to attack. You put a brake on the cell’s suicide trigger and can breathe a sigh of relief. That doesn’t mean you’re safe yet, though. The cell is well aware of what’s at stake, and has other weapons in its arsenal to deploy against you. If you want to succeed, you have to be quick. The cell is already making viral particles, but you’re a greedy little bastard. It should make more, and it should do it fast. So what can you do? You can step on the gas – for example, by mimicking growth signals. Usually, growth means that the cell has to make new cellular components. But if you promote growth now, the extra resources will just be used to make more viral particles. Perfect. All that activity takes energy, though, so you have to be sure that the cell’s power plants supply enough. You manipulate the mitochondria some more. By now, the cell is well aware that something is wrong, and it has activated all its stress signals. As you know, stress can trigger autophagy, and infection is no exception. The cell’s garbage collectors defend against viruses by collecting viral particles and destroying them. But that’s no problem – you just inhibit autophagy so they can’t harm you. Gradually, the cell grows desperate. It frantically calls for help from the immune system and tries to warn other nearby cells so they can prepare for virus infection in advance. If the immune system’s specialised virus killers find the infected cell, they’ll promptly destroy it. And in general, you’re just not very fond of these guys. Some immune cells, B-cells, make antibodies, for instance. And antibodies can bind and neutralise specific viruses once an infection is discovered. So in collaboration with your relatives in other infected cells, you take on the immune system, doing everything in your power to deceive it and fight back. As long as that strategy is working, you can continue making more viral particles. Eventually, you’ll have produced so many that the cell is completely crammed. Then it’s time to move on. You give the cell the death blow by bursting it, so that all the virus particles are released into the infinite ocean in search of the next victim.
Pretty dire, isn’t it? Fortunately, no viruses possess all these weapons. But just in that little review, we encountered mitochondria, growth signalling, cellular suicide, autophagy, and the immune system. That’s a lot of the ageing-related areas we’ve discussed so far. But in fact the list of ways viruses can impact ageing is even longer. For example:
In short, microbes don’t just increase the risk of age-related disease, they also influence all the things we know play a role in ageing itself. That makes them an even more obvious target for us.