Immune Rejuvenation
In the ponds of Mozambique and Zimbabwe, there are tiny turquoise fish called killifish. To the untrained eye, they look like ordinary aquarium fish. But when it comes to research on ageing, they’re much more than that. Killifish are among the world’s shortest-lived vertebrates (animals with a backbone) and they only live a few weeks. This makes them well-suited for studies on ageing because researchers get their results quickly.
Like all other animals, the tiny killifish have microbiomes in their guts, whether they’d like to or not. Actually, many of the bacterial species in the guts of killifish are the same ones living in you and me, making killifish a good model organism for studying gut microbiomes, too. Thus, we arrive at the intersection of gut microbes and ageing.
You see, the ecosystem of the gut changes over time in killifish. As the fish age, they lose diversity in the number of species in the gut, so that a few types of bacteria become dominant while suppressing others. This is exactly the same thing that happens in humans. So scientists in Germany have set out to investigate how these age-related changes in gut bacteria impact ageing and lifespan. The researchers raised killifish until they reached middle-age, and then gave them a course of antibiotics to eradicate the bacteria in their guts. That alone was actually enough to help the fish live longer, but the researchers also wanted to know whether gut bacteria could be beneficial. So, after some of the middle-aged killifish had their gut bacteria wiped out, the scientists recolonised their guts with gut bacteria from young fish. This treatment extended the life of the killifish even further than the antibiotic treatment alone. It seems that certain gut bacteria can help keep us young. But of course, these are the very types of bacteria that we often lose as we age.
Now, I’m not recommending you start popping antibiotics like they’re candy. If you do that, you will probably eradicate beneficial bacteria and just improve the odds for harmful ones even more. We might one day have therapies to specifically target those gut bacteria that are causing trouble. But for now, it’s worth remembering that the German researchers also found gut bacteria that helped the killifish. If we want some of the same effect, it might be worth trying to support these fellows. The bacteria found to be life-extending by the killifish researchers were largely from species that subsist on dietary fibre. These guys are easy to support: just feed them more fibre. In return, they produce a compound called butyrate, which has several health-promoting effects. Among other things, butyrate interacts with the immune system, and it makes the cells lining the gut grip together more tightly. This is important because the intestinal system tends to get leaky as we age. This leakiness means that bacteria from the gut can enter the bloodstream, where they cause trouble – not necessarily because they’re doing anything, but because our immune system goes crazy. Our immune system reacts strongly to two bacterial molecules called lipopolysaccharide (LPS) and peptidoglycan. This reaction is helpful if the bacteria is part of some kind of acute infection, but if they’re just the result of a passive, low-level stream of microbes into the body, there’ll be constant immune activation, and that ends up being harmful.
In general, we see this kind of low-level activation of the immune system a lot in old people. One reason could be an increase in pathogens, but just like everything else in our bodies, the immune system also simply gets worse as we age.
The increased low-level activation of the immune system is called ‘chronic inflammation’, inflammation being what happens when the immune system is activated. You’ll recognise it as warmth, redness, pain and swelling. Not all of this inflammation seems to derive from activation against pathogens. In old people, there is something called ‘sterile inflammation’, meaning activation of the immune system against no particular enemy. This phenomenon is also called ‘inflamm-ageing’. The reason it becomes harmful is because our immune system is not particularly careful. It is evolved to fight infections that used to be life-or-death. So, like soldiers at war, the immune system can’t be too concerned about its home. If it manages to kill the bad guys but damages some tissue in the process, that’s okay. The alternative could be death.
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The final piece of the puzzle between microbes and ageing, then, is the immune system itself. We know it starts firing mistakenly in old age. We know it gets worse at fighting pathogens in old age. And we know that many of the genetic variants linked to ageing involve the immune system somehow. But in addition to all this, it seems that an aged immune system in itself promotes ageing. This is illustrated by some research from the University of Minnesota. Here, researchers have created mice in which the immune system ages prematurely. This has all the effects listed above, but it also promotes the ageing of various other organs. One reason is that old immune cells can turn into zombie cells, with all the damage that entails. Another is that an ageing and weak immune system fails to remove the other zombie cells that appear in various organs. So, one of the most obvious anti-ageing therapies is actually rejuvenating the immune system.
To achieve immune rejuvenation, researchers target an organ called the thymus. This little organ sits in the chest cavity and is used as a kind of nursery for T-cells – the generals of the immune system. T-cells are made in the bone marrow, but they travel to the thymus to mature. Here, they learn to distinguish self from non-self and finish their development. However, unfortunately, the thymus fares badly during ageing. It undergoes what is called ‘thymic involution’, where the little organ gradually shrinks and turns into fat. This means we gradually lose our ability to train the generals of the immune system. How fast the thymus diminishes varies between people, but it shrinks between one and three per cent annually in all adults. By the time we reach old age, there’s not much left at all.
The decline of the thymus is the number one reason our immune systems get weaker with age. If we could somehow rejuvenate it, it’s possible that the rejuvenated immune system would simply fix a lot of the problems we’ve been discussing in this book. The rejuvenated immune system would clear out zombie cells efficiently. It would be much better at fighting cancer. And it would certainly have no problems with some of the pathogens that haunt old people. Think about how influenza can be harmful in old age but is mostly unproblematic in youth, for instance. In support of this idea, Russian researchers have transplanted thymus tissue from young mice on to old mice. The experiment wasn’t particularly pleasant, because the researchers had to transplant the tissue on to the eyes of the poor mice. This is sometimes done because there is low immune activity in the eyes, and thus less risk of losing the graft. But the rather horrifying experiment proved the point, and the young thymus tissue extended the lifespan of the mice.
You probably don’t want to replicate the exact experimental set-up described above, but scientists are currently making strides in building ‘spare’ thymuses from stem cells. The idea is the same as the one we encountered in the section on stem cells – guide stem cells to become cells of the thymus, and then transplant them to people in need. There are proof-of-concept experiments where researchers have made new thymic tissue for mice, so young immune systems in old people might become a reality in the future.
Until then, we actually know at least one method that can potentially halt the decline of the thymus a little. Researchers have managed to partially regenerate the thymus in old mice by giving them zinc supplements. In a clinical trial, other researchers have proved that zinc supplements can also reduce the amount of infections in older people, so maybe the same thing is happening in humans.