The One to Unite Them All
In 2016, the Nobel Prize in Medicine was awarded to Japanese biologist Yoshinori Ohsumi. His contribution: research into something in our cells called ‘autophagy’. ‘Auto’ means ‘self’, and ‘phagy’ means ‘eating’ or ‘devouring’. So autophagy means ‘self-eating’. That might sound like some kind of horrible disease, but it is actually a vital process that keeps us healthy. You see, when cells ‘eat themselves’, they don’t just randomly gobble up stuff. Autophagy is used to specifically break down damaged cellular components, whether they are individual molecules or entire cellular ‘organs’ – what is called organelles.
You can consider autophagy as the cell’s garbage collection system. The cell uses small bubble-like structures (like garbage bags) to engulf damaged molecules or cellular components. Then it transports the ‘garbage bags’ to special organelles called lysosomes, which are like recycling stations. Lysosomes contain various enzymes that break down the cellular garbage into its building blocks. And afterwards, these building blocks can be released and reused for making new molecules.
This garbage/recycling system – and others like it – actually unites everything we have discussed so far. For one, autophagy is what awaits us at the bottom of our rabbit hole. We started at growth hormone being released from the pituitary gland. Upon reaching the liver, we learned that growth hormone promotes production of IGF-1. And when IGF-1 binds to cell receptors, it activates the protein complex mTOR. Now, to be fair, mTOR does a lot of things, many of which impact health. But the thing that is most obviously tied to ageing is that mTOR controls the cellular garbage collection system. Specifically, when mTOR is active, it blocks autophagy. And in turn, all the growth-promoting signals that activate mTOR do the same thing. So when rapamycin blocks mTOR, it essentially blocks the blocker, cancelling it out. This might sound a little confusing, but the bottom line is that blocking growth signals ends up activating autophagy. As a result, rapamycin only prolongs the life of laboratory organisms as long as autophagy is functional. If autophagy is broken, rapamycin stops working. So it really does seem like we have reached the end of this whole thing.
Besides all the stuff relating to growth, though, autophagy is also a vital part of hormesis. It’s important to remember that while damage can strengthen us in the long run, it is not the actual damage that is beneficial. For instance, right after you go for a run, you are weaker than you were before. And free radicals – the rampaging bull – are harmful. The reason they can make us stronger over time, is that our cells have the ability to repair and subsequently improve. The first step is exactly what autophagy does: collecting and disposing of damaged molecules. So autophagy is a key part of hormesis, too. If the cellular garbage collection system doesn’t function optimally, various forms of hormesis stop extending the lifespan of laboratory organisms.
Unfortunately, despite its importance to lifespan, autophagy slowly declines with age. For reasons not entirely understood, our cellular garbage collectors get lazy and bad at their job over time. This is one of the reasons cells tend to accumulate old and damaged proteins as they age. It was once believed old cells filled up with ‘cellular junk’ like this because they were more sensitive to damage than young cells. But actually, it’s just as important that old cells are simply bad at removing junk, making it accumulate. So should you and I try to increase autophagy in our cells? Studies in mice suggest so. When scientists artificially increase autophagy activity in mice, the mice get stronger and leaner, and ultimately, they also live longer. On the other hand, if autophagy is inhibited in mice, damaged molecules quickly accumulate, and the mice become weak and sickly.
(Scientists cannot make mice that completely lack autophagy, because this would prove lethal before the mice are even born.)
The fighting naked mole-rat
Naked mole-rats are much better than their close relatives, mice, at surviving stressors such as DNA-damaging chemicals, heavy metals or extreme heat. At the same time, the cells of naked mole-rats have considerably more autophagy activity than the cells of mice. Naked mole-rats also have higher activity in another cellular waste disposal system – the proteasome system – which specifically deals with breaking down damaged proteins. Similarly, other small yet long-lived mammals, bats, upregulate autophagy as they age. The increased activity among the cellular garbage collectors could be the reason bats and naked mole-rats live so much longer than other mammals of the same size.
When summer arrives, the population of my home town, Copenhagen, seems to triple. If you also live somewhere with dark and cold winters, you probably recognise the allure of the summer sun. Most of us enjoy some sunbathing, and some turn summers into a months-long quest for the perfect tan.
What actually happens when you sunbathe is that your skin is exposed to UV radiation and gets damaged by it. This initiates a cascade of signals inside your cells, which eventually makes them produce the pigment melanin to protect themselves.
Sunbathing is no problem in small doses – it might even be hormetic – but if you overdo it, your risk of skin cancer and wrinkles increases dramatically. Wouldn’t it be a lot easier if we didn’t have to risk skin cancer (and turning into a raisin) to get a tan? A clever way to do this would be to find another way to initiate the signal cascade normally induced by UV-damage. That is, fake the signal that eventually makes us produce melanin. If done right, your cells wouldn’t be able to tell the difference. They would just see the message: ‘Make more melanin,’ and they’d comply. Some scientists have actually already proven this strategy in the lab. They have succeeded in using a special molecule to kick-start melanin production in both mice and human skin samples. So maybe future sunscreen will not just be used to protect you from the sun – it might also be what makes you tan without the need to lie on a sunbed for hours.
You can imagine a similar strategy for autophagy. Right now, our best bet for activating autophagy is either blocking various growth signals or using hormesis. Both options come with potential side effects. And besides, despite all these efforts, your cellular garbage collectors will still get lazy as you age. What we need is another way to deliver the message ‘go clean up’. Perhaps we could even find ways to stimulate autophagy more strongly in old age than we can at present.
I’m happy to report that the first candidate for an autophagy booster has already been found, though we are still awaiting human trials. This compound reliably increases autophagy in cells, and when scientists add it to the drinking water of mice, they live longer than normal – even if the treatment starts later in life. The molecule in question is called spermidine. You can probably guess where it was originally discovered, but don’t worry. There are other sources of spermidine.
First, your cells actually produce spermidine and similar compounds themselves. However, our own spermidine production tends to decrease with age, just like autophagy does. And right now, we don’t know of any reliable way to reverse this.
Second, spermidine is also produced by some species of gut bacteria. However, once again, we don’t know how to influence this process. Other gut bacteria break down spermidine, and the whole thing is too complicated to mess with at present.
Fortunately, the third option – diet – is easier to influence. Spermidine is found in many foods, and studies even show that a higher spermidine intake is associated with a lower risk of death. If you want to increase your spermidine intake, the best bet is wheatgerm. Actually, spermidine cannot be made into a supplement, so even if you do see spermidine ‘supplements’, they will just be wheatgerm with extra spermidine content. Besides that, other spermidine-containing foods include soy beans, certain mushrooms, sunflower seeds, corn and cauliflower. If you’re more adventurous, you can also try eel liver, adzuki beans or durian fruit.