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If You’re Getting Old, You Can Blame Klotho

An Ancient Greek goddess plays an important role in ageing, but beware the hype around its omnipotence

There is no shortage of stories professing the existence of a Fountain of Youth somewhere in the world, always just out of reach. Bathing in its water was claimed to undo the damage of old age. Nowadays, if we are to listen to the hype emanating from the scientific literature, it seems the Fountain of Youth was inside of us all along.

Its name is klotho, which makes it sound like a third-rate Marvel comic book villain. But klotho is not an extradimensional supervillain clothed in purple; it is the name of a protein our bodies make and it plays an important role in ageing. If you Google “klotho,” one of the common searches that will be suggested to you is “how to increase klotho naturally.” Because if scientists discover something that taps into our anxieties, you can bet someone out there will turn it into a product, service, or natural lifestyle intervention in the name of wellness.

Tom and Jerry-atric

It happened by accident, as so many scientific discoveries do.

A team of researchers in Japan in the 1990s were introducing a gene into mice. This may sound like a strange thing to do, but transgenic mice have been around in earnest since the 1980s and are very useful. Mice have their own set of genes that code for the proteins that will make and sustain a mouse, much like we have our own genes that make us human. (Importantly, though, we share the vast majority of our genes with mice, so we are not that dissimilar.) With a transgenic mouse, a foreign gene is introduced into the cells of mice. It can be used to study a human disease in mice, for example. But in the 1990s, the technique for introducing these transgenes was somewhat crude. While the Japanese scientists were studying hypertension in mice by introducing a gene that coded for a molecule involved in heart failure, something happened. One of these mice started to behave like an old person.

The mouse was nicknamed klotho. In Greek mythology, Klotho (often spelled Clotho in English) was one of three goddesses referred to as the Fates. Klotho would spin the thread of life; Lachesis would measure it out; and Atropos would cut it. They were the divine manifestation of destiny. The klotho mouse developed normally for a couple of weeks. But then it seemed to be hit by an ageing spell. It developed an abnormal walking pattern reminiscent of how humans with Parkinson’s disease move around. Its genitalia atrophied. Its aorta, the main blood vessel coming out of the heart, began to calcify extensively. Its bone and hair density both diminished and it developed emphysema. The scientists were able to reproduce these findings in other mice. Normal laboratory mice tend to survive for a couple of years at least. These mice died on average after two months.

The cause of this premature ageing was not the gene they had received but where that gene had inserted itself. If a transgene integrates in the middle of an important gene in the mouse’s genome, it will disrupt this gene, much like a highway is suddenly rendered unusable thanks to a roadblock. In this case, the transgene had disrupted a mouse gene which the researchers decided to call klotho. (Gene names are italicized, whereas those of their protein products are not.) When the scientists would neutralize klotho’s expression in mice, the animals would develop premature ageing. When they would overexpress it, the mice would live longer. Even though the klotho gene was silent in most organs of the mouse and only made the klotho protein in a few anatomical sites, the physical changes to the mouse were all-encompassing, which made the scientists think that klotho might behave like a hormone, circulating from tissue to tissue as a molecular messenger. And the scientists found that we too had a klotho gene: it is 85% identical to the mouse version.

The main klotho protein (sometimes referred to as alpha-klotho) exists in the body in three known forms. You can think of the first form as a flower. Our cells have membranes, and many proteins stick out from them like flowers growing out of the soil. This is the “transmembrane” form of klotho. It is planted at the surface of a cell and isn’t going anywhere. But sometimes, this transmembrane protein gets cut, and like a broken flower during a heavy rainfall, it gets washed away and starts circulating around. This is the ”soluble” form of klotho. Finally, through a common trick known as alternative splicing, the RNA transcribed from the klotho gene can end up making a much shorter protein that can’t grow out of the cell like a flower but that is free to circulate in the blood. This is the “shed” form of klotho. It is still unclear what changes in the body can alter the pace at which klotho is shed into circulation.

The klotho protein is predominantly made in parts of the kidney and in a network of vessels in the brain known as the choroid plexus. But because the shed and soluble forms of klotho can travel around the body, klotho is said to have pleiotropic effects, which is when a single gene influences more than one observable trait. An insufficiency of the klotho protein has been associated with kidney problems, cardiovascular disease, cancer, neurological issues like cognitive deficits and Alzheimer’s disease, as well as lung, bone, and metabolic problems, like osteoporosis and diabetes. That does not make klotho the cause of these varied diseases, though; its low levels have simply been found at those metaphorical crime scenes, like those of so many other molecules.

What I’ve presented so far evokes a fairly simple narrative. Klotho is a sort of master controller of ageing and its related diseases. Dial it down and the years will catch up to you. Dial it up and you’ll live forever.

Would that it were so simple.

Challenges as old as dirt

When hearing about the latest research findings on blogs or podcasts, it’s easy to miss the forest for the trees and become fascinated by a single molecule that appears to be the key to an important facet of health. In truth, our bodies are teeming with molecules, and a process as complex as ageing is governed by many more molecules than just klotho, and these types of processes have many redundancies and buffers as well. Klotho interacts with a fair number of molecules but is not the only one to do so. In short, the human body at the molecular level looks more like a beehive than a single drone doing all the work.

But even when we focus on klotho and the role it plays in ageing, we rub against a common problem in biomedical research: what we’re using to look for klotho is not all that reliable. Antibodies are commonly used to detect a protein in the lab. The antibody is supposed to recognize a protein of interest (and only that protein). Once it is bound to it, it will be bound to by a second antibody that carries something visible or detectable, like a colour pigment or a fluorescent molecule. The issue is that many commercially available antibodies meant to be specific for one protein are revealed not to be, and tests done using an antibody from company A often do not match the same tests done using a similar antibody from company B, and antibodies sold for klotho detection have not escaped from this problem. Therefore, some of the knowledge we’ve acquired about where klotho is in the body and what happens to its levels in this or that condition may not be correct. More rigour is needed to vet the very tools used to study klotho.

That hurdle hasn’t stopped scientists from speculating about and, in some cases, testing actual therapies that involve increasing the levels of klotho in the body, often in laboratory animals. Here too, however, we face challenges. Simply ingesting the protein wouldn’t work, as our digestive enzymes would chop it up into its building blocks, to be used to assemble different proteins in our body. Injecting people with the protein would be of no value in trying to reach the brain, for example, because klotho is so big, it is not thought to be able to move through the blood-brain barrier, a sort of anatomical border control that limits which molecules and microorganisms can enter the brain and potentially harm it. Scientists are thus experimenting with gene therapy and with small molecules that can increase the natural production of klotho protein in the body.

Of course, some claim that this increase can be triggered by eating the right food or consuming the right dietary supplement. Studies done in rodents have been published claiming that the red pigment astaxanthin, the flavone baicalin, the fungus extract cordycepin, the molecule curcumin present in turmeric, the ginseng root, the plant compound lingustilide also known as dong quai, the venerated resveratrol from red wine, and a chemical found in a medicinal herb and referred to as tetrahydroxystilbene glucoside all increase the production of klotho in the body. It may be true to an extent (if the studies are competently done), but that doesn’t mean that regularly drinking red wine will let you live forever and protect you from disease (quite the opposite, actually). A single ingredient can temporarily increase the production of many proteins and decrease the production of many more. It’s always more complicated than it looks.

But one free way of increasing klotho seems to be to exercise. A dozen studies have reported that the concentration of klotho protein in the blood goes up by a significant amount after exercising regularly for at least three months. This marks klotho as a target of interest in the race to find an exercise pill. Some people end up bed bound for long periods of time, because of a spinal cord injury or a coma, which can have a major negative impact on their cardiovascular system. Wouldn’t it be nice to give them a pill that mimics exercise? I’m sure there would also be a profitable market outside of hospitals. Who wouldn’t want the benefits of exercising without leaving the couch?

Klotho is thus a very interesting protein. Exactly what it does as we get older remains to be fully elucidated, yet zooming out of this particular area of research, one thing does remain true: exercising is the closest thing to a Fountain of Youth we have yet to find. And you don’t have to travel the world to access it.

Take-home message:
- Klotho is a gene that makes a protein that is involved in slowing down ageing and which has been implicated in a number of diseases
- However, klotho is only one of many molecules involved in ageing and age-related diseases, and much of the information scientists have gathered about klotho depends on antibodies which have often been shown not to be specific to klotho


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