Selling Klotho Gene Therapy For Longevity: Visionary Or Reckless?

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Soon, you will be able to buy a gene therapy that will instruct your cells to make klotho – an ‘anti-ageing’ protein that has been shown to extend lifespan and improve cognitive function in mice. To get it, though, you’ll have to travel oversees to bypass most countries medical regulations, since this therapy has not been clinically approved for use in humans. This therapy, sold by a company called Minicircle, promises to improve longevity and boost cognition. Is this a visionary attempt to fast track true anti-ageing therapies, evading the excessive red tape and outdated medical dogma, or is this a reckless venture that invites disaster? Let’s discuss this gene therapy, the evidence behind it, and the merits (or lack thereof) of selling unapproved treatments to those who want them.

Move Slowly And Try Not To Kill Anyone

It can sometimes be frustrating to observe the glacial pace at which new drugs are developed. We live in a world in which new technologies can potentially be conceived, prototyped and brought to market in less than a year. Meanwhile, drug development frequently takes a decade or longer, only to be abandoned in the final stages of testing when the drug in question fails to yield sufficient benefits in humans. However, this slow pace does have an important purpose. The former Facebook motto of ‘move fast and break things’ might pay off when you are breaking web infrastructure, but not when you’re breaking human lives. For this reason, there are many strict regulatory hoops a company must jump through before they are even allowed to test a new medicine in humans, let alone sell it in most countries.

It is always possible to argue that the pendulum has swung too far and that regulation is too risk-averse. There are situations in which the uncertain risk of allowing a drug to be used is outweighed by the certain risk of allowing a disease to progress. But how do we make this risk calculation for a drug that targets something like ageing? Unfortunately, there is currently no way to prove that a treatment slows ageing other than by following the recipients throughout life and confirming that they live longer and get age-related diseases later in life. This would take a long time, would be prohibitively expensive, and neither the benefits nor the long-term side effects might become apparent for decades. It’s more likely that the first successful anti-ageing therapies will emerge from trials for the prevention or treatment of specific age-related diseases in at-risk people, where the risk/reward calculation is much easier to make. Once the long-term safety profile of such a drug is established, its use may then widen to slowing ageing in healthy people.

Not everyone is willing to wait however long it takes for this to happen, however. In their view, ageing is an incurable disease with a 100% fatality rate, and they are willing to take to take a shot in the dark for a chance to delay this disease a little longer, or even a lot longer. That finally brings us to Minicircle, a company offering unapproved klotho gene therapy to anyone willing to travel to Panama, Honduras or the Bahamas, where regulation is more permissive. Minicircle describe this treatment as a ‘highly prized life-extension gene therapy known for its broad health and cognition benefits’. But what exactly is klotho gene therapy, and what is the evidence behind it? Moreover, what is the justification for rushing ahead to make this therapy available before proper regulatory approval?

Klotho: How Does It Work?

Klotho is an enzyme that appears to be implicated in human ageing. It’s named after Clotho who, in Greek mythology, spins the thread of human life. Klotho has three subfamilies: α-klotho, β-klotho, and γ-klotho. α-klotho is the main subfamily of interest when it comes to ageing, and from now on when we mention klotho, you can assume we are talking about α-klotho.

So, why do scientists believe klotho is important in ageing? Levels of this enzyme decline with age in humans, while higher levels of klotho in late life are associated with better health. This by itself doesn’t indicate that declining klotho causes ageing – thousands of proteins see their levels rise or fall throughout life and many of these changes are secondary effects of more fundamental processes driving ageing. However, experiments in mice suggested that klotho was different. Mice that are genetically engineered to have higher levels of klotho live longer and also have better cognitive function in old age, while mice lacking klotho show the reverse effect. In fact, even young mice given klotho appear to have better cognitive function, suggesting that klotho is doing more than just slowing cognitive ageing.

How is klotho doing this? This protein has several known mechanisms, and probably has undiscovered mechanisms as well. The lifespan extension appears to be partly related to klotho’s effect on signalling by the blood sugar lowering hormone insulin and insulin-like growth factor 1 (IGF-1), both of which are implicated in ageing. Klotho also helps regulate calcium and phosphate balance by controlling their absorption by the kidneys, and suppresses inflammation and oxidative stress throughout the body. In the brain, this protects neurons from toxicity. Klotho is also important for the maintenance of myelin (the protective sheath surrounding nerve fibres and that accelerates electrical impulses) and for synaptic plasticity (the remodelling of synaptic connections in the brain that forms the basis of learning). These are far from being klotho’s only proposed effects and mechanisms, and more continue to be uncovered.

Klotho: Does It Work?

So, animal evidence shows that klotho extends lifespan and improves cognition, and we have some idea of how it achieves this. What is the evidence that klotho has similar effects in humans? Well, there isn’t any – at least none that has been published. There is currently a clinical trial planned to test the effectiveness of klotho gene therapy in patients with motor neuron disease (also known as ALS). This trial is being conducted by a company called Klotho Neurosciences, and will use gene therapy to enhance the production of klotho by muscle tissue. The FDA granted this treatment ‘orphan drug designation’ last year (2025), which essentially means it would not ordinarily be profitable (due to the rarity of the targeted disease) and so may receive government funding. The preparations for this trial are expected to be finished towards the end of this year.

Minicircle’s Klotho Gene Therapy

This finally brings us to Minicircle, the Texas-based company that will soon be selling klotho gene therapy. The general principal of this therapy is similar to the aforementioned therapy for motor neuron disease, but targeting adipose tissue (fat) instead of muscle. Small circular DNA segments containing the gene that encodes klotho will be injected into abdominal fat. This DNA is then absorbed by fat cells, which will use it as an instruction book to manufacture klotho, turning the fat tissue into a ‘klotho factory’. This DNA doesn’t integrate into the human genome, but remains separate from the chromosomes in its circular form. This means the effects aren’t permanent – the circular DNA will eventually be broken down, with effects estimated to last about a year.

Now, Minicircle isn’t going into this completely blind. They are already using the same method to deliver a different gene therapy (follistatin gene therapy) and report that this is well-tolerated by recipients. They have also conducted a small clinical trial in 24 healthy volunteers in order to assess the safety and efficacy of klotho gene therapy. This was a ‘proof of concept’ study with no control group, and the results haven’t been published yet. It’s also important to mention that these studies were conducted in various regions outside the US where regulations are less strict. This includes Próspera, a special economic zone operating within Honduras that retains a degree of fiscal and legal autonomy from the national government. While Próspera does have rules governing how clinical trials are run, companies operating there opt in to these rules, with the option to take the path of weakest oversight. Minicircle’s previous gene therapy trials were given scientific and ethical approval by a review board that is part of the GARM clinic (Global Alliance for Regenerative Medicine). This is the clinic that actually administers Minicircle’s gene therapies. So, just to be clear, the scientific rigour of these clinical trials is being overseen by the in-house board of an organisation that profits monetarily should those clinical trials be successful.

So, to summarise, there is no published human data to suggest that klotho gene therapy is safe or effective. Even if Minicircle’s trial produces positive results, this is still far below the standard of evidence required to get a therapy cleared for sale in most countries. A trial of 24 individuals could easily miss a serious side effect that only occurred in, say, 1 in 30 recipients. So regardless of how good the results of this trial look, anyone who voluntarily receives this therapy is still very much putting themselves forward as a human guinea pig.

What Could Go Right?

If someone wants to fly to Honduras and pay for an unapproved gene therapy, why stop them? It’s not like Minicircle are marketing their therapy towards people with incurable diseases, taking advantage of their desperation and giving them false hope. These are healthy people who want to take a gamble – aren’t they doing the rest of us a service by offering themselves as test subjects?

There are a few issues with this line of thinking. Absolutists may argue that people should have the ultimate right to take any decision they like with their own health, even if it’s risky, but even those who hold this view would agree that the person needs to be fully informed of those risks. The problem here is that regulators don’t just exist to decide when an unproven treatment may or may not be tested in humans – they also exist to ensure that when trials do go ahead, recipients are sufficiently informed of the potential risks and benefits. Given the relaxed regulatory conditions under which this gene therapy is being administered, we are relying on those running the trial to apply the same standards that would be demanded of them if they were operating in, for example, the US or EU. Minicircle states that it adheres to rigorous safety protocols, including informed consent.

This brings us to another issue with the ‘willing guinea pig’ line of argument, which is data collection. Putting ethics aside for a moment, if the argument is that letting people test an unapproved therapy will advance science faster, we must keep in mind the fact that this is dependent on rigorous data collection, both during clinical trials and after a drug goes to market. Drugs that have gone through accelerated approval (and therefore don’t have as much clinical trial data as would be desired) usually require extensive post-market monitoring so that safety and efficacy data continues to improve. Given that this klotho gene therapy has not undergone the full series of clinical trials, close monitoring of recipients would be necessary. However, it isn’t entirely clear how much monitoring recipients will receive, given that most will be flying to an island to receive the therapy before returning to their respective countries. Diminished regulatory oversight is also a problem here – we are essentially relying on those conducting the trial to publish accurate data, when they are also the ones selling the expensive gene therapy. This is of course a potential conflict of interest, as there is a monetary incentive to avoid publishing negative data.

Even if things go well and a company does genuinely adhere to best ethical and data collection practices, it is hard not to be at least somewhat sceptical of results that are produced in a compromised regulatory environment. At best, success stories might accelerate progress somewhat, but regulators are still going to want to see clinical trial results before they would ever approve a gene therapy like this for sale to patients, let alone to healthy people. At worst, these practices risk stepping on the toes of those who try to do things by the book. A disastrous outcome in which participants died or developed serous health conditions could tarnish the name of klotho and the legitimate research associated with this protein. This would be a shame, as based on the animal data and mechanistic findings, klotho looks like it could have a great deal of potential for improving many aspects of human health.