The likely first longevity drug is based on sketchy science. This is bad for science and bad for longevity.
If you are interested in the longevity scene, like I am, you probably have seen press releases about the dog longevity company, Loyal for Dogs, getting a nod for efficacy from the FDA. These have come in the form of the New York Post calling the drug “groundbreaking”, Science Alert calling the drug “radical”, and the more sedate New York Times just asking, “Could Longevity Drugs for Dogs Extend Your Pet’s Life?”, presumably unaware of Betteridge’s Law of Headlines. You may have also seen the coordinated Twitter offensive of people losing their shit about this, including their lead investor, Laura Deming, saying that she “broke down crying when she got the call”.
And if you have been following Loyal for Dogs for a while, like I have, you are probably puzzled by this news. Loyal for Dogs has been around since 2021. Unlike any other drug company or longevity company, they have released almost zero information (including zero publications) about their strategy for longevity. It’s surprising, to say the least, to see a company go from zero information to efficacy nod, because, well, what are you basing your efficacy on? How did you recruit your patients and veterinary partners to help you with efficacy? Did you make them all sign some incredibly airtight NDAs? If so, why?
These thoughts swirling around my head, I waded through the press releases trumpeting the end of dog death as we know it in order to figure out what exactly Loyal is doing for dog longevity. And, what I found first surprised me, then saddened me. Loyal did not prove efficacy in dog longevity. They found a path around the FDA instead. That’s the surprising part. The sad part is that, in doing so, they relied on some really sketchy science. And I think that, based on their trajectory, they won’t just be the first company to get a drug approved for longevity. They will be the first one to get a longevity drug pulled for non-efficacy as well, and put the field back years.
So let’s start with how they got their drug approved in the first place. Well, they didn’t. To get drugs approved in animals, you need to prove three things: efficacy, safety, and manufacturing consistency. Normally, efficacy is the hardest part of this, because you have to prove to the FDA that your drug cures the disease that it’s supposed to. This is especially hard in aging, because any aging trial would take a long time. Loyal found a way around that. If you can instead prove to the FDA that it would be too difficult to test your animal drug for efficacy before releasing it, they allow you to sell the drug first, and prove the efficacy later. This is a standard called “reasonable expectation of effectiveness”.
So, what exactly did Loyal show to the FDA to prove that there was a reasonable expectation their drug would be effective in aging? Well, it’s hard to tell, because, again, Loyal has released very little data. But, based on the NYT article and their blog post, I can sketch out a basic idea of what they did.
Loyal’s longevity drug is an injectable insulin-like growth factor 1, or IGF-1, inhibitor. As the name suggests, IGF-1 is closely related to insulin and is regulated by insulin. Also as the name suggests, IGF-1 causes things to grow. High IGF-1 causes acromegaly, the condition that makes people look like storybook giants.
Loyal gave their IGF-1 inhibitor to healthy laboratory dogs (and possibly diabetic dogs, although it’s hard to tell). Lo and behold, it lowered IGF-1. It probably also reduced insulin. They then looked at healthy pet dogs, and found that big dogs had higher levels of IGF-1, which is one of the reasons they’re big. Small dogs had lower levels of IGF-1. Small dogs, as we all know, live longer than big dogs. Therefore, Loyal said, our IGF-1 inhibitor will extend the life of dogs.
Needless to say, this is bad science. Really bad science. There are holes big enough in this to walk a Great Dane through, which I’ll talk about in a sec. Apparently, though, this reasoning was good enough for the FDA. So, Loyal got their “reasonable expectation of effectiveness” nod. Cue fanfare and crying and me being surprised.
Ok, so that’s how they did it. But...why did they do it? No wait, that’s an easy one. Money. Sorry. Ok, better question: should we believe them?
No! God, no. Their reasoning is terrible! Correlation does not equal causation! Just because small dogs have lower levels of IGF-1 and live longer does not mean that lower levels of IGF-1 cause dogs to live longer! And, even if they did, there’s no reason to believe that lowering levels of IGF-1 would reverse any of the “damage” caused by high levels of IGF-1! The big dogs will still be big!
And, actually we can even go further than that. Not only is Loyal’s reasoning wrong, their facts are wrong as well. Let’s look at some of the claims in their blog post, shall we?
They say
“In large- and giant-breed dogs, breeding for size caused these dogs to have highly elevated levels of IGF-1, a hormone that drives cell growth. High IGF-1 effectively drives these dogs to grow large when they’re young, but high IGF-1 levels in adult dogs are believed to accelerate their aging and reduce their healthy lifespan.” Then they put this “figure”.
This figure, although attractive, is misleading at best. IGF-1 contributes to body size in dogs, but it’s not a straightforward relationship. Like, look at this figure from Connecting serum IGF-1, body size, and age in the domestic dog (2011).
This is, granted, a less attractive graph than Loyal’s. Theirs has cute little figures of dogs and this one just has black squares. But, this is way more recent and based on 88 dogs. Their references, which I can’t find (and they didn’t even provide proper citations for), are from 1984 and 1998, and based on an unclear number of dogs. I am more inclined to trust this graph.
And what does it say? Well, that IGF-1 levels do tend to go up with increasing bodyweight, but it’s not a straightforward relationship. Among dogs with bodyweight around the 20-30 pound mark, it looks like IGF-1 levels can vary from 20-ish to close to 300 ng/mL. Now, could I cherry pick and find a small dog with a low level of IGF-1 and a big dog with a high level of IGF-1 and say “big dogs have up to 28x the level of IGF-1 of small dogs”? Yes, I could. But that would be incredibly misleading.
Meanwhile, if we look at the exact same paper, we also get this data on the relationship between IGF-1 and age in dogs.
Hm...let’s see what we think of the idea that low levels of IGF-1 are associated with longer lifespans. Well, based on the fact that there are plenty of 12+ year old dogs with IGF-1 levels at the 100+ ng/mL mark, I’d say that relationship also seems pretty weak. I mean, sure, the highest levels of IGF-1 are in puppies, but the 4th highest IGF-1 level is in a dog that’s over 16, and the 5th highest is in a dog that’s like 12.5.
So, not only should Loyal definitely not say that “high IGF-1 levels accelerate dog’s aging”, but they shouldn’t even really say that they’re strongly associated with them. It’s a weak correlation at best (r=.0677).
I hope you now see why I think this longevity drug ironically doesn’t have long to live. There’s no way, given the data, that this drug will cause dogs to live longer. It may, however, cause dangerous side effects in dogs. IGF-1 inhibitors do in humans (oh, did I forget to mention that IGF-1 inhibitors have existed for humans for decades, and they have zero evidence of being longevity drugs? My bad. Now I have). IGF-1 inhibitors can cause low levels of blood platelets, elevated liver enzymes, and hyperglycemia. Hopefully, if this drug does cause harmful effects in dogs, it will be caught in the safety trials and the drug won’t be released.
But, even if the drug is safe, it will be a waste of time and a waste of money for dog owners to give it to their pets. This drug should have never made it this far, and, if it does get actually approved, it’s going to spectacularly fail its actual efficacy trials and bring a lot of legitimate longevity companies down with it.
And, for the record, I know I’m not the only one that thinks this. I’ve had multiple conversations with other aging-adjacent people who also think this. But nobody is willing to stick out their neck and actually call Loyal out. I mean, hell, I’m writing this anonymously and I’m still a little nervous. But, I’ll say it here and now: the dog emperor has no clothes.
Note: I’m not affiliated with Loyal or any other longevity organization, I’m going off the same outside information as the author.
I think there’s a substantial chance that this criticism is misguided. A couple points:
The term “efficacy nod” is a little confusing, the FDA term is “reasonable expectation of effectiveness”, which makes more sense to me, it sounds like the drug has enough promise that the FDA thinks its worth continuing testing. They may not have actual effectiveness data yet, just evidence that it’s safe and a reasonable explanation for why it might work.
I don’t know what the standard practices are for releasing trial data, especially for an initial trial like this. Are we sure this isn’t standard practice? Even if it isn’t, I don’t think this is sufficient to assume that Loyal is being disingenuous.
Take the outside view here, both Loyal and the FDA have veterinarians who seem to think that the drug is promising.
I also think there’s a reasonable argument to be made for an IGF-1 inhibitor in large-breed dogs. Large breed dogs often die of heart disease which is often due to dilated cardiomyopathy (heart becomes enlarged and can’t pump blood effectively). This enlargement can come from hypertrophic cardiomyopathy (overgrowth of the heart muscle). I don’t know if it’s known why large breed dogs have hypertrophic cardiomyopathy, but maybe IGF-1 makes the heart muscle grow over a dog’s lifetime which would suggest that an IGF-1 inhibitor is worth trying. It’s also suggestive that diabetes is a risk-factor for cardiomegaly (enlarged heart).
With this in mind, we can answer the next point:
So my theory says that high IGF-1 over a lifetime progressively increases the size of the heart muscle until you get dilated cardiomyopathy. Stopping IGF-1 even in middle age might help. We can falsify this theory by checking if large breed dogs show heart enlargement over their lifetime (instead of growth stopping after puberty like it should). Why would heart muscle keep growing while nothing else does? I’m not sure.
Now we can turn to the question: do large breed dogs actually have elevated IGF-1?
Looking at your first figure, the answer seems to be yes! There’s a straightforward correlation between bodyweight and IGF-1 concentration, the slope would likely be higher without the 3 outliers on the right. Notice also that the sample doesn’t have many large breed dogs (great danes weigh 110-180 lbs). I would guess that those 3 dogs are large breed dogs, and they do in fact have IGF-1 levels higher than most of the dogs in the sample.
Now lets turn to the second plot, we see that IGF-1 concentration decreases with age. Remember that there is survivorship bias at higher ages, large breed dogs with higher IGF-1 will die at around 72 months while chihuahuas will live over 150 months. Declining IGF-1 with age is exactly what we should see if we expected IGF-1 to correlate with longevity! The plot supports the theory that IGF-1 is important for aging, you can’t cherry-pick outliers and ignore the overall relationship in the plot.
I’m no expert, but I think there’s interest in IGF-1 inhibitors for longevity. To quote Sarah Constantin:
I would guess this is one of the reasons Loyal had an interest in IGF-1 inhibitors from the outset.
The dose makes the poison! Every drug has negative effects at a high enough dose, the trials will determine if these actually arise at the dose they are using.
I’m no expert, but this evidence doesn’t seem sufficient to stop research on this drug. Will it prove safe or effective? Will it also benefit human health? I have no idea, but unless we discover that the drug is hurting patients, I think its fine for Loyal to carry on.
Dilated cardiomyopathy and hypertrophic cardiomyopathy are two different conditions that I’ve not seen co-occur. They are basically sign-flipped versions of each other.
Dilated cardiomyopathy is when heart tissue becomes weaker and thinner. It stretches out like an overfilled balloon, and can’t beat with the same strength. Symptoms include tiredness, shortness of breath, in severe cases progressing into inability to circulate blood (heart failure).
Hypertrophic cardiomyopathy is when the heart tissue becomes stronger and thicker. The inner heart space becomes too narrow and can cause a heart valve to get stuck in the “closed” position, stopping the outflow of blood. This type of cardiomyopathy often stays asymptomatic and undiagnosed by routine checkups, until one day a young athletic person presents with a symptom of “sudden cardiac death”.
The only feature they both share in common that comes to mind is that the heart becomes larger on X-ray (Cardiomegaly).
Thanks for the clarification! Do you know if either condition is associated with abnormal levels of IGF-1 or other growth hormones?
That’s what I thought too, but the FDA’s website indicates that a company that gets conditional approval can sell a drug where they have adequately demonstrated safety but have not demonstrated efficacy. The company can then sell this provisionally approved drug for 4.5 years after receiving conditional approval without having to demonstrate efficacy.
That said, conditionally approved drugs have to have a disclaimer on the packaging that says “Conditionally approved by FDA pending a full demonstration of effectiveness under application number XXX-XXX.”.
I personally don’t expect very high efficacy, and I do expect that Loyal will sell the drug for the next 4.5 years. However, as long as Loyal is clear about the nature of the approval of the drug, I think this is basically fine. People should be allowed to, at their own expense, give their pets experimental treatments that won’t hurt them and might help them. They should also be able to do the same for themselves, but that’s a fight for another day.
Agreed! Beyond potentially developing a drug, think Loyal’s strategy has the potential to change regulations around longevity drugs, raise profits for new trials, and bring attention/capital to the longevity space. I don’t see many downside risks here unless the drug turns out to be unsafe.
It can change regulations around longevity drugs in both directions. If the product gets brought by people and found ineffective, people will complain that the FDA was not stringent enough and the FDA has the motivation to be more stringent.
Are there examples of ineffective drugs leading to increased FDA stringency? I’m not as familiar with the history. For example, people agree that Aducanumab is ineffective, has that cause people to call for greater scrutiny? (genuinely asking, I haven’t followed this story much).
There are definitely examples of a drug being harmful that caused increased scrutiny. But unless we get new information that this drug is unsafe, that doesn’t seem to be the case here.
There was a congressional inquiry that then tasked the FDA to:
So the FDA was tasked to do more bureaucracy.
When it comes to this drug, the drug is approved as an animal drug which at the moment does not require clinical trials to be approved. If there’s a case of a lot of animal owners being dissatisfied with the FDA for allowing ineffective animal drugs, that does support a call to regulate animal drugs more like human drugs that require clinical trials to be marketed.
On the slight chance that it does end up improving life expectancy of big dogs prone to DCM because it reduces chances of death due to cardiomegaly, would this then be a cardiovascular drug and not a longevity drug? And are the endpoints anything related to cardiac health outcomes (EF/ heart size/others)?
An extension of the logic would be that all cardiac interventions are longevity interventions because heart diseases are the most common cause of death. That seems odd. Were COVID vaccines longevity interventions cz over time the restored the dip in average life span brought about by the pandemic? (This might just be me not understanding the distinctions around what makes a longevity drug in general; is the goal increasing life, increasing quality of life in later decades, or to reduce overall ageing process/wear and tear starting at a young point ie 40s in humans)
I agree that the difference between disease-treating interventions (that happen to extend life) versus longevity interventions is murky.
For example, would young people taking statins to prevent heart disease be a longevity intervention?
https://johnmandrola.substack.com/p/why-i-changed-my-mind-about-preventing
See this post arguing that rapamycin is not a longevity drug:
https://nintil.com/rapamycin-not-aging
Broadly, I’m not too concerned with what we classify a drug as as long as its safe, effective, well-understood, and gets approved by regulatory authorities.
Some Manifold markets:
I agree there’s something strange about Loyal’s strategy.
But it’s not like all aging researchers act like they back Loyal’s approach. Intervene Immune has been getting good biomarker results in human trials by taking nearly the opposite approach: raising IGF-1 levels for a while.
I wrote a longer discussion about IGF-1 and aging in my review of Morgan Levine’s book True Age.
This is a bit of a tangent, but is there a biological meaning to the term “longevity drug”? For a layman like me, my first guess is that it’d mean something like “A drug that mitigates the effects of aging and makes you live longer even if you don’t actively have a disease to treat.” But then I’d imagine that e.g. statins would be a “longevity drug” for middle-aged men with a strong family history of heart disease, in that it makes the relevant population less susceptible to an aging-related disease and thereby increases longevity, yet the posts talk about the prospect of creating the “first longevity drug” so clearly it’s being used in a way that doesn’t include statins. Is there a specific definition I’m ignorant of, or is it more of a loose marketing term for a particular subculture of researchers and funders, or what?
Good questions. “Senolytics” (which lyze senescent cells) come to mind as another class of such drugs. Perhaps the idea is that LOY-001 would be the first drug that is officially and explicitly identified as a longevity drug. Statins and senolytics have such a status only unofficially.
Why are you nervous to predict the drug doesn’t work? Your take seems reasonable and opinion isn’t liable so?
Just going off a hunch, mostly the asymmetry of risk and award?:
Award: Spread the gospel of probabilistic truth, personal intellectual growth potentially
Risk: retaliation (especially if the author is in the field), harassment, threats, law suits, wait… just more kinda of retaliation really. And potentially been seen as some one against the field of anti-aging despite an attempt at doing good science.
One side aspect of this is that the founder seemed to be the person who’s responsible for the campaign to get Aubrey de Grey out of SENS.
I think we should start with something smaller. Like rats, or smaller still.
Can you keep a cactus or flower alive forever? What about a bug? Starting small and then eventually being able to help larger animals and humans seem like an obvious choice here, but I’ve never heard about somebody trying to extend the life of snails or simple plants before.
I’ve read enough about nootropics to know that biology is complicated and that you can’t just give X drugs because X correlates with Y and because Y is good.
It’s bad science. And yeah, there’s lots of money in promoting “healthy things” which aren’t actually healthy, and in strongly exaggerating positive effects and not warning about side-effects. In order to get other people to give you money or invest in your ideas, you often have to lie or exaggerate. This is a fundemental problem of society, if not just how things work.
I think there is extensive longevity research on smaller animals. For example, for fruit flies a cursory search turns up
Protocols to Study Aging in Drosophila
Ageing in Drosophila: The role of the insulin/Igf and TOR signalling network
On the developmental theory of ageing. I. Starvation resistance and longevity in Drosophila melanogaster in relation to pre-adult breeding conditions
Analysing variation in Drosophila aging across independent experimental studies: a meta-analysis of survival data
Cultural artifacts: a comparison of senescence in natural, laboratory-adapted and artificially selected lines of Drosophila melanogaster
Sex-specific effects of interventions that extend fly life span
Testing an ‘aging gene’ in long-lived Drosophila strains: increased longevity depends on sex and genetic background
I haven’t done a similar search for lab mice (Mus musculus), but I expect that such a search would turn up similar results.
I think moving on to dogs does make sense, but my uninformed inclination is to agree with OP that I’m not super hopeful about the efficacy of LOY-001. Although also I’d like to point out that this is a treatment for dogs, and so I think it’s good that the FDA is not being extremely strict when safety has been demonstrated and there’s a halfway plausible story of efficacy. Unless this causes a backlash against the FDA doing sensible things I guess.
Well, I see that there’s a lot of research, but it’s all quite minor, like allowing a specific species to live 10% longer by messing with a few genes. This is more or less rounding-errors in the grand quest for human immortality, at least from my birds-eye perspective. If we can’t make a simple insect or plant live forever, then I don’t think we understand death well enough to warrant experimenting with dogs and humans.
Ethically, it’s also better to experiment with very simple life-forms, and if we can’t make those live forever, then we have no hope with humans.
To begin with, death is fascinating in that things generally grow bigger and stronger and better, and then just suddenly start to degenerate despite still having all the resources which lead to growth. Logically speaking, death isn’t actually required in any sense, and yet it seems to happen in basically all forms of life ever discovered or created. More interestingly, it also seems to happen for things like countries, companies, products and communities, even as they change for the sake of “improvement”, so if some natural law was to limit the life-span of all things to some level of total internal activity (perhaps entropy?), we could prove immortality to be impossible.
This “activity” law seem to be true, you can probably make things live longer by decreasing the rate of metabolism, but the total amount of actions is the same, you’re just making them happen more slowly. So it’s likely that a lot of drugs can make us live longer, but that there’s a hidden cost (another post suggests that igf-01 could lead to slower recovery of injury, so perhaps the drug just makes one live ‘slower’ rather than ‘longer’). That said, life appear to have a optimal amount of resistance optimal for growth, both too little exercise and too much exercise will cause us to die faster.
Not to downplay the value or difficulty of more tedius and “safe” approaches to science. Immortality is obviously a very difficult topic.
I think using dogs for life extension research makes at least as much sense as raising pigs for food.
I think this is a function of “create a new instance of something” being an easier problem than “fix a broken instance of that thing”. If there are any types of damage that you can’t fix, you will accumulate those types of damage over time. Consider teeth—pretty simple to grow, but once they’re exposed to the world your body can’t repair them, so they’ll degrade over time.
Relatedly, I’m pretty bullish on the “grow a new copy of the things that are breaking down and replace the worn out ones with new ones” approach for those organs where it’s viable to do so. Unfortunately that does not include brains.
That makes sense! If it’s ‘cheaper’, then evolution will choose it. Thinking about it, I also think that we sometimes kill or replace parts of something so that the rest can live. If we have bad habits, then we need to kill said habits before they kill us.
I’ve long thought that adaptability is important to survival, and that inflexibility means death, but it makes sense that we haven’t evolved ways to heal all kind of damage, and that certain noise/damage/waste accumulate until we break.
Depending on what you meant by “we should start with” this comment might not apply.
I would think an interesting comparison to add to the argument’s in the OP (And, I thought it a good call out. Thanks.) might be looking at IGF-1 in naked mole-rats. They seem to have a good track record with respect to aging processes. If they don’t show the implied relation between IGF-1 and their good aging attribute then why expect that in dog, or cats, other pet animals (or farm animals) or humans?
What is “a good track record with respect to aging processes” referring to?
Very late response but that was just saying, from my cursory knowledge, that everyone seems to agree that naked mole-rats do not seem to display the same aging related problems other species do.
ChatGPT’s opinion on IGF-1 in naked mole rats:
I suspect that the answer for “what are they basing efficacy on” is “animal testing on dogs”, and that’s also why you’re not hearing them announce the specifics to the general public.
I mean … how else are you supposed to test a novel treatment for dogs? I don’t have a good sense for the space, but my prior is higher on silence-given-no-testing than silence-given-tests-on-the-eventual-target here. If they had tests on dogs that showed significant results, I’d expect the headline/pitch/whatever to be “Double the remaining lifespan of your dog!” or something.
I agree that that’s the only realistic way. That doesn’t mean I expect it to be popular or something Loyal wants to draw attention to.
Wouldn’t lowering igf-1 also lead to really shity quality of life from lower muscle mass and much longer recovery times from injury?
My first thought as well. IGF-1 exists for a reason. Growth is universally necessary for development, repair and function.
FYI there is a long history of the study of IGF in aging. EG see here or here.
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Another point of concern is the long-acting nature of Loyal’s drug which, I believe, is to be injected every 3 to 6 months. Long-acting effects mean potentially long-acting side effects (in a [healthy] patient population that can’t speak to report them).