The likely first longevity drug is based on sketchy science. This is bad for science and bad for longevity.

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.

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?

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.

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.

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:

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!

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.

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?

I'm no expert, but I think there's interest in IGF-1 inhibitors for longevity. To quote Sarah Constantin:

There’s a _lot _of evidence that the IGF/insulin signaling/growth hormone metabolic pathway is associated with aging and short lifespan, and that inhibiting genes on that pathway results in longer lifespan. IGF-receptor-inhibiting or growth-hormone-inhibiting drugs could be studied for longevity, but haven’t yet.

I would guess this is one of the reasons Loyal had an interest in IGF-1 inhibitors from the outset.

IGF-1 inhibitors can cause low levels of blood platelets, elevated liver enzymes, and hyperglycemia

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.

Some Manifold markets: 

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?

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.

Why are you nervous to predict the drug doesn't work? Your take seems reasonable and opinion isn't liable so?

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.

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?

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.

Wouldn't lowering igf-1 also lead to really shity quality of life from lower muscle mass and much longer recovery times from injury?

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.

FYI there is a long history of the study of IGF in aging. EG see here or here.

The LessWrong Review [? · GW] runs every year to select the posts that have most stood the test of time. This post is not yet eligible for review, but will be at the end of 2024. The top fifty or so posts are featured prominently on the site throughout the year.

Hopefully, the review is better than karma at judging enduring value. If we have accurate prediction markets on the review results, maybe we can have better incentives on LessWrong today. Will this post make the top fifty?

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).