The first thing you learn in a business class is the concept of product-market fit. Essentially, it's a measure of how well a product meets the demands of the customers it was designed for. In longevity biotech, customer demand is very clear - everybody ages. But as we already know, people either do not care or do not trust longevity extension efforts for a variety of reasons. Perhaps one of the ways to make people more interested in longevity extension, in general, is to first focus on longevity-adjacent problems that people actually recognize as such. One way to do that, of course, is to focus on age-associated diseases, such as cancer and Alzheimer’s. People absolutely care about those things and solving them would (a) extend the mean lifespan/healthspan and (b) potentially shine some light on the complexity of aging itself. This is where longevity biotech and classical biotech converge - given there are few regulatory shortcuts to tackle aging directly, most longevity biotech companies go into clinical development targeting age-associated diseases, with the hope of adapting their therapeutics for aging itself in the future. The caveat, of course, is that this is an inherently suboptimal strategy, but this is a topic for another post.
I believe there may be problems even more adjacent to the central thesis of longevity biotech than the ones many longevity biotech companies decide to tackle, and addressing such could make longevity biotech more favorable as a whole. In this series, I want to focus on current and emergent themes of research and development that I think have the highest chance of advancing further, and thus favorably shifting public opinion in favor of longevity biotech.
First contender - Longevity extension for pets
When I was 7 years old, my grandma bought me a budgie, whom I called Karlusha. He was rather shy and reluctant to talk, but nonetheless a sweet little parrot. I woke up one day in an unusually good mood, it was sunny outside (something quite rare in Russia) and I did not have to go to school for some reason. I instantly wanted to share this goodness with Karlusha, but when I lifted the veil of his cage, I saw him laying motionless on the bottom. The details of that day are incredibly vivid, I even remember the drawing I made in MS Paint to put it in his little parrot coffin. While Karlusha was with us for just 3 short years, the pain of losing him kept our family from having pets ever again.
Turns out that Russian weather is not conducive to parrot longevity, since Karlusha died of September cold exposure, while those greenbois are chilling outside in December in Barcelona
Fortunately, most people get much more time with their pets than I had with mine. The average lifespan of a budgie is between 5 to 8 years, but some parrots can live up to a hundred years of age. The most popular pets, dogs and cats, do not live much longer than budgies though. While there are statistical outliers, the average lifespan of dogs is between 10 to 13 years, very much dependent on the breed, while cats live on average 12 to 18 years. If you look into my Instagram feed, you will see that 90% of it is cats, and very often I see the anguish of owners dealing with their beloved cats nearing the end. People may have strong opinions about extending human longevity, but I have not heard anyone ever say that the lifespan and healthspan of their pets, or pets in general, should not be extended. Each year added to beloved Buddy’s or Puffball’s life is going to echo in people’s minds - longevity extension is not that bad!
Research
The effort has also considerable practical considerations for longevity research as a whole. First of all, while nematodes, mice and other poor critters aging and dying in the name of science bring value, pets experience aging in similar ways to us - they live in the same environments, experience similar eating habits, and are much more genetically heterogenous than lab animals. Sorry, critters. Secondly, and this is more true for dogs, there are correlations between breeds and lifespan, studying which may shine more light on the genetic component of aging.
Not surprisingly, there is a growing field of adapting our knowledge of longevity extension to pets (almost exclusively dogs). The first thing that comes to mind is of course the Dog Aging Project, spearheaded by professors Matt Kaeberlein and Daniel Promislow. The Project is a large observational study (n= ~40000) looking into aging dynamics in dogs owned by people. A subset of the Project’s participants will be enrolled in a clinical trial (TRIAD) testing rapamycin, with the magnitude of lifespan extension being the primary endpoint - as of April, 85 dogs have been enrolled in the trial. While the TRIAD trial hasn’t produced any results yet, the Project itself has published a number of papers, showing, for instance, a significant inverse relationship between physical activity and canine cognitive dysfunction (aka dog Alzheimer’s), that dogs who were fed only once a day were generally healthier and most importantly, that rapamycin did not cause adverse effects in dogs and led to a trend of improvement in cardiac functions. Several other research initiatives that study longevity in dogs, namely Vaika and Darwin’s Ark, merit attention - successes will undoubtedly lead to a wider acceptance of the longevity narrative and spark the market fire.
Since writing this, news came that NIA is pulling the Dog Aging Project’s funding, which is frustrating and infuriating, to put it mildly. Petitions do work in the West, so I urge you to sign one to save the DAP. See Professor Kaeberlein’s Xeet on how to help here - spread the word
Startups
It is not like the markets don’t have some tinder - a number of startups are up for the challenge already. The most well-known is of course Loyal, who are developing a pipeline of enigmatic therapeutics, LOY-001 and LOY-002. LOY-001 is purported to “target a cellular mechanism that is hypothesized to cause large and giant breed dogs to age faster” and is administered once every 3-6 months, while LOY-002 is intended to extend lifespan in older dogs across most sizes and comes in a daily pill format. While no one knows for sure, and the company has been rather secretive about its targets, the best hypothesis in my opinion is that LOY-001 is some sort of long-acting IGF-1 inhibitor. Since it was found previously that a certain IGF-1 allele is a major determinant of small size in dogs, and given how this Wired piece described Loyal’s CEO, Celine Halioua, a-ha moment for creating the company, I think this is a very compelling hypothesis. IGF-1 is coincidentally a major driver of anabolism and thus aging, mice with GH/IGF-1 axis knockouts, such as the famous Ames dwarf mice have been found to live longer (but shittier) lives. LOY-002 can be just about anything, but many speculate it is a rapamycin or metformin analog.
Overall, this essay could end right here - I wrote this draft (May 2023), and since then Loyal came back with breathtaking news that the FDA has accepted the Reasonable Expectation of Effectiveness section of Loyal’s conditional approval application for LOY-001, effectively making it the first therapy in existence being lined up for clinical trials testing longevity as a primary endpoint. Without a doubt, this is the biggest achievement in the field since its inception and creates a very exciting precedent for animal and human longevity biotech companies alike. The media response has also been very positive. With that said, I think it’s safe to say that it’s even more beneficial to explore other companies building in the space.
Gene therapy companies, namely Genflow Biosciences and Rejuvenate Bio, that aim to overexpress certain longevity-related genes have animal therapeutics in their pipeline. Genflow Biosciences (LSE:GENF) are developing an AAV-based gene therapy delivering a SIRT6 variant found in centenarians, which is expected to enter Phase I trials in humans ‘soon’, with a comparable dog SIRT6 version for the canine program, which is in preclinical stage currently. Coincidentally, my Master’s research was centered around SIRT6 (albeit knockout), so I have bias hopes for their approach. At the same time, AAV-based delivery for a transient (its cDNA) therapy such as this one may not be the best course of action due to mounting immunity. I wish they were focusing on dogs first too, since it seems to me that the period during which the therapy would be effective before immunity sets in could move the needle more significantly in dogs due to their shorter overall lifespan, but that’s just a thought.
Rejuvenate Bio’s approach is based on transient expression of FGF21, TGFβ1 and αKlotho, all known for their roles in aging, with three different combinations (with no information on RJB-03 nature) being currently tested in preclinical experiments against a number of age-associated diseases in humans. In dogs, the company has launched pilot trials of RJB-01 (FGF21+TGFβ1) in mitral valve disease and obesity/diabetes, and have programs for kidney failure, osteoarthritis and even epigenetic reprogramming in earlier stages. While I personally think it may be risky to have such a number of programs at this stage in terms of resource allocation, and having in mind the same concerns on AAVs, I think that having a combinatorial approach, as compared to using just one gene, may have considerably more chances of success. Eager to see their pilot trial results.
There are a few other companies developing specific therapeutics against age-associated diseases in companion animals, and even more companies derailing the anti-aging supplement hype train on our beloved pets - for instance, a company associated with David Sinclair, Animal Bioscience, has recently launched the LeapYears, a supplement for dogs that incorporates an NAD+ booster (are you surprised?) and some senolytic (quercetin?). David Sinclair famously mentioned that he was giving his dogs NMN in his book Lifespan, so it was only natural that this was going to happen. Since Prof. Sinclair is good at identifying and/or creating the hypest of the hype, I think it is a good sign overall for the field of longevity extension in companion animals.
Finally, since this piece was initially written, a novel company announced its existence - Epiterna. While not much is known about the company, its mission is “to translate these discoveries into longer, healthier and happier lives – for companion dogs and cats, and for people”. The is founded and led by the epigenetic reprogramming mastodon Alejandro Ocampo, so the hopes are high here. In a recent reply, Alejandro shared the following information:
Pretty excited about the intersection between animal longevity and HTS. I’m also excited to see them operating out of Europe - if the piss-reeking streets of Gracia in Barcelona taught me anything, it’s that Europeans freaking love their dogs :D
Markets
Aside from the fact that pet parents would do anything to extend the lifespan of their lovely pet, it is worth noting that the pet market itself is expanding. It is thought that this expansion is primarily driven by Millennials not committing to kids and the COVID-19 pandemic - people got themselves a dog to be able to leave their home cell, or go themselves a cat to keep them company. In the US, the percentage of households with dogs increased from 38.4% to 44.5% between 2016 and 2022, while the percentage of households with cats increased from 25% to 29% in the same period (source). In Europe, the pet market compound annual growth rate has doubled during COVID times, while in Asian countries the trend is even more pronounced. Google Trends corroborates this thesis:
Conversely, since the proportion increased dramatically in 2020, we can expect to see a ‘Silver Petnami’ by the end of this decade, and the markets know this - most significantly, the pet oncology and pet insurance markets are expected to grow at 12% and 17% compound annual growth rate, respectively. The latter is particularly interesting - only about 2% of dogs have been insured in the US in 2017, but that number rose to more than 3% in 2021. That may not sound like a large increase, but keep in mind that the number of dogs rose about 30% in this period. With owners getting better educated on the positives of having pet insurance, this is poised to considerably grow in the next few years, and we all know how aligned insurance companies and longevity companies are. Don’t take it from me, take it from the investment arm of a global leader in insurance, Allianz. So in all, everything has aligned perfectly to allow pet longevity to dominate the longevity biotech narrative in the coming years
Potential emerging trends
Now that we’ve established that pet longevity is here to slay, what can founders-to-be start working on now? While there are many possibilities, I see the following extensions of the trend. First, as you may have noticed, there are no advanced interventions out there to extend cat longevity, which is surprising since cats are better are a more popular pet worldwide (despite being somewhat less numerous, 370 million cats vs 471 million dogs):
Cats also rule the Internet, so injecting the longevity narrative through cute cat content, all while extending their lifespan, could be pivotal for the field. Cats are probably not targeted by longevity extension approaches currently since they generally live longer and don’t have the same genetic burdens as dogs that cause considerable disparities in the latter’s lifespans. However, that would make them an even closer aging model to humans - so if you, my dear reader, are looking to start a longevity company, this is a great niche to fill. Competitors are already aligning though - Epiterna and a nascent stealth company I know are working in this space, so better hurry.
Second, most pet longevity therapeutic development is happening in the US, with a smaller portion of startups arising in Europe. Given the aforementioned astronomic rise of pets in Asia, particularly in China and the emerging economies of Southeast Asia (Indonesia, Thailand and the Philippines), it could be useful to focus on those markets specifically. The chemical matter is the same everywhere, but the APAC market has its peculiarities, so being aligned with it from the beginning may give nascent companies a market (and potentially regulatory) advantage. Generally, my gut feeling is that the Asian markets are more receptive to longevity therapeutics due to a culture that respects preventive approaches and longevity, but that is a topic for another post…
Finally, a trend that I envision to be a logical continuation of the pet longevity thesis is larger companion pet (i.e. horse) and livestock longevity extension. While some companies like Gordian are working on horse models of disease, longevity extension itself in horses and livestock is potentially a very lucrative business. With cars killing the layman horse industry for good in the early 20th century, horses are now akin to living supercars, though their HORSEPOWER (lolol see what is did here) is lacking. Nonetheless, while an average horse costs somewhere between $1000 and $10000, some purebred race horses will cost you hundreds of thousands, potentially millions of dollars. However, the time span when horses are considered “productive” is about 15 years - as such, it could be a lucrative (yet niche) to extend this productivity span by a couple of years. The livestock market could be more lucrative - sheep are only useful for wool production for 6 years, egg-laying chickens are useful for about 3 years, milk cows for up to 4 years. Nonetheless, this sector probably does not have much translatability to humans, so should be pursued only by the passionate in both longevity and agrotech.
Conclusion
As I have shared in one of my previous posts, one of the main problems that the longevity field is experiencing is humanity’s collective denial of aging being something undesirable, and more effort should be put into making longevity extension ‘cool’. With that said, what better way could there be to convince people that healthspan and lifespan extension is not only desirable but also possible, than making our pets live longer while being cheaper and easier to get to the market?
Let’s make all dogs live as long as Bobi and extend our lifespans in the process.
Bobi, 1992-2023