Ozempic For Sleep

Thanks for key conversations & early feedback: Andrew Payne, Luke Piette, George Church, Michael Retchin, Flora Guo, Merrick Smela, Greta Tuckute, Misha Yagudin, Tyler Cowen, Helena Rosengarten.

This is favorite family in the world — the Johnsons from Utah.

Many of them carry a gene which allows them to only sleep 5 hours a night.[1] They're joining Mozart, Thomas Edison, Sigmund Freud, Margaret Thatcher, Barack Obama, and my lab colleague Yuki in having the Short Sleeper Syndrome.

Sequencing families like the Johnsons, researchers found that needing less sleep is usually caused by a few changes in single proteins:

• A less-stable version of an inhibitory adrenaline receptor (ADRB1: A187V);
• Variations in a glutamate receptor (GRM1: R889W or S458A)[3];
• A more active receptor of wakefulness-promoting neuropeptide S (NPSR1: Y206H)^[1];
• And most well-researched, a less-stable version of DEC2, which inhibits the wakefulness hormone orexin (Y362H or P385R).

Of course, there's uncertainty which of these could be how effective. Some of the DEC2 researchers have moved on. Fact remains that something makes ~1% of all people sleep less.

Here's the surprise: Sleep is fundamental to baseline function, happiness, productivity, health, and not being a zombie. Yet, these specific sleeplessness mutations don’t seem detrimental. You'd think those people are always tired, prone to various diseases, and dying early. 

But we're not seeing that at all. 

These neurobiological pathways seem to decrease sleep need because they upregulate mechanisms we now see as beneficial. For example, the sleep-less allele of DEC2 is a worse inhibitor of orexin — there's more orexin activity. Orexin is a key hormone promoting wakefulness. As part of its complex downstream effects, it improves mood and happiness, decreasing stress, and perhaps focus.[5][6] Perhaps these gene variants accelerate sleep in ways we don't quite understand?

The limited data point to a clear direction: Moving along this sleep ↔ wakefulness axis seems to be mostly beneficial. These people are more vital, happier, bursting with energy, and perhaps healthier in the long-term. See below for how the researchers describe them.

The limited mouse studies support this picture: Mice with the human version of the sleep-less gene (or similar changes) sleep less in a healthy way — both knock-outs of DEC2 [8] and knock-ins of the human variant [9]. The complete knock-outs are especially interesting: Their complete lack of DEC2 wasn't detrimental, but rather these mice were healthy, viable, and fertile — and were awake more and earlier. They seem to live healthy lives, with the fascinating bonus of being prone to less Alzheimer's — in a 5XFAD Alzheimer model mice with DEC2-P384R (the human mutation) and NPSR1-Y206H, they have much less tau and amyloid plaques accumulating in their brains.[7]

Note that in research, mouse models are always a very limited test for what would work in humans. But here, we know it's already tested by nature in humans, and we mostly apply a human mutation in mice to verify.

Why didn't it get selected for then? The plausible evolutionary constraint here is clear: Sleeping less would've burnt more calories and gotten your ancestors killed by nighttime predators. Mother Evolution would've rather had you get more zzz's.^[1]

That's a brief outlook over the foundational research. But what does that look like day-to-day? What does it feel like? Here's the leading researchers surprisedly describing their research subjects naturally born with those "sleepless" variants:

As a bonus, they seem to be slimmer than average, more optimistic, more psychologically resilient, have a higher pain tolerance, and are even immune to jet lag. [10]

Not only are their circadian rhythms different from most people, so are their moods (very upbeat) and their metabolism (they're thinner than average, even though sleep deprivation usually raises the risk of obesity). They also seem to have a high tolerance for physical pain and psychological setbacks. [10]

"They encounter obstacles, they just pick themselves up and try again," Dr. Jones says.[10]

“They were not just awake, they were driven. It was torture for them to do nothing,” Jones said. “They like to run marathons – many of our natural short sleepers ran marathons – including mountain marathons where you go straight up. One of them decided he was going to build a violin, and he did.[10]

The drive they have is physical, but also psychological: ‘I’m gonna do this.’ It’s really quite remarkable [...][15]

Adding fun anecdote: My lab mate Yuki is also a short sleeper. She is constantly on her feet. She's one of the happiest and highest-energy people I know. She's also one of the few people who are always in the lab. And she's a professional violinist, and she has time to surround herself with wholesome people, and she walks 10 miles a day, and she plays so much badminton to obliterate me in a match. She says: “It feels like I have a cheat code in life.”

By sleeping less, these humans and mice live more. We spend some 20 years of an 80-year life asleep. With a hypothetical sleep-decreasing therapy, that could be 10 years of sleep instead.

It could be adding 10 years of more life: 80 year lifespan, 8 hours a day asleep; compared to 80 years and 4 hours a day asleep. I challenge the reader to note a current putative longevity medication that could get even close to this, while having similar plausible benefits on mood, happiness, productivity and neuroprotection.

This is crazy.

The obvious question: Could we democratize this natural advantage — what would giving it to everyone look like? Here's an outline of what that could look like.

Remember, we have proof-of-concept. Humans naturally born with these gene alleles sleep less, are more active and happy, and do so apparently without severe downside. Same for our mouse models.

Can we make it work in adult mammals? If you don't have the privilege of being born with these variants, can modern technology safely induce the same phenomenon? Of course, safety being absolutely key, initial development has to be in animal models. One could iterate the development of the therapy in mice, and try to find a treatment that is both safe and effective at reducing sleep needs. 

Here's some quick notes on ozempic for sleep or a vaccine for sleep

• AAV-based therapies to restore orexin signaling (which DEC2 inhibits) in narcoleptic mice already work, increasing wakeful time by 13% and decreasing wake bouts by a fifth (more single stretches wakefulness) [21]
  • The actual approach could end up using this kind of AAV delivery and/or plasmids carrying a base editing system, decreasing the efficacy of DEC2 suppressing orexin in the brain by making the protein less functional. Or directly upregulating orexin.
• Dual orexin antagonists (blocking both OX1R and OX2R) are in human trials and potentially promising for chronic insomnia [22]
  • So what about small-molecule orexin agonists in the morning? Yes, that's plausible:
• The first direct orexin agonists are running human trials, such as TAK-861 [23]
  • Farther-out idea: What about automatic orexin peptide administration in sync with your personal circadian rhythm (think of insulin pumps)? 
  • Small molecules are also so much easier to get FDA-approval for.
• Weirder ideas:
  • Semi-permanent (months?) silencing the mRNA transcripts, e.g. with siRNA, short hairpin RNA, etc
  • Flagging DEC2 or other inhibitor proteins for faster intracellular degradation
  • Destabilizing the protein, snipping in variants, etc.
  • Insert extra copies of the wakefulness mechanisms

There's a lot of room to explore here: We're already given at least 6 mutations whose effects to potentially emulate; we could target inhibitors and/or the wakefulness mechanisms themselves; we could try lots of different paths (molecules, antibodies, editing, RNA, simulation, …). That makes it such an interesting problem to work on, and de-risks the project a little. Keep in mind: intra-brain editing is currently hard™️. But people are feverishly working on it. Somehow there must be a way to do this safely and effectively. Check out Helena Rosengarten's way more detailed post speculating on concrete approaches to this.

The possible therapeutic upside is impressive as well.

• Narcolepsy — often caused by orexin dysregulation — affects 1 in 2000 Americans.
• Idiopathic hypersomnia affects 1 in 10,000.
• Chronic fatigue syndrome affects 1 in 100. Most of these are hard to treat.
• Sleep apnea affects 1 in 4, mostly caused by obesity — yet a therapy improving daytime function could alleviate symptoms. Combined with GLP-1 agonists, we might virtually cure sleep apnea.

More interesting applications to look into: Cognitive decline, Alzheimer's, Parkinson's; Military personnel; shift workers & jet lag; treatment-resistant depression. Combined current market size: $16 billion.^[1] And expected to grow dramatically in the upcoming decades. And the market cap isn't capped — who wouldn't want to sleep less if it were an easy and safe therapy?

Consider GLP-1 agonists (semaglutide/Ozempic/Wegovy, tirzepatide/Mounjaro) which were developed for diabetes initially. Yet, they are mounting up more and more evidence that they prevent or treat: Diabetes, obesity, Alzheimer's, Parkinson's, drug addiction, gambling addiction, PCOS, cardiovascular disease, and more.

Most pharmaceuticals fail. Biology is hard and complex. Really complex. This is likely to fail by default too.

But even with our limited tools in biology, we do get really big successes — sometimes by leveraging metabolic levers to push us to an optimum that evolution didn't care about.

Luckily, we are out of the savannahs. In our modern age, perhaps it's not too crazy to imagine ozempic but for sleep.

Readings of interest:

Check out Helena's detailed write-up here. Luke Piette's outline here.

1. https://www.cnn.com/2021/06/22/health/short-sleep-gene-wellness-scn/index.html
2. https://en.wikipedia.org/wiki/Familial_natural_short_sleep
3. https://www.cell.com/current-biology/fulltext/S0960-9822(20)31441-X
4. [ft]
5. Neurobiology of the Orexin System. https://pmc.ncbi.nlm.nih.gov/articles/PMC8870430/
6. Orexins and Stress. https://pmc.ncbi.nlm.nih.gov/articles/PMC6345253/
7. Familial natural short sleep mutations reduce Alzheimer pathology in mice. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9042888/
8. https://journals.sagepub.com/doi/10.1177/0748730411419782
9. https://pubmed.ncbi.nlm.nih.gov/29531056/
10. https://www.wsj.com/articles/SB10001424052748703712504576242701752957910
11. ^
12. ^
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15. https://www.cnn.com/2021/06/22/health/short-sleep-gene-wellness-scn/index.html
16. [rm]
17. [rm]
18. [rm]
19. [rm]
20. [rm]
21. Orexin Gene Therapy [...] in Narcoleptic Mice. https://pmc.ncbi.nlm.nih.gov/articles/PMC3700709/
22. Orexin receptor antagonists [...]. https://www.nature.com/articles/s41398-024-03087-4
23. https://firstwordpharma.com/story/5826341
24. [rm]
25. https://www.astralcodexten.com/p/semaglutidonomics
26. https://www.astralcodexten.com/p/why-does-ozempic-cure-all-diseases
27. https://en.wikipedia.org/wiki/Orexin
28. https://www.ucsf.edu/news/2019/08/415261/after-10-year-search-scientistsfind-second-short-sleep-gene
29. https://bigthink.com/health/genetic-short-sleeper/

While writing this, someone pointed out that Luke Piette also wrote:

https://lukepiette.posthaven.com/reducing-sleep-1

If we could reduce the inhibitory effects of DEC2, reduce the level of inhibitive capabilities of beta-1 adrenergic receptors (involved in ADRB1), or increase the sensitivity of NPSR1 G protein encoded receptors to NPS, we could reduce sleep time without harming cognitive processes or long term health.