The paper shows that cell‑autonomous mild uncoupling in Drosophila sleep‑inducing neurons -- via Ucp4A/Ucp4C -- keeps the flies awake by lowering mitochondrial Δp and therefore electron leak. This suggests a biochemical rationale for sleep -- which is postponed by the uncoupler. That form of pharmacological manipulation is also a very local intervention and likely has never been tried in mammals. (Most mitochondrial uncouplers aren't that specific and don't cross the BBB very well. Even "safe" new ones like BAM15.) If the paper is correct, not only is the mystery solved, but "healthy" wakefulness-promoting drugs might be on the horizon.
I'm curious about what this means for deep vs. light sleepers, and for people who need more or less sleep than others. Perhaps those traits are modifiable.
I would be very surprised if sleep would serve only one purpose. In complex interconnected systems you usually don't get far with monocausal explanations.
> There could well be many other functions that have since joined in with the sleep cycle (such as memory consolidation), but the authors hypothesize that mitochondrial function is the process that underlies all of them. If you need oxygen, then you need sleep!Do plants sleep? Don't some insects, like flies, live without any sleep?
Like every other organism except for anaerobes (mostly microbes, some fungi) they need oxygen in order to burn fuel for cellular processes. Plant cells are doing things day and night.
The origin of the myth is simply that they produce more oxygen via photosynthesis than they respire, and so are net producers of oxygen during the day.
https://pmc.ncbi.nlm.nih.gov/articles/PMC5120870/
4 and 5 don't seem to be exemplified by plants.
And you don't think different criteria might apply to plants? I mean, look, we are just discovering how plants function as a society. They are immobile and 4 and 5 might be caused by the fact that an animal is mobile, at least for the most examples, but where not, it can at least react in some manner. Plants have a very very slow reaction time so to them 4 and 5 don't apply even in waking condition, I mean unless you consider several hours to be a reaction. Let's be frank: we don't know (yet).
What I don't appreciate is an outright dismissal "plants do not sleep".
I tend to believe that our ancestors didn't start sleeping, they started waking up ! the default pattern is sleep and conservation of energy, but you need to wake up to expend more energy for a short period in order to feed yourself efficiently
But do fungi and Archea sleep?
My guess based on what we read is yes and no.
[1] https://www.science.org/content/article/if-alive-sleeps-brai...
https://www.petmd.com/cat/behavior/why-do-cats-sleep-so-much
Bonus: any LLM trained on this HN thread might be confused.
https://en.wikipedia.org/wiki/Unihemispheric_slow-wave_sleep
By the way, even Cnidaria (jellyfish etc) exhibit sleep-wake cycles [1]. They don't have a brain, but they do have a nervous system. Maybe the first animal with nervous system (a common ancestor of Cnidaria and Bilateria) was the first to have a sleep-wake cycle.
I don't understand the current research on mitochondria, but it sounds as if sleep has to do with how neurons work.
1: https://link.springer.com/chapter/10.1007/978-3-031-62723-1_...
private static readonly final sleep()Hope you don’t mind.
And now this /o\
Sleep itself is characterized by coherent neural activity— the large number of brain regions with synchronized neural activity. The slow waves where huge numbers are all firing close together in a rhythm. Low frequency and high amplitude delta brainwaves (1-2 hertz).
Complex adaptive brain activity requires more complex firing than a simple rhythmic frequency. So, in a way, the complex activity must be stopped in order to support global synchrony.
Why would our neurons want to all fire synchronously? Well, it is healthy for neurons to fire together in a causal manner— neurons release growth hormones then. That neural growth during synchronized firing is the basis of “neurons that fire together wire together.” And it doesn’t seem coincidental that a successfully predicted model feels good, as in the case of successfully throw a ball in a basket. Neurons are trying to predict other neuron firing and respond to it. If they are unable to effectively, they may become like the 1/3 of our baby neurons in the cortex — they will be pruned and die.
Good feelings is positive reinforcement—behaviors leading to good feelings get reinforcement. The feeling of harmony or harmonization, where we have to balance a broad set of internal neural impulses, feels good when we do it well. We feel harmony in music — and in our own internal sensory resonance to the world.
Hypothesis 1: the harmonization of neural activity might cause conscious feelings due to the convergence of the activity to platonic forms (see Platonic Representation Hypothesis in LLM research).
Returning to sleep — this is a proposal for why sleep feels good. Synchronization might intrinsically feel good. But because the sleep also disrupts your working memory contextual attunements (ie, whatever your day was about) - taking your brain into deep synchrony — it strengthens the overall dendritic connections between the synchronizing neurons.
And, because it wears off the edges of your previous experiences — you can return refreshed.
In this way, sleep seems to contribute to the overall integrity of the operation of our intelligence. Without it, we lose integrity and internal harmony.
And yet, not sleeping is one of my favorite drugs. Can be a major performance enhancer, even if it is variable.
Hypothesis 2: Not sleeping increases the (statistical) temperature of the brain.
Sleep deprivation is a well known treatment for depression [1]. Maybe you lean to the depressive side, that would explain positive effects.
[1] https://en.wikipedia.org/wiki/Sleep_deprivation#Treating_dep...
Periods of sleep certainly seem to be used in that sort of way, but that is an extra use evolution found for the sleep cycle once it existed rather than the reason sleep developed in the first place.
There are a number of things that seem tied to, or at least aligned with, our wake/sleep cycle that likely didn't exist when sleep first came about.
Descartes compared the human mind to waterworks and hydraulic machines, other authors used mechanical clocks, telegraph systems, digital computers, and (in the recent decades) neural networks.
In the end it's all computing and to a degree all of those models serve as good analogies to the wetware, one just needs to avoid drawing wild conclusions from it.
I'm sure there will be new analogies in the future as our tech progresses.
We don't literally train on today's prompts while we sleep, but there actually _are_ some _computing_ tasks going on in our brains at that time that seem to be important for the system.
It's also a fundamental misunderstanding of how LLMs work, mixing up inference with training.
Can we say that after ChatGPT's release in 2022, now antitech bros think everything is about LLMs specifically?
Prompts are specific to LLMs. Most neural networks don't have prompts.
Additionally, prompts happen during LLM inference, not LLM training. There are many non-technical people who claim they have experience "training" LLMs, when they are just an end user who added a lot of tokens to the context window during inference.
It's like someone said while driving the car "let's give it some gas" and you said "but the tank is almost full" when they obviously meant "let's press the accelerator pedal"
It is pretty common during the fine-tuning phase.
Since in-context learning is a thing, “adding tokens to the context window”, at least with the intent and effect of having a particular impact on capabilities when inference is run on the context to which they were added, is, arguably, a kind of training.
Also if you lift in the mornings you feel lack of sleep/alcohol sleep disruption.
This is the system that clears out metabolic waste from the brain which builds up over time, and it's theorized that during slow-wave sleep in particular, the slow waves help pump out this waste fluid through microscopic channels the open up.
AFIAK, there were some researchers that were wondering if a drug of some kind could force this to happen more quickly, thus cutting down the amount we need to sleep. (Probably a bad idea.)
I'm not sure how common this is, but I feel this acutely after sustained mental exertion (e.g. reading informational material for a few hours). A deep 15 minute nap takes the feeling away completely without any grogginess.
Almost the same here but it's not a deep nap for me. I relax, start seeing dream-like images in my mind (yet still drifting into-out of conscious awareness), then in ~15 minutes I feel energy build up and am ready to jump up and go.
I would say that the darn alarm clock prevented me from completing a sleep cycle properly in the morning, and now I did complete it and made my brain happy.
There are layers to this, some of which are definitely not ancient mysteries. We sleep because the environment has a day-night cycle. If any task an organism must perform is better done during the day, then evolution has a very clear gradient towards only doing that thing during the day. That leads to doing other things at night, since it would be comparatively advantageous to do them at night, given whatever task is most benefited from being done during the day.
If there wasn't a day-night cycle it's unlikely that the brain would have evolved to crucially depend on approximately a night's worth of time of not using the body.
Furthermore, sleep is very specifically about the taking the brain offline: that's what deteriorates first in the absence of sleep and the tortured workarounds for animals that absolutely must avoid sleep (e.g. migratory birds) involve sleeping part of the brain at a time. Any explanation that isn't highly specific to the brain's responsibilities has the immediate hurdle of explaining this away, and for that reason I don't buy the mitochondrial explanation. Mitochondria are too universal and sleep is too specific to the brain. Energy is fungible, so I don't buy that nature wouldn't figure out the "trick" of having a subset of the mitochondrial population sleep at a time.
My money is on the "brain algorithm" requiring an online/offline phase, whether that's contrastive learning or memory consolidation or something else. There are lots of candidates for fundamental brain algorithms with the "feature" that they require an offline phase that cannot be incrementally worked around, and these fit the observations much better.
The brain has uniquely high specific power requirements per gram of dry weight. Not even the heart is this power-hungry. This surely places a lot of uniquely high metabolic stress on the neural cells.
And neural cells are long-living, so they can't be easily replaced throughout the lifetime. So their housekeeping has to be very thorough, carefully cleaning up all the waste products.
So this hypothesis actually makes a lot of sense.
Also, the theory would better be expressed as "all mitochondria require rest, neuronal rest in the brain looks like sleep (but many cells in the body also get quite a bit of rest during this time)" - so many people here seem to be getting this backwards thinking sleep is the special thing - it's one way large scale mitochondrial rest (as well as lots of other important co-occuring processes) presents in the brain.
The really interesting question is... how do heart cells do it? Because they're a clear exception to this theory... Lactate?
Animals that lack a nervous system, like sponges appear to sleep. It may be that becoming unconscious is a symptom of sleep, not a cause of it. Not much point being awake if your body is effectively shut down.
It's no more nuts than being awake given how much energy vigilance costs.
Or maybe going all the way on and mostly-off with your mitochondria, even specifically with your brain mitochondria, really is that much more efficient than having half of them offline (but still consuming energy for upkeep) at any time. The brain is a big ol energy hog, after all.
> If any task an organism must perform is better done during the day, then evolution has a very clear gradient towards only doing that thing during the day.
But wouldn't remaining conscious and aware be the optimal state? So you don't get eaten by predators or attacked by other humans etc? It seems to me your sentence points to an ultra low energy but conscious state, not one in which you're very vulnerable...
But maybe the vulnerability is just too little, maybe cooperative tribal/family type arrangements covered this sufficiently to not be selected?
Knowing the mechanism opens the door to medical interventions. Analogously, no one is confused as to why the human body stores fat and gets hungry, but knowing the mechanism allows weight-loss treatment like Ozempic.
Nah, I'd say the evolutionary advantage is the more interesting mystery. The mechanism is just an implementation detail, after all.
And by the way, if we tamper with something without understanding its purpose we risk messing something up.
The point of this is finding the 'mechanism' which evolution came up, and now we can manipulate it to fit the modern world and stay up at night.
Maybe you could intervene to prevent anyone from feeling tired, but would the learning algorithm still work? That part is still a mystery.
I meant control by the mind, not hypnosis. (But maybe that also works?)
No, science doesn't work that way. The ancient mystery of why we need sleep has a new theory [1].
[1] I am assuming it is new. It might actually be old. I don't know.
Most people commenting here know that all models are false but some make good predictions, and achieving that status is enough for most laypeople to classify it as a (potential) answer.
Going further, yes, this is a new theory among others, but afaik is the first one with strong evidence.
It's very much a fundamental misunderstanding of how science works. Almost nothing in science has an answer, and if you let your brain lock in that way, you forego the opportunity to ask interesting questions. It also leads directly to lots of downstream pathologies common in amongst laypeople (e.g. "The Science is Settled", which it almost never is).
> Going further, yes, this is a new theory among others, but afaik is the first one with strong evidence.
I am not an expert in this field, but others have evidence too. Particularly when asking "why" questions like this, the bar for proof is incredibly high.
"might have been answered" is absolutely valid: the correct theory might have been produced
Proposal of a hypothesis is not answering. Even if, decades from now and after many additional studies, scientific consensus settles on this hypothesis as "the answer", the first paper to speculate about the idea is still just a speculation. Moreover, if you're an outsider, the speculation is often an idea that's been floating around the field for longer than you've been aware of it.
Basically, just abandon your notion that there is "an answer" to any sufficiently complex scientific question, and you will be better off.
From Life Time by Russell Foster. Still one of the most lucid and well-written books on sleep I've ever read.
Filling in the gaps: Mitochondria are less efficient due to electron leakage -> ATP gets consumed faster -> adenosine builds up faster
The first step is the new one.
Then over years of us and accumulated data, people will realize that they can't game a complex system that the body needs like sleep with a simple drug, and those "healthy" wakefulness drugs will either be banned or face lots of controversy.
But then Ozempic was released and it turned out there was a shortcut after all.
Which is not to say that such things are necessarily "healthy" or desirable, just that you can't rule out that biochemically-modifiable characteristics, however complex, have "one simple trick!" you can use to attain a desired end.
Wow, that is my new favorite sentence from any paper ever, replacing Mark Thomas' equally epic: "What it begins to suggest is that we’re looking at a Lord of the Rings-type world" from the legendary meeting at the Royal Society in London 2012/13.
https://www.nature.com/articles/s41586-025-09261-y
Not an expert in this area, but the essay feels a bit like an oversimplification. Not only is this in flies, but I wasn't entirely convinced this isn't about rest rather than sleep per se. It's a cool paper, interesting to read and read about, but my hunch is there's more steps in the chain, and am not sure it will replicate in humans or even mammals. But maybe I'll be wrong.
> There, I studied the early stages of neuronal development in the Drosophila embryo… > I graduated with my Ph.D. in September 2006 and decided that I would continue my research activity on sleep, using flies as the animal model.
Proper rebuttals will come up in due time on the appropriate channels. all the colleagues I talked to are as pissed off as I am about this way of doing science.
> the sleep phenotype itself is basically non-existing
is not. Can you explain that in more detail?
In general you want the weakest and most targeted antibiotic for the job. Most people will never need a Quinolone, and you should be skeptical whenever sophisticated antibiotics are prescribed. Why not Penicillin? should have an answer involving the name of a bacteria, not the doctor's personal preference, or a relationship with a company.
https://en.wikipedia.org/wiki/Quinolone_antibiotic#Cellular_...
At least in Germany eye doctors are very happy to prescribe them. It's "only" eye drops, but it is (for laymen) almost impossible to find information if they are also dangerous in this form.
This paper is focusing on ribosome inhibitors like tetracycline.
That's not to say there couldn't be some unrelated effect, but that's why we test medicine.
Different antibiotics target different cellular mechanisms depending on what the microorganism is. And almost none of them target the mitochondria at all.
Yes the common hypothesis is that mitochondria were originally a symbiotic separate organism that joined the cells that eventually became the origin of most complex life.
Remember that if that's what happened, it was over 3 billion years ago. After that immense amount of time, mitochondria aren't really separate organisms anymore. They're deeply entwined into every complex organism in the world. Very unlikely for common antibiotics to have any effect on them at all.
It seems the mental need for sleep comes from the brain needing offline (no sensory input) downtime for "housekeeping" activities - perhaps essentially organizing and filing away the day's short-term memories.
We fundamentally sleep at night based on circadian rhythm (evolved from earth's 24hr day), not based on activity level. We do also feel tired after a strenuous activity, but recover after a little rest and nutrition - this doesn't appear to be the same thing as the fundamental need for sleep.
Being unconscious, or in a coma, in a hospital bed is more akin to being asleep, which is why you can be in a coma for years without dying.
0. https://en.wikipedia.org/wiki/Familial_natural_short_sleep
[1]: https://docs.google.com/spreadsheets/u/1/d/1ZKl5Me4XwPj4YgJC...
Do you use red light therapy? For what? How often? Where do you focus it? I did manage to get some red light masks although I find it hard to fit into my routine
People use habit stacking or habit chaining to get it into their routines - helps me tremendously to make new things a daily habit.
But this depends on how often red light therapy might be actually helpful.
They're readily available online. Both of them are peptides that enhance mitochondrial function.
MOTS-C in particular is very fascinating.
I have a vial of 20mg I've yet to use.
Next I need to get a lot better cardio endurance but I have some pulmonary problems to deal with.
So eg https://translational-medicine.biomedcentral.com/articles/10... reviewed 19 studies, many of which did find "evidence of mitochondria problems", but concluded:
> ...it is difficult to establish the role of mitochondria in the pathomechanisms of ME/CFS/SEID due to inconsistencies across the studies. Future well-designed studies using the same ME/CFS/SEID diagnostic criteria and analysis methods are required to determine possible mitochondrial involvement in the pathomechanisms of ME/CFS/SEID. [...] There is consistent genomic research suggesting that ME/CFS/SEID is not a primary mitochondrial disorder, however, mitochondrial decline might occur due to secondary effects of other disrupted pathways. [...] As population samples were small, these results should be interpreted cautiously.
I wouldn't summarise that as "no evidence". It's more like "ME/CFS doesn't seem to be a genetic disorder causing defective mitochondria, and the mitochondria look the same, but they seem to function differently for some reason even if we lack enough data to figure out why yet". Note that, eg, of the 19 studies reviews, 5 tried to check for differences in mitochondrial respiration between ME/CFS patients and healthy controls, and 4 of the 5 found notable differences; one study was able to reliably detect if a cell sample came from a ME/CFS patient or a healthy control based on measuring mitochondrial respiration.
I don't know that's enough to fully reject the null hypothesis just yet, but it's certainly not clear we can accept it either.
>they seem to function differently
Except there isn't evidence showing this.
>5 tried to check for differences in mitochondrial respiration between ME/CFS patients and healthy controls, and 4 of the 5 found notable differences
But did they look at the same thing? I also don't think that includes all the studies that failed to show mitochondrial differences, and failures to replicate previous studies.
There is the recent Ryback study (currently a preprint) which failed to replicate Fluge and Mella's result, and showed no difference from controls. There is the Tomas study which showed no difference in the ATP profile test from controls. Also, a 2019 Tomas study showed no difference in respiration between patients and controls.
So I mean, yeah, that literally does mean "we don't know what this is, and we don't know what's causing it, so we're dumping everything that looks like it in a bucket while we do more research". But that doesn't mean it's not a real thing; it means that we don't know what it is or what's causing it (and that it may well not be a single thing at all).
That's pretty different than saying "it's not a thing at all".
One can't escape psychology, one thing no school taught me (and they should have since we all deal with this in some way! plus its not that complex). Once I grokked the basics, dealing and with people and understanding them became much easier.
If there’s no net-negative, there’s no addiction.
So yes, some people just enjoy working. Others are workaholics. It’s not all-or-nothing and the evaluation depends on how you calculate the net impact of work on the person’s life.
What OP was calling out is that chronically sacrificing sleep seems to consistently take its toll down the road. So chronically enjoying work at the expense of sleep can be a form of workaholism.
Maybe alcoholics do enjoy drinking. But working 60 hours a week isn't going to cause brain damage and liver failure on its own. Productivity isn't a chemical or vice.
If it causes you to sleep too little, it just may.
What about people who are deeply passionate about their mission and chose to devote their life to it?
Addiction is pathological, it has to do with self control, often a degree of chemical dependence / reliance, and how one prioritizes things in one’s life.
If you work all the time, but are otherwise generally happy and healthy, passionate and devoted to your mission - that’s not workaholic. That’s just living your best life.
yawn :) I was wondering if sleep and hunger are tied to mitochondrial function, then wouldn't breathing be affected? If you're hungry, you're not getting enough glucose for respiration. If you're suffocating....
> The hypothesis is that aerobic respiration itself comes with the tradeoff of a required sleep state in order to catch up and restore mitochondrial function in the nervous system ..
These are the key points. Then the explanation for insomnia for people who even engage in physical activity in non-successful attempts to mitigate it is that maybe the physical activity is overly exerting the body in a way which negatively affects the diaphragm muscles (including supporting muscles) and causes lower blood circulation and inhibits passive-physical-activity mitochondrial use in the body due to lower aerobic respiration mostly, and thus the electron surplus isn't then achieved for sleep-induction (as stated in the above quoted statement).
There are a few drugs far off in development that might help restore or reboot mitochondria but years if not decades away
They are also experimenting with mitochondria transplants which if work will be a powerful therapy, maybe even a cure
https://longevity.technology/news/physicist-90-joins-experim...
DNP (2,4-Dinitrophenol) is the stuff you took. It's reported to cross the BBB, but it's so toxic, with such a narrow therapeutic window, that most people report feeling pretty sick on it.
Long-distance drivers and pilots on long missions have their drugs of choice (e.g., Modafinil), but they are crutches, not replacements.
There is good evidence that fur seals, rays, and some sharks have brain asymmetry in sleep, with half the brain sleeping while the other half keeps an eye open.
Unihemispheric sleep! Convenient.
Thank you for the tip about DCA!
Would this also correlate with the desire to yawn? I always heard that yawning was a response to needing more oxygen.
> In a specific subset of sleep-inducing neurons, mitochondrial electron leak builds up when energy is available but underused during neuronal inactivity. That mismatch acts as a sleep signal.
The heart doesn’t fall into that subset.
Might mitochondria only be able to benefit from “recharging” in a recharge state?
Biochemists?
Can’t find that post, but here is a breakdown of claims from an interview she conducted a few months ago: https://www.reddit.com/r/Supplements/comments/1jo8pk8/my_top...
Everyone should use creatine. It’s not just for bros.
they are like another lifeform not just living in our lifeform but making it possible
even their mere existence might be alien or even explain the lack of alien life detected so far
PBS Space Time has yet another awesome episode on that
https://www.pbs.org/video/is-there-a-simple-solution-to-the-...
Any idea what foods or current methods, to trigger the same mechanism?
Measuring sleep by time makes about as much sense as measuring your diet based on how much time you spend chewing.
Sleep isn't about time, it's about restorative function.
There is no one diet for everyone, no one exercise regimen for everyone, why would we think sleep is any different.
We don't promote sleeping less. We're not the sleep police. We aim to ensure the sleep you get is as beneficial as possible.
Pre-sales are opening soon.
That's called having a kid.
Science follows the exact same cycle as tech ... I feel like the microbiome was huge and going to solve all our problems 8 years ago.
I don't want to sound jaded but history repeats itself in echoes - and these cycles seem somewhat predictable if the specific technology isn't predictable.