Why sleep keeps us young
Welcome back, neuron lovers!
In this week's episode of From Our Neurons to Yours, we're talking about the neuroscience of sleep. Why is slumber so important for our health that we spend a third of our lives unconscious? Why does it get harder to get a good night's sleep as we age? And could improving our beauty rest really be a key to rejuvenating our bodies and our minds?
To learn more, I spoke with Luis de Lecea, a professor in the Department of Psychiatry at Stanford, who has been at the forefront of sleep science since leading the discovery of the sleep-regulating hormone hypocretin 25 years ago.
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De Lecea's research aims to understand the mechanisms behind sleep regulation and develop interventions to improve sleep quality and efficiency. With support from the Knight Initiative for Brain Resilience at Wu Tsai Neuro, De Lecea is collaborating with Stanford psychiatry professor Julie Kauer and colleagues to understand the role of sleep centers in neurodegeneration.
In our conversation, de Lecea explains the role of the hypothalamus and the sleep hormone hypocretin in regulating sleep and we discuss how lack of sleep can cause damage to cells and organ systems, leading to effects similar to premature aging.
As usual, Shakespeare put it best:
“Sleep that knits up the raveled sleave of care,
The death of each day's life, sore labor's bath,
Balm of hurt minds, great nature's second course,
Chief nourisher in life's feast.”
— Macbeth
Learn more
- Learn more about the de Lecea laboratory
- Why Does My Sleep Become Worse as I Age? (New York Times, 2022)
- Losing sleep in adolescence makes mice less outgoing as adults (Stanford Scope Blog, 2022)
- Sleep and the Hypothalamus (Science, 2023)
- Hyperexcitable arousal circuits drive sleep instability during aging (Science, 2022)
Episode Credits
This episode was produced by Michael Osborne, with production assistance by Morgan Honaker, and hosted by Nicholas Weiler. Cover art by Aimee Garza.
Episode Transcript
Nicholas Weiler:
This is From Our Neurons to Yours, a podcast from the Wu Tsai Neurosciences Institute at Stanford University. On this show, we crisscross scientific disciplines to bring you to the frontiers of brain science. I'm your host, Nicholas Weiler.
Today, we are starting deep in the midbrain in a structure called the hypothalamus. This is a control center for keeping the body's key systems regulated and in balance. Here, specialized clusters of neurons produce hormones that can control functions like heart rate, body temperature, hunger, and thirst. And one of these clusters regulates a process that is so critical to our health that it takes up a third of our lives. These are the neurons that control sleep.
Sleep is both mysterious and completely essential for our health and wellbeing. It restores our energy, lays down our memories, clears toxic waste from our cells, and repairs damage to our DNA. And if we don't get good sleep, the opposite is true. Lack of sleep causes havoc throughout your body, from your immune system to your digestive tract. In fact, the effects of sleep loss are most comparable to premature aging. From cells to organ systems, everything just degrades.
The brain is particularly vulnerable to lack of sleep, but until very recently, neuroscientists knew almost nothing about the interplay between sleep and the brain. It wasn't until 25 years ago, when scientists discovered the sleep centers of the hypothalamus, that our scientific understanding of sleep really took off. Today's guest has been at the forefront of this field since participating in the 1998 discovery of the sleep hormone, hypocretin.
Luis de Lecea:
My name is Luis de Lecea. I'm a professor in the department of Psychiatry at Stanford, and my lab is interested in the neuronal underpinnings of the sleep regulation. In other words, which neuronal structures decide when we sleep and when we stay awake.
Nicholas Weiler:
I'm really excited for this conversation. Sleep is a topic near and dear to my heart as a parent of young children. But before we get into your work on how the brain controls sleep and its health benefits and what happens when we don't get enough of it, I wonder if you could do some scene setting for us. Can you describe what is happening in our brains when we sleep? You could start with what happens as we fall asleep, and then just what is going on in the brain during our sleeping hours.
Luis de Lecea:
The short answer is that there are many active processes in the brain while we sleep. One of the functions of sleep is to recover from the intense neuronal activity during wakefulness, and there are several stages of sleep, and we don't probably know enough about each of them.
But overall, the idea is that information has to be preserved, and actually, there are processes that are optimized during sleep, and those recovery processes include restoring synaptic activity, neural activity, but also restoring immune function, restoring physiological variables that are important to keep under control, so that when we wake up, we are ready to engage in this dangerous environment.
Nicholas Weiler:
I'm curious. We're going to talk a little bit about how our brain controls falling asleep and staying asleep, I think. Does it make sense to ask where does sleep start in the brain? Or does it start everywhere at once?
Luis de Lecea:
No, that's a great question. Again, we're only starting to learn about when and how does sleep start, and there are several areas in the brain that can initiate sleep. It's likely but unclear whether they talk to each other, and there is the process that was discovered only a decade ago of local sleep, and that means that part of our brains are asleep while the rest of the brain is awake, and vice versa.
Nicholas Weiler:
That corresponds with my lived experience, I think.
Luis de Lecea:
I think many of us have experienced that dissociation.
Nicholas Weiler:
One last question on this vein: if we're just looking at the brain, sleep seems like such a distinct state, but my understanding is that the brain is no less active, in a sense, during sleep. Our energy consumption during sleep is not a lot less than it is when we're awake, so the brain's doing a lot while we're asleep.
By looking at the brain, not with the eyes, but scientifically, by recording from the brain, can you see clearly the difference between being awake and being asleep? And what does that difference look like?
Luis de Lecea:
Yeah. Since the 1950s, the main tool that sleep scientists have used to determine whether the brain is asleep or awake is the electroencephalogram, the EEG in short, and indeed the waveform, the brainwaves recorded in the EEG are very distinct depending on the state of vigilance or the state of sleep, and based on EEG signals, we can classify the four stages of sleep, and one and two and three and REM sleep, and also many of the processes that take place during those sleep stages.
Nicholas Weiler:
And the EEG is generally recorded across the skull, so there's sort of a transition between different types of rhythmic activity, so that you can see that during the day or when we're alert, the activity looks one way that we're processing information, interacting with the outside world. And then when we're asleep, it gets more regular?
Luis de Lecea:
Yes, there is a gradual synchronization of cortical activity, which is reflected in the EEG, as what we call slow wave activity, which means that the brainwaves are broader, so the amplitude of the other waves is much, much bigger, and it's slower, as we call it, so the frequency of the oscillation is slower than what we observe during wakefulness.
Nicholas Weiler:
Interesting, so cells across the brain start sort of generally firing together in a way that they don't during the day?
Luis de Lecea:
That's correct.
Nicholas Weiler:
So you started talking about the various ways we know that sleep is restorative, helps us recover from the trials of the day in maybe both physiological and psychological ways. It wasn't very long ago, I think, that sleep was really a total mystery to science. I remember talking to one scientist years ago, telling me that, as far as we knew, the only reason we need to sleep is that if we don't, we get sleepy, which is obviously a joke, but it reflected that there was just a lot we still didn't know about the process.
But that seems like that's changed in the past decade or so. We're starting to understand the brain systems, it regulates sleep, and how critical it is for our health in many ways. I wonder if you could list just a few of the things we now know that are going on in the brain to keep the brain healthy as we sleep.
Luis de Lecea:
Yeah, indeed. We've learned a lot in the past couple of decades on what happens while we sleep, and a lot of it has come from the discovery that there are nuclei deep in the brain, the hypothalamus, that make the decision whether to sleep or stay awake.
Nicholas Weiler:
In this context, nuclei meaning clusters of neurons of a particular kind.
Luis de Lecea:
Clusters of neurons. That's correct. I think that one of the main discoveries in the last couple of decades is that these identified neurons in the hypothalamus are responsive to a very, very broad range of signals that code variables that are important for sleep stability. Let me give you an example.
We, as humans, sleep eight hours during the night, and mostly it's during the night, so there's a signal in the brain that tells us, "Okay, it's nighttime, so it's okay to go to sleep." And this circadian signal is transmitted to these centers in the brain and letting them know that it's now okay to fall asleep.
But there are situations in the wild, and you can imagine that you're about to fall asleep, but there's a predator behind you, and of course, it's not a good idea to fall asleep in that environment. There are stress signals that override the circadian clock. And how all of this is processed is something new that we have no idea how it happened, and now we are understanding a lot more about it.
And not only, of course, are we understanding the relationship between circadian rhythms and sleep, stress and sleep, but there are a whole bunch of variables: heart rate, blood pressure, breathing and core body temperature, lots of variables that are being integrated in these neurons that were unknown only a couple of decades ago, and that we're now understanding how the whole process is getting integrated and the coherent signal comes out of that.
Nicholas Weiler:
And so these systems are critically important for making sure that we sleep, generally, at the right time and the right amount and that we stay asleep at night. Other animals, I guess cats are a good example, tend to sleep in clusters throughout the day and night, and humans sleep in a big chunk at night.
We hear a lot in public health and in the news, in the science of sleep, that we're not getting enough sleep. It's really bad for our health. It's really critical. You've mentioned that sleep is important for resetting from brain activity during the day. We do consolidation of memory, which is the fancy neuroscience way of saying we move what happened today into long-term storage, depending on how interesting it was.
There's been a lot of recent study of the brain trash collection, literally cleaning itself out, cleaning out metabolic junk that accumulates during the day. So if all of these things are interrupted, obviously that's not so great, but maybe you can tell us more specifically, what do we know about the health consequences of not getting enough good quality sleep?
Luis de Lecea:
Interestingly, the consequences of sleep loss overlap in many ways with of aging.
Nicholas Weiler:
Of aging?
Luis de Lecea:
I'm talking about accumulation of DNA damage, for instance, proteostasis, ER stress at the cellular molecular level.
Nicholas Weiler:
These are just various things are going wrong with our cells if we're not getting enough sleep.
Luis de Lecea:
Exactly. And the damage is accumulating, not only at the DNA level, at the protein level, at many levels. And as you just mentioned, one of the [inaudible 00:10:39] functions of sleep is to clean up that junk, that mess, and if we don't sleep, then that junk accumulates, and our cells age more rapidly. That is a very simplistic way of describing sleep function, but I think it's quite accurate in some ways.
Nicholas Weiler:
Interesting. People are trying to come up with ways of measuring your cellular age or immunological age or metabolic age, so this would suggest that if someone is not sleeping enough, you could look at their cells and they would look older than their biographical age?
Luis de Lecea:
That's correct. There's this relatively new hypothesis that our lab is actually working on, and I just mentioned it, DNA damage, that one of the functions of sleep is to restore the DNA damage accumulated during the day. That conceptually makes a lot of sense. Obviously, you repair the freeway not when it's in rush hour. You repair it when there's no traffic or there's less traffic. That is one function.
But again, during aging we see a little bit of the same, in the sense that damage accumulates, then the cells starts responding to that DNA damage in ways that are deleterious to the cell function and misallocating energy and being less efficient at performing cellular functions, and our goal there is to come up with a cellular biomarker of the sleep need and tell whether someone has slept enough or not.
Nicholas Weiler:
It's so interesting that losing sleep mimics some of the effects of aging of cells, just generally not functioning as well as they should, because our sleep tends to get worse as we age, so there's this dual nature that we also don't get enough sleep as we age.
Luis de Lecea:
That's correct. That's a vicious circle. And along that line, with a recent paper from our group, has shown a new mechanism that can explain the changes in sleep architecture as we age. Essentially both humans and many animals, the main feature in the aged animals is that it's more fragmented, so it is less efficient at cleaning up the mess.
Nicholas Weiler:
Right. As you get older, you literally take more cat naps and less sleep during the night.
Luis de Lecea:
Exactly. And the mechanism for that change was unknown, and we published this paper last year highlighting one of the reasons why sleep gets more fragmented as we age.
Nicholas Weiler:
I want to get to that in just a moment, but I quickly wanted to ask, we've been talking about how not sleeping enough looks a lot like aging when you look at cells. Cells look older. Is there any thought that the aging process in the brain is driven by the loss of sleep, in part? If we rejuvenated sleep, would we rejuvenate the brain?
Luis de Lecea:
Yes. This is exactly one of the conclusions of our paper. If we restore sleep architecture by tapping into this mechanism, essentially restoring sleep architecture, rejuvenating sleep architecture in aged animals, they're able to perform better and cognition is improved, and there are a whole bunch of things that get better.
Of course, this is not to say that sleep can cure everything or can cure aging, but it's clear that there is a correlation between the amount of sleep and the consequences of accelerated aging.
Nicholas Weiler:
I want to jump into your paper from last year, and also the work that you're doing now, to track this down. To do that, we need to look back just a little bit about what we've learned about how the brain regulates sleep. Let me lay out my understanding from looking at some of this, and you can let me know if I'm on the right track, here.
A lot of this goes back actually to early studies of narcolepsy and neurons in the hypothalamus that use the chemical transmitter called hypocretin. The study that your lab published last year in Science basically showed that it seems like one of the reasons why our sleep declines as we age is that a particular protein in these hypocretin neurons that tell us when to go to sleep stops functioning properly, which basically removes a normal break on the cell's activity, so now they basically have too much electrical activity, this break is not functioning, they get hyper excitable, and that tends to keep us awake when we should be sleeping. Is that the big picture of what you found?
Luis de Lecea:
That's a fantastic, very eloquent description. Yes, it is
Nicholas Weiler:
So now you're part of a team of researchers here at Stanford, including Julie Cower, Inma Kobos, Bryce Goodier, who are funded by the Knight Initiative for Brain Resilience to study these links between sleep and neurodegeneration in the brain. Can you help us see the link there? How does this science paper from last year about the hypocretin neurons link to neurodegeneration and immune function?
Luis de Lecea:
Yeah. Again, this is a follow-up of a decade of work trying to establish the circuitry, fundamentally determining a sleep architecture, and we learned several years ago that the hypocretin system is pretty much at the core of what decides when to sleep and when not to sleep, is connected with the brain reward system, the dopaminergic neurons in the ventral tegmental area.
Nicholas Weiler:
Oh, interesting. Yeah, dopamine seems to be connected to everything in the brain. We hear about dopamine so often.
Luis de Lecea:
That's correct. My group and others have shown that not only this connection exists, but the dopaminergic neurons are really important to get started in the sleep process. Essentially, you have to inhibit dopamine in order to fall asleep.
Nicholas Weiler:
Interesting. And dopamine is, you mentioned, reward. It's also involved in motivation. I have young kids, so again, I think about this a lot. Getting them less excited before going to bed, maybe making yourself a little bored in order to fall asleep.
Luis de Lecea:
Absolutely. Absolutely. In animals, for instance, we learned that preparatory phase for sleep can be measured by the way animals build nests. Mammals build nests in order to have a full night's sleep that is secure, that is safe. If you inhibit dopamine at the right time of the day, then these mice start building nests almost compulsively in preparation for sleep. If the nest is already present, it has already been built, then the animals fall asleep immediately if you inhibit dopamine.
And the opposite is also true. If you stimulate dopamine in this proprietary phase, then you disrupt the subsequent phases of sleep, and this is probably one of the basis for insomnia or stress, and excessive dopamine activity can obviously impair our ability to fall asleep.
Nicholas Weiler:
Right, like scrolling on our phones and that kind of thing.
Luis de Lecea:
Right.
Nicholas Weiler:
Hijacks the dopamine system. Now that you're zeroing in on some of these mechanisms, like this protein in the hypocretin neurons that takes the break off of our wakefulness system or the involvement of dopamine in telling the brain, "When things aren't exciting, you can relax and fall asleep," is the idea that we could now find ways to interact with those to improve our sleep, and by the way, rejuvenate our brains?
Luis de Lecea:
Yeah, that's exactly the goal. If we have entry ways to manipulate those signals that determine sleep architecture, then we hope that we'll be able to treat sleep disorders and dysfunctions of the sleep wake cycle, particularly in Parkinson's patients or Alzheimer's patients. They have a lot of problems falling asleep or staying asleep, so we hope that by learning more about these mechanisms, we're going to be able to intervene better and rejuvenate their sleep architecture and optimize their sleep wake cycle.
Nicholas Weiler:
Well, as soon as we get to clinical trials in the general population, I'm happy to sign up for sleep improving therapies. One thing I'm curious, we've been talking about improving the quality of sleep. We're talking about treating insomnia, treating this breakup of normal sleep architecture that makes people have trouble sleeping at night and then nap during the day, which is less effective for our brains; that even if we're getting the same amount of sleep, having it broken up means we're not getting the same benefits.
It would be great to be able to sleep better and longer, but I know there are a lot of people that sometimes it feels like a bit of a drag that we have to sleep for a third of our lives to get these rejuvenating benefits as we understand sleep more, is there any thought that we could potentially make it more efficient so that we need to sleep less?
Luis de Lecea:
Yes. That's also one of our goals. Again, I really enjoy sleeping very much, and I think it's a very pleasurable activity, but as you just mentioned, there are circumstances where you may want to have a more efficient sleep, and there are examples in the animal kingdom where this is the case. For instance, migrating birds, they can sleep only for maybe 15 minutes while they're migrating and they have these optimized patterns of sleep. Or marine mammals, like dolphins, they sleep with half of their brain so they can keep navigating as they sleep.
Yes, of course, these are wild examples of what is possible in nature, and I think it may be possible to manipulate sleep in humans in a way that is more efficient without changing our brain architecture, so I think it's definitely possible and it's something that we should be looking into.
Nicholas Weiler:
Fantastic. I'm really sad that we're running short on time here, because I would love to keep talking about all of this. This is definitely stimulating my dopamine system, but we'll just have to have you back on and talk more about modifying sleep and everything that we're coming to learn about it. Luis, thank you so much for joining us on the show.
Luis de Lecea:
Thank you. It was my pleasure.
Nicholas Weiler:
Thanks so much again to our guest, Luis de Lecea. You can learn more about his research in the show notes. We're very excited for season two of From Our Neurons to Yours. If you are, too, please take a moment to give us a review on your podcast app of choice, and share this episode with your friends. That's how we grow as a show and bring the stories of the frontiers of neuroscience to a wider audience. This episode was produced by Michael Osborne with production assistance by Morgan Honiker. I'm Nicholas Weiler. See you next time.
