Luis de Lecea interviewed by Nicholas Weiler. https://neuroscience.stanford.edu/news/why-sleep-keeps-us-young

"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?"

--- SoupGate-Win32 v1.05
* Origin: fsxNet Usenet Gateway (21:1/5)

On Wednesday, November 22, 2023 at 8:40:45 PM UTC, ltlee1 wrote:

Luis de Lecea interviewed by Nicholas Weiler. https://neuroscience.stanford.edu/news/why-sleep-keeps-us-young

"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?"

About the "you repair the freeway not when it's in rush hour" analogy, brain cells are bigger and cellular space is smaller while the animal is awake.
https://www.nih.gov/news-events/nih-research-matters/how-sleep-clears-brain

"Dr. Maiken Nedergaard and her colleagues at the University of Rochester Medical Center recently discovered a system that drains
waste products from the brain. Cerebrospinal fluid, a clear liquid surrounding the brain and spinal cord, moves through the brain
along a series of channels that surround blood vessels. The system is managed by the brain’s glial cells, and so the researchers
called it the glymphatic system.

The scientists also reported that the glymphatic system can help remove a toxic protein called beta-amyloid from brain tissue.
Beta-amyloid is renowned for accumulating in the brains of patients with Alzheimer's disease. Other research has shown that brain
levels of beta-amyloid decrease during sleep. In their new study, the team tested the idea that sleep might affect beta-amyloid
clearance by regulating the glymphatic system. The work was funded by NIH’s National Institute of Neurological Disorders and
Stroke (NINDS).

The researchers first injected dye into the cerebrospinal fluid of mice and monitored electrical brain activity as they tracked the dye
flow through the animals’ brains. As reported in the October 18, 2013, edition of Science, the dye barely flowed when the mice were
awake. In contrast, when the mice were unconscious — asleep or anesthetized — it flowed rapidly.

Changes in the way fluid moves through the brain between conscious and unconscious states may reflect differences in the space
available for movement. To test the idea, the team used a method that measures the volume of the space outside brain cells. They
found that this “extracellular” volume increased by 60% in the brain’s cortex when the mice were asleep or anesthetized.

The researchers next injected mice with labeled beta-amyloid and measured how long it lasted in their brains when they were asleep
and awake. Beta-amyloid disappeared twice as quickly in the brains of mice that were asleep.

Glial cells control flow through the glymphatic system by shrinking and swelling. The hormone noradrenaline, which increases alertness,
is known to cause cells to swell. The researchers thus tested whether the hormone might affect the glymphatic system. Treating mice
with drugs that block noradrenaline induced a sleep-like state and increased brain fluid flow and extracellular brain volume. This result
suggests a molecular connection between the sleep-wake cycle and the brain’s cleaning system."

--- SoupGate-Win32 v1.05
* Origin: fsxNet Usenet Gateway (21:1/5)

On Friday, November 24, 2023 at 3:09:21 PM UTC, ltlee1 wrote:

On Wednesday, November 22, 2023 at 8:40:45 PM UTC, ltlee1 wrote:

Luis de Lecea interviewed by Nicholas Weiler. https://neuroscience.stanford.edu/news/why-sleep-keeps-us-young

"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?"

About the "you repair the freeway not when it's in rush hour" analogy, brain cells are bigger and cellular space is smaller while the animal is awake.
https://www.nih.gov/news-events/nih-research-matters/how-sleep-clears-brain

"Dr. Maiken Nedergaard and her colleagues at the University of Rochester Medical Center recently discovered a system that drains
waste products from the brain. Cerebrospinal fluid, a clear liquid surrounding the brain and spinal cord, moves through the brain
along a series of channels that surround blood vessels. The system is managed by the brain’s glial cells, and so the researchers
called it the glymphatic system.

The scientists also reported that the glymphatic system can help remove a toxic protein called beta-amyloid from brain tissue.
Beta-amyloid is renowned for accumulating in the brains of patients with Alzheimer's disease. Other research has shown that brain
levels of beta-amyloid decrease during sleep. In their new study, the team tested the idea that sleep might affect beta-amyloid
clearance by regulating the glymphatic system. The work was funded by NIH’s National Institute of Neurological Disorders and
Stroke (NINDS).

The researchers first injected dye into the cerebrospinal fluid of mice and monitored electrical brain activity as they tracked the dye
flow through the animals’ brains. As reported in the October 18, 2013, edition of Science, the dye barely flowed when the mice were
awake. In contrast, when the mice were unconscious — asleep or anesthetized — it flowed rapidly.

Changes in the way fluid moves through the brain between conscious and unconscious states may reflect differences in the space
available for movement. To test the idea, the team used a method that measures the volume of the space outside brain cells. They
found that this “extracellular” volume increased by 60% in the brain’s cortex when the mice were asleep or anesthetized.

The researchers next injected mice with labeled beta-amyloid and measured how long it lasted in their brains when they were asleep
and awake. Beta-amyloid disappeared twice as quickly in the brains of mice that were asleep.

Glial cells control flow through the glymphatic system by shrinking and swelling. The hormone noradrenaline, which increases alertness,
is known to cause cells to swell. The researchers thus tested whether the hormone might affect the glymphatic system. Treating mice
with drugs that block noradrenaline induced a sleep-like state and increased brain fluid flow and extracellular brain volume. This result
suggests a molecular connection between the sleep-wake cycle and the brain’s cleaning system."

"Ah, to sleep, perchance … to shrink your neural connections? That's the conclusion of new research that examined subtle changes in the brain during sleep.

The researchers found that sleep provides a time when the brain's synapses — the connections among neurons—shrink back by nearly 20 percent. During this time, the synapses rest and prepare for the next day, when they will grow stronger while
receiving new input—that is, learning new things, the researchers said.

Without this reset, known as "synaptic homeostasis," synapses could become overloaded and burned out, like an electrical outlet with too many appliances plugged in to it, the scientists said.

"Sleep is the perfect time to allow the synaptic renormalization to occur … because when we are awake, we are 'slaves' of the here and now, always attending some stimuli and learning something," said study co-author Dr. Chiara Cirelli of the University
of Wisconsin-Madison Center for Sleep and Consciousness. [10 Things You Didn't Know About the Brain]

"During sleep, we are much less preoccupied by the external world … and the brain can sample [or assess] all our synapses, and renormalize them in a smart way," Cirelli told Live Science.

Cirelli and her colleague, Dr. Giulio Tononi, also of the University of Wisconsin-Madison, introduced this synaptic homeostasis hypothesis (SHY) in 2003.

Now, Cirelli and Tononi have direct visual evidence of SHY after observing the shrinking of synapses in mice while the animals slept, an intricate experiment spanning four years. The researchers described their findings today (Feb. 2) in the journal
Science."

https://www.scientificamerican.com/article/sleep-shrinks-the-brain-and-thats-a-good-thing/

--- SoupGate-Win32 v1.05
* Origin: fsxNet Usenet Gateway (21:1/5)