There’s a lot of interesting stuff in the post, but the following counter-point you offer to “the idea that sleep’s purpose is metabolite clearance” I can’t quite follow:
The paper is called “Sleep Drives Metabolite Clearance from the Adult Brain”. The abstract says:
The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.
At the same time, the paper found that anesthesia without sleep results in the same clearance (paper: “Aβ clearance did not differ between sleeping and anesthetized mice”), meaning that clearance is not caused by sleep per se, but instead only co-occurrs with it. Authors did not mention this in the abstract and mistitled the paper, thus misleading the readers. As far as I can tell, literally nobody pointed this out previously.
I’m not quite following the meaning that clearance is not caused by sleep per se, but instead only co-occurrs with it bit. So yes, sleep allegedly results in X (clearance), that you can also get through, e.g., anesthesia. I don’t see how this is more misleading than a statement like exercise results in autophagy which you can also get by using exercise mimetics hypothetically would be (if/when we had enough data on exercise mimetics, for ex.). Basically, you can get to a good thing (clearance/autophagy) in both of these cases through various means. Why would this be a misleading thing to say about sleep/exercise?
Is the idea that we should be seeking to anesthetize ourselves (without sleep) to get these specific benefits at least, instead of committing to more sleep (which would be an overkill in this presentation)?
Not responding to the broader reaction to this paper in your post btw, just this one bit. Thanks
EDIT: I also want to note that you don’t seem to address the role of sleep in immune function/lowering systemic inflammation markers beyond Walker’s failures of citations. There’s a bunch of literature on this on pubmed etc., which tbf I haven’t reviewed in detail so perhaps it’s all bunk! But it would’ve been good to have insight into that, as my impression ATM is that sleep certainly strengthens your immune system and lowers systemic inflammation.
Here’s the #1 link on Google Scholar that comes up on a search for “inflammation sleep deprivation” (> 800 citations).
They’re looking at inflammatory cytokine levels (CRP, IL-6, and TNF-a), which I can confirm (biomedical engineering MS student currently studying immunology) are key drivers of the inflammatory response, though the immune system is a complex interconnected pathway without a straightforward protein “gas pedal.” Here’s my quick interpretation of the abstract in terms of the support it lends for the sleep deprivation/inflammation connection.
Pros:
n > 50,000, no evidence of publication bias
Found sleep disturbance (poor sleep, sleep complaints) associated with CRP and IL-6, and shorter sleep duration (< 7 hours/night) with CRP.
The researchers do note in the last sentence findings from another study that “Indeed, treatment of insomnia has been found to reduce inflammation and together with diet and physical activity represents a third component in the promotion of sleep health.” The insomnia treatments in the linked study were CBT and tai chi.
Cons:
Neither experimental sleep deprivation nor sleep restriction was associated with CRP, IL-6, or TNFα.
Nothing at all was associated with TNF-a (which the researchers chalk up to “low statistical power” with n = 672, as opposed to the n=34,000 for CRP and n=3,000 for IL-6).
The biggest effects were for people with sleep disturbance and complaints, but one interpretation is that this is due to an underlying autoreactive or pathogenic immune response that causes poor sleep.
My takeaway from this study is that it actually lends strong support to the idea that inflammation is not driven by sleep deprivation. The right interpretation seems to be that if you’re having sleep disturbances, then your doctor may want to check for an inflammatory cause.
However, the authors themselves say in the discussion that “sleep disturbance is associated with inflammatory disease risk and all-cause mortality, possibly by effects of sleep disturbance on inflammatory mechanisms.”
The authors think that sleep deprivation enhances TLR-4-stimulated production of IL-6 and TNF-a. The immune pathway starting with TLR-4 is well-established, and you can find it covered in a good textbook like Janeway.
The key component of these authors’ argument, though, is linking sleep deprivation to that pathway. As evidence, they cite a 2006 study (n=30) that assessed IL-6 and TNF-a production with an experimental manipulation comparing levels after 8 hours of sleep vs. 4 hours of sleep. Then they took blood assays at 8 AM, 12 PM, 4 PM, 8 PM, and 11 PM. This study has a lot of problems:
“Data were analyzed using SAS statistical software (version 9.13; SAS Inc, Cary, NC). Missing values were handled using cell-wise deletion.” Missing data is a common problem in research, but there are sound statistical methods for dealing with it. Deleting the missing values is not one of them. And how the heck are these researchers missing data when they’re collecting it themselves?
“Compared with baseline levels, the percentage of monocytes expressing IL-6 and TNF-α was significantly increased at 8 AM after PSD (t107 = −2.3; P<.05); this increase normalized at subsequent time points.” So they found an increased percentage of monocytes expressing IL-6 and TNF-a at 8 AM, but not at 12 PM, 4 PM, 8 PM, or 11 PM. No mention of multiple comparison corrections in their analysis, but let’s hope they did it and didn’t tell us about it. Also, unlike their nonsignificant P-values, which are given precisely, they merely say “P < .05.” So then they went on to the exploratory analysis.
“The number of monocytes was not different at the 8 AM time point after PSD (t1,29 = −0.3; P>.85).”
Finding elevated monocyte cytokine expression at 8 AM, they also looked at transcription in these monocytes at only this timepoint, and found that indeed, mRNA is at 6-fold (IL-6) and 2-fold (TNF-a) levels.
All participants had their sleep deprivation on day 4, after 3 days sleeping in a lab having their blood drawn 5 times a day.
Let’s just say that this is not strong evidence of sleep deprivation-driven inflammation. But it is probably some evidence. This paper (but not the original metastudy) also links to 5 other papers buttressing its claim of a sleep deprivation-inflammation causal link.
I’m not going to go this in-depth into all of them, but let’s at least get the takeaways:
Elevated lymphocyte levels found both after sleep deprivation and in the afternoon and evening of the day following sleep. I have to admit I find the abstract confusing: they say that a decrease in monocytes, NK cells, and lymphocytes may “serve to support ongoing immune defense.” That’s the opposite of how I’d interpret a low level of white blood cells. But maybe I’m missing something.
Sleep deprivation reduces NK and cellular immune responses in humans. The title says it all.
The study finds impairment in vigilance after sleep deprivation to 6 hours of sleep/night, increases in IL-6 secretion and, in men but not women, TNF-a, as well as decreases in cortisol.
“Relative to the partial sleep deprivation condition, subjects in the total sleep deprivation condition had elevated plasma levels of sTNF-αRI on day 2 (P = .04), day 3 (P = .01), and across days 2 to 4 of sleep loss (P = .01) and elevated levels of IL-6 on day 4 (P = .04).”
“The CRP concentrations increased during both total (88 hours awake) and partial (4.2 hours of sleep) sleep deprivation conditions, but remained stable in the control condition.”
Note that in these studies, the researchers are commonly taking frequent blood samples. For example, in that last study, they took hourly blood samples. They’re being continuously monitored, catheterized, in a lab environment, sleeping with a catheter, and getting their rectal body temperature taken. Again, I think we have to worry about the potential confounding impact of stress, blood loss, etc on driving this immune response.
Looking at the results from these 5 studies, we see a mix of effects. In sleep deprivation, sometimes inflammatory cytokines are up, but other times, inflammatory cells are down. Results are there but inconsistent.
Moreover, and crucially, these are short-term studies that don’t investigate the health impacts we’d actually care about from inflammation. That’s not their fault—they’re a valuable contrbution to scientific knowledge—but we can only learn so much from studies like this. I am not ready to accept with any great confidence a claim that “sleep deprivation shreds your immune system” based on this data.
There’s a lot of interesting stuff in the post, but the following counter-point you offer to “the idea that sleep’s purpose is metabolite clearance” I can’t quite follow:
I’m not quite following the meaning that clearance is not caused by sleep per se, but instead only co-occurrs with it bit. So yes, sleep allegedly results in X (clearance), that you can also get through, e.g., anesthesia. I don’t see how this is more misleading than a statement like exercise results in autophagy which you can also get by using exercise mimetics hypothetically would be (if/when we had enough data on exercise mimetics, for ex.). Basically, you can get to a good thing (clearance/autophagy) in both of these cases through various means. Why would this be a misleading thing to say about sleep/exercise?
Is the idea that we should be seeking to anesthetize ourselves (without sleep) to get these specific benefits at least, instead of committing to more sleep (which would be an overkill in this presentation)?
Not responding to the broader reaction to this paper in your post btw, just this one bit. Thanks
EDIT: I also want to note that you don’t seem to address the role of sleep in immune function/lowering systemic inflammation markers beyond Walker’s failures of citations. There’s a bunch of literature on this on pubmed etc., which tbf I haven’t reviewed in detail so perhaps it’s all bunk! But it would’ve been good to have insight into that, as my impression ATM is that sleep certainly strengthens your immune system and lowers systemic inflammation.
Sleep Disturbance, Sleep Duration, and Inflammation: A Systematic Review and Meta-Analysis of Cohort Studies and Experimental Sleep Deprivation (schi-hub link).
Here’s the #1 link on Google Scholar that comes up on a search for “inflammation sleep deprivation” (> 800 citations).
They’re looking at inflammatory cytokine levels (CRP, IL-6, and TNF-a), which I can confirm (biomedical engineering MS student currently studying immunology) are key drivers of the inflammatory response, though the immune system is a complex interconnected pathway without a straightforward protein “gas pedal.” Here’s my quick interpretation of the abstract in terms of the support it lends for the sleep deprivation/inflammation connection.
Pros:
n > 50,000, no evidence of publication bias
Found sleep disturbance (poor sleep, sleep complaints) associated with CRP and IL-6, and shorter sleep duration (< 7 hours/night) with CRP.
The researchers do note in the last sentence findings from another study that “Indeed, treatment of insomnia has been found to reduce inflammation and together with diet and physical activity represents a third component in the promotion of sleep health.” The insomnia treatments in the linked study were CBT and tai chi.
Cons:
Neither experimental sleep deprivation nor sleep restriction was associated with CRP, IL-6, or TNFα.
Nothing at all was associated with TNF-a (which the researchers chalk up to “low statistical power” with n = 672, as opposed to the n=34,000 for CRP and n=3,000 for IL-6).
The biggest effects were for people with sleep disturbance and complaints, but one interpretation is that this is due to an underlying autoreactive or pathogenic immune response that causes poor sleep.
My takeaway from this study is that it actually lends strong support to the idea that inflammation is not driven by sleep deprivation. The right interpretation seems to be that if you’re having sleep disturbances, then your doctor may want to check for an inflammatory cause.
However, the authors themselves say in the discussion that “sleep disturbance is associated with inflammatory disease risk and all-cause mortality, possibly by effects of sleep disturbance on inflammatory mechanisms.”
The authors think that sleep deprivation enhances TLR-4-stimulated production of IL-6 and TNF-a. The immune pathway starting with TLR-4 is well-established, and you can find it covered in a good textbook like Janeway.
The key component of these authors’ argument, though, is linking sleep deprivation to that pathway. As evidence, they cite a 2006 study (n=30) that assessed IL-6 and TNF-a production with an experimental manipulation comparing levels after 8 hours of sleep vs. 4 hours of sleep. Then they took blood assays at 8 AM, 12 PM, 4 PM, 8 PM, and 11 PM. This study has a lot of problems:
“Data were analyzed using SAS statistical software (version 9.13; SAS Inc, Cary, NC). Missing values were handled using cell-wise deletion.” Missing data is a common problem in research, but there are sound statistical methods for dealing with it. Deleting the missing values is not one of them. And how the heck are these researchers missing data when they’re collecting it themselves?
“Compared with baseline levels, the percentage of monocytes expressing IL-6 and TNF-α was significantly increased at 8 AM after PSD (t107 = −2.3; P<.05); this increase normalized at subsequent time points.” So they found an increased percentage of monocytes expressing IL-6 and TNF-a at 8 AM, but not at 12 PM, 4 PM, 8 PM, or 11 PM. No mention of multiple comparison corrections in their analysis, but let’s hope they did it and didn’t tell us about it. Also, unlike their nonsignificant P-values, which are given precisely, they merely say “P < .05.” So then they went on to the exploratory analysis.
“The number of monocytes was not different at the 8 AM time point after PSD (t1,29 = −0.3; P>.85).”
Finding elevated monocyte cytokine expression at 8 AM, they also looked at transcription in these monocytes at only this timepoint, and found that indeed, mRNA is at 6-fold (IL-6) and 2-fold (TNF-a) levels.
All participants had their sleep deprivation on day 4, after 3 days sleeping in a lab having their blood drawn 5 times a day.
Let’s just say that this is not strong evidence of sleep deprivation-driven inflammation. But it is probably some evidence. This paper (but not the original metastudy) also links to 5 other papers buttressing its claim of a sleep deprivation-inflammation causal link.
I’m not going to go this in-depth into all of them, but let’s at least get the takeaways:
Elevated lymphocyte levels found both after sleep deprivation and in the afternoon and evening of the day following sleep. I have to admit I find the abstract confusing: they say that a decrease in monocytes, NK cells, and lymphocytes may “serve to support ongoing immune defense.” That’s the opposite of how I’d interpret a low level of white blood cells. But maybe I’m missing something.
Sleep deprivation reduces NK and cellular immune responses in humans. The title says it all.
The study finds impairment in vigilance after sleep deprivation to 6 hours of sleep/night, increases in IL-6 secretion and, in men but not women, TNF-a, as well as decreases in cortisol.
“Relative to the partial sleep deprivation condition, subjects in the total sleep deprivation condition had elevated plasma levels of sTNF-αRI on day 2 (P = .04), day 3 (P = .01), and across days 2 to 4 of sleep loss (P = .01) and elevated levels of IL-6 on day 4 (P = .04).”
“The CRP concentrations increased during both total (88 hours awake) and partial (4.2 hours of sleep) sleep deprivation conditions, but remained stable in the control condition.”
Note that in these studies, the researchers are commonly taking frequent blood samples. For example, in that last study, they took hourly blood samples. They’re being continuously monitored, catheterized, in a lab environment, sleeping with a catheter, and getting their rectal body temperature taken. Again, I think we have to worry about the potential confounding impact of stress, blood loss, etc on driving this immune response.
Looking at the results from these 5 studies, we see a mix of effects. In sleep deprivation, sometimes inflammatory cytokines are up, but other times, inflammatory cells are down. Results are there but inconsistent.
Moreover, and crucially, these are short-term studies that don’t investigate the health impacts we’d actually care about from inflammation. That’s not their fault—they’re a valuable contrbution to scientific knowledge—but we can only learn so much from studies like this. I am not ready to accept with any great confidence a claim that “sleep deprivation shreds your immune system” based on this data.