Sleep disturbance, sleep duration, and inflammation: A systematic review and meta-analysis of cohort studies and experimental sleep deprivation
Open accessAbstract
Background Sleep disturbance is associated with inflammatory disease risk and all-cause mortality. Here, we assess global evidence linking sleep disturbance, sleep duration, and inflammation in adult humans. Methods A systematic search of English language publications was performed, with inclusion of primary research articles that characterized sleep disturbance and/or sleep duration or performed experimental sleep deprivation, and assessed inflammation by levels of circulating markers. Effect sizes (ES) and 95% confidence intervals (CI) were extracted and pooled using a random effect model. Results A total of 72 studies (n>50000) were analyzed with assessment of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor α (TNF). Sleep disturbance was associated with higher levels of CRP (ES 0.12; 95% CI 0.05 – 0.19) and IL-6 (ES 0.20; 95% CI 0.08 – 0.31). Shorter sleep duration, but not the extreme of short sleep, was associated with higher levels of CRP (ES 0.09; 95% CI 0.01 – 0.17) but not IL-6 (ES 0.03; 95% CI −0.09 – 0.14). The extreme of long sleep duration was associated with higher levels of CRP (ES 0.17; 95% CI 0.01 – 0.34) and IL-6 (ES 0.11; 95% CI 0.02 – 0.20). Neither sleep disturbances nor sleep duration was associated with TNF. Neither experimental sleep deprivation nor sleep restriction was associated with CRP, IL-6, or TNF. Some heterogeneity among studies was found, but no evidence of publication bias. Conclusions Sleep disturbance and long sleep duration, but not short sleep duration, are associated with increases in markers of systemic inflammation.
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Disrupted sleep may activate inflammatory processes, such as elevations in IL-6 and CRP, according to observational and experimental studies.
“That disrupted sleep may lead to activation of inflammatory processes (e.g., elevations in interleukin-6 [IL-6] and C-reactive protein [CRP]) has received substantial support from observational and experimental studies (Irwin et al., 2016; Irwin & Piber, 2018).”
From Sleep and suicide: A systematic review and meta-analysis of longitudinal studies (2020) · cites this paper as Irwin et al., 2016
The Results and Discussion report that sleep disturbance was associated with higher circulating IL-6 and CRP, supporting the observational part of the claim. The Discussion says experimental sleep loss activated cellular inflammatory pathways but did not raise circulating inflammatory markers; thus experimental evidence does not support the cited example of elevated IL-6 and CRP. (LLM, conf=0.88)
Experimental — accuracy not yet measuredElevation of pro-inflammatory cytokines is associated with sleep disruption.
“their elevation is associated with both sleep disruption (Irwin et al., 2016)”
From Physiological feelings (2019) · cites this paper as Irwin et al., 2016
Sleep has a restorative effect on the immune system, the endocrine system, facilitates recovery of the nervous system and metabolic cost of the waking state, and has an integral role in learning, memory and synaptic plasticity.
“Sleep has been shown to have a restorative effect on the immune system, the endocrine system, facilitate the recovery of the nervous system and metabolic cost of the waking state and has an integral role in learning, memory and synaptic plasticity, all of which can impact both athletic recovery and performance.”
From Sleep and Nutrition Interactions: Implications for Athletes (2019) · cites this paper as [18]
Sleep disturbances and short sleep duration are behavioural risk factors for inflammation and are associated with increased risk of illness and disease.
“Sleep disturbances and short sleep duration are behavioural risk factors for inflammation, associated with increased risk of illness and disease, which can be modified to promote sleep health.”
From Sleep and Nutrition Interactions: Implications for Athletes (2019) · cites this paper as [18]
Sleep disturbance and extremes of sleep duration affect risk factors of inflammatory disease and contribute to all-cause mortality.
“Research has demonstrated that sleep disturbance (i.e. insomnia) and extremes of sleep durations affect risk factors of inflammatory disease and contribute to all-cause mortality [18,22].”
From Sleep and Nutrition Interactions: Implications for Athletes (2019) · cites this paper as [18]
Long sleep duration (>8 h per night) was associated with increased IL-6 (ES: 0.11 (0.02-0.20)) and increased CRP (ES: 0.17 (0.01-0.34)).
“Short sleep duration (< 7 h per night) was associated with increased IL-6 (ES: 0.29 (0.05–0.52)), while long sleep duration (> 8 h per night) was also associated with increased IL-6 (ES: 0.11 (0.02–0.20)) but also increased CRP (ES: 0.17 (0.01–0.34)) [18].”
From Sleep and Nutrition Interactions: Implications for Athletes (2019) · cites this paper as [18]
Short sleep duration (<7 h per night) was associated with increased IL-6 (ES: 0.29 (0.05-0.52)).
“Short sleep duration (< 7 h per night) was associated with increased IL-6 (ES: 0.29 (0.05–0.52)), while long sleep duration (> 8 h per night) was also associated with increased IL-6 (ES: 0.11 (0.02–0.20)) but also increased CRP (ES: 0.17 (0.01–0.34)) [18].”
From Sleep and Nutrition Interactions: Implications for Athletes (2019) · cites this paper as [18]
In a meta-analysis, sleep disturbance (poor sleep quality, insomnia) was associated with increased levels of IL-6 (ES: 0.20 (0.08-0.31)) and CRP (ES: 0.12 (0.05-0.19)).
“In a recent meta-analysis sleep disturbance (i.e., poor sleep quality, insomnia) was associated with increased levels of IL-6 (ES: 0.20 (0.08–0.31)) and CRP (ES: 0.12 (0.05–0.19)) [18].”
From Sleep and Nutrition Interactions: Implications for Athletes (2019) · cites this paper as [18]
Sleep has a pivotal role in performance, training adaptations and recovery.
“Sleep also has a pivotal role to play in performance, training adaptations and recovery [1,18].”
From Sleep and Nutrition Interactions: Implications for Athletes (2019) · cites this paper as [18]
Sleep disturbances and sleep deprivation are risk factors for inflammation, which can be treated or managed to promote recovery and/or performance.
“Similar to nutrition, sleep disturbances (difficulty initiating or maintain sleep) and sleep deprivation (not getting enough sleep) are risk factors for inflammation [18,42], which can be treated or managed to promote recovery and/or performance.”
From Sleep and Nutrition Interactions: Implications for Athletes (2019) · cites this paper as [18]
How sleep disturbance is assessed-validated questionnaire versus single item-affects the heterogeneity of sleep-immune effect estimates, with questionnaires yielding stronger effects.
“the strength and quality of assessment of sleep disturbance (ie, validated questionnaire vs single item) contribute to heterogeneity of effects linking sleep to immune outcomes; stronger effects are found when questionnaires are used (Irwin and Olmstead et al, 2016).”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin and Olmstead et al, 2016
In healthy adults, our meta-analysis found no significant effect of total, partial, or restricted sleep deprivation on CRP, IL-6, or TNF markers.
“our recent meta-analysis did not find any significant effect of sleep deprivation, inclusive of total-, partial, and sleep restriction, on markers of CRP, IL-6, and TNF in healthy adults (Irwin et al, 2016)”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
Experimental sleep deprivation has yielded mixed results due in part to differences in duration of sleep deprivation and selection of cytokine measure.
“experimental sleep deprivation has yielded mixed results due in part to differences in duration of sleep deprivation and the selection of the cytokine measure of inflammation (Irwin and Olmstead et al, 2016).”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin and Olmstead et al, 2016
Sleep disturbance was associated with higher IL-6 (ES 0.20; 95% CI 0.08-0.31).
“and IL-6 (ES.20; 95% CI = 0.08-0.31)(Irwin et al, 2016).”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
Extreme long sleep duration was associated with higher IL-6 (ES 0.11; 95% CI 0.02-20).
“and IL-6 (ES.11; 95% CI = 0.02-20).”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
Neither sleep disturbance nor sleep duration was associated with TNF, though low statistical power with 672 participants tempers this conclusion.
“Neither sleep disturbances nor sleep duration was associated with TNF, although this conclusion is tempered by low statistical power with only 672 participants.”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
Sleep disturbance was associated with higher CRP (ES 0.12; 95% CI 0.05-0.19).
“Sleep disturbance was associated with higher levels of CRP (ES.12; 95% CI = 0.05-0.19)(Figure 5)”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
Shorter sleep duration was not associated with IL-6 (ES 0.03; 95% CI -0.09 to 0.14).
“but not IL-6 (ES.03; 95% CI: -0.09 to 0.14).”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
When sleep disturbance was assessed with more robust validated measures, increases in CRP and IL-6 were found; single-question symptom reporting yielded mixed effects.
“when sleep disturbance was assessed using more robust and validated measures, increase in CRP and IL-6 was found.Yet, when assessment was by simple symptom reporting with reliance on only a single question, there were mixed effects”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
A meta-analysis provided the first global evidence linking sleep disturbance, sleep duration, and inflammation in adult humans.
“This meta-analysis provided the first global evidence linking sleep disturbance, sleep duration, and inflammation in adult humans”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
Shorter sleep duration, but not the extreme short-sleep category, was associated with higher CRP (ES 0.09; 95% CI 0.01-0.17).
“Shorter sleep duration, but not the extreme category of short sleep, was associated with higher levels of CRP (ES.09; 95% CI = 0.01-0.17)”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
Meta-regression suggested larger effect sizes were associated with younger age and greater proportion of female subjects.
“meta-regression results suggested that larger ES were associated with younger age and greater proportion of female subjects within the sample (Irwin et al, 2016).”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
Sex differences were statistically significant only for sleep disturbance predicting IL-6 and continuous sleep duration predicting CRP.
“However, these sex differences were only statistically significant for sleep disturbance predicting IL-6 and sleep duration continuously predicting CRP.”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
Meta-analytic findings found long sleep duration, but not short sleep duration, associated with increased CRP and IL-6.
“Meta-analytic findings have also examined extremes of sleep duration, and found that long sleep duration, but not short sleep duration, were associated with increase in CRP and with increase in IL-6 (Irwin et al, 2016).”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
Extreme long sleep duration was associated with higher CRP (ES 0.17; 95% CI 0.01-0.34).
“The extreme category of long sleep duration was associated with higher levels of CRP (ES.17; 95% CI = 0.01-0.34)”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
The effect size linking sleep disturbance with IL-6 was larger than that for CRP.
“Finally, it is not surprising that the ES linking sleep disturbance with IL-6 were larger than those found for CRP.”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Irwin et al, 2016
Suggested causal links to adverse health outcomes for short sleep duration include inflammation.
“As for short sleep duration, the suggested causal links to adverse health outcomes included a series of pathologies including, hyperactivation of the sympathetic nervous system, 26 insulin resistance, 27 endothelial dysfunctions, 28 and inflammation.29”
Administration of a TNF antagonist to abstinent alcohol-dependent patients counteracted increases in REM sleep, which are prospectively associated with the risk of alcoholic relapse.
“Along a similar line, administration of a TNF antagonist to abstinent alcohol-dependent patients counteracted increases in REM sleep, which are prospectively associated with the risk of alcoholic relapse (260).”
From The Sleep-Immune Crosstalk in Health and Disease (2019) · cites this paper as [260]
A recent meta-analysis did not find a consistent association between short sleep and inflammation.
“A recent meta-analysis did not find a consistent association between short sleep and inflammation(57).”
From Sleep: important considerations for the prevention of cardiovascular disease (2016) · cites this paper as [57]
A recent meta-analysis found no consistent relationship between sleep duration and inflammation.
“A recent meta-analysis found no consistent relationship between sleep duration and inflammation,77”
From Sleep, Health, and Society (2017) · cites this paper as [77]
Chronic sleep dysfunction is associated with, and predicts, higher daytime levels of inflammatory markers such as CRP and IL-6.
“prospective longitudinal studies and meta-analyses show that chronic sleep dysfunction is associated with, and predicts, higher daytime levels of known indicators of inflammation, such as C-reactive protein (CRP) and interleukin 6 (IL-6).”
From Towards an Integrative Account of Potential Mechanisms Mediating the Path From Sleep Dysfunction to Hallucinations (2025) · cites this paper as [78]
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The Sleep-Immune Crosstalk in Health and Disease
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“, CRP and IL-6) than short sleep duration (259), supporting the importance of a better understanding of the inflammatory consequences of disturbed sleep.”
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Sleep health: Reciprocal regulation of sleep and innate immunity
Irwin, M. R., & Opp, M. R. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.148 · Cited by 624 · see citing works
Self-citationSleep, circadian rhythm, and gut microbiota
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“, elevations in interleukin-6 [IL-6] and C-reactive protein [CRP]) has received substantial support from observational and experimental studies (Irwin et al., 2016; Irwin & Piber, 2018).”
BackgroundPace-Schott, E. F., Amole, M. C., Aue, T., Balconi, M., Bylsma, L. M., Critchley, H., Demaree, H. A., Friedman, B. H., Gooding, A. E. K., Gosseries, O., et al. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.05.002 · Cited by 221 · see citing works
“disruption (Irwin et al., 2016) and circadian misalignment (Wright et al.”
Napping: a public health issue. From epidemiological to laboratory studies
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“Similar to nutrition, sleep disturbances (difficulty initiating or maintain sleep) and sleep deprivation (not getting enough sleep) are risk factors for inflammation [18,42], which can be treated or managed to promote recovery and/or performance.”
BackgroundInfluentialPsycho-Neuroendocrine-Immune Interactions in COVID-19: Potential Impacts on Mental Health
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Self-citationSleep: important considerations for the prevention of cardiovascular disease
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Sleep disturbances and dementia risk: a multicenter study
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Carroll, J. E., Cole, S. W., Seeman, T. E., Breen, E. C., Witarama, T., Arevalo, J. M. G., Ma, J., & Irwin, M. R. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.08.024 · Cited by 129 · see citing works
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Circadian depression: A mood disorder phenotype
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Habitual sleep as a contributor to racial differences in cardiometabolic risk
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Insomnia and Telomere Length in Older Adults
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Self-citationKuhlman, K. R., Robles, T. F., Dooley, L. N., Boyle, C. C., Haydon, M. D., & Bower, J. E. (2018) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2018.02.001 · Cited by 67 · see citing works
Braune, K., Gajewska, K. A., Thieffry, A., Lewis, D. M., Froment, T., O'Donnell, S., Speight, J., Hendrieckx, C., Schipp, J., Skinner, T., et al. (2021) · Journal of Medical Internet Research · doi:10.2196/25409 · Cited by 67 · see citing works
Insomnia and inflammation: A two hit model of depression risk and prevention
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Self-citationCho, H. J., Eisenberger, N. I., Olmstead, R., Breen, E. C., & Irwin, M. R. (2016) · Translational Psychiatry · doi:10.1038/tp.2016.23 · Cited by 64 · see citing works
Self-citationPro-inflammatory cytokines and psychotherapy in depression: Results from a randomized clinical trial
Del Grande da Silva, G., Wiener, C. D., Barbosa, L. P., Gonçalves Araujo, J. M., Molina, M. L., San Martin, P., Oses, J. P., Jansen, K., Dias de Mattos Souza, L., & Azevedo da Silva, R. (2016) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2016.01.008 · Cited by 60 · see citing works
Sleep disturbances and inflammatory biomarkers in schizophrenia: focus on sex differences
Lee, E. E., Ancoli-Israel, S., Eyler, L. T., Tu, X. M., Palmer, B. W., Irwin, M. R., & Jeste, D. V. (2019) · The American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2018.09.017 · Cited by 58 · see citing works
Self-citationSleep deprivation predisposes allergic mice to neutrophilic lung inflammation
Nunes, J. O. F., Apostolico, J. D. S., Andrade, D. A. G., Ruiz, F. S., Fernandes, E. R., Andersen, M. L., Keller, A. C., & Rosa, D. S. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2017.06.025 · Cited by 43 · see citing works
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Neuro-, Cardio-, and Immunoplasticity: Effects of Early Adversity
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Internet-Based Cognitive-Behavioral Therapy for Insomnia in Adults With Asthma: A Pilot Study
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Night shift schedule alters endogenous regulation of circulating cytokines
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No phenotypic or genotypic evidence for a link between sleep duration and brain atrophy
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Four nights of sleep restriction suppress the postprandial lipemic response and decrease satiety
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Clinical Phenotype of Depression Affects Interleukin-6 Synthesis
Zadka, Ł., Dzięgiel, P., Kulus, M., & Olajossy, M. (2017) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2016.0074 · Cited by 20 · see citing works
Physical activity, sleep and risk of respiratory infections: A Swedish cohort study
Ghilotti, F., Pesonen, A.-S., Raposo, S. E., Winell, H., Nyrén, O., Trolle Lagerros, Y., & Plymoth, A. (2018) · PLOS ONE · doi:10.1371/journal.pone.0190270 · Cited by 18 · see citing works
Cao, Q., Zhao, H., Yao, J., & Liang, Y. (2021) · Current Psychology · doi:10.1007/s12144-019-00200-5 · Cited by 13 · see citing works
Sheaves, B., Cropley, V. L., Moseley, P., Woodruff, P. W. R., Punton, G., Speth, C., Speth, J., Meerlo, P., & Brederoo, S. G. (2025) · Schizophrenia Bulletin · doi:10.1093/schbul/sbaf107 · Cited by 6 · see citing works
- Authors
- Irwin, M. R., Olmstead, R., & Carroll, J. E.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Irwin, Michael R.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 80
- Issue
- 1
- Pages
- 40-52
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC4666828
- OpenAlex
- W646218571
- Semantic Scholar
- bdb003f18c999bfe89d91452fb4dfe262be26c76
- Cited by
- 2,085
- References
- 130
- Citations by year
- 2026: 255 · 2025: 348 · 2024: 261 · 2023: 306 · 2022: 251 · 2021: 212 · 2020: 158 · 2019: 109 · 2018: 85 · 2017: 50 · 2016: 45 · 2015: 5
- FWCI
- 8.01
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Aging (R01-AG034588)
- National Institutes of Health (Grant Nos. R01-CA119159, R01-HL079955, R01 HL095799, P30-AG028748, P30-AG017265)
- Topics
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and related disorders
- Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Keywords
- sleep disorders, sleep duration, inflammation, C-reactive protein, interleukin-6, TNF-α, sleep restriction, long sleep, short sleep duration, inflammatory markers
- MeSH terms
- Adult, Humans, Inflammation, Sleep, Sleep Deprivation, Sleep Wake Disorders
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