A new preprint suggests that continuous sleep disruption might drive health problems via increased cellular senescence in visceral fat tissue .
Sleep and health
Until recently, the impact of sleep on human health was largely overlooked, including for healthcare professionals who work long hours. Now, scientists are beginning to understand that impaired sleep quality drives multiple diseases, including age-related diseases. Among other things, it has been linked to metabolic dysfunction , hypertension , systemic inflammation , and dementia .
In this study, which was authored by a group of scientists including Judith Campisi and Eric Verdin of the Buck Institute and published as a pre-print that has not been peer-reviewed yet, the researchers investigated the role of sleep in one of the underlying processes of aging, cellular senescence.
Elevated senescence markers
The researchers created a model of impaired sleep quality that does not substantially affect sleep quantity: mice put in a circular enclosure were gently awakened about three times a minute by a rotating bar. Given that mice sleep in five-minute bouts (and fall asleep almost instantly), this roughly corresponds to a human being awakened twice per hour. The researchers confirmed sleep disruption by measuring levels of the pro-inflammatory cytokine IL-6, which were considerably higher in the study group.
At the end of the 30-day study period, the middle-aged mice were sacrificed, and tissues were analyzed for expression levels of two markers of senescence, the proteins p16 and p21, as well as for several SASP factors. In the brain, heart, testes, and liver, the levels of these markers were unchanged compared to the control group, but they were significantly elevated in visceral adipose tissue (VAT). This fat is more dangerous than skin fat and has been linked to conditions such as systemic inflammation . The researchers then repeated the experiment with younger mice and got similar results, suggesting that the youthful phenotype does not protect from the unhealthy effects of sleep disruption.
The researchers ran several other tests, including on the popular senescence marker β-galactosidase. This marker became elevated in tissues from sleep-disrupted (SD) mice even earlier than other senescence markers, suggesting that β-galactosidase might be useful for detecting senescence at early stages. Senescence was also inferred from alterations in nuclear morphology.
What causes it?
Senescence can be caused by several stressors. The researchers explored the possibility that in this case, the culprits were DNA breaks and oxidative stress. Markers of both types of stress were elevated in SD mice, which means that these pathways could indeed contribute to the increased senescence.
Obesity has also been linked to cellular senescence. While prior studies of sleep deprivation in mice produced controversial results in terms of weight gain, probably depending on the type of sleep disturbance and other aspects of experiment design, in this new study, no weight gain was recorded. On the contrary, SD mice initially had lost some weight, after which it stabilized. This weight loss happened despite increased food consumption in SD mice.
Obviously, sleep disruption can cause stress, which can contribute to senescence. The researchers investigated this possibility by measuring corticosterone, a known marker of stress. However, this did not differ significantly between the study group and controls. The researchers also established that elevated senescence markers were not caused by p16-positive immune cells infiltrating tissues. The immune cells in VAT had the same levels of p16 in both groups, and the non-immune cells contributed to higher senescence in the study group.
Sleep disruption is endemic to modern society and is caused by many social circumstances such as shift work, newborn care, and chronic stress. Our study establishes a novel connection between a social determinant of health and aging. This data lays the groundwork to study the impact of senescent cells in those with frequently disturbed sleep. For example, chronic inflammation is exacerbated by the accumulation of senescent cells and is a key risk factor for many age-related diseases, such as heart disease. Moreover, type 2 diabetes in humans has been linked to senescent adipose cells. We uncover a potential target that could mitigate the systemic impact of sleep loss, as removing senescent cells can improve endothelial repair and metabolic dysfunction.
 Timonina, D., Hormazabal, G. V., Heckenbach, I., Anderton, E., Haky, L., Floro, A., Riley, R., Kwok, R., Breslin, S., Ingle, H., Tiwari, R., Bielska, O., Scheibye-Knudsen, M., Kasler, H. G., Campisi, J., Walter, M., & Verdin, E. (2023). Chronically disrupted sleep induces senescence in the visceral adipose tissue of C57BL/6 mice. bioRxiv, 2023-10.
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