Our circadian rhythms, or body clocks, are governed by light-dark cycles and play an important role in human health. However, shift work, or working outside of the hours of 7 AM to 6 PM, results in a desynchronization of these rhythms.1 This dysregulation is implicated in multiple human disorders including cancers, metabolic disease, obesity, diabetes, and vascular diseases.2-5 However, existing studies are unable to separate disease risk from other factors such as smoking or socioeconomic status. With remote work becoming the norm, the study of inconsistent sleep-wake schedules and their effect on our health will only become more important.
David Earnest, a professor at the Texas A&M Health Science Center, is interested in circadian rhythms and their effect on the cardiovascular system. “It was really only about 10 or 15 years ago that studies really started to come forward, particularly human epidemiological studies, to show that people doing shift work are at higher risk for a lot of human health disorders,” said Earnest. In a 2016 study, Earnest and his colleagues successfully showed that strokes had more severe outcomes in rats who experienced light-dark cycle shifts similar to humans in shift work positions.6 However, he wanted to see whether these effects would persist later in life when stroke risks are higher. In a study recently published in Neurobiology of Sleep and Circadian Rhythms, Earnest and his group found that circadian rhythm dysregulation in rats not only increases stroke severity immediately, but can also affect stroke outcomes later in life.7
Shift work occurs most often between 16 and 24 years of age, whereas strokes are more likely to occur in middle age when individuals typically move to a more common work schedule. Earnest and his group replicated this by exposing younger rats to shifting light-dark cycles and then returning them to consistent light-dark cycles until they reached the equivalent of human middle age. The researchers found that when they induced stroke following this protocol, the rats had increased functional deficits and mortality when compared to rats that did not experience cycle shifts. This effect was specifically amplified in females and showed that even if shift work ends at an early age, it can have significant effects later in life.
“I think the fact that they emphasize this might be happening in females is surprising. Because normally the literature right now says females are protected from stroke,” said Lauren Hablitz, a professor at the University of Rochester Medical Center, who was not involved in the study. According to Earnest, while at younger ages females are generally more protected from stroke when compared to males, at middle age, females are not only more susceptible to strokes but also have more severe outcomes.
The people who do stroke research normally don't believe this is a real thing, so the more times we can say this, the more they start believing us.
- Lauren Hablitz, University of Rochester Medical Center
“The idea that circadian misalignment at one stage of life means that you're going to respond differently to the effects of stroke [later in life], I think that's actually really exciting,” said Peter Liu, an investigator at the Lundquist Institute at the University of California, Los Angeles who was not involved in the study. “And if true, it makes you wonder, what is driving that?”
Earnest and his group also found that the shifted light/dark cycles promoted a long-term inflammatory phenotype, particularly circulating levels of the inflammatory cytokine IL-17A and a gut bacterial microbiome-derived inflammatory mediator lipopolysaccharide (LPS). “So what we're looking at [now] is how that interaction between the gut and the brain impacts how shifted work cycles affect the response to stroke,” said Earnest.
Earnest hopes this work will bring more attention to the consequences of circadian desynchronization. “The people who do stroke research normally don't believe this is a real thing, so the more times we can say this, the more they start believing us,” said Hablitz.
- F.A.J.L. Scheer et al., “Adverse metabolic and cardiovascular consequences of circadian misalignment,” PNAS, 106:4453-58, 2009.
- A. Knutsson et al., “Increased risk of ischaemic heart disease in shift workers,” Lancet, 2:89-92, 1986.
- B. Karlsson et al., “Is there an association between shift work and having a metabolic syndrome? Results from a population based study of 27,485 people,” Occup Environ Med, 58:747-52, 2001.
- F. Tüchsen et al., “A 12 year prospective study of circulatory disease among Danish shift workers,” Occup Environ Med, 63:451-55, 2006.
- C.H. Kroenke et al., “Work characteristics and incidence of type 2 diabetes in women,” Am J Epidemiol, 165:175-83, 2007.
- D.J. Earnest et al., “Sex differences in the impact of shift work schedules on pathological outcomes in an animal model of ischemic stroke,” Endocrinology, 157(7):2836-43, 2016.
- D.J. Earnest et al., “Sex differences in the diathetic effects of shift work schedules on circulating cytokine levels and pathological outcomes of ischemic stroke during middle age,” Neurobiol Sleep Circadian Rhythms, 13:100079, 2022.
