Circadian rhythms protect and heal our eyes

Ophthalmology Updates: Our eyes are more than just windows to the soul; they are also governed by internal clocks. A groundbreaking study by researchers from the Beijing Institute of Ophthalmology-China unveils the critical role of circadian rhythms in maintaining ocular health. This Ophthalmology Updates news report delves into the study's findings, explaining how our biological clocks influence eye functions and potentially offering new avenues for treating eye conditions.


The circadian rhythm of the ocular surface is influenced by diabetes. Diabetes influences the rhythmic expression of five core clock genes (Clock, Bmal1, Per2, Cry1, and Rev-erbα) in the normal murine corneal epithelium. Diabetes attenuated the circadian rhythm of corneal epithelial mitosis with delayed corneal wound-healing. In addition, diabetes also enhanced the emigration fluctuation of neutrophils and the circadian rhythm of γ δ T-cells’ recruitment to the limbal region.

The Biological Clock and Our Eyes
Circadian rhythms are the body’s natural cycles that regulate various physiological processes over a 24-hour period. These rhythms are controlled by a master clock located in the brain and by individual clocks in various tissues, including the eyes. The research team, led by Dr Xiaozhao Zhang and Dr Ying Jie, investigated the presence and function of these clocks in the ocular surface - the cornea, conjunctiva, and related tissues.
 
The researchers highlighted that disruptions in these rhythms, whether due to genetic factors or environmental influences, could lead to various health issues.
 
Clock-Driven Gene Expression
At the core of circadian rhythms are clock genes, which regulate the expression of numerous other genes. In the ocular surface, these genes follow a precise 24-hour cycle, influencing various cellular activities such as cell division, metabolism, and immune responses. The study team conducted extensive RNA sequencing on mouse corneal tissues, revealing that nearly 25% of the genes exhibit significant rhythmic expression.
 
Interestingly, most of these genes peaked during the dark phase, which aligns with the nocturnal nature of mice. This finding suggests that the timing of gene expression is crucial for optimal eye function and health.
 
Key Genes Involved
The core clock genes identified in the study include:
 
-CLOCK: This gene encodes a protein that forms a complex with BMAL1, acting as a master regulator of the circadian rhythm.
 
-BMAL1: Partnering with CLOCK, BMAL1 helps regulate the transcription of other clock genes.
 
-PER1, PER2: These genes produce proteins that interact with the CLOCK-BMAL1 complex to inhibi t their own transcription, creating a feedback loop.
 
-CRY1, CRY2: Similar to PER genes, CRY genes also produce inhibitory proteins that regulate the CLOCK-BMAL1 activity.
 
-REV-ERBα, REV-ERBβ: These genes help fine-tune the circadian rhythms by repressing the activity of BMAL1 and other genes.
 
The study found that these genes and their protein products create a feedback loop that ensures the precision of circadian rhythms, which in turn regulate numerous other genes involved in eye health.
 
Daily Oscillations in the Ocular Surface
The study also uncovered that the cornea undergoes daily fluctuations in shape and thickness, correlating with the activity of clock genes. For example, the corneal epithelium - a layer of cells on the surface of the cornea - renews itself in a circadian manner. Disrupting the normal light-dark cycle can adversely affect this renewal process, leading to various eye problems.
 
In addition to 24-hour cycles, the researchers discovered shorter biological rhythms, such as 12-hour cycles, which also play a role in ocular surface functions. These shorter cycles are associated with essential metabolic processes, further emphasizing the complexity and importance of circadian rhythms in eye health.
 
The Impact of Diabetes on Eye Rhythms
One of the significant findings of this study is the impact of diabetes on the circadian rhythms of the eye. Diabetes is known to cause various eye problems, including diabetic keratopathy, which affects the cornea. The research showed that diabetes disrupts the expression of key clock genes, leading to impaired corneal cell division and delayed wound healing.
 
In diabetic mice, the rhythmic expression of core clock genes such as CLOCK, BMAL1, and PER2 was significantly altered. The expression of these genes was downregulated, while CRY1 and REV-ERBα were upregulated. This disruption resulted in a loss of the normal circadian pattern of cell division and wound healing in the cornea. However, administering insulin helped restore some of these rhythms, highlighting the potential for circadian-based therapies in managing diabetic eye conditions.
 
Influence of Environmental Light
Environmental light cycles are vital in regulating circadian rhythms. Continuous exposure to light or constant darkness can disrupt the normal functioning of the ocular clocks, leading to adverse effects on eye health. For instance, prolonged light exposure can impair the cornea's ability to repair itself, emphasizing the need for maintaining regular light-dark cycles.
 
Detailed Study Findings
The study involved collecting corneal tissues from adult male mice every three hours over a 24-hour light-dark cycle. The RNA sequencing data revealed that 6,034 genes in the cornea exhibited significant rhythmic expression. These genes are involved in various biological processes, including:
 
-Cell Growth and Proliferation: The study showed that genes involved in cell cycle regulation and DNA replication peaked at specific times of the day, correlating with periods of increased cell division.
 
-Metabolism: Genes regulating glucose and lipid metabolism followed a circadian pattern, suggesting that the eye’s energy needs vary throughout the day.
 
-Immune Response: The expression of immune-related genes also exhibited daily rhythms, indicating that the eye’s defense mechanisms are influenced by circadian clocks.
 
The researchers noted that most of the rhythmic genes peaked during the dark phase (night), which aligns with the nocturnal behavior of mice. This pattern likely reflects the increased metabolic and repair activities that occur during the animal’s active period.
 
Future Prospects and Potential Therapies
Understanding the link between circadian rhythms and eye health opens new avenues for treatment. For example, optimizing the timing of eye surgeries or administering medications at specific times of the day could enhance their effectiveness. Moreover, therapies targeting the circadian clock could improve the management of chronic eye conditions like dry eye syndrome and diabetic retinopathy.
 
The study also suggests that lifestyle changes, such as maintaining regular sleep patterns and managing light exposure, could help support eye health. Future research will likely focus on developing circadian-based interventions to prevent and treat eye diseases.
 
Conclusion
This pioneering study underscores the importance of circadian rhythms in maintaining ocular health. By understanding how these biological clocks operate and influence eye functions, we can develop new strategies to enhance eye care and treat various eye conditions.
 
The study findings were published in the peer-reviewed journal: Biomolecules.
https://www.mdpi.com/2218-273X/14/7/796
 
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