Circadian rhythm
The circadian clock is an internal timing system that allows organisms to adapt biological processes and behavior to the geophysical time and it is operated by a set of genes and proteins hardwiring transcriptional and translational regulatory feedback loops. In mammals, these feedback loops drive the oscillatory expression of various target genes and regulate cellular processes involved in development, including metabolism and cell cycle.[1][2][3][4][5]
Epigenetic age predictions with epigenetic clocks display a 24-h periodicity. Most epigenetic clocks addressing different aspects of aging exhibited significant oscillations with the youngest and oldest age estimates around midnight and noon, respectively.[6] Maintaining a robust circadian rhythm under various perturbations and stresses is essential for the fitness of an organism. Clock proteins are typically organized into highly dynamic nuclear bodies and engage in transient interactions with their protein partners. In particular, endogenous clock proteins, PER2, BMAL1, and CRY1, in human U2OS cells dynamically assemble into nuclear microbodies and engage in transient interactions among themselves and with chromatin.[7] Clustering of the gene sets involved in the glycolysis pathway, oxidative phosphorylation revealed five clock-controlled metabolism-related candidate genes ALDH3A2, ALDOC, HKDC1, PCK2 and PDHB. Among these top candidates, hexokinase (HK) domain containing 1 (HKDC1), which catalyzes the phosphorylation of glucose,[8] oscillated with the best p-value and the highest relative amplitude.[9]
HKDC1 expression is specifically regulated by TFEB (Transcription factor EB) and is a direct target gene of TFEB. TFEB–HKDC1 axis plays an essential role in PINK1/Parkin-dependent mitophagy by PINK1 stabilization, presumably through the interaction of HKDC1 with TOM70 (translocase of outer mitochondrial membrane protein 70). [10] Additionally, HKDC1 and the VDACs (Voltage-dependent anion-selective channels) with which it interacts are important for the repair of damaged lysosomes, possibly as a result of regulating mitochondria–lysosome contact.[10] Moreover, HKDC1 plays a key role in preventing DNA damage–induced cellular senescence in human cells through the maintenance of both mitochondrial and lysosomal homeostasis. HKDC1 is upregulated upon lysosomal stress and lack of HKDC1 led to defective clearance of damaged lysosomes.[10] HKDC1 deficiency results in mitochondrial dysfunction, increased numbers of hyperfused mitochondria, impaired mitophagy, and the accumulation of damaged lysosomes, all of which are implicated in cellular senescence and multiple diseases exhibiting a senescence-like phenotype. Therefore, HKDC1, which is the direct downstream target of TFEB, functions as a convergent factor regulating both mitochondrial and lysosomal homeostasis, and plays an important role in attenuating cellular senescence by improving mitochondrial and lysosomal function.[10]
Intriguingly, clock genes-mediated circadian oscillations are remarkably dampened in pluripotent stem cells (PSCs) and gradually develop following differentiation. Why, despite the fact that most of the core clock genes (Per1, Per2, Clock, Bmal1, Cry1 and Cry2) were found to be expressed in PSCs, circadian oscillations are dampened in PSCs? It is assumed that the sequential progression from pluripotency to the initiation of cellular differentiation, coupled with epigenetic alterations, facilitates the precise spatial temporal expression of clock component proteins such as PER1, BMAL1, and CLOCK. These proteins are essential for the emergence of circadian clock oscillations.[11] Circadian rhythm can be restored by artificially inducing its restoration through a combination of exogenous expression of BMAL1 and inhibition of polycomb repressive complex 2 in induced pluripotent stem cells.[12]
Interestingly, human iPSCs necessitate a three- to four-fold-longer differentiation period compared to mouse embryonic stem cells (ESCs)/iPSCs to establish circadian oscillations of gene expression. This difference may potentially reflect the variances in gestational periods between mice and humans[13][11]
The light at night (LAN) as a potent disruptor of the circadian system
In humans, melatonin is secreted during the dark phase of the light–dark cycle. Daytime melatonin levels are hence comparatively very low. Light is considered to be the most potent circadian synchronizer for humans, although non-photic time cues, such as meal times, physical activity and social interaction, also play a part in synchronization of the circadian system. Even low intensity light, as emitted by recent technologies such as LEDs, computer screens or televisions, mobile phones, and tablets is capable of acting on the clock, thus leading to a phase delay and a slowing of melatonin secretion.[14] LAN suppresses melatonin expression from the pineal gland. Melatonin has been characterized as the “hormone of darkness”, as it is normally expressed at night and suppressed at daytime. This hormone is implicated in the synchronization of the circadian rhythms and is also believed to have beneficial metabolic actions; low levels of melatonin have been associated with obesity, as well as with glucose dysregulation.[15]
Meta-analyses in experienced shift workers have demonstrated a connection between shift work and physical health outcomes,[16] including cardiovascular disease,[17][18][19] weight gain,[20][21][22] type-2 diabetes,[23][24] and several cancer types.[25]
Association of light at night with cancer
The majority of epidemiological studies of the link between cancer and shift work have reported an increase in the order of 50 to 100% for breast cancer among women who work night shifts.[26][27][28]
References
- ↑ Sukumaran, S., Almon, R. R., DuBois, D. C., & Jusko, W. J. (2010). Circadian rhythms in gene expression: Relationship to physiology, disease, drug disposition and drug action. Advanced drug delivery reviews, 62(9-10), 904-917. PMID: 20542067 PMC2922481 DOI: 10.1016/j.addr.2010.05.009
- ↑ Xiao, Y., Yuan, Y., Jimenez, M., Soni, N., & Yadlapalli, S. (2021). Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms. Proceedings of the National Academy of Sciences, 118(28), e2019756118. PMID: 34234015 PMC8285898 DOI: 10.1073/pnas.2019756118
- ↑ Yuan, Y., & Yadlapalli, S. (2024). Regulation of circadian rhythms by clock protein nuclear bodies. Proceedings of the National Academy of Sciences, 121(5), e2321334121. PMID: 38232300 PMC10835046 (available on 2024-07-17) DOI: 10.1073/pnas.2321334121
- ↑ Pivovarova-Ramich, O., & Malin, S. K. (2024). Circadian rhythm in obesity. Frontiers in Endocrinology, 15, 1387889.
- ↑ Liu, X. L., Duan, Z., Yu, M., & Liu, X. (2024). Epigenetic control of circadian clocks by environmental signals. Trends in Cell Biology. PMID: 38423855 DOI: 10.1016/j.tcb.2024.02.005
- ↑ Koncevičius, K., Nair, A., Šveikauskaitė, A., Šeštokaitė, A., Kazlauskaitė, A., Dulskas, A., & Petronis, A. (2024). Epigenetic age oscillates during the day. Aging Cell, e14170. PMID 38638005 doi:10.1111/acel.14170
- ↑ Xiao, Y., Yuan, Y., Jimenez, M., Soni, N., & Yadlapalli, S. (2021). Clock proteins regulate spatiotemporal organization of clock genes to control circadian rhythms. Proceedings of the National Academy of Sciences, 118(28), e2019756118. PMID: 34234015 PMC8285898 DOI: 10.1073/pnas.2019756118
- ↑ Farooq, Z., Ismail, H., Bhat, S. A., Layden, B. T., & Khan, M. W. (2023). Aiding cancer’s “Sweet Tooth”: Role of hexokinases in metabolic reprogramming. Life, 13(4), 946. PMID: 37109475 PMC10141071 DOI: 10.3390/life13040946
- ↑ Fuhr, L., El-Athman, R., Scrima, R., Cela, O., Carbone, A., Knoop, H., ... & Relógio, A. (2018). The circadian clock regulates metabolic phenotype rewiring via HKDC1 and modulates tumor progression and drug response in colorectal cancer. EBioMedicine, 33, 105-121. PMID: 30005951 PMC6085544 DOI: 10.1016/j.ebiom.2018.07.002
- ↑ 10.0 10.1 10.2 10.3 Cui, M., Yamano, K., Yamamoto, K., Yamamoto-Imoto, H., Minami, S., Yamamoto, T., ... & Nakamura, S. (2024). HKDC1, a target of TFEB, is essential to maintain both mitochondrial and lysosomal homeostasis, preventing cellular senescence. Proceedings of the National Academy of Sciences, 121(2), e2306454120. PMID: 38170752 PMC10786298 (available on 2024-07-03) DOI: 10.1073/pnas.2306454120
- ↑ 11.0 11.1 Agriesti, F., Cela, O., & Capitanio, N. (2024). “Time Is out of Joint” in Pluripotent Stem Cells: How and Why. International Journal of Molecular Sciences, 25(4), 2063. PMID: 38396740 PMC10889767 DOI: 10.3390/ijms25042063
- ↑ Kaneko, H., Kaitsuka, T., & Tomizawa, K. (2023). Artificial induction of circadian rhythm by combining exogenous BMAL1 expression and polycomb repressive complex 2 inhibition in human induced pluripotent stem cells. Cellular and Molecular Life Sciences, 80(8), 200. PMID: 37421441 DOI: 10.1007/s00018-023-04847-z
- ↑ Umemura, Y., Maki, I., Tsuchiya, Y., Koike, N., & Yagita, K. (2019). Human circadian molecular oscillation development using induced pluripotent stem cells. Journal of Biological Rhythms, 34(5), 525-532. PMID: 31368392 PMC6732938 DOI: 10.1177/0748730419865436
- ↑ Chang, A. M., Aeschbach, D., Duffy, J. F., & Czeisler, C. A. (2015). Evening use of light-emitting eReaders negatively affects sleep, circadian timing, and next-morning alertness. Proceedings of the National Academy of Sciences, 112(4), 1232-1237.PMID: 25535358 PMC4313820 DOI: 10.1073/pnas.1418490112
- ↑ Kim, M., Vu, T. H., Maas, M. B., Braun, R. I., Wolf, M. S., Roenneberg, T., ... & Zee, P. C. (2023). Light at night in older age is associated with obesity, diabetes, and hypertension. Sleep, 46(3), zsac130. PMID: 35729737 PMC9995772 DOI: 10.1093/sleep/zsac130
- ↑ Moreno, C. R., Marqueze, E. C., Sargent, C., Wright Jr, K. P., Ferguson, S. A., & Tucker, P. (2019). Working Time Society consensus statements: Evidence-based effects of shift work on physical and mental health. Industrial health, 57(2), 139-157.
- ↑ Zeng, Q., Oliva, V. M., Moro, M. Á., & Scheiermann, C. (2024). Circadian effects on vascular immunopathologies. Circulation Research, 134(6), 791-809.
- ↑ Lo, E. H., & Faraci, F. M. (2024). Circadian Mechanisms in Cardiovascular and Cerebrovascular Disease. Circulation Research, 134(6), 615-617.PMID: 38484030 DOI: 10.1161/CIRCRESAHA.124.324462
- ↑ Xu, Y. X., Zhang, J. H., & Ding, W. Q. (2023). Association of light at night with cardiometabolic disease: A systematic review and meta-analysis. Environmental Pollution, 123130. PMID: 38081378 DOI: 10.1016/j.envpol.2023.123130
- ↑ Xu, Y. J., Xie, Z. Y., Gong, Y. C., Wang, L. B., Xie, Y. Y., Lin, L. Z., ... & Dong, G. H. (2024). The association between outdoor light at night exposure and adult obesity in Northeastern China. International Journal of Environmental Health Research, 34(2), 708-718. PMID: 36628496 DOI: 10.1080/09603123.2023.2165046
- ↑ Zhang, X., Zheng, R., Xin, Z., Zhao, Z., Li, M., Wang, T., ... & Xu, Y. (2023). Sex-and age-specific association between outdoor light at night and obesity in Chinese adults: A national cross-sectional study of 98,658 participants from 162 study sites. Frontiers in Endocrinology, 14, 1119658. PMID: 36891055 PMC9987422 DOI: 10.3389/fendo.2023.1119658
- ↑ Fleury, G., Masís‐Vargas, A., & Kalsbeek, A. (2020). Metabolic implications of exposure to light at night: lessons from animal and human studies. Obesity, 28, S18-S28.
- ↑ Her, T. K., Li, J., Lin, H., Liu, D., Root, K. M., Regal, J. F., ... & Cao, R. (2024). Circadian Disruption across Lifespan Impairs Glucose Homeostasis and Insulin Sensitivity in Adult Mice. Metabolites, 14(2), 126.
- ↑ Vetter, C., Dashti, H. S., Lane, J. M., Anderson, S. G., Schernhammer, E. S., Rutter, M. K., ... & Scheer, F. A. (2018). Night shift work, genetic risk, and type 2 diabetes in the UK biobank. Diabetes care, 41(4), 762-769. PMID: 29440150 PMC5860836 DOI: 10.2337/dc17-1933
- ↑ Muscogiuri, G., Poggiogalle, E., Barrea, L., Tarsitano, M. G., Garifalos, F., Liccardi, A., ... & Vettor, R. (2022). Exposure to artificial light at night: A common link for obesity and cancer?. European Journal of Cancer, 173, 263-275. PMID: 35940056 DOI: 10.1016/j.ejca.2022.06.007
- ↑ Ward, E. M., Germolec, D., Kogevinas, M., McCormick, D., Vermeulen, R., Anisimov, V. N., ... & Schubauer-Berigan, M. K. (2019). Carcinogenicity of night shift work. The lancet oncology, 20(8), 1058-1059. https://doi.org/10.1016/S1470-2045(19)30455-3
- ↑ Erren, T. C., & Morfeld, P. (2024). Circadian epidemiology: Structuring circadian causes of disease and practical implications. Chronobiology International, 41(1), 38-52. PMID: 38047448 DOI: 10.1080/07420528.2023.2288219
- ↑ Touitou, Y., Reinberg, A., & Touitou, D. (2017). Association between light at night, melatonin secretion, sleep deprivation, and the internal clock: Health impacts and mechanisms of circadian disruption. Life sciences, 173, 94-106.
