Biological rhythms

Health

Biological rhythms are critically important in keeping cells youthful

By Juman Hijab

Reading time: minutes

Original date: August 31, 2023  

Updated: September 3, 2023

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Biological rhythms: Hormone levels

Pikovit. Circadian rhythm: Melatonin and cortisol cycles. Shutterstock.com, ID 2174779955.

The nature of biological rhythms

Biological rhythms are repetitive, cyclical changes in the cells of living creatures. They are part of nature. These cycles creates dynamic variations in an animal's internal signals, hormones, and behavior and are essential for their survival. Biological rhythms help living beings adapt to their environment, conserve energy, and coordinate their activities (1, 2, 3, 4, 5, 6).

This article focuses on the cyclical character of biological rhythms in our body.

  • Just like the tides, there is a rhythmic ebb and flow of signals in our cells.
  • When the rhythmicity is disrupted and replaced by chronic stimulation, affected cells experience dysfunction
  • In many cases, chronic stimulation can lead to cellular senescence.

In effect, it is critical for cells - particularly stem cells - to have periods of stimulation alternating with periods of quiescence.

Circadian rhythmicity

All creature's cells have cyclical rhythms. These are regulated by internal clocks. Circadian (daily) rhythms are roughly 24 hours long and help animals regulate their sleep-wake cycle, body temperature, and hormone levels. Thus, melatonin levels peak at night in animals whereas cortisol levels peak just before waking (2).

In our body, circadian rhythms are regulated by the suprachiasmatic nucleus (SCN), which is a group of ~ 20,000 neurons located in the hypothalamus (4). The SCN receives signals from the environment, such as the light-dark cycle, and uses these signals to set the body's internal clock.

It was thought that only the group of cells in the SCN have internal clocks. It turns out that almost all cells have internal clocks that control their biology (4, 5). For instance, circadian rhythms can control timing of cell proliferation (3), even in the absence of SCN involvement. 

Disturbed circadian rhythms and poor health

The cycling biology in cells is due to "clock genes" that respond to environmental cues. Ten percent of the genes in tissues are estimated to be under circadian regulation (3). Each cell has its own internal clock that manifests oscillations separate from those of the SCN master clock. Researchers have documented cycling levels of ions (particularly calcium), mRNA, and proteins based on a cell's internal clock (4).

Circadian rhythms in our master clock depend on cyclical cues from the environment. When those cues are irregular, the SCN cells become dysfunctional (5). For example, chronic exposure to light at night, abnormal sleep patterns, and shift work result in metabolic abnormalities. In support of this, shift workers have been found to have  a higher incidence of diabetes and obesity.


Shift work and abnormal circadian rhythms


While some of us may say that eating at night seems to be the culprit for people doing shift work, it is only part of the problem. Abnormal circadian rhythms create a negative metabolic environment. Thus, experiments done in subjects who underwent forced circadian misalignment showed glucose metabolism disarray, inverted cortisol rhythms, and increased blood pressure even after 10 days of altered circadian rhythms.

Moreover, studies have noted that sleep deprivation and poor sleep quality are also linked with diabetes, metabolic syndrome, and obesity. Interestingly, animal studies have shown that disruption of the "clock" genes in the SCN leads to mice that eat a lot and are obese (5). Furthermore, animals with deficient production of melatonin seem to be more susceptible to cancer and the life-span of animals with an abnormal SCN clock is shorter.

Artificial light ages the hypothalamus' Suprachiasmic nucleus

In our modern day society, we are exposed to artificial light for much longer hours than is healthy. Unfortunately, the SCN cannot tell the difference between artificial light and daylight. Chronic stimulation by artificial light and aging are two major reasons for disrupted biological rhythms: 

  1. Chronic light stimulation shows the same circadian rhythm dysfunction in animals and humans, replicating the dysfunction that happens with experimental disruption of SCN cells (810
  2. Aging clearly affects the SCN cells (78910). Older people lose sleep at night and have difficulty staying awake during the day. There is decreased circadian rhythmic electrical activity in SCN neurons as well as a decrease in the hormone release from the cells. 

Unfortunately, when the SCN neurons are stressed over time, their cells: 

  • exhibit greater oxidative damage
  • have less anti-oxidant molecules produced
  • have evidence of neuro-degeneration 
  • produce pro-inflammatory cytokines
  • reduced their production of melatonin

Thus, a vicious cycle is set up: disrupted circadian rhythms lead to abnormal metabolic and neurohormonal systems. The latter lead to chronic inflammatory states. As has been discussed previously, chronic inflammatory states lead to cellular senescence. This further exacerbates an already dysfunctional suprachiasmic nucleus, worsening the SCN's ability to recalibrate to a normal biological rhythm.


....and an aging circadian rhythm has a negative effect on stem cells


When the SCN is dysfunctional, it will lead to abnormal peripheral circadian rhythms, creating havoc in the body's normal metabolic functions (5). This affects all the cells in the body. In particular, stem cells are also affected. Rather than focus on having rhythmic stem cell-focused functions (DNA replication and differentiation of the cells), they change their focus to DNA repair, responding to the increased ROS molecules, and becoming more involved in chronic inflammatory processes.

Basically, their genes change from homeostasis-type genes to stress-related genes  (1112).


....and aging stem cells lead to an aging organism


Having strong stem cells - a lot of them - equals agelessness. The disruption of circadian rhythms in stem cells can have a number of negative consequences for health. It can increase the risk of developing chronic diseases, such as cancer and heart disease. It can also lead to premature aging. 

Conclusion

The suprachiasmatic nucleus (SCN) is the master circadian pacemaker in the body. It is located in the hypothalamus and receives signals from the environment, such as the light-dark cycle, to set the body's internal clock. The SCN then sends signals to other parts of the body, including the peripheral tissues, to synchronize their circadian rhythms.

Biological rhythms show up in sinusoidal patterns of gene activation: stimulation followed by quiescence.

When circadian rhythms are disturbed, there are changes in the pattern of expression of the genes. This leads to loss  of the cyclical changes in (25): 

  •  the levels of neurotransmitters (like dopamine and melatonin)
  • the levels of hormones (like growth hormone and cortisol)
  • metabolic functions (such as insulin, increased glucose). 


Biological rhythms are critical to keep cells youthful. When there is too much stimulation (even if its a natural element, such as light), cells exhibit oxidative stress. Consequently, chronic disturbance in circadian rhythms can lead to changes in sleep-wake cycles, metabolic health, and physical as well as mental health (13) .

References


  1. Ma MA, Morrison EH. Neuroanatomy, Nucleus Suprachiasmatic. [Updated 2023 Jul 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. 
  2. Jones JR, Chaturvedi S, Granados-Fuentes D, Herzog ED. Circadian neurons in the paraventricular nucleus entrain and sustain daily rhythms in glucocorticoids. Nat Commun. 2021 Oct 1;12(1):5763. doi: 10.1038/s41467-021-25959-9. PMID: 34599158; PMCID: PMC8486846.
  3. Andersen B, Duan J, Karri SS. How and Why the Circadian Clock Regulates Proliferation of Adult Epithelial Stem Cells. Stem Cells. 2023 Apr 25;41(4):319-327. doi: 10.1093/stmcls/sxad013. PMID: 36740940; PMCID: PMC10128966.
  4. Mohawk JA, Green CB, Takahashi JS. Central and peripheral circadian clocks in mammals. Annu Rev Neurosci. 2012;35:445-62. doi: 10.1146/annurev-neuro-060909-153128. Epub 2012 Apr 5. PMID: 22483041; PMCID: PMC3710582.
  5. Huang W, Ramsey KM, Marcheva B, Bass J. Circadian rhythms, sleep, and metabolism. J Clin Invest. 2011 Jun;121(6):2133-41. doi: 10.1172/JCI46043. Epub 2011 Jun 1. PMID: 21633182; PMCID: PMC3104765.
  6. Noguchi T, Leise TL, Kingsbury NJ, Diemer T, Wang LL, Henson MA, Welsh DK. Calcium Circadian Rhythmicity in the Suprachiasmatic Nucleus: Cell Autonomy and Network Modulation. eNeuro. 2017 Aug 18;4(4):ENEURO.0160-17.2017. doi: 10.1523/ENEURO.0160-17.2017. PMID: 28828400; PMCID: PMC5562299
  7. Olde Engberink AHO, de Torres Gutiérrez P, Chiosso A, Das A, Meijer JH, Michel S. Aging affects GABAergic function and calcium homeostasis in the mammalian central clock. Front Neurosci. 2023 May 16;17:1178457. doi: 10.3389/fnins.2023.1178457. PMID: 37260848; PMCID: PMC10229097.
  8. Farajnia S, Michel S, Deboer T, vanderLeest HT, Houben T, Rohling JH, Ramkisoensing A, Yasenkov R, Meijer JH. Evidence for neuronal desynchrony in the aged suprachiasmatic nucleus clock. J Neurosci. 2012 Apr 25;32(17):5891-9. doi: 10.1523/JNEUROSCI.0469-12.2012. PMID: 22539850; PMCID: PMC6703600.
  9. Verma AK, Singh S, Rizvi SI. Aging, circadian disruption and neurodegeneration: Interesting interplay. Exp Gerontol. 2023 Feb;172:112076. doi: 10.1016/j.exger.2022.112076. Epub 2022 Dec 24. PMID: 36574855.
  10. Inokawa H, Umemura Y, Shimba A, Kawakami E, Koike N, Tsuchiya Y, Ohashi M, Minami Y, Cui G, Asahi T, Ono R, Sasawaki Y, Konishi E, Yoo SH, Chen Z, Teramukai S, Ikuta K, Yagita K. Chronic circadian misalignment accelerates immune senescence and abbreviates lifespan in mice. Sci Rep. 2020 Feb 13;10(1):2569. doi: 10.1038/s41598-020-59541-y. PMID: 32054990; PMCID: PMC7018741.
  11. Solanas G, Peixoto FO, Perdiguero E, Jardí M, Ruiz-Bonilla V, Datta D, Symeonidi A, Castellanos A, Welz PS, Caballero JM, Sassone-Corsi P, Muñoz-Cánoves P, Benitah SA. Aged Stem Cells Reprogram Their Daily Rhythmic Functions to Adapt to Stress. Cell. 2017 Aug 10;170(4):678-692.e20. doi: 10.1016/j.cell.2017.07.035. PMID: 28802040.
  12. Benitah SA, Welz PS. Circadian Regulation of Adult Stem Cell Homeostasis and Aging. Cell Stem Cell. 2020 Jun 4;26(6):817-831. doi: 10.1016/j.stem.2020.05.002. PMID: 32502402.
  13. Ishihara A, Courville AB, Chen KY. The Complex Effects of Light on Metabolism in Humans. Nutrients. 2023 Mar 14;15(6):1391. doi: 10.3390/nu15061391. PMID: 36986120; PMCID: PMC10056135.


Tags

aging, senescence, stem cell


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