endogenous rhythms importance

Posted comment on ´In Sync: How to Take Control of Your Many Body Clocks`  by Catherine de Lange and published in New Scientist 16th April 2016 3069 p. 30

SUMMARY

De Lange begins her article by describing one example of how the body`s own natural timing system determines behaviour. She describes an example of chrononutrition (which is where a person eats and drinks at the same time day after day) and research carried out on this type of timing by Gerda Pot, a nutrition researcher, whose grandmother exhibited this type of behaviour. Research has shown that the body`s timing system is not a single time piece, but many ´units` with the function of synchronizing the different tissues and organs for optimal performance at different times of the day. Disruption of this synchronization can result in functioning problems and possibly illness.

The idea of body clocks is not new and de Lange describes the history of the findings associated with them. Although the first written report was written over 300 years ago by a French astrophysicist, research interest grew in the 1970s. It was then that researchers identified the suprachiasmiatic nucleus located in the hypothalamus that monitored light and dark signals from the external environment and converted this information into control of physiological processes such as hormone release, body temperature and appetite. Hence, external timing was converted into internal circadian rhythms. In 2014, Hogenesch described a further timing system not limited to the brain but consisting of circadian genes found in 12 mouse organs such as heart, lungs, liver and skin so that functioning of these organs varied over the course of a day.  This system involves the activation of two genes by external influences causing appropriate gene cascades and bursts of cellular activity. Feedback from the products switches off the instigating genes.

Continuing with the topic of circadian rhythms and eating habits de Lange describes in her article work carried out in 2000 which showed that the peripheral gene clocks could be decoupled from the central suprachiasmiatic nucleus pacemaker. Research showed that this could be carried out by simply changing the time at which mice ate relevant to their sleeping patterns. It was found that if mice could only eat during the day, a time they would normally be asleep, then their peripheral clocks shifted by 12 hours. The liver adapted the fastest to this new time schedule taking 3-4 days, but by one week other organs had also adapted, eg. heart, kidney and pancreas. However, it was found that the light activated suprachiasmiatic nucleus clock remained unchanged. Researchers found that the timing shift of the organs had consequences to the health of the animals since those mice whose body clocks had shifted 12 hours were more likely to gain weight and acquire fatty livers. It was also found that if the time windows for eating were restricted then the mice responded similarly to mice on a calorie-controlled diet regardless of the levels of food intake. Therefore, it was concluded that external cues could reset the peripheral clocks leading to desynchronization with the central brain body clock and causing problems with food digestion. This view was confirmed by Pot who looked at the eating habits of 5000 people and found that those who ate at irregular times had a higher increased risk of a metabolic syndrome including diabetes decades later.

Continuing with the topic of endogenous rhythms and eating, De Lange also quotes in her article the work of Garaulet who suggested that weight gain was linked to the circadian clocks of dieters being desynchronised. Garaulet found in 2014 that dieters who had a healthy circadian clock lost more weight. She also found that some people who have a certain variant of peripheral clock gene have difficulty losing weight. Timing of eating also appears to play a role with people who eat their main meal before 3pm losing a quarter more body mass than those eating later. Garaulet`s investigation also showed that when lean, healthy women ate later than usual within one week  their metabolism had slowed causing glucose intolerance and alterations in the daily variation of cortisol. Therefore, weight loss could be linked to not just dietary intake, but also timing of eating and genetics.

In her article, de Lange shows that circadian rhythms and body clocks are important for other physiological functions as well as eating and the digestive system. For example the heart is affected by a cortisol rush at the start of the waking day and the lungs are more efficient during the most active times of the day. Changes in bodily functions linked to time and disruption of synchronization have also been linked to mental diseases, eg. depression, Alzheimer`s illness, Parkinson`s disease and schizophrenia and could explain the higher incidence of metabolic and psychological conditions observed in those people that regularly work night shifts.

De Lange concludes her article with a look at how the knowledge that bodily rhythms can affect physiological functions could be used to a person`s advantage. She gives examples of how personal weight or jet lag may be controlled better by taking into consideration a person`s circadian rhythms, eg. timing of meals, and timing of drug administration. Timing of drug administration was found to affect possibly the drug`s efficacy, eg. nocturnal asthma and a delayed release formula of prednisone, or blood pressure medications increased efficiency if taken before going to bed. Hogenesch shows that the majority of America`s commonly prescribed drugs targets pathways with circadian rhythms and that since most drugs have a short half-life of 6 hours, the timing of administration relative to relevant endogenous rhythms could have a significant impact on drug efficacy. He suggested that treatment of one illness in particular that of cancer, could benefit by consideration of circadian rhythms. Cancerous cells are normally arrhythmic, but drug transport systems maintain the normal physiological circadian rhythms and therefore the timing of the drug therapy could be manipulated to maximize harm to the tumour and minimum harm to the rest of the body.

De Lange concludes her article by expressing her anticipation of the future of chronobiology as more and more evidence appears that lead us to believe that we should be looking at our personal circadian rhythms as a key to helping optimal health and well-being.

COMMENT

Endogenous rhythms are a complicated topic with external Zeitgebers and internal instigators, possible interrelation and rhythmic physiological mechanisms and de Lange describes in her article one such rhythm that of temporal eating patterns and how they can be linked to body weight changes. What makes this article interesting is that even though we are in charge of what we do and this can be independent of actual environmental conditions (eg. the time at which we go to sleep is not related to when the sun actually goes down) our endogenous rhythms keep us functioning to internal ´clocks` that are common to others and evolutionarily conserved. Naturally, such an important influence on physiological processes has been the subject of research over decades not just with human subjects, but with other species too, but the influence is still not fully understood, nor how we can use them to our physical or mental advantage. There have been of course over the decades advancements in the knowledge about the field and there have been numerous studies on the Zeitgebers, interrelativity and desynchronisation. There has also been in-depth research into brain areas like the suprachiasmatic nucleus and the identification of pacemaker clock genes controlling internal RNA and protein synthesis leading to changes in activity and hence, overall cellular functioning. These advancements have led to explanations of how endogenous rhythms may affect the physiological functioning of living organisms.

My own views on the subject like many others support the concept that endogenous rhythms whether involving the whole organism or single cells are the work of two systems divided according to the sources of the relevant signals that govern them. The first system involves the external signals (Zeitgebers) such as light or temperature and involves a ´receiver` of some description. In the case of the former this is the suprachiasmatic nucleus and pineal gland. This type of endogenous rhythm could even include environmental electromagnetic forces linked to lunar cycles and the hypothetical electric signals of Burr`s life fields. It could also include the indirect rhythms such as physical activity for example which are a result of the more direct light-dark environmental rhythm. Just like in the definition of endogenous rhythms these signals are likely themselves to be rhythmic and lead to internal rhythmic expression of biological variables and a temporal organization of these rhythms. In these cases, the biological variables are likely to be hormones, enzymes or even in the case of Burr`s life fields the hypothetical electric signals.

The other system is newer and consists of internal signals, the sources of which are cellular clock genes. These are active systems capable of self-sustained oscillations leading to rhythmic optimal cellular functioning based ultimately on protein synthesis. In 2003, Reinberg and Ashkinazi described their circadian genetic model and a set of essential genes which produced an exact 24 hour cellular rhythm. They showed a set of polygenes that could add or substract 0.8 hrs leading to an assembly of genes creating a 20-28hour circadian rhythm. Cellular function is controlled by the clock genes which affect transcription and hence, this type of rhythmic activity is sensitive to RNA and protein synthesis inhibitors. Reinberg and Ashkinazi also suggested that the clock polygenes are usually repressed when the external Zeitgebers were present. However, others indicate that this may not be the case (a view that I share) with both central and peripheral systems working together either functioning at same time but on different systems, or releasing their hold on their respective systems so that one dominates over the other for a known period of time.

Therefore, knowledge of how the endogenous rhythms are brought about is fairly advanced, but there are still major problems in finding out accurately how the rhythms affect physiological functioning and hence, how we can use them to our physiological and mental advantage. Some of the difficulties with endogenous rhythms are as follows:

  • One of the major problems is inter-individual variability. This makes it difficult to associate single signals to specified effects and to measure changes in these signals and effects with time. Normally, a strong Zeitgeber means there is a strong influence on the system in question, but even this can demonstrate inter-individual variability, and hence suitable systems and effects are difficult to ascertain accurately for a significant number of participants.
  • Another problem is that the biological variable of the endogenous rhythm can change not only with time as expected, but over time, too. The expected effects can be seen as a wave function of regular timing, but when amplitudes also change, this demonstrates inconsistency. Age or drug use can cause such an effect which makes definitive conclusions difficult to make.
  • The ideal research finding would be that one signal causes one rhythm, but research has found that interaction between rhythms and effects is possible and therefore temporal organization is important. Ticher found 7 groups of functioning rhythms such as physiological (37 individual rhythms), cognitive (32), endocrine (27), metabolites (14), organic molecules (25), cellular components (18) and 15 rhythms of enzymatic activity and correlations have been found between the acrophases of many different groups. Masking can also alter the rhythms observed making it difficult to ascertain the different signals and their specific effects. Animal studies and particularly the use of transgenic mice may make the investigations easier and extend the limit of research possibilities.
  • Another difficulty relates to research into desynchronization of an endogenous rhythm which may be easy to observe, but difficult to interpret. For example, plasticity of systems and quick adaptability (eg. changes in response to jet lag changes occur within days and these are an example of transient desynchronization) may mask the effect of desynchronisation. Also some changes are examples of allochronism where one or several rhythms are desynchronized, but not to the detriment of the organism, hence the overall effect may be masked. However, some are examples may be of desynchronism, ie. those causing illness or changes that cannot be positively adapted to. Therefore, it can be difficult to interpret effects of the relevant endogenous rhythms, eg. drug administration can have immediate drastic changes on functioning, but hides more long-term subtle effects on other endogenous rhythms such as eating or sleeping.

Therefore, the topic of endogenous rhythms is interesting, but complicated and when we are talking about controlling rhythms and working to the advantage of individuals then we have to be aware that this is difficult to achieve and even more difficult to assess. Certain signals producing common rhythmic changes such as light-dark, sleep-wake, body temperature are probably better researched than the internal gene clock led rhythms. However, individual variations and the multitude of factors involved even in these systems make it difficult for definitive statements to be made. Availability of transgenic animal species, better testing, improved recording, and superior mathematical computer programmes for analysing data may lead to advancements in endogenous rhythms research both internally and externally instigated and if drug (or even diet) success can be improved by taking endogenous rhythms into consideration then the effort is worth it. This topic like the hypothesized Burr`s life fields and electric signals must be understood in order to completely explain human physiology.

Since we`re talking about the topic:

….can we assume that the circadian rhythms of sleep-wake, body temperature, physical activity of transgenic mice mimicking dementia are the same as normal control mice? Does the administration of anti-inflammatory drugs to those transgenic mice have any effect on these important endogenous rhythms?

…..could the grip strength of dominant hand and non-dominant hand and indicating brain hemisphere differences be investigated with reference to novel eating and sleeping patterns and certain drug administration regimes known to cause brain activity changes?

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