Normal, Nostalgia & the importance of Circadian Clocks

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“Nostalgia” was first identified in 1688 by Swiss physician Johannes Hofer who recorded the impact of nostos (homecoming) and algia (pain) on Swiss soldiers abroad. He mused that nostalgia is part of what it means to be “modern”.

No longer recognised as a medical diagnosis, this gnawing feeling of loss (often exaggerated by those who seek to politicise it) speaks to a world of rapid transformation and the severing of settled identities. It can be seen as collective or personal, reflecting a societal loss or yearning for a personal return to a previous experience.

Prior to the 19th century, normal meant “regular”, and “governed by a rule”: a right angle was “normal”, while the French, (the originating language) Ecoles Normales colleges trained model teachers for a new rational era. It came to its modern use via astronomy where, in what would come to be known as “normal distribution”, an arrangement of a data set in which most values cluster in the middle of the range and the rest taper off symmetrically toward either extreme.

Benignly, the science of normality produced advances in public health; malignly, it acted as a ‘bed of Procrustes’ to lop off offending social limbs. Depending on its ­definition, “normal” could be used as a weapon against anyone who failed to fit its parameters. Most infamously, it powered the racial pseudoscience that led Sir Francis Galton to coin the term and strategy of eugenics, culminating in the forced sterilisation of “degenerate” populations across America and Europe.

Why are these understandings related to health care?

What people consider normal or typical depends on how much they know. This can be mediated by referencing a collective data set, as is done in medicine, but within the range of any report or related range, there are invariably differences, which means that ‘normal distribution’ covers a wide spread. This in turn leads to variations that need to be assessed in context and invariably familiarises people with the understanding that medicine is an art, as well as a science. It is after all the most humane of sciences and the most scientific of humanities.

Normality as an ideal is a useful tool but is naturally unrealistic. In clinical practice, normality is the basis of all comparisons[1]. From normality, we derive both health and disease, with implications from patient self-perception and practitioner-patient communication to the goal of clinical intervention, health insurance policies and public health measures[2].

Any model to reflect what may be regarded as normality must also address diversity. And for this, to be understood in the context of care, the aspect of process which reflects the ability to adapt to a certain context, internally and externally is of great advantage[3]. In effect, it recognises that we structure these environmental responses, rather than submitting to them.

It is also important to consider that for normality to be achieved, what a person wants to achieve is important. Autonomy should be considered, valued, and recognised. Individuals are entitled to transform themselves, both by changing their physical and psychological aspects and by practising their values and preferences.

Timing and median targets dominate much of decision-making in health care that ultimately seeks to modify self-organisation to achieve health and reflect the interpretation of needs and application, which is embedded into experience and recollection. Yet these decisions rarely consider the cellular circadian clocks so important in our body’s collective responses.

Nostalgia provides us with a narrative that varies according to multiple intersecting experiences and overlays expectations and health targets. The most common interpretation equates normality with health, although this notion is intuitive it is often wrong. There are very few individuals that are optimally healthy and as such there are large communities of people adapted to living with diseases or dysfunctions of self-organisation.

Research in 2019, indicated that only 12.2% of American adults are metabolically healthy and as the UK is on a similar trend with inactivity, body mass excess and other parameters, there is likely to be population correlation[4]. Worldwide obesity rates have tripled since 1975, with 650 million adults obese back in 2016, according to the World Health Organization. In 2019, the OECD declared that developed countries’ plans to tackle the problem were largely failing. And the Covid-19 pandemic increased rates of obesity and underscored that obesity puts people at greater risk for infectious disease and related outcomes[5],[6].

Adoption of ‘new normal’, i.e metabolic disorganisation becoming so common that it is seen by the population as being normal, denies the power of nostalgia to recognise this misconception, as at the midpoint of the 20th century, obesity (a primary cause of metabolic dysfunction) was almost non-existent. The obesity described in Englands Parliamentary report of March 2022 is alarming in the speed at which it is affecting more people than ever, at a pace of approximately 0.5% of the population per annum. Far in excess of any change that can be singularly attributed to genetics and instead is indicative of the many changes in societal and environmental pressures, expressing certain phenotypes[7]. Genetic factors identified so far make only a small contribution to obesity risk-and qualifies that our genes are not our destiny.

Circadian rhythms link the past with normal

Most of our physiological functions are governed by an untold number of carefully synchronised biological clocks that each complete one cycle about every 24 hours. Those cycles are known as circadian rhythms, after the Latin for “about” (circa) and “day” (dies).

Circadian rhythms, in other words, are relevant to more physiological events than just sleep. But few realised how relevant until 2014, when a professor of pharmacology at the University of Pennsylvania called John Hogenesch published a paper with his colleagues showing that almost half of the genes in mice produce proteins on a 24-hour schedule[8].

Western medicine has long been sceptical of studies that tout the health benefits of synchronising treatments with biological cycles as traditional Chinese and Ayurvedic medicine does, in large part because there was no scientific explanation for the results. But as data continues to demonstrate that medicine, exercise, food and sleep are reactive to, and with these rhythms, their importance is becoming far greater.

In effect, cells rely on a mixture of programmed ‘nostalgia and normal’ to perform their obligations. A change in the timing of which can result in significant changes in function, something that represents a nuance in systems biology that deserves more comprehension and application. Such internal misalignment, or dysregulation, can throw our physiology out of balance.

Understanding how these cellular clocks in us work will enable us to control them and improve our health, keeping us vigorous for longer. Now, they just tick relentlessly toward one end. Conceptually speaking, at least, if you could slow them down or pause them at will, it would be altering our relationship with time itself.

How does that work?

In brief, the circadian system comprises a coupled network of molecular/cellular- and tissue-level oscillators, hierarchically coordinated by the hypothalamic suprachiasmatic nuclear circadian pacemaker.

The suprachiasmatic nucleus is wired directly to the retina, and in the 1980s, it was confirmed that the brain clock could be calibrated by sunlight or artificial light, which signals when it’s daytime. Receiving light consistently when you first wake up, and waking up at the same time each day, can help keep the clock on track so that, in turn, you fall asleep at an optimal hour; it can also prevent a weakening of your circadian rhythms or a decrease in their amplitude. The area of light based medicine (video by MedCram) is already showing real opportunity for clinical management in immune enhancement.

This results in less contrast between an active phase and rest phase, which, in the case of sleep, can potentially translate into feeling more tired during the day and waking more often at night. Robust rhythms, however, require that the brain does not receive light signals at night. Some studies show that even while you’re sleeping, dim light can penetrate your closed eyelids and confuse the clock.

A publication in Sleep linked any night-time light exposure during sleep to a substantial increased risk of obesity, diabetes and hypertension in older adults[9].

How can I use it?

One of the great promises of circadian medicine is its D.I.Y. appeal: Establishing the optimal time to eat or exercise, for example, could change behaviour immediately, free of charge, not only to minimise the harm but also to maximise the health benefits of given activities. Professional athletes and their trainers, for instance, know that physical performance typically peaks in the late afternoon or early evening. (Most world records are broken in the evening.) In February 2022, Cell Metabolism published an “atlas of exercise metabolism” that showed how, for mice, the metabolic effects of running on mini-treadmills changed over 24 hours[10].

The implication is that by establishing the relationship between our clock genes and the genes governing metabolism and inflammation and modifying the workings of clock genes to speed up or slow down those processes throughout the body we may be able to prevent disease and thereby remain healthy into old age.

Personalised circadian medicine may be an important part of the future. The timing of our clocks varies by individual, set by the sun, indoor lighting, genetic predisposition, our behaviour, our age, and one another[11].

Researchers hope to develop a quick and easy method for telling what phase, or phases, your organs are in. But for now, absolute precision is not required to improve the coordination and strength of your biological rhythms. The primary recommendation is to expose yourself to as much sunlight as you can during your day especially as it is related to non-vitamin D immune enhancement, as well as Vitamin D induction, especially upon waking, dimming the lights before sleep and making your bedroom really dark, exercising and eating at a time that is consistent and relevant to health[12].

When to Eat?

Look to ingest most of your calories/nutrients earlier in the day. Most of all, try to keep your schedule consistent across the week, including weekends.

Metabolism isn’t just about the digestion of food. It’s also about how all our cells use energy to perform the tasks required to keep us alive and functioning. The more efficiently they can do that, while simultaneously replicating and repairing themselves, the better off we tend to be.

Food it seems can unsynchronise the clock in your head from the clocks in your body and when they’re not communicating well with each other, optimal responses from the body are not achieved. Food overrides the clocks in all our peripheral tissues. It does not directly affect the brain tissue. The brain keeps going with the sun, but the clocks in the body are more controlled by the food that we eat[13]. Including the circadian production of the very important appetite and insulin mediating hormone GLP-1 from the pancreas. Animal and human studies have shown that the western diet high in ‘fat and sugar’ adversely affects the production of this small peptide that tells your pancreas that you’ve just eaten and need insulin and signals to your brain to stop eating.[14]

This circadian misalignment, due to mistimed eating, results in abnormal metabolic regulation/ homeostasis, and consequently, increased cardiometabolic risks, including the development of obesity, type 2 diabetes, and ultimately CVD[15].

An idea popularised by the work of Prof Satchin Panda author of the Circadian Code who as a consequence has recommended the application of time-restricted feeding as well as light, exercise and sleep to improve metabolic health, seeking to hack this process for the betterment of health[16].

For example, reviewing the most common of all metabolic disruptions as Journalist H.L. Mencken wrote “for every complex problem there is a solution that is clear, simple and wrong.” That observation aptly describes a prevailing attitude toward type 2 diabetes, which characterises diabetes as a problem that could clearly be fixed if people would simply move more and eat less. It clearly needs more levers to be pulled than these to achieve resolution.

Conclusion

Chronotherapy is gaining scientific understanding and clinical applications are emerging. But to conclude, one interesting study revealed how nostalgia serves a homeostatic function, allowing the mental simulation of previously enjoyed states, including states of bodily comfort; in this case, making us feel warmer or increasing our tolerance of cold, in effect changing the state of normal[17]. Another demonstrates how nostalgia can also mitigate pain[18].

Just think how we might liberate people constricted in choice, by a diminution of their expected normal, by utilising nostalgia as well as the other approaches to optimise circadian outcomes.

 

References

[1] Koeslag JH. “What is Normal?” South African. Med J. 1993;83(1):47–50 50

[2] Catita, M., Águas, A. & Morgado, P. Normality in medicine: a critical review. Philos Ethics Humanit Med 15, 3 (2020)

[3] Rudnick A. The ends of medical intervention and the demarcation of the Normal from the pathological. J Med Philos. 2000;25(5):569–80

[4] Araújo J, Cai J, Stevens J. Prevalence of Optimal Metabolic Health in American Adults: National Health and Nutrition Examination Survey 2009-2016. Metab Syndr Relat Disord. 2019 Feb;17(1):46-52

[5] Robinson E, Boyland E, Chisholm A, Harrold J, Maloney NG, Marty L, Mead BR, Noonan R, Hardman CA. Obesity, eating behavior and physical activity during COVID-19 lockdown: A study of UK adults. Appetite. 2021 Jan 1;156:104853.

[6] Jayanama K, Srichatrapimuk S, Thammavaranucupt K, Kirdlarp S, Suppadungsuk S, Wongsinin T, Nanthatanti N, Phusanti S, Pitidhammabhorn D, Sungkanuparph S. The association between body mass index and severity of Coronavirus Disease 2019 (COVID-19): A cohort study. PLoS One. 2021 Feb 16;16(2):e0247023.

[7] Loos, R.J.F., Yeo, G.S.H. The genetics of obesity: from discovery to biology. Nat Rev Genet 23, 120–133 (2022).

[8] Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB. A circadian gene expression atlas in mammals: implications for biology and medicine. Proc Natl Acad Sci U S A. 2014 Nov 11;111(45):16219-24

[9] Kim M, Vu TH, Maas MB, Braun RI, Wolf MS, Roenneberg T, Daviglus ML, Reid KJ, Zee PC. Light at night in older age is associated with obesity, diabetes, and hypertension. Sleep. 2022 Jun 22:zsac130

[10] Sato S, Dyar KA, Treebak JT, Jepsen SL, Ehrlich AM, Ashcroft SP, Trost K, Kunzke T, Prade VM, Small L, Basse AL, Schönke M, Chen S, Samad M, Baldi P, Barrès R, Walch A, Moritz T, Holst JJ, Lutter D, Zierath JR, Sassone-Corsi P. Atlas of exercise metabolism reveals time-dependent signatures of metabolic homeostasis. Cell Metab. 2022 Feb 1;34(2):329-345.e8

[11] Greco CM, Sassone-Corsi P. Personalized medicine and circadian rhythms: Opportunities for modern society. J Exp Med. 2020 Jun 1;217(6):e20200702

[12] Cherrie M, Clemens T, Colandrea C, Feng Z, Webb DJ, Weller RB, Dibben C. Ultraviolet A radiation and COVID-19 deaths in the USA with replication studies in England and Italy. Br J Dermatol. 2021 Aug;185(2):363-370

[13] Katsi V, Papakonstantinou IP, Soulaidopoulos S, Katsiki N, Tsioufis K. Chrononutrition in Cardiometabolic Health. J Clin Med. 2022 Jan 7;11(2):296

[14] Martchenko A, Brubaker PL. Effects of Obesogenic Feeding and Free Fatty Acids on Circadian Secretion of Metabolic Hormones: Implications for the Development of Type 2 Diabetes. Cells. 2021 Sep 3;10(9):2297.

[15] Mason IC, Qian J, Adler GK, Scheer FAJL. Impact of circadian disruption on glucose metabolism: implications for type 2 diabetes. Diabetologia. 2020 Mar;63(3):462-472. doi: 10.1007/s00125-019-05059-6. Epub 2020 Jan 8. PMID: 31915891; PMCID: PMC7002226

[16] Crose A, Alvear A, Singroy S, Wang Q, Manoogian E, Panda S, Mashek DG, Chow LS. Time-Restricted Eating Improves Quality of Life Measures in Overweight Humans. Nutrients. 2021 Apr 23;13(5):1430

[17] Zhou X, Wildschut T, Sedikides C, Chen X, Vingerhoets AJ. Heartwarming memories: Nostalgia maintains physiological comfort. Emotion. 2012 Aug;12(4):678-84

[18] Kersten M, Swets JA, Cox CR, Kusumi T, Nishihata K, Watanabe T. Attenuating Pain With the Past: Nostalgia Reduces Physical Pain. Front Psychol. 2020 Oct 13;11:572881

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