AGING AND CIRCADIAN RHYTHM
Contents
Introduction
The link between aging and circadian rhythm is a growing area of research and discussion. There are increasing amounts of literature that link changes in sleep and circadian rhythms with normal aging processes (Goldsmith, 2016) and the detrimental affects associated with this. We start with giving an introduction on the basics of aging and circadian rhythm separately. Following this we go deeper into the subject on how the aging is linked with circadian rhythm. Included in this part are points such as the age-related folate deficiency, endocrinology, how the lipid metabolism is affected with age and light, and we discuss some experiments connected to the topic aging and circadian rhythm. We also look shortly at the effect of circadian rhythm on aging.
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Circadian Rhythms
All types of homeostatic control exhibit different types of rhythmicity. A yearly cycle would be circannual, or the 24 hour cycle which is circadian (Sjaastad et al, 2003).
Circadian rhythm, also known as sleep/wake cycles, are endogenous rhythmic changes within a periodicity of 24 hours that are under the control of a pacemaker entity - the master clock. In other words one can say that the circadian clock is an outward manifestation of an internal timing system (Reppert and Weaver, 2002). These rhythmic changes are synchronised by environmental stimuli to allow daily fluctuations in biochemical, physiological, and behavioural activities.
Circadian rhythms can be observed in organisms ranging from the protozoa to humans. If we take a look at how it is coordinated in the mammals, it has been shown that the circadian system is formed by a set of coordinated peripheral oscillators under control of a master clock located in the suprachiasmatic nucleus (SCN), of the hypothalamus (Arellanes-Licea et al 2014). These secondary (peripheral) clocks are also influenced by hormonal and extracellular signalling especially those associated with feeding whilst the master clock is mainly influenced by light changes detected in the retina (Mattis and Sehgal, 2016).
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Negative Feedback Loops
The circadian rhythm system works via a molecular oscillator comprised of negative feedback loops of transcription and translation. The 2 clock genes BMAL1 and CLOCK start the process in early circadian day. They are transcriptional factors which initiate the transcription of genes with promoters containing circadian E-box elements including PERIOD (Per) and CRYPTOCHROME (Cry). Per and Cry are negative feedback repressors for BMAL1 and CLOCK, therefore during the early circadian night they repress BMAL1 and CLOCK mediated transcription by forming complexes. This therefore downgrades their own production so throughout the night the amount of Per and Cry decreases. The decrease in Per and Cry means BMAL1 and CLOCK once again become able to function enabling the start of a new circadian day.
BMAL1 and CLOCK also target the expression of nuclear receptors rev-erbα and ROR. These inhibit and activate in turn the transcription of BMAL1 producing cycling of BMAL1 mRNA.
Circadian rhythms affect many genes in this way resulting in tissue level and circuit level oscillations which ultimately generate overt rhythms of physiology and behavior (Mattis and Sehgal, 2016).
Aging
One of the things that characterize aging is the decrease in mitochondrial functions due to mutations in the mitochondrial DNA. This affects the cells ability to divide and grow resulting in many different manifestations of age. Mammalian aging has many different manifestations including cancer, heart disease, stroke, arthritis, cataracts and other sensory deficits, muscle weakness and decreased immune response.
These processes can involve or may be caused by oxidation from molecules such as reactive oxygen species (ROS), free radicals, radiation damage, pathogens and mechanical wear and tear. (Goldsmith, 2016) There is a theory that in higher ROS levels the pro-oxidant levels can be responsible for changes in the synchronisation of the circadian rhythm, and also negatively affect the aging and age related pathologies. It could also be that higher levels of oxidation from species such as ROS could cause more DNA mutations which are proven to be responsible for some of these age related changes (Arellanes-Licea et al, 2014).
There are in fact two independent but connected processes of aging, however it is unknown as to how the second impacts the first. The first (primary aging) is the gradual process of bodily deterioration that takes place throughout life. This process is genetically programmed and happens independently from external factors. The theories behind this are outlined below. Secondary aging is considered to be more haphazard and therefore a harder process to characterise. Otherwise known as senescence this secondary process likely results from external factors. These can be a wide range of things e.g. disease, lack of physical activity, unhealthy activity or habits (smoking etc.), poor nutrition and/or exposure to hazardous materials (Fonseca Costa et al, 2015).
Melatonin
Another age related effect is a decrease in the amount of melatonin being circulated. Melatonin is a natural anti-oxidant with many anti-aging properties. It is a major factor influencing the regulation of circadian rhythms and it has been suggested that nocturnal melatonin production is mediated by a non-rod, non-cone system (i.e. the light detected by these cells in the eye have no effect on the amount of melatonin produced nightly). It is thought that melanopsin is in fact a circadian photoreceptor acting independently from the rod and cone cells of the eye. This is due to the localization of melanopsin gene expression and immunoreactivity however it is not yet clear if melanopsin is sufficient on its own for circadian photoreceptors (Reppert and Weaver, 2002).
Theories
There are two modern evolutionary theories surrounding the reasons for aging; programmed and non-programmed. Both theories rely on the modification of Darwin’s survival of the fittest explanation to evolution to the effect that: after a certain age there is a decline in evolutionary force (Goldsmith, 2016).
The non-programmed aging theory revolves around the idea that each species has an evolutionary need to survive and reproduce within a species specific period. After this period therefore there is no net evolutionary advantage to being able to survive and reproduce. In other words there is no distinct advantage or disadvantage to being able to live longer so the evolutional force is developed to work towards setting a minimum internally determined lifespan for each species rather than a maximum (Goldsmith, 2016).
The programmed aging theory (or theories as there are actually more than one working around the same idea) also states that there is a specific age beyond which the need to survive and reproduce decreases to zero. This theory however then goes on to suggest there is an evolutionary disadvantage to living beyond this age. The force of evolution therefore is directed towards developing an optimum lifespan to prevent the evolutionary costs of living too long or too short a time. There is supposedly an evolved biological mechanism known as an aging program that purposely limits individual lifespans (Goldsmith, 2016).
Aging and Circadian Rhythms
In humans, the 3 main changes in circadian properties associated with aging are:
- The amplitude of the circadian rhythm is reduced.
- There is backwards shift in the 24 hour sleeping period dependant on the SCN.
- There is also disruption in the nocturnal sleep with aging. In other words, there is a disruptive affect on the major sleeping period dictated by the circadian rhythm of sleep and wakefulness (Arellanes-Licea et al, 2014).
Age Related Folate Deficiency's Affect On Circadian Rhythms
Various age related circadian disturbances can be shown in the elderly population, where two of them are decreased responsiveness to light and dampened amplitudes of rhythmicity. Experiments conducted on mice looked for a connection between lack of folate (vitamin B9) – a condition common in the elderly - and these circadian changes. Folate deficiency is known to lead to reduced global DNA methylation, and in this way affect transcription and DNA repair as well as hyper-homocysteinemia, a recognized risk factor for thrombosis. These experiments showed that after six weeks of dietary folate deficiency and hence consecutive hyper-homocysteinemia, three typical circadian dysfunctions were verified to be connected to low folate levels. These features are: dampened melatonin rhythm, decreased circadian amplitude of vasopressin and the clock protein PERIOD 2 (PER2) in the master clock and reduced responsiveness to light that mimic aging-induced changes. Daily oscillations of the clock protein PERIOD 1( PER1) was on the other hand not significantly changed .It is worth mentioning that these differential effects for PER1/PER2 patterns in the master clock of folate-deficient mice resemble age-induced transcriptional changes (Challet et al, 2013).
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Circadian Rhythms Affect On Lipid Metabolism
Biological aging will have an effect on changing the metabolism and volume on adipose tissue storage. Furthermore, recent evidence show that circadian processes will play a role in endorsing adipogenesis, lipodystrophy and obesity.
The weight of the brown, epididymal, inguinal and retroperitoneal adipose storage will reduce with increasing age, but the total body weight will not.
As in other experiments, mice were also used here as the examined species. They found that the expressed transcriptome, in both brown and white adipose depots and in the liver of both populations (young and old), displayed evidence of circadian rhythmicity. Meanwhile the oscillating mRNAs differed remarkably across tissues and between age groups. The amplitude of Cry1 – a component of the negative arm of the circadian apparatus – and downstream regulators – such as Reverbα – were comparatively higher in the older cohorts than in the younger as a function of circadian time. Overall, transcription levels differed significantly for expressed sequences between the populations as a function of age. Of these, the adipose tissue of the inguinal region was the lowest, the brown adipose tissue tested the highest and the liver was in the middle. These results included transcripts encoding proteins within the official and non-official Wnt pathways (signal transducting pathways made of proteins that pass signals into a cell through cell surface receptors). Since the Wnt pathway regulates adipose stem cell differentiation and shares a critical enzyme with the circadian mechanism, glycogen synthase kinase 3β, the intersection between these two essential regulatory mechanisms merits further investigation with respect to biological aging of adipose tissues.
Outside of the central nervous system, adipose tissue physiology exhibits some of the most robust associations with seasonal, diurnal, and circadian rhythms. The serum levels of glucocorticoids and melatonin (factors with potent adipogenic properties) display circadian oscillations.
Alternatively, but not exclusively, differences in species and adipose tissue depots may also be contributory factors (Sutton et al, 2013).
Circadian Rhythm Endocrinology
In humans the most pronounced 24 hour variations are the functions of the adrenal cortex. The brain is affected by outer and inner stimuli, that again stimulated the hypothalamus to secret hypothalamic hormones, in this case they will have an effect on the anterior pituitary, that again will secrete ACTH. ACTH will influence the adrenal cortex. The Hypothalamus regulate the ACTH secretion to be highest in the night, and early morning.
Other hormones with circadian rhythm include TSH, FSH and LH (Sjaastad et al, 2003).
As melatonin has already been discussed, we will not go further into its functions here.
Biological Aging Impact On Activity Profiles
As we have discussed earlier, in the presence of 24 hour light-dark intervals, the circadian rhythm has a period of exactly 24 hours. If an animal would live under conditions of continuous light, the circadian rhythm would deviate somewhat from the 24 hour-cycle. Nevertheless, deviating is limited to just a few hours, so the body must have pattern generators that functions independently to light (Sjaastad et al, 2003).
Physical activity is considered to be a marker for circadian biological rhythms. Experiments have been done with younger and older mice, where their wheel running activity was compared. This was explored under conditions of a constant 12:12 hour light/dark cycle. Since these studies was stretched over several months, the younger mice reached 8-9 months of age, while the older mice reached 28-29 months. The results showed that the nocturnally active older mice started the wheel-running activity significantly later than the younger mice after the onset of light out period. Additionally, in contrast to the younger population, they would continue their running activity after the lights were turned on. The same population of mice, both younger and older, were also examined under a prolonged period of darkness. Evaluation of the results obtained from these experiments, showed that the older animals were able to keep an oscillatory physical activity pattern under the dark conditions, but the timing of their peak level of activity drifted in comparison to the younger cohort (Gregory et al, 2013).
Circadian Affect On Aging
To look at it from a different point of view, the effect of the circadian rhythm on aging, we see that the circadian rhythm helps the synchronisation of metabolism and physiology to make the body optimize its energy use. However, the circadian rhythm will be affected by the aging process and its abilities to synchronize will decline. With the declining effect of the circadian rhythm, and the increased changes that come with age the damages to the body might accumulate and increase the risks of death (Costa and Ripperger, 2015).
Conciousness and Sleep
The need for sleep is further reduced in the elderly (Sjaasted et al, 2003).
In the brain the thalamus and the hypothalamus centres are responsible for activation and inhibition of the upper brain areas. The thalamus and hypothalamus have also been found to be involved in regulation of sleep-wake cycle.
Sleep consolidation and circadian rhythm will break down with normal aging, so if there are any changes in these it might be a part of what makes aging a risk factor for disorders like Alzheimer´s disease (AD) (Mattis and Sehgal, 2016).
Conclusion
In conclusion; it would appear aging and circadian rhythms impact each other in a negative feedback cycle. Increased age decreases the rhythmicity of circadian rhythms and their ability to synchronise. Meanwhile the decreased circadian rhythm activity associated with aging increases the likelihood of developing the outward manifestations of aging.
From the points mentioned above, we can agree with the theory that there is a connection with aging and circadian rhythm. It is clear that several factors of the circadian rhythm will be affected with increasing age including, sleep patterns, fat depositions and activity profiles. These factors are all closely associated with other bodily processes and the deteriorative progressions of aging and upon investigation, will again bring us back to the endocrinology and physiology associated with circadian rhythms.
References
1. Arellanes-Licea, E.; Caldelas, I.; Ita-Pérez, D.; Diáz Munoz, M. (2014): The Circadian Timing System: A Recent Addition in the Physiological Mechanisms Underlying Pathological and Aging Processes. Aging and Disease, 5(6):406-418. doi: 10.14336/AD.2014.0500406
2. Challet, E.; Dumont, S.; Mehdi, M.K.M.; Allemann, C.; Bousser, T.; Gourmelen, S.; Sage-Ciocca, D.; Hicks, D.; Pévet, P.; Claustrat, B. (2013): Aging-like circadian disturbances in folate-deficient mice. Neurobiology of aging, 34(6):1589-1598. doi: 10.1016/j.neurobiolaging.2012.11.021
3. Fonseca Costa, S.S.; Ripperger, J.A. (2015): Impact of the circadian clock on the aging process. Frontiers in neurology, 6:43. doi: 10.3389/fneur.2015.00043
4. Goldsmith, T.C. (2016): Emerging programmed aging mechanisms and their medical implications. Medical Hypothesis, 86:92-96. doi: 10.1016/j.mehy.2015.10.015
5. Mattis, J.; Sehgal, A. (2016): Circadian rhythms, Sleep, and Disorders of Aging. Trends in Endocrinology & Metabolism, 27(4):192-203. doi: 10.1016/j.tem.2016.02.003
6. Reppert, S.M.; Weaver, D.R. (2002): Coordination of circadian timing in mammals. Nature, 418(6901):935-41.
7. Sutton, G.M.; Ptitsyn , A.A.; Floyd, Z.E.; Yu, G.; Wu, X.; Hamel, K.; Shah, F.S.; Centanni, A.; Eilertsen, K.; Kheterpal, I.; Newman, S.; Leonardi, C.; Freitas, M.A.; Bunnell, B.A.; Gimble, J.M. (2013): Biological aging alters circadian mechanisms in murine adipose tissue depots. AGE, 35(3):533-47. doi: 10.1007/s11357-012-9389-7
Books
1. Sjaastad, Ø.V.; Hove, K.; Sand, O.; (2003): Physiology of Domestic Animals. 1st Ed. Finland: Gummerus printing
Figures
1. Figure 1. The Circadian Timing. From wikimedia commons
2. Figure 2. The structure of Folate. From wikimedia commons
Diagram
1. The Circadian Clock. Selfmade diagram