Circadian Rhythms and Ageing
Intraterrestrial life extends down at least 5 km and animals are found even in the deepest oceans. The biosphere is, therefore, dominated by dark, largely “arrhythmic” habitats, and in terms of biomass, most of life on earth resides in places isolated from the direct effects of the sun…studies of species that live away from the sun are a very small fraction of rhythmic physiology research. A D Beale 2016.
But it is known that some of the species in arrhythmic habits have a relatively long life span, and can be highly resistant to cancer. These include examples that refute the age-related oxidative degeneration theory.
These species can face oxygen and food deprivation. A lack of a robust circadian clock means that they do not have to adapt their foraging to daily cycles, – leading to a weak (or no) coupling between circadian rhythms and metabolism. Such a coupling between circadian rhythms and redox/the metabolism is found in animals that experience regular sunlight, and is known to influence stem cell biology and hence tissue development, homeostasis and regeneration.
|Species Circadian Rhythms||Age Span||Stem Cells, Regeneration and Cancer|
|The naked Mole-rat
Solitary and social mole rats show clear circadian rhythms and entrainment when monitored in a laboratory, but eusocial naked mole rats and Damaraland mole rats show attenuated or no circadian clock rhythms..G Bloch 2013.
|The longest-lived rodent with a lifespan over 30 years.
Reactive Oxygen Species production does not control the aging process
|Differences have also been recently found in the mole rats pluripotent stem cells. S Miyawaki – 2016.
Protected against tumorigenesis and show a striking decline in the appearance of senescent phenotype although they express clearly elevated levels of ROS and oxidative damages
Although circadian rhythms have been described in the nematode Caenorhabditis elegans at the behavioral level, these rhythm are not robust. In contrast to other animal models, no circadian transcriptional rhythms have been identified
|Studies indicating that the increase in oxidative stress, e.g., by knocking out antioxidants, can extend the lifespan of Caenorhabditis elegans (C. elegans. Also see A Salminen 2013.||The only cells that form genuine tumours in C. elegans are stem cells, and the likely reason why C. elegans doesn’t get other forms of cancer is that, unlike in mammals (and many other animals) there are no adult somatic stem cells that can serve as the origin of a tumour. N V Kirienko (2010)|
|The Proteid Proteus Anguinus
No apparent daily rhythm of activity or resting metabolic rate. H Hervant 2015
Because it doesn’t extend much energy, its metabolic rate mostly stays at its baseline rates, while most animals’ metabolisms are often running much above their basal rate.
|Proteus anguinus, a small cave salamander has a predicted maximum lifespan of over 100 years, an adult average lifespan of 68.5 years, an age at sexual maturity of 15.6 years and lays, on average, 35 eggs every 12.5 years.||Neotenic axolotls such as the proteus anguinus are able to regenerate full appendages unlike their amphibian relatives (A lovita 2015),
Neither its basal metabolism nor antioxidant activities explain why this animal sits as an outlier in the amphibian size/longevity relationship. Y Voituron 2015.
Recent sequencing of the Hydra magnipapillata has reveal that it has lost both Clock and Cycle. S Tomcsyk 2015, but still displays a photoperiodic behaviour in response to life cycles. (Taddei-Ferretti and Musio 2000).
|Findings indicate that asexual polyps from most hydra species have extraordinarily long lifespans.
|In Hydra, FoxO is expressed in stem cells, and appears to respond to stress. Reduction in FoxO levels in the H. vulgaris AEP strain negatively affected the proliferation of stem cells, the speed of the budding process, the growth of Hydra population, and the production of immune peptides. S Tomcsyk 2015
Hydra tumor cells migrate, appear to be resistant to programmed cell death. . T Domazet-Lošo 2014.
|The Mexican Blind Cave Fish
Research also shows that although the blind cavefish has a circadian clock when kept in an environment of daily cycles of light and dark, this is repressed in cave environments. Current results point to an internal timing process in the blind cave fish – perhaps related to the feeding patterns of the blind cave fish. When food does.
|The Mexican blind cave fish store up high fat reserves (which would be expected to accelerate ageing), and yet they are a healthy and relatively long lived species|
They follow a much longer clock cycle, but their life is mainly spent underground. Tina Hesman Saey July 2015.
|A life span of up to 17 years (the longest life span of any insect in North America)|
Examples of Long Lived Species with Weak Circadian Rhythms.Some of these species also evidence the following characteristics.
- Low body temperature and/or lack of thermoregulation (e.g the naked molerat is cold blooded.)
- Intermittent calorie restriction e.g the naked mole rate A Lovita 2015.*
- Oxygen restriction.
- An aberrant melatonin system (the naked mole rat). Melatonin is a potent free radical scavenger and a regulator of redox active enzymes. It is secreted during darkness and plays a role in various physiological responses, including regulation of circadian rhythms, sleep, homeostasis, retinal neuromodulation, and vasomotor responses. It preserves mitrochrondial homeostasis, reduces free radical generation, and protected ATP synthesis. M L Fanjul-Moles 2015.
- Differences in expression level of clock genes e.g significantly raised expression of per 2 and higher expression of DNA repair genes, and a greater ability to repair DNA damage. (The Mexican Blind Cave Fish).
- Light independent magnetoreception (e.g proteus anguinus and the naked mole rat).
- Neoteny (e.g Proteus anguinus and (the naked mole rat)
- Eye degeneration.
- Altered pain receptors (the naked mole rat).
(* fasting is being be investigated as a possible anti-ageing strategy for human beings)
Another factor that may be of importance is the microbial population in these species (particularly gut bacteria), as research is beginning to reveal a strong association between gut bacteria and host circadian rhythms.
Current research leaves it unclear whether the above species are also lacking circadian rhythms generated through redox oscillations (e.g via peroxiredoxin). So it is not clear whether this type of redox oscillation would span more than 24 hours if it were not coupled to a circadian clock system.
Circadian Rhythms, Redox and the Metabolism
For many species dwelling above ground there will have been an evolutionary need to develop a strong link between circadian rhythms and the metabolism. This would support alignment to a 24 hour/12 month cycle – providing stress resistance to biotic and abiotic cues, influenced behaviours such as foraging, reproduction and migration (i.e response to changes in light and temperature).
In species that required robust circadian rhythms, the loss of circadian rhythms during the ageing process may result in damage. Mouse models without functional circadian clocks sometimes exhibit reduced life expectancy. This may be due to their inability to properly control and synchronize energy expenditure, affecting, for example, the integrity of neurons in the brain.
The Coupling of Circadian Rhythms and Redox/Metabolism in Species that Live Above Ground
The emerging association being made between circadian rhythms and redox/the metabolism.
Cellular reactive oxygen species (ROS) sensing and metabolism are tightly regulated by a variety of proteins involved in the redox (reduction/oxidation) mechanism… accumulating evidence indicates that ROS also serve as critical signalling molecules in cell proliferation and survival P D Ray 2012. Recently, it has become apparent that the cellular redox state oscillates in vivo and in vitro, with a period of about one day (circadian). M Putker 2016.
Recent findings strongly suggest that the circadian clockwork is involved in complex cellular programmes that regulate endogenous ROS and also defend the organism against exogenous oxidative challenge. Current evidence seems to support the conclusion that the responses to ROS are mediated both through the regular function of the molecular clockwork and the involvement of the TTFL (transcription–translation feedback loops producing oscillations with a period of approximately 24 hours) genes in extra-circadian pathways. Lisa Wulund 2015, Nishio 2015, N B Milev 2015. A Stangherlin 2013.
Recently, it has been found that the redox cofactor FAD stabilises the clock protein cryptochrome (CRY), modifying rhythmic clock gene expression. In mice it has been found that:
- FAD stabilizes Cryptochrome (CRY) proteins by competing with FBXL3.
- FAD concentration in the nucleus has a daily rhythm
- FAD lengthens the circadian period
- In vivo knockdown of Riboflavin kinase (Rfk) alters CRY and PER1 expression rhythms.
A Harino et al (2017) have concluded that light-independent mechanisms of FAD regulate CRY and contribute to proper circadian oscillation of metabolic genes in mammals.
In animals, the current understanding of cellular circadian rhythms throughout an organism is that while the core clock genes are oscillating in most tissues and in the midst of enormous environmental pressures, metabolic circadian oscillations are strongly shaped by the environment…feeding is a critical modulator of the internal clock and, in addition to affecting synchronicity between the central pacemaker and metabolically active peripheral tissues A Ribas-Latre 2016
S A Brown (2014) has provided an overview of the molecular mechanisms involved in circadian clocks and then discuss how such mechanisms can influence stem cell biology and hence tissue development, homeostasis and regeneration.
A number of studies have also suggested strong links between circadian rhythms and cancer. Sassone-Corsi 2016. R V Puram 2016. SA. Huisman 2016, N M Kettner 2016. XM Tan – 2015, Antoch et al., 2013, C H Johnson CH 2010, S Sahar 2009, ; Fu et al., 2002,Cao et al., 2009; Yang et al., 2009.
It has also been proposed that interplay between the enzyme TERT and circadian oscilators may contribute to ageing. S S. Fonseca Costa 2015. W D Chen 2014. Sirtuin 1 (SIRT1) is involved in both aging and circadian-clock regulation, yet the link between the two processes in relation to SIRT1 function is not clear. R H Wang 2016. SIRT1 can stimulate the expression of antioxidants via the FoxO pathways. And interaction between SIRT1 and ROS signaling provokes in a context-dependent manner a decline in autophagy and a low-grade inflammatory phenotype, both being common hallmarks of ageing. A Salminen – 2013. Endogenous circadian clocks orchestrate several metabolic and signaling pathways that are known to modulate lifespan, suggesting clocks as potential targets for manipulation of metabolism and lifespan. S D Katewa 2016.
Examples Of Relatively Long Lived Species That Experience Sunlight
Beyond the examples above there are a large range of animals that evidence alternatives to classical models of strong 24 hr circadian rhythms (via transcription translation feedback loops). Some of these live above ground, but have had to adapt (their metabolism) to a particular environment. It may be more fruitful for those seeking anti-ageing strategies for human beings to focus on these species.
Around-the-clock and ultradian activity patterns are more common than is generally appreciated, particularly in herbivores, in animals inhabiting polar regions and habitats with constant physical environments, in animals during specific life-history stages (such as migration or reproduction), and in highly social animals. G Bloch 2013. Patterns of activity and the related biological clock can vary. Tina Hesman Saey July 2015.
- The relatively long-lived caribou (Rangifer tarandus) has a weak circadian (24hr) clock. Tina Hesman Saey July 2015, although it still has seasonal cycles such as mating and migration dictated by light sensitive melatonin.
- The long lived elephant is active both at night and during the day; they are least active during the hottest part of the day (responding to temperature). Activity also changes according to environmental changes during the year. Despite having 100 times more cells, elephant cancer mortality is less than 5%, compared to 11-25% in humans. Evolution has duplicated a tumor preventative p53 gene and provided them with increased resistance.
- Gymnosperms currently hold the longevity record for living organisms e.g., the Welwitschia mirabilis. It has been questioned whether circadian rhythms exist in gymnosperms. Data suggests clock gene conservation in gymnosperms, but functional differences in clock function between gymnosperms and other plant taxa, with rapid dampening of circadian rhythms found in Picea abies. SGyllenstrand 2013.
It would be interesting to see relevant data for other long lived species e.g Pinus longaeva, planarian Worms,Taxus brevifolia, Balaena mysticetus (the Bowhead Whale lives a double centenarian lifespan and it weighs a couple of tonnes, yet cancer is a rarity in this species and it exhibits neoteny), turritopsis dohrnii, and somniosus microcephalus.
Such species may have ‘prolonged clocks’ (which still have the gears of standard circadian clocks, but the clock no long responds to light), no clock, or a jammed clock, etc.
Data on species that weak circadian rhythms but are not held to be particularly long lived, would also be informative. It may able possible to identify factors that apply in the case of species that have weak robust circadian rhythms but have an average or relative short life span in order to hone in on those factors that are unique to species that are long lived.
Investigation of bacteria with and without circadian rhythms, is also likely to be informative.
In a bacterial population, aging and rejuvenation goes on simultaneously. E. coli divides, a septum forms in the middle of the dividing cell and then the two daughter cells are pinched apart. As the cell wall seals the break, the two daughter cells end up with one “old” end and one newly-formed end. When the two daughters go on to divide, the process is repeated. The original old ends gets passed on from generation to generation. Division is thought to take place around every 30 minutes. CU Rang – 2012. E Coli is not thought to have circadian rhythms, although a clock can be transplanted into the bacteria. A H Chen 2015.
In comparison cynaeobacteria has circadian rhythms and these control the bacteria’s rate of cell division (their method of reproduction) in single cells. “These cells have to keep dividing, and the circadian oscillator regulates when they divide” Q Yang 2010.
It would therefore be interesting to compare the cell division/’ageing’ process in the two types of bacteria. There is some evidence that the process in cynaeobacteria is somewhat different from that of e-coli. D Mandakovic 2016.
October 2016. This article merely joins up other peoples work into an overall system. These works have been referenced so it is clear that others have provided the individual pieces of evidence that have been used to shape a specific systems approach.
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