Could the circadian-redox coupling influence ageing?

[NinaMS]

The biosphere is dominated by dark, largely “arrhythmic” habitats, and most of life lives away from the direct effects of the sun...studies of species that live away from the sun are a very small fraction of chronobiological research.

Perhaps unsurprisingly, when I have then looked at some studies on long lived species in such environments, I have found that a number have hard to quantify circadian rhythms. The long lived eusocial naked mole rats shows attenuated or no circadian clock rhythms, and although circadian rhythms have been described in the nematode Caenorhabditis elegans at the behavioral level, these rhythms appear to be relatively non-robust. As is widely known cancer is rare (although not unknown) in the naked mole-rat and C. elegans rarely acquires the kinds of tumours that can be readily observed in other animals.

I looked more widely and found that the very long lived proteid proteus anguinus, an obligate cave-dweller, shows no apparent daily rhythm of activity or resting metabolic rate. In addition, recent sequencing of the long lived Hydra magnipapillata has reveal that it has lost both Clock and Cycle. but still displays a photoperiodic behaviour in response to life cycles. Tumors have been found in Hydra, but these tumors affect only female Hydra polyps and resemble ovarian cancers in humans.

I would need to collect a lot more evidence on various species before arriving at a solid hypothesis, but I would be interested to know what research has already been undertaken on any links between circadian rhythms and longer lived species.

A lack of a robust circadian clock can offer species benefits (e.g major energy saving benefits (30-40%) in the case of the blind cave fish), if they do not have to adapt their foraging to daily cycles. Species living away from the light can also survive without circadian regulated anti-oxidant processes that respond to strong sunlight.

This also made me think what might be the implications of a weakly coupled circadian-redox system in longer lived species.

Recent findings strongly suggest that the circadian clockwork is involved in cellular programmes that regulate endogenous ROS and protect the organism. 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.

In addition, Redox signals are important regulators of cellular homeostasis and recently, it has become apparent that the cellular redox state oscillates in vivo and in vitro, with a period of about one day (circadian). Oxidation–reduction cycles of peroxiredoxin proteins are thought to constitute a universal marker for circadian rhythms in all domains of life. And they may not be unique in their ability to undergo redox oscillations since many other proteins are susceptible to oxidation of their cysteine residues by peroxide.

The redox-circadian coupling might also potentially be found in SIRT 1. SIRT1 is involved in both aging and circadian-clock regulation. SIRT1 can stimulate the expression of antioxidants via the FoxO pathways, and recent studies have demonstrated that an increased level of ROS can both directly and indirectly control the activity of SIRT1 enzyme. For instance, ROS can inhibit SIRT1 activity by evoking oxidative modifications on its cysteine residues.

There are also implications for morphogenesis. Circadian rhythms permeate mammalian cell biology, and significant proportions of gene expression and metabolism are circadian regulated with a commensurate impact upon biological function. So it should not be surprising that from cell division to signal transduction from inflammation to neuronal long-term potentiation circadian rhythms modulate cellular activity to support anticipated demand. And increasingly evident is that metabolic homeostasis at the systems level relies on accurate and collaborative circadian timing within individual cells and tissues of the body. 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. Studies have shown that clock genes can indeed directly influence stem and progenitor cell fate. Circadian clock genes have recently been found to modulate human bone marrow mesenchymal stem cell differentiation, migration, and cell cycle. H Boucher 2016.

A number of studies have suggested strong links between circadian rhythms and cancer. In rodent studies exploring how cancer in one organ spreads to others, it was found that lung adenocarcinoma sends signals to the liver through an inflammatory response, which rewires the circadian mechanisms that manage metabolic pathways. Sassone-Corsi 2016.

So could a weaker circadian-redox coupling result in a slower metabolism (one where redox/the metabolism is not oscillating on a 24 hr cycle) and slower ageing in some species (particularly those that do not live in direct sunlight) and perhaps resistance to cancer. There may be a number of associated factors beyond weak circadian rhythms including low body temperature,calorie restriction, oxygen restriction, neoteny, etc, which are also found in some of the longest lived species.

It might be possible explore some of the ideas raised in this posting by looking at aging and rejuvenation in bacterial populations. E Coli is not thought to have circadian rhythms, although a clock can be transplanted into the bacteria. It would be interesting to see if there are any differences in the 'ageing' (cell division) process between e-coli with - and without - a clock.

So models such as the naked mole rat might potentially be less useful for understanding how to slow ageing in humans than species such as relatively long lived species that live in daylight including the caribou and elephant, which have an extended clock (e.g with the caribou's clock mainly being seasonal, and the elephant foraging both day and night). For those dwelling above ground there may have been an evolutionary need to develop a strong link between circadian rhythms and the metabolism (i.e nutrition, photosynthesis, respiration, etc), responding to more extreme changes in light and temperature, supporting migration, and stress resistance to biotic and abiotic cues. In such species the loss of robust circadian rhythms may result in accelerated ageing.

[NinaMS]

I should have also mentioned in the above post, that there are underground/ocean based species which appear to have weak circadian rhythms (including in the metabolism) and do not have very long lifespans. The Mexican blind cave fish is one of these, so the weak circadian clock in itself could not be the full explanation for differences in ageing. However there are still findings of interest in relation to the blind cave fish. They stored up high fat reserves, and yet they are a healthy and relatively long lived species. 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. The expression level of Period 1 is very low and not oscillating and there is a significantly raised expression of per 2. There is also a higher expression of DNA repair genes, and a greater ability to repair DNA damage. 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 become available to the blind cave fish - perhaps once a year, - the fish are able to eat without limit and store as much fat as they can.