Reactive oxygen/nitrogen/sulphur species (ROS/RNS/RSS) production and related oxidative stress and distress are important considerations in understanding the major physiologic effects on mammal's sleep-wake states, aging, and lifespan. Yet there are few reports on the regulation of ROS/RNS/RSS, the redoxome, metabolomics, bioenergetics and the thermal state during the circadian sleep-wake cycling (or resting-active phases), aging, and disease, and therefore these issues warrant attention. Even life expectancy alone seems determined not by one but by several interactive physiologic effects. A well-known explanation is provided by the “free-radical theory of aging” [1], where species with higher metabolic rate produced more oxidative stress resulting in a shorter lifespan; however, this relationship does not hold for all species [2]. The earlier “rate of living hypothesis” [3,4] states that the lower the metabolic rate of a species, the longer its life expectancy.

Species generally do not have free-radical and metabolic steady states; therefore, life expectancy hypotheses are complicated by diurnal and seasonal variations in the metabolic rate of a species and consequently its temporal production of ROS. Mammals and birds with smaller mass generally have a higher mass-specific metabolic rate, but they also sleep longer [5]. Mice sleep four times longer than elephants, which sleep for only 3.5 hours daily. Human resting energy expenditure is highest in the biological afternoon and evening and reduced by 10–30% at its lowest during sleep [6,7]. The circadian changes in ROS levels were measured in leukocytes of adults aged 21–25 years old and found to significantly peak at night at 6 p.m. and again at 3 a.m [8]. There is no question that eukaryote cells have extensively evolved with the bioenergetic advantages of atmospheric oxygen and the cytotoxicity of ROS, so much so that ROS and redox-signalling molecules are essential facets of multicellular organisms. Therefore, the diurnal oscillatory nature of ROS is critical when considering redox-controlled biological mechanisms associated with sleep-wake metabolic states of mammals and birds.

In general, metabolism scales with body size and temperature; the basal metabolic rate per gram of body weight of a mouse is about seven times greater than in humans. One estimate of the total energy expenditure of a sedentary man suggests one-tenth is accounted for by physical activity, one-tenth is adaptive, facultative thermogenesis (due to cold or dietary intake), and eight-tenths are due to the basal/resting metabolic rate [9]. About two-thirds of the resting metabolic rate is dedicated to homeothermy, that is, to maintaining a stable core temperature; therefore, homeothermy accounts for about 50% of the total energy expenditure in humans and a similar percentage in mice of far higher total energy expenditure. Thermoregulation in birds and mammals of their internal temperature is within a few degrees Celsius, and this internal temperature is generally higher than that of their surroundings, requiring both physiologic and behavioral mechanisms [10]. It has been estimated from patients with fever that the metabolic rate increases by 13% per oC [11]. The reason for this elevated and finely tuned body temperature in endothermic/homeothermic species is unknown [10]. The core and brain temperatures of rodents and humans (children and adults) are about 1 °C less in the early wake phase, i.e., morning in humans, compared to the late evening [12]. A crucial aspect of the redox/bioenergetics/temperature regulatory hypothesis we develop is that the lowering of core temperature during sleep increases oxidative stress in isolated mitochondria, necessitating uncoupling proteins (UCPs) to lower ROS levels and raise heat production.

It is recognized that the circadian rhythms of physiological processes at all organizational levels in the body are controlled by central and peripheral “clocks,” with the “redox clock” being one of the latter [13]. Four-fifths of protein-coding genes in at least one of 64 tissues and brain regions from baboons exhibited 24 rhythms in expression, with peak transcription during the early morning and late afternoon [14]. In mammals, the central circadian clock is the suprachiasmatic nucleus (SCN) of the hypothalamus that genetically oscillates and is primarily influenced by light. The mammalian target of rapamycin (mTOR) has a key role in the entrainment of the SCN. Downstream targets of mTOR complex 1 (mTORC1) promotes protein synthesis and glutathione synthesis [15]. The SCN also entrains oscillators in extra-SCN brain regions and peripheral tissues. However, every cell in the body has its own reciprocal circadian rhythm-redox state timekeeping and even the SCN could be modulated by the redox state downstream of free radical, nitric oxide •NO [16].

Oxidative stress arises from redox imbalance or bias between antioxidants and pro-oxidants. Over 90% of mammalian oxygen consumption is by mitochondria, which are also the major cellular source of ROS such as superoxide radicals O2•−, hydroxyl radicals •OH, peroxides compounds H2O2 and the peroxide functional group ROOR [17,18]. RNS include •NO and the powerful oxidant, peroxynitrite ONOO−. Oxygen is normally reduced via the mitochondrial electron transport chain (ETC) by four electrons to water when they arrive at cytochrome c oxidase, the terminal ETC complex, known as complex IV (CIV). Alternatively, oxygen is terminally reduced by one, two or three electrons respectively, via mitochondrial redox carriers, CI, CII and CIII yielding ROS, namely O2•−, H2O2, or •OH, respectively. These mitochondrial ROS are generated by ≪2.0% of ETC electrons that leak from the ETC, mostly via CI, and interact with oxygen not consumed by mitochondrial respiration [19].

Antioxidant enzymes are a principal means of counteracting this oxidative stress. These enzymes include catalase, glutathione peroxidase (GPX), peroxiredoxin (PRX), superoxide dismutase (SOD), and thioredoxin. Oxidative stress is also lessened by non-enzymatic antioxidants of glutathione (γ-glutamyl-cysteinyl-glycine (GSH)), melatonin, uric acid, vitamins C and vitamin E. Antioxidant enzymes in humans usually peak in the morning (e.g. catalase, GPX, PRX,and SOD), whereas most non-enzymatic antioxidants peak in the evening (melatonin, vitamin C, GSH, but not uric acid) [20,21]. The understanding of human circadian trends of antioxidant enzymes and antioxidants are augmented by rodent and other animal studies, taking account of species differences and that animals such a rodents have a nocturnal wake state in contrast to the diurnal activity of humans [22].

Two important mitoprotective redox mechanisms are anion carriers and post-translational modifications of protein thiols [23]. The mitochondrial anion carrier protein family, located in the mitochondrial inner membrane includes the subfamilies of the UCPs and adenine nucleotide translocase (ANT); the latter catalyzes the exchange of the adenosine diphosphate (ADP) anion for adenosine triphosphate (ATP). Anionic fatty acids, superoxide and peroxidation products transfer across the mitochondrial inner membrane via UCPs and ANT activating the inducible proton leak [24]. The mitochondrial coupling efficiency, calculated as the ATP generated by oxidative phosphorylation per molecule of oxygen consumed, is reduced by the proton leak and the energy is converted to heat. Mitochondrial proton leaks and uncoupling of mitochondrial electron transport from phosphorylation, are principal means of counteracting oxidative stress by reducing the mitochondrial inner membrane potential that lessens the electron leakage along with ROS generation [25,26]. Protein post-translational modifiers of many types are involved in circadian regulation, some reversible, including phosphorylation, glycosylation, ubiquitination, methylation, and acetylation. Our focus is on the reversible cysteine oxoforms, S-glutathionylation (-S-SG-) and S-nitrosylation (-S-NO) that provide proteins with redox respiratory protective measures to minimize oxidative and nitrosative stress.

On examination of the redoxome, bioenergetics and thermal regulatory processes, we hypothesize that the interactome, metabolic, and physiological sleep-wake oscillations are strongly regulated especially by cellular cysteine-mediated post-translational modifications of proteins and mitochondrial respiratory uncoupling. One effect of this is to reduce cellular protein synthesis during sleep and simultaneously act as a mitoprotective and mitorestorative mechanism. In the second section, circadian post-translational modifications and redox couples are described. In the third section, the primary mechanisms controlling mitochondrial bioenergetics are described such as anion carriers (including UCPs) and anion carrier mediators (such as thyroid hormones and melatonin) and the temporal separation of substrate or futile cycles is described. The fourth section describes how core temperature affects mitochondrial heat shock response, oxidative stress and temperature-dependent rhythms. The fifth section gives the implications of the redox/bioenergetics/temperature regulatory hypothesis (Fig. 1) in terms of uncoupling theories, childhood development, aging and related-diseases, hibernation in animals and the effects of space radiation. In the sixth section, the implications of the hypothesis are given in view of sleep theories, followed by the concluding final section.