Uncoupled redox stress: how a temporal misalignment of redox-regulated processes and circadian rhythmicity exacerbates the stressed state

Abstract

Diurnal and seasonal rhythmicity, entrained by environmental and nutritional cues, is a vital part of all life on Earth operating at every level of organization; from individual cells, to multicellular organisms, whole ecosystems and societies. Redox processes are intrinsic to physiological function and circadian regulation, but how they are integrated with other regulatory processes at the whole-body level is poorly understood. Circadian misalignment triggered by a major stressor (e.g. viral infection with SARS-CoV-2) or recurring stressors of lesser magnitude such as shift work elicit a complex stress response that leads to desynchronization of metabolic processes. This in turn challenges the system's ability to achieve redox balance due to alterations in metabolic fluxes (redox rewiring). We infer that the emerging 'alternative redox states' do not always revert readily to their evolved natural states; 'Long COVID' and other complex disorders of unknown aetiology are the clinical manifestations of such rearrangements. To better support and successfully manage bodily resilience to major stress and other redox challenges needs a clear perspective on the pattern of the hysteretic response for the interaction between the redox system and the circadian clock. Characterization of this system requires repeated (ideally continuous) recording of relevant clinical measures of the stress responses and whole-body redox state (temporal redox phenotyping). The human/animal body is a complex 'system of systems' with multi-level buffering capabilities, and it requires consideration of the wider dynamic context to identify a limited number of stress-markers suitable for routine clinical decision making. Systematically mapping the patterns and dynamics of redox biomarkers along the stressor/disease trajectory will provide an operational model of whole-body redox regulation/balance that can serve as basis for the identification of effective interventions which promote health by enhancing resilience.

Keywords: Long COVID; chronobiology; reactive species; redox medicine; stress.

Figure 1.

Panel (a) Evolution of (homeostasis-related) biological systems with time. Many biological regulation systems change over time (hormesis) while striving to maintain physiological states of equilibrium in response to changes in the internal or external environment. The set point of these equilibrium states can be constant (homeostasis), move with time (allostasis), or evolve gradually over time (homeorhesis). In biology, most processes show hysteresis such that a greater force is required to nudge the system to a different state than maintaining it at a given state and the systemic response lagging behind the driving force attempting to change its state (not shown). Panel (b) Evolution of biological systems due to processual and relational adaptation—a ‘Tree of life’. Systems evolve in response to different biochemical and ecological situations (aptation) with multiple trajectories. Instead of being defined by programmed processes related to a specific finality (teleological purpose; reaching a multi-level equilibrium), evolution of living entities results from the competition of multiple trajectories depending on kinetic performance and multi-layered physiological interactions. Orange open circles correspond to stress situations, marking ‘branching points’ where changes in environmental conditions and/or intrinsic functioning lead to development of multiple adaptative paths. Red closed circles correspond to trajectories that could not be supported internally or externally (dead-ends). The situation where we find ourselves now could easily have been at any other branching point. Organismal evolution is therefore a ‘Tree of Life’ with junctions, branches and extinctions, but also many different historical trajectories. Our inability to describe this evolution is due to a teleological bias (if it is like that, it is because it had to be like that) and a presumed impossibility of achieving a contrafactual evolution (there is only one timeline). Panel (c) Temporal synchronization of major biological and regulatory systems. Most biological processes obey circadian rhythmicity and are coupled via biological clock mechanisms. Colour code refers to coupling status (from green—coupled, to black—uncoupled). Arrow positions refer to synchronization status of each cycle with one another. Under standard conditions, most biological cycles are coupled ‘in phase’ (green), slightly ‘out of phase’ (different arrows) or ‘uncoupled’ (red circles). Increases in stress (in time and amplitude) challenge the integrity of the oscillator network and its coupling to redox-related processes, and more physiological and biochemical processes become gradually uncoupled, eventually causing desynchronization of major biological cycles.