‘Molecular habituation’ as a potential mechanism of gradual homeostatic loss with age

Abstract

HighlightsConstitutive signals indicate homeostatic dysregulation but their effect on signal transduction remains largely unexplored.A theoretical approach is undertaken to examine how oxidative stress may affect redox signal transduction.Constitutive signals can result in a ‘molecular habituation’ effect that interferes with information transmission.The robustness of such a theoretical observation to the underlying methodology hints at the generality of this principle.

On the mechanisms underlying attenuated redox responses to exercise in older individuals: A hypothesis

“…Attenuated adaptive responses are also seen in mice lacking Cu, Zn superoxide dismutase (SOD1null mice), a model of accelerated muscle aging where muscle mitochondrial ROS generation is also elevated [ 61 ]. In contrast, Martinez-Guimera and colleagues developed a molecular model to explain how chronic increased ROS activities might interfere with redox signalling pathways [ 62 ]. They identified that, in a process termed “molecular habituation”, a sustained ROS signal reduced the responsiveness of signalling pathways through prolonged activation of negative regulators, such as occurs in aging with upregulation of regulatory proteins for ROS, including catalase, glutathione peroxidase1, thioredoxin (Trx)1 and 2, and peroxiredoxins (Prx) 3–6 [ 60 , 63 , 64 ].…”

Exercise-Induced Mitohormesis for the Maintenance of Skeletal Muscle and Healthspan Extension

“…Reactive oxygen species (ROS), in acute and sublethal doses, are beneficial and confer health effects through a variety of mechanisms. However, there is an age-related increase in chronic ROS production which diminishes both stress resistance (prevention of a tipping point from adaptive to maladaptive response) and resilience (adaptive response and return to homeostasis) [55]. This unmitigated increase in ROS disrupts the redox signaling pathways necessary to defend against and adapt to oxidative challenges.…”

“…Redox homeostasis, the maintenance of many redox circuits, is impaired with age. In its simplistic form (Figure 1a–d), a redox circuit is comprised of a signal (Figure 1a), a redox sensor (Figure 1b), the activation of a response pathway (Figure 1c), and the functional outcome of the response (Figure 1d) [55]. In a broad sense, a bout of stress leads to an increase in a stress signal (indicated by an increase in the y-axis of Figure 1a), which then leads to the modification of a sensor to an activated state (increase in y-axis of Figure 1b).…”

“…With age, in a seemingly paradoxical manner, there is an increase in baseline antioxidant enzyme expression (Figure 1g, response pathway) in response to unmitigated elevated levels of ROS (Figure 1e, signal) and increased cysteine oxidation (Figure 1f, sensor). However, due to desensitization to the signal and increased sensor activation [55], the impaired redox circuit fails to elicit a functional adaptation or enhance antioxidant capacity (Figure 1h) [61]. This is partially due to the fact that Nrf2 activity decreases with age [62,63].…”

“…While there is still much to elucidate regarding the desensitization of redox circuitry, a modeling paper published in 2018 suggested that persistently elevated levels of stress or inflammation lead to “molecular habituation”, which leads to the desensitization of essential adaptive pathways [55]. Elevated levels of ROS (the signal) impair redox signaling by disrupting the initiation (via a sensor) of an adaptive response to the stress, thereby impairing the ability to functionally adapt to the stress [64,65].…”