Cell Senescence and Central Regulators of Immune Response

Abstract

Pathways regulating cell senescence and cell cycle underlie many processes associated with ageing and age-related pathologies, and they also mediate cellular responses to exposure to stressors. Meanwhile, there are central mechanisms of the regulation of stress responses that induce/enhance or weaken the response of the whole organism, such as hormones of the hypothalamic-pituitary-adrenal (HPA) axis, sympathetic and parasympathetic systems, thymic hormones, and the pineal hormone melatonin. Although there are many analyses considering relationships between the HPA axis and organism ageing, we found no systematic analyses of relationships between the neuroendocrine regulators of stress and inflammation and intracellular mechanisms controlling cell cycle, senescence, and apoptosis. Here, we provide a review of the effects of neuroendocrine regulators on these mechanisms. Our analysis allowed us to postulate a multilevel system of central regulators involving neurotransmitters, glucocorticoids, melatonin, and the thymic hormones. This system finely regulates the cell cycle and metabolic/catabolic processes depending on the level of systemic stress, stage of stress response, and energy capabilities of the body, shifting the balance between cell cycle progression, cell cycle stopping, senescence, and apoptosis. These processes and levels of regulation should be considered when studying the mechanisms of ageing and the proliferation on the level of the whole organism.

Keywords: acetylcholine; adrenaline; cell cycle; cell senescence; hypothalamic–pituitary–adrenal axis; immune response; melatonin; neuroendocrine regulators; neurotransmitters; thymic hormones; thymosines.

Figure 1

Simplified representation of signalling pathways related to cell senescence.

Figure 2

Schematic representation of effects of glucocorticoids on intracellular processes and signalling pathways related to senescence, apoptosis, and cell cycle regulation. ↑—stimulation, ↓—inhibition.

Figure 3

Schematic representation of effects of adrenaline and noradrenaline, sympathetic system neurotransmitters on intracellular processes and signalling pathways related to senescence, apoptosis, and cell cycle regulation. ↑—stimulation, ↓—inhibition, αARs—α-adrenoreceptors, βARs—β-adrenoreceptors.

Figure 4

Schematic representation of effects of acetylcholine, the parasympathetic system neurotransmitter, on intracellular processes and signalling pathways related to senescence, apoptosis, and cell cycle regulation. ↑—stimulation, ↓—inhibition, α7nAchRs—α7-nicotinic acetylcholine receptors, mAChR—muscarinic acetylcholine receptors.

Figure 5

Schematic representation of intracellular and extracellular effects of prothymosin-α (ProTα) and thymosin-α (Tα). Adapted from our earlier publication [144].

Figure 6

Schematic representation of intracellular and extracellular effects of lamina-associated protein 2 (LAP2) and its fragment thymopoietin (Tmpo). Adapted from our earlier publication [144].

Figure 7

Schematic representation of intracellular and extracellular effects of thymosin-β4 (Tβ4) and its fragment AcSDKP. Adapted from our earlier publication [144].

Figure 8

Schematic representation of effects of melatonin on intracellular processes and signalling pathways related to senescence, apoptosis, and cell cycle regulation. ↑—stimulation, ↓—inhibition.

Figure 9

Hypothetic scheme showing the balancing effects of immune response regulators on signalling pathways that control cell cycle, senescence, and apoptosis. βAR—β-adrenoreceptors; AchRs—acetylcholine receptors; α2AR—α2-adrenoreceptors; Tmpo—thymopoietin.