Additive framework of hormonal waves explains species and age differences in circadian intraocular pressure rhythm

Abstract

Elevated intraocular pressure (IOP) is the primary risk factor for glaucoma, yet IOP demonstrates significant circadian rhythms, and their disruption heightens disease susceptibility. A paradox exists in that both diurnal and nocturnal animals experience nocturnal IOP elevation despite their contrasting behavioral chronotypes. Here, we developed a minimal mathematical framework where IOP rhythms arise from the linear superposition of two sinusoidal signals: adrenal glucocorticoids (GC) and norepinephrine (NE) from the superior cervical ganglion. In both diurnal and nocturnal species, NE levels increase at night, while GC levels peak oppositely in the morning and evening. A meta-analysis of published datasets showed that IOP peaks in the early night for nocturnal animals and in the late night for diurnal animals, aligning with the predicted maxima of the combined GC and NE sine waves. In aged mice and following superior cervical ganglionectomy, IOP rhythms shifted in phase and decreased in amplitude and mean level; these changes were accounted for by selectively reducing the NE components amplitude in the model. Conversely, in diurnal humans, aging results in a delayed IOP phase, which is replicated by diminishing NE amplitude. Thus, species differences, age-related changes, and the effects of sympathetic ablation on IOP can be coherently explained by the combination of the two zeitgeber signals with distinct phases. This straightforward yet robust framework offers a unifying concept for the circadian regulation of IOP across species and may inform the development of novel diagnostic algorithms and chronotherapeutic strategies for glaucoma. SignificanceGlaucoma is a leading cause of irreversible blindness, and its major risk factor, intraocular pressure (IOP), exhibits a circadian rhythm. A long-standing paradox is that IOP rises at night in both diurnal humans and nocturnal rodents, despite their opposite activity patterns. We showed that IOP rhythms can be explained by the superposition of two sine waves representing adrenal glucocorticoid and sympathetic norepinephrine rhythms. This framework parsimoniously accounts for species differences, aging effects, and the impact of sympathetic ganglionectomy on the IOP. By reducing a complex physiological process to the interaction of two entrainment signals with distinct phases, our model provides new mechanistic insights into circadian ocular physiology and highlights potential strategies for age-specific monitoring and therapeutic timing in glaucoma.