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

Elevated intraocular pressure (IOP) is the primary risk factor for glaucoma, yet IOP demonstrates significant circadian rhythms whose underlying mechanisms remain incompletely understood, and disruption of this rhythm 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 in which 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 phase and decreased amplitude; these changes were accounted for by selectively reducing the NE amplitude in the model. In diurnal humans, aging delayed IOP phase, which is replicated by diminishing NE amplitude. Thus, species differences, age-related changes, and the effects of sympathetic ablation on IOP could be largely accounted for within this simplified qualitative framework. This framework provides a unifying conceptual basis for the circadian regulation of IOP across species and may inform novel diagnostic algorithms and chronotherapeutic strategies for glaucoma.