Presbyopia and Glaucoma: Two Diseases, One Pathophysiology? The 2017 Friedenwald Lecture
The proximate cause of presbyopia is a loss of crystalline lens deformability, which proceeds along the same timeline as the loss of accommodation with age ( ). However, there is also an age-related loss of morphologic responses to pilocarpine in rhesus monkey and human CM ( , ). – In both humans and nonhuman primates, CM structure and function is preserved long after presbyopia is complete. In monkeys there is little to no histologic or ultrastructural change, the number of muscarinic cholinergic receptors and their intrinsic activity is unchanged, and the value of the Michaelis constant (Km) and the maximum rate of reaction (Vmax) of the enzymes responsible for the synthesis and degradation of the cholinergic neurotransmitter acetylcholine (choline acetyltransferase and acetyl cholinesterase) are unchanged ( ). In short, nothing suggests that the CM is incapable of normal contraction. Indeed, isolated CM strips from monkeys of all ages, placed in a perfusion chamber/tissue bath and connected to force transducers/strain gauges, generate the same contractile force in response to the same dose of the cholinomimetic drugs carbachol and aceclidine throughout the lifespan ( ). Yet, in situ by histologic metrics after tissue fixation in the presence of pilocarpine or atropine , or in live monkeys by UBM video imaging in real time with stimulation of CM contraction via an electrode permanently implanted in the midbrain Edinger-Westphal nucleus, , CM movement progressively decreases with aging, more so in the forward vector than the centripetal vector) ( ). This constellation of findings suggests posterior restriction of CM forward and inward movement, so that in essence the contraction becomes isometric. , This has obvious implications for presbyopia pathophysiology—essentially a lens and CM double hit against accommodation, but that discussion is for another day. Of more immediate interest is the nature of the restriction and its implications for the optic nerve. In the rhesus monkey, which develops presbyopia on the same time scale relative to lifespan as the human, the posterior CM tendons and the elastic lamina of Bruch's membrane become “collagenolized” and stiffen with age ( , , ). , Consequently, the CM's mobility when it contracts is limited, whether measured histologically postmortem or in vivo by UBM. , , In both humans and monkeys, the forward movement in young eyes at the ora serrata is ∼1.0 mm ( ; ), declining gradually to about 0.40 mm and 0.15 mm in elderly monkeys and humans, respectively. Near the optic nerve head, the movement is considerably less, about 0.13 mm in the young monkey, declining to ∼0.02 mm in the elderly ( , ) (Croft MA, et al. IOVS 2014;55:ARVO E-Abstract 2647). Engineering/physical principles tell us that if the “rubber band” in the young eye becomes a “steel cable” in the older eye and if the contractile force generated by the muscle is unchanged, the force transmitted to the insertion (i.e., the lamina cribrosa and perhaps the optic nerve itself) is dramatically increased. At present, we have no method for measuring these forces at the nerve head or the nerve, but techniques in development may allow that, at least in the monkey (Fernandes J, et al. IOVS 2019;59:ARVO E-Abstract 2434) . The effects that these forces or their change with age might have on the healthy functioning of the optic nerve are unknown. Interestingly, the prevalence of POAG in humans begins to rise from essentially 0% at about the same age that the last vestiges of accommodation are lost (i.e., the mid-40s), to ∼5%, ∼10%, and ∼25%, respectively, in elderly (over 75 years) Caucasians, African Americans, and pure blood Black Afro-Caribbeans. In older (aged ≥80) Latinos living in the Los Angeles area, the prevalence of POAG is 21.8%. Other forces are also at play. Outstanding histologic and other research has been reported regarding the vitreous structure , , – and its possible role in accommodation and presbyopia. Jongbloed and Worst reported on the cistern structure within the vitreous compartment. The base of the cistern resides in the optic nerve (ON) region and the branches of the cistern extend forward to the anterior vitreous. In the in vivo rhesus monkey, we have shown that the tips of the cistern branches in the anterior vitreous attach to the intermediate vitreous zonule (Croft MA, et al. IOVS 2016;57:ARVO E-Abstract 1378; ). As the CM contracts and moves forward and inward, the lens thickens (the anterior lens pole moves anteriorly and becomes more sharply curved) and the central posterior lens pole/capsule moves backward ( ), , the fibrillar structures within the central vitreous (Croft MA, et al. IOVS 2014;55:ARVO E-Abstract 2647) (Croft MA, et al. IOVS 2015;56:ARVO E-Abstract 3568) (Croft MA, et al. IOVS 2016;57:ARVO E-Abstract 1378) (Croft MA, et al. IOVS 2017;58:ARVO E-Abstract 2477) (Croft MA, et al. ESCRS Abstract 2014 FP-5069) (including the anterior hyaloid, Cloquet's canal, and possibly the cistern trunk 33 ) move posteriorly toward the optic nerve head ( ). The accommodative posterior movement of the central vitreous includes the region of the vitreous very near the optic nerve head itself ( ). This strongly suggests that there is a fluid wave—and consequently a pressure change—impacting the nerve head. Simultaneously, the fibrillar peripheral vitreous, some of which is attached to the intermediate vitreous zonule (including the tips of the cistern branches near the anterior vitreous ; ), moves anteriorly and inwardly ( ). Disaccommodation gives the reverse movements ( ). In addition to pressure gradients, these fluid movements may generate shear stress at the nerve head. Whether these vitreal forces are bad, good, or irrelevant for the nerve is impossible to say, but we can say that they likely gradually decrease with age (see below) and become small once presbyopia becomes complete, again at about the age when POAG begins to appear. , And, of course, any of the effects may not be on the nerve directly but rather on the astrocytes and other glial elements associated with the nerve head and the lamina. Although accommodative vitreous movements may be reduced to a small amount with age, several other phenomena occur with age and also need to be considered. There is an age-related increase in lens thickness. The anterior lens pole encroaches on the anterior chamber, and the posterior lens pole is in a more posterior position in the older eye, encroaching on the anterior central vitreous. With age, the CM moves far less in a forward direction (65% and 85% loss in monkeys and humans, respectively), but the movements in the centripetal direction are less reduced (i.e., ∼20%). , Furthermore, the central vitreous liquifies with age, perhaps allowing more pressure on the optic nerve via the fluid current, lens position, and accommodative pressure spikes. During accommodation in both young monkeys and humans, there is a slight change (a small notch) in the scleral contour in the region of the limbus ( ). In older resting presbyopic eyes, there is inward bowing (increased concavity) of the sclera in the region of the limbus, and the inward bowing is more pronounced during accommodation ( ). Although older forward muscle movements are reduced, a substantial amount of centripetal muscle movement remains. Coupled with the posterior lens pole being positioned more posteriorly with age, the inward bowing of the sclera and the presence of the cisternal trunk in the region of the optic nerve (with the branches of the cistern extending to and attaching to the vitreous zonule) may all contribute to a greater pressure spike toward the optic nerve during accommodation in the aged eye. Focusing requires a continuous zeroing in on the target, much as a gunner acquires a target's range. This constant, high frequency, microcontraction/relaxation generates its own force fluctuations on the surrounding structures and fluidics, which may also affect the optic nerve and may diminish with age. The anterior longitudinal region of the CM, with its tendinous attachment to the scleral spur, TM, inner wall of SC, and Schwalbe's line, is also challenged by aging. – The TM stiffens – and forward CM movement is severely restricted (more than is the centripetal vector) by the posterior stiffening, so that the TM deformation and recovery associated with accommodation and disaccommodation are progressively lost. The deformation/recovery cycle may contribute to the “self-cleaning” ascribed to the TM, – and thus, its loss may contribute to the TM stiffening , and accumulation of collagen and other extracellular matrix materials seen with aging, , especially in glaucomatous eyes. , These changes may impede the outflow of aqueous humor, as evidenced by and perhaps accounting for the age-related increase in outflow resistance seen in both monkeys , and (at least in Western) human , populations. We do not know whether the internal contraction/relaxation mechanisms possessed by the TM/SC might change with age and affect CM movement and, thereby, the optic nerve. Although all the biomechanics at play are not clear, altered forces and decreased deformation of the TM during accommodative effort seem likely, perhaps contributing to increased outflow resistance. 

The ocular anterior and posterior segments are linked both structurally and functionally, and their intellectual separation in both the clinical and research enterprises is counterproductive to advances. The accommodative mechanism and its aging are much more complex than generally realized, and extralenticular changes with age may play an important role in the pathophysiology of presbyopia, glaucomatous optic neuropathy, impaired aqueous outflow, and the frustrating inability of current intraocular lenses to provide more than 1.75 to 2.00 diopters of dynamic accommodation, , which is not quite enough for fine near vision in subpar lighting conditions. 

Supplement 1 Click here for additional data file. 

