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(Investigative Ophthalmology and Visual Science. 2003;44:2118-2125.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.02-0569
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Aqueous Humor Dynamics and Trabecular Meshwork and Anterior Ciliary Muscle Morphologic Changes with Age in Rhesus Monkeys

B’Ann True Gabelt,1 Johannes Gottanka,2 Elke Lütjen-Drecoll,2 and Paul L. Kaufman1,3

1From the Department of Ophthalmology and Visual Sciences and the 3Wisconsin Regional Primate Research Center, University Of Wisconsin, Madison, Wisconsin; and the 2Department of Anatomy, University Erlangen-Nürnberg, Erlangen, Germany.


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
PURPOSE. To determine in rhesus monkeys the age-dependence of uveoscleral outflow (Fu) and morphology of the trabecular meshwork (TM) and anterior ciliary muscle (CM).

METHODS. Intraocular pressure (IOP) was measured by Goldmann applanation tonometry in monkeys under ketamine anesthesia. After anterior chamber cannulation under pentobarbital anesthesia, aqueous humor formation (AHF), anterior chamber volume, trabecular outflow, and Fu were determined isotopically. The CM and TM were examined by light and electron microscopy.

RESULTS. IOP increased significantly with age in monkeys aged 3 to 29 years. AHF and anterior chamber volume were unchanged. Fu was decreased, and trabecular outflow increased in monkeys aged 25 to 29 years compared with the remaining monkeys. Morphologically, there was a significant increase in the thickness of the elastic fibers of the trabeculum ciliare covering the anterior tips of the CM, and an increase in extracellular material between the muscle tips. The number of TM cells decreased with age, whereas the amount of fibrillar material and sheath-derived plaques increased. This increase was less pronounced in the middle filtering portion of the cribriform region than in the anterior and posterior portions.

CONCLUSIONS. The decline in Fu in very old rhesus monkeys with normal IOP parallels that seen in normotensive aging humans. This may be correlated with thickening of the elastic fiber sheath in the CM tips in addition to other morphologic changes. The TM findings are analogous to those in the aging human eye and are consistent with the age-related decrease in outflow facility reported in both humans and monkeys.

Intraocular pressure (IOP) in normal healthy humans remains relatively stable or slightly increases with age in many Western populations,1 2 3 4 while decreasing with age in the Japanese population.5 Studies of aqueous dynamics in humans have shown that, with age, aqueous flow,2 6 7 8 tonographic outflow facility,2 6 8 9 and anterior chamber volume all decrease,3 8 whereas episcleral venous pressure is unchanged.2 8 Until recently, the only measurements of uveoscleral outflow (Fu) in humans were obtained in a few eyes with ocular melanomas.10 Fluorophotometric estimates of outflow facility in humans have shown a decrease with age.8

Similarly, IOP in normal, healthy, free-ranging rhesus monkeys remains relatively constant with age, after an initial juvenile hypertensive phase.11 12 13 Outflow facility, as well as its response to intracameral pilocarpine, declines with age.14 Morphologic changes in the ciliary muscle (CM) in aging rhesus monkeys, including increases in the number of pigmented cells between the CM bundles with the anterior longitudinal region being affected last, suggests that uveoscleral outflow (Fu) may also be affected.15 16

In the present study we determined in rhesus monkeys the correlation with age of Fu, rate of aqueous humor formation (AHF), rate of trabecular outflow, and anterior segment volume. We also examined the possible role of previously unstudied age-related morphologic changes in the anterior portion of the CM and the trabecular meshwork (TM) that could alter uveoscleral and trabecular outflow.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Animals and Anesthesia
On the day before or on the same day as Fu studies, IOP (Goldmann applanation)17 and slit lamp biomicroscopy were performed in monkeys that were under intramuscular ketamine anesthesia (10 mg/kg). For Fu studies, 24 rhesus monkeys (Macaca mulatta), ages 3 to 29 years (human equivalent, ~8–73 years) were anesthetized with intramuscular injection of ketamine followed by intravenous administration of pentobarbital (10–15 mg/kg; maintenance dose of 5–10 mg/kg as needed, usually every 1 to 1.5 hours). A femoral artery was then cannulated for subsequent blood sampling. Eight additional animals were used for determinations of blood-equivalent albumin space (described later).

Quantitative morphologic studies were conducted on CM and TM from 12 other rhesus monkeys, aged 3.5 to 34 years, killed at the University of Wisconsin-Madison and subsequently sent to the University of Erlangen. Different structural parameters from monkeys in the current study have been reported earlier15 (Table 1) .


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  		TABLE 1. Monkeys Used for Morphology Studies

 
AHF, Flow to Blood, Fu, Anterior Chamber Volume, Blood-Equivalent Albumin Space
AHF was measured by dilution of radioiodinated monkey albumin20 dissolved in Bárány perfusate19 according to the method of Sperber and Bill.21 Each anterior chamber was cannulated temporally with three 23-gauge needles: outflow on top, pressure in the center, inflow on the bottom. The inflow and outflow needles were connected to a closed circuit containing a peristalic pump and a loop that passed through a well detector (Canberra, Meriden, CT). The circuit for the right eye contained I-125 albumin solution, and the circuit for the left eye contained I-131 albumin solution, each at a concentration of approximately 5 x 106 counts per minute (cpm)/mL. Cold albumin was added to a final concentration of 0.1%. The circuit volume was 1.231 mL, and the circulation rate was 150 to 200 µL/min. There was no additional infusion of isotope solution during the experiment. The entire experiment was run at spontaneous IOP, which was approximately 10 mm Hg for monkeys under pentobarbital anesthesia.

After cannulation of the eyes and a 5- to 10-minute equilibration period at spontaneous IOP, the mixing pump was started. Radioactivity in the well detector loop was measured for 1 minute with a multichannel analyzer (series 30; Canberra) every 5 minutes for the next 120 minutes. Blood samples of 1 mL were taken from the femoral artery every 10 minutes beginning at 40 minutes and the radioactivity measured with a gamma counter (Packard Instrument Co., Meriden, CT).

Anterior chamber volume was calculated from the initial decrease in circuit isotope concentration. AHF was determined from the slope of the disappearance of radioactivity from the circuit. Flow into the bloodstream (flow to blood) was calculated from the radioactivity recovered in the blood samples (corrected for the decreasing concentration in the anterior chamber) and the blood-equivalent albumin space. Fu was calculated as the difference between AHF and flow to blood.

Blood-equivalent albumin space was determined on a separate occasion in six of these same animals, in five additional animals aged 4 to 22 years, and in three of these same animals plus three additional animals aged 24 to 30 years, by constantly infusing I-125 monkey albumin into the saphenous vein and sampling blood from a femoral artery at 10- or 15-minute intervals for 2 hours. The resultant regression equation for the 4- to 22-year age group was applied to flow to blood calculations for animals 3 to 23 years of age, and the equation from the 24- to 30-year group was applied to flow to blood calculations for animals 25 to 29 years of age, unless the monkey’s own data were available (n = 9), in which case those data were used.

Analysis
AHF, Fu, and flow to blood data were analyzed with the two-tailed, unpaired t-test for differences with unequal variances compared with 0.0. Probabilities for slopes were calculated by regression analysis using Minitab software (Minitab, Inc., State College, PA).

All experiments were in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and the University of Wisconsin institutional animal care and use committee.

The fixed specimens were cut into 1- to 2-mm wedges encompassing cornea, TM, and iris and ciliary body posterior to the ora serrata and embedded in Epon. Semithin sections (1 µm) and ultrathin sections (60 nm) were cut with an ultramicrotome (Reichert, Vienna, Austria). Semithin sections were stained with toluidine blue, and ultrathin sections were counterstained with lead citrate and uranyl acetate. Semi- and ultrathin sections of the TM and CM tips were investigated in four different sectors of the circumference of the eye.

Quantitative evaluation was performed in semithin sagittal sections of the four different portions of the circumference. The number of trabecular cells (defined as cells with nucleus in the section) were counted in the entire meshwork in that section. In ultrathin sections of the chamber angle, the area occupied by sheath-derived plaques (the sheaths of the elastic fibers) and fibrillar material under the inner wall of Schlemm’s canal was measured. Measurements were performed with a computer-based morphometric system (Quantimed 500; Leica, Cambridge, UK) at x3000 on a video screen. The area of the cribriform region analyzed was 315 µm2 and was located in the middle filtering part of the meshwork, avoiding both the anterior and posterior ends of Schlemm’s canal. The length of the area was 45 µm along the inner wall of the canal and extended 7 µm from the inner wall into the cribriform region. In addition, the diameter of cross sections through elastic fibers was measured.

In sagittal ultrathin sections through the CM tips of the longitudinal and reticular part of the muscle the diameter of 10 elastic fibers per section in the trabeculum ciliare was measured. As the morphology of the elastic fibers was in general similar in the different quadrants, quantitative evaluations were performed only in one randomly chosen section per eye.


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Physiology
Slit lamp biomicroscopy showed that the anterior segments of all animals were free of cells, flare, and ocular abnormalities before experimentation. IOP increased significantly as age increased from 3 to 29 years (n = 22, P = 0.039, Fig. 1 , Table 2 ). However, there was no significant difference in the mean IOP between the various groups.



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  		FIGURE 1. IOP increased in the monkeys with age. The slope of the linear regression line (not shown) of IOP with age for all animals (3–29 years, n = 22) was significantly different from 0.0 (P = 0.039; r2 = 0.197).

 

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  		TABLE 2. Effects of Aging on Aqueous Formation and Drainage in Rhesus Monkeys

 
Total AHF remained constant throughout life (Fig. 2 , Table 2 ). The increase in flow to blood and decline in Fu were precipitous in the 25- to 29-year group, rather than changing uniformly throughout the life span. The regression of flow to blood and Fu versus age in the 3- to 23-year-old animals was not significant (Figs. 3 4) . However, mean Fu, Fu/AHF, and flow to blood/AHF were significantly different between the 25- to 29-year group and the others groups (Table 2) . Anterior chamber volume estimated by isotope dilution did not change with age in this study (Fig. 5 and Table 2 ).



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  		FIGURE 2. Aqueous humor formation (AHF) rate did not change with age in rhesus monkeys (n = 24).

 


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  		FIGURE 3. Flow to blood (FTB) increased very little with age in rhesus monkeys until rather late in life. The slopes of the linear regression lines (not shown) for rate of (A) FTB or (B) FTB/AHF (aqueous humor formulation) versus age in all animals (3–29 years, n = 24) or for animals 3 to 23 years (n = 19) were not significantly different from 0.0.

 


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  		FIGURE 4. Uveoscleral outflow (Fu) decreased very little with age in rhesus monkeys until rather late in life. The slopes of the linear regression lines (not shown) for rates of (A) Fu or (B) Fu/AHF (aqueous humor formulation) versus age in all animals (3–29 years, n = 24) or in animals 3 to 23 years (n = 19) were not significantly different from 0.0.

 


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  		FIGURE 5. Anterior chamber (AC) volume remained essentially constant with age (n = 24).

 
The regression equation in pooled data from animals aged 4 to 22 years for blood-equivalent albumin space as a percentage of body weight versus time (n = 11) was 8.157 + (0.011 x minutes from the start of I-125 albumin infusion). A slightly different regression equation was obtained for blood-equivalent albumin space measured in pooled data from monkeys 24 to 30 years of age (n = 6): 7.623 + (0.011 x minutes from the start of I-125 albumin infusion).

Morphology
In rhesus monkeys the trabeculum ciliare connecting the uveal portion of the TM with the iris root and thereby covering the CM tips consisted of a network of collagen and elastic fibers. On the aspect facing the anterior chamber, this network was covered by TM cells. On the aspect facing the CM bundles, the elastic and collagen fibers of the trabeculum ciliare were continuous with the connective tissue between the CM bundles and the basement membrane of the CM cells. With increasing age, the fibrillar material within the trabeculum ciliare and the intermuscular spaces at the muscle tips increased. The elastic fibers gained a homogeneous-appearing electron-light sheath that also increased with age. Quantitative evaluation of the diameter of the elastic fibers including the sheath material revealed that the increase in thickness was linear (Figs. 6 7A) .



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  		FIGURE 6. Electron micrographs of the ciliary muscle tips of a 3.5-year-old monkey (A, B) and a 34-year-old monkey (C, D). The extracellular material within the trabeculum ciliare surrounding the muscle tips increased with increasing age. Thick bundles of collagen fibers appeared in the old monkey’s eye (C, arrows). The sheath of the elastic fibers (arrows) in old monkeys (D, arrows) is also much thicker than in younger animals (B, arrows) MC, ciliary muscle cell. Scale bar, 1 µm.

 


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  		FIGURE 7. Elastic fiber thickness changed with age. (A) In the ciliary muscle (CM) tips, elastic fiber thickness including the sheath material increased significantly with age (slope of linear regression, P < 0.001, not shown). (B) Elastic fiber thickness changes in the trabecular meshwork (TM) in the subendothelial region of Schlemm’s canal were more variable but also increased significantly with age (slope of linear regression, P = 0.024, not shown). r2 = 0.764 (A) and = 0.413 (B).

 
In the TM the number of TM cells decreased significantly with increasing age (Fig. 8) . In the cribriform region there was also an increase in the amount of extracellular material and increased thickness of the elastic fiber sheaths. Quantitative evaluation of the diameter of the elastic fibers in the middle filtration area of the cribriform region showed that the thickening in that area was less prominent and the interindividual variability greater than at the muscle tips (Fig. 7B) . The area of sheath-derived plaques directly underneath the inner wall of Schlemm’s canal in the middle filtration area was highly variable, but there was a tendency toward an increase with age (Fig. 9A) . The area of optically empty spaces within this region remained constant with age (Fig. 9B) , as did the area occupied by fibrillar material and by cells (Figs. 9C 9D) . This was true, however, only in the middle filtering portion of Schlemm’s canal. In the adjacent posterior portion of the inner wall, the increase in fibrillar material and the increase in thickness of the sheaths of the elastic fibers were much more pronounced in old monkeys than in young animals (Figs. 10 11) .



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  		FIGURE 8. Trabecular meshwork (TM) cell counts significantly decrease with age (slope of linear regression, P = 0.002, not shown). r2 = 0.723.

 


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  		FIGURE 9. In the middle, filtering portion of Schlemm’s canal, the area occupied by sheath-derived plaques (A), fibrillar material (B), empty space (C), or cells (D), became more variable with age, but the correlation was not significant.

 


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  		FIGURE 10. Electron micrographs of the inner wall region of Schlemm’s canal (SC) in a 2-year-old (A, B) and a 34-year-old (C, D) monkey. In both the young and the old animals, there was more extracellular material in the posterior part of SC (B, D) than in the middle, presumably main filtering, portion (A, C). In the old monkey, there was more extracellular material directly adjacent to the inner wall than in the young one. Part of this material was formed by thickened sheaths of elastic fibers (sheath-derived plaques; arrows). Scale bar, 2 µm.

 


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  		FIGURE 11. Higher magnification of the sheath-derived plaques (arrows) underneath the inner wall of Schlemm’s canal (SC) in a 34-year-old monkey. EL, elastic fiber. Scale bar, 1 µm.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
In this study, Fu appeared to decline significantly in rhesus monkeys older than 25 years compared with younger age groups, even as close in age as 19 to 23 years. Based on existing human data,8 Fu also decreases in healthy humans older than 60 years (equivalent to our 25- to 29-year old monkeys) compared with 20- to 30-year-olds. Whether there is a gradual or a dramatic decline in Fu in humans has not been determined. Townsend and Brubaker22 calculated Fu to be 34% ± 12% of AHF in control eyes of 24-year-old humans, similar to our finding in our 3- to 23-year-old monkeys (37% ± 4%). Purported monkey versus human differences in Fu in earlier comparisons are probably due largely to age and/or disease state differences, rather than to species differences. A study by Bill and Philips10 of Fu in humans was undertaken in 48- to 73-year-old eyes, most of which harbored malignant melanomas. They suggested that the increase in polysaccharide material that often occurs in choroidal melanomas probably impedes flow through the TM and CM. The large scatter and the weak correlation in the plots of Fu or flow to blood or Fu versus age in our monkeys (r2 ≤ 0.1; Figs. 3 4 , respectively) indicates that experimental noise or other factors are also at play.

Previous studies showed an age-related decrease in total outflow facility in both monkeys14 and humans.2 6 9 In humans, reduced formation of giant vacuoles in the inner wall endothelium of Schlemm’s canal has been proposed to account for the age-related increase in outflow resistance (Roy S, Boldea R, Leuba S, Mermoud A, ARVO Abstract 733, 2001) but this is only one of many possibilities. The amount and induction of mRNA for various matrix metalloproteinases decreased with age of porcine trabecular cell cultures exposed to 15 and 50 mm Hg of pressure for 72 hours (Ehrich D, Tripathi BJ, Tripathi RC, Duncker GIW, Gotsis S, ARVO Abstract 748, 2001). In human TM cells, there may also be a passage-number–related reduction in matrix metalloproteinase activity (Williams GC, Borrás T, Pizzo SV, ARVO Abstract 764, 2001). Findings in both of the latter studies suggest a reduced capacity to break down extracellular material, which could contribute to a reduction of outflow either through the TM or through the Fu pathway. Also, a reduction in CM movement23 reflected by the onset of presbyopia in humans and monkeys which is complete by approximately 55 years in humans and 25 years in rhesus monkeys,24 could contribute to an environment in which extracellular material could accumulate in the CM and TM outflow pathways.25

In our study and inferred from Toris et al.,8 the flow of fluid through the trabecular outflow pathway actually appears to increase with age when the starting IOP is normal. Trabecular outflow facility was not measured as part of the present study. An increase in trabecular flow would not by itself rule out a decrease in trabecular outflow facility.

However, if trabecular outflow facility (Ctrab) and Fu decrease while AHF remains stable, IOP must increase or episcleral venous pressure (Pe) must decline, based on the Goldmann equation: AHF = Ctrab (IOP - Pe) + Fu. Because IOP appears to increase with age in the monkeys we studied (Fig. 1) , whereas AHF remained unchanged and Fu decreased, a decrease in trabecular outflow facility with age is possible. Our morphologic and physiological data suggest that the age-related increases in IOP in this sample of monkeys may reflect changes in the uveoscleral as well as the trabecular outflow pathway (discussed later). However the physiologic changes in aqueous humor drainage in our studies appear not to occur uniformly throughout life but change rather precipitously at 25 years of age. Morphologic changes seem to occur more uniformly with age. It may be that a threshold in morphologic changes must occur before there are any changes in physiologic response.

The increased appearance of isotope in the blood in older animals can be explained in two ways: Either almost all the fluid goes through the TM, or Fu channels empty into the blood more promptly. In the first case, the normal elevation in IOP with age may produce a widening of the paracellular channels between the inner-wall endothelium26 and a loosening of the cell–cell attachments that form them, allowing more fluid to flow through this route in a nondiseased eye. The second possibility suggests that Fu channels become more "leaky" or are otherwise altered with age. However the change in Fu was not continuous throughout life, but rather occurred precipitously in very old age. If the vasculature in general becomes more leaky with age, then the blood-equivalent albumin space in monkeys aged more than 25 years would be expected to be greater than in those aged less than 19 years, which was not the case. In adult humans, leakiness remained largely unchanged from 18 to 77 years.27 Scleral hydraulic conductivity does not appear to change with age in humans (Noury AM, Jackson TL, Hodgetts A, Marshall J, ARVO Abstract 3580, 2001). If we assume the same blood-equivalent albumin space in all animals, then the difference in Fu in the two age groups is even more striking (Gabelt BT, Kaufman PL, ARVO Abstract 2749, 2000).

There has been a debate about whether Fu actually passes through the sclera versus flowing into the choroidal blood.28 However, these arguments in no way negate the use of protein tracers as a marker. Any protein appearing in the blood shortly after its introduction into the anterior chamber can be assumed to have been carried to the blood by transtrabecular flow. Therefore the calculation of Fu as the difference of AHF and flow to blood would not depend on the exact route of Fu.

Prior studies of the aging CM have revealed some cellular changes that seem unlikely to have consequences for bulk fluid flow through the tissue, which is more likely to depend on events in the intermuscular spaces and perhaps especially at the anterior entrance to those spaces at the trabeculum ciliare. The trabeculum ciliare is a network of elastic and collagen fibers between the iris root, the uveal portion of the TM, and the CM tips. It is covered by cells anteriorly and connected to the basement membrane of the CM cells and the connective tissue between the CM bundles at their tips posteriorly. Aqueous humor must pass through the spaces of the trabeculum ciliare to gain entrance to the spaces between the CM tips, which constitute the entrance to the Fu pathway.

In the present study, there was a significant increase in thickness of the elastic fibers of the trabeculum ciliare with age in rhesus monkeys. Cross sections through the elastic fibers and their sheaths form the so called sheath-derived plaques.29 Sheath-derived plaques at the muscle tips increase with age in human eyes and especially so in glaucomatous eyes.29 The plaques at the muscle tips in old rhesus monkeys presumably are not large enough to reduce Fu themselves but may indicate a general increase in extracellular material in the CM tips and a consequent reduction in the size of the "gateway" openings for entrance of aqueous humor into the Fu pathways.

The number of pigmented cells in the inner and posterior parts of the CM in rhesus monkeys increases with age,15 but the most anterior portions are spared until after age 20 years, at which point the spaces between the muscle fiber bundles contain a greatly increased number of pigmented cells compared with younger animals. This is especially prominent after age 25 years when pigmented cells are present even between the tips of the anterior longitudinal portion of the muscle. The correlation with the dramatic decrease of Fu over age 25 is noteworthy but could be either a contributing factor to or the result of decreased Fu.

With increasing age in rhesus monkeys, we found an increase in sheath-derived plaques and fibrillar material in the juxtacanalicular region and a decrease in overall cellularity of the TM. All these findings also occur in human eyes with increasing age. After filtration surgery in young normal monkeys increased plaque formation also occurred in the TM, presumably consequent to underperfusion.30 If underperfusion causes plaque formation in our old monkeys, this could explain why changes in the TM show more interindividual variability (between animals of the same age) than do the CM entrance changes. Because AHF does not decline noticeably with age, the flow may wash out and degrade sheath material in the TM. This would be less true in the muscle tips with severely reduced Fu.

In conclusion, our results in monkeys and those of Toris et al.8 in humans, using independent techniques with different assumptions and potential flaws, both indicate that Fu decreases at older ages in eyes with normal IOP and normal findings in biomicroscopy. This decrease in Fu with age could be especially important in elderly patients with glaucoma, in whom outflow facility through the TM is also compromised.31


   Acknowledgements
 
The authors thank the Wisconsin Regional Primate Research Center for making available to us rhesus monkeys of various age groups for the in vivo studies and for providing eyes from animals euthanatized for other protocols, and Jennifer Seeman, DVM, for providing expertise in performing femoral artery cannulations for blood collection.


   Footnotes
 
This is Wisconsin Regional Primate Research Center publication number 42-012.

Supported by National Eye Institute Grant EY02698 (PLK); an unrestricted departmental grant from Research to Prevent Blindness and physician-scientist awards (PLK); Grant RR00167 from the Wisconsin Regional Primate Research Center; and Grant SFB319 from the Academie of Science, Mainz, Germany (EL-D).

Submitted for publication June 11, 2002; revised November 12, 2002; accepted November 17, 2002.

Disclosure: B.T. Gabelt, None; J. Gottanka, None; E. Lütjen-Drecoll, None; P.L. Kaufman, None

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Paul L. Kaufman, Department Ophthalmology and Visual Sciences, F4/328 CSC, 600 Highland Avenue; Madison, WI 53792-3220; kaufmanp{at}mhub.ophth.wisc.edu.


   References
Top
 Abstract
 Methods
 Results
 Discussion
 References
 

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