Key words."

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AGE-RELATED C H A N G E S O F T H E H U M A N CILIARY M U S C L E . A Q U A N T I T A T I V E M O R P H O M E T R I C STUDY

SVENJA T A M M a, E R N S T T A M M b and J O H A N N E S W. R O H E N b

"Department of Ophthalmology, Schwabachanlage 6 and hDepartment of Anatomy, Krankenhausstr. 9.

University of Erlangen-Niirnberg, D-8520 Erlangen ( F. R. G. ) (Received August 19th, 1991)

SUMMARY

The age-related changes o f the ciliary muscle of human eyes (33-87 years) were studied on histological meridional sections. Eighty-five melanoma eyes and 10 eyes of normal donors were investigated. The total area and the length of the muscle, the area of the three main portions and the distance of the inner apex of the muscle to the scleral spur were determined and correlated with age. Total area and length of the muscle show a continuous and significant decrease with age. The area of the longitudinal and reticular portion continuously decreases, whereas the area of the circular portion significantly increases with age. The decrease in area is more pronounced in the longitudinal portion than in the reticular portion of the muscle, which shows an age-related increase in connective tissue. In addition, the distance of the inner apex o f the muscle to the scleral spur shortens continuously. Thus, with increasing age the ciliary muscle adopts an anterior-inward position. A similar form is seen in young eyes after ciliary muscle contraction only. There might be a functional relationship between the observed age-changes in the ciliary muscle system and the phenomenon o f the so-called qens paradox' (steepening of the anterior and posterior curvatures o f the disaccommodated lens with age).

Key words."

Ageing; Presbyopia; Ciliary muscle; Human eye; Morphometry;

Histology

INTRODUCTION

Presbyopia, the age-related loss of accommodative amplitude, is a universal, con- sistent and predictable consequence o f human ageing. It has been suggested that len- Correspondence to." Ernst Tamm, Anatomisches Institut, Universit/it Erlangen-Nfirnberg, D-8520 Erlangen, Germany.

Printed and Published in Ireland

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210

ticular factors, like a decreased elasticity o f the lens capsule [I ]. a decrease m ~hc refractive index of the lens

[21.

or changes in architecture o f ciliary bod~, a n d / ~ m u l a [31 contribute to presbyopia.

C y n o m o l g u s m o n k e y s (Macaca/U,scicMari,s), or rhesus m o n k e y s I.l:la¢aca mttlalltl!

show an age-related decline in a c c o m m o d a t i v e amplitude, which parallels the loss o f v o l u n t a r y a c c o m m o d a t i o n in h u m a n s [4,5]. In presbyopic rhesus monke>s, the ciliary muscle loses its configurational response to topically administered pilocarpine [6]. Also video-recording of ciliar', b o d y coronal width, after central eleclrical stimulation o f y o u n g and old monkeys, shows loss o f measurable ciliar> bod~ movement with age, indicating loss of effective ciliar> muscle contraction [7]. Thus. thc ciliary muscle o f old m o n k e y s is not able lo move anterior-inwardly during stimulation, but is restrained to a posterior position which is typical for thc relaxed muscle o f y o u n g animals. These findings suggest that age changes in Ihe ciliar\ muscle and its posterior attachment contribute Io presbyopia m m o n k e \ eye>

It is not known whether similar processes are also involved ill human prcsbyopia.

In contrast to the findings in monkeys, it has been reported that the ageing human ciliary muscle acquires a position lhr anterior-inwardly, similar to that or a contracted muscle [8.9]. To obtain c o m p a r a b l e data with thosc on m o n k e y eyes [6] we investigated the age-related changes in ciliary muscle structure a.td posilion ill h u m a n eyes using m o r p h o m e t r i c a l methods.

M A T E R I A L S A N D M E T H O D S

Ninety-five eyes from 53 female and 42 male h u m a n d o n o r s (age 33-X7 years.

mean 63.2. median 65.17) were investigated. Eighty-five eyes (46 female, 39 male) were from the files o f the O p h t h a l m i c Pathological L a b o r a t o r y of the D e p a r t m e n t o f O p h t h a l m o l o g y , University o f Erlangen-Nfirnberg (Head: Prof. Dr. G.O.H, N a u m a n n ) and had been enucleated because o f malignant posterior choroidal m e l a n o m a . The age o f the t u m o r eyes ranged from 3 3 - 8 7 years. In addition ll) h u m a n a u t o p s y eyes (6 t'emale, 4 male, age 4 1 - 8 4 ) were studied. The a u t o p s y eyes had been enucleated 2 - 2 2 h alter death. N o n e o f the d o n o r s had a history o f a b n e r malities in the anterior segment o f the eye. In none o f the t u m o r eyes was the anterior half o f the eye infiltrated by' the tumor. No d o n o r had undergone intraocular surger>

before or showed signs o f secondary glaucoma. The mean length o f the bulb after fixation was 23.6 + 1.1 111111 {mean -+ S.D.), in none o f the eyes was the bulb smaller than 22 mm or larger than 26 ram. Before enucleation, the runlet eyes had been treated with tropicamide ( M y d r i a t i c u m R o c h e ~' ). The a u t o p s y eves were incubated alter enucleation for 1 I1 in I% atropine-sulfate (Atropin l%-Dispersa ~ ~.

Immediately after enucleation ( t u m o r eyes) or alter incubation m atropine (autopsy eyes), the eyes were fixed as a whole in a solution o f 4% p a r a f o r m a l d e h y d e and 1% glutaraldehyde li-~r 4 - 5 days. After fixation, the eyes were dissected with a razor blade by two parallel meridional cuts, one on each side o f the optic nerve entrance, at a distance o f 2 - 4 m m f i o m the nerve head. The cuts extended all t h r o u g h the eve

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to the cornea. The orientation of the cut was horizontally in the autopsy eyes. In the tumor eyes, the orientation was chosen so as to avoid cutting the tumor (for details, see N a u m a n n [10]). The middle part of the bulb (containing the tumor) was embed- ded in paraffin in the usual way [11]. Paraffin sections were made at a thickness of 5/~m. The sections were stained with Masson's trichrome stain. Care was taken that the orientation of the paraffin block was such that the central region of the pupil and of the optic nerve head were both present in one section.

F r o m all sections, drawings outlining the perimeter of the ciliary muscle, the chamber angle and the adjacent sclera were made using a drawing microscope (Zeiss Winkel 127012) at a magnification of x 91. In addition, a line was drawn between the meridional and the reticular portion of the muscle. The drawing was checked at higher magnifications. Furthermore, the outlines of all muscle bundles in the region of the inner apex o f the muscle, which contained only circular muscle cells, were drawn and their areas added as a measure of the circular portion of the muscle. Mus- cle bundles containing both transversely and obliquely cut muscle bundles were regarded as parts of the reticular portion. Thus the drawings of the circular portion outlined muscle cell area only, while the outlines of both reticular and longitudinal portion included both area of muscle ceils and area of intramuscular connective tissue.

With a m o r p h o m e t r i c device ( M o r p h o m a t 30, Fa. Zeiss) the total area of the ciliary muscle, the areas o f its different portions, and its length and width were evaluated. In addition, the inner apical position of the muscle was measured. A perpendicular was dropped from the widest part o f the area containing the muscle bundles of the circular portion to the outer outline of the longitudinal portion of the ciliary muscle. The distance between the point where the two lines met and the anterior tip of the longitudinal portion of the ciliary muscle at its insertion to the scleral spur was evaluated as a measure of the 'inner apical position' o f the ciliary muscle (Fig. 1).

To check for regional differences, measurements from different quadrants of the eyes were grouped separately. Due to the different positions of the tumor, the plane of the sectioning was different in the individual t u m o r eyes. Therefore, the tumor eyes were subdivided in two groups: (a) eyes cut horizontally (position of the ciliary muscle between 2 and 4 o'clock or 8 and 10 o'clock, e.g. nasal and temporal quadrant); (b) eyes cut vertically (position of the ciliary muscle between 11 and 1 o'clock and 5 and 7 o'clock, e.g. upper and lower quadrant). The measurements from each different q u a d r a n t were then evaluated separately.

F o r each parameter, the mean o f three measurements, which were done on different days, was taken and plotted as a function o f age. Correlations were defined as significant if P ~ 0.01 according to the Geigy Scientific Tables [12]. For testing the difference between the correlations of the different quadrants, a two-tailed Stu- dent's t-test was used (P _< 0.05). Additionally, the ratio between area of muscle cells and intramuscular connective tissue was estimated semiquantitatively.

The three different portions o f the muscle (longitudinal, reticular and circular)

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212

= L o n g i t u d i n a l Portion

= R e t i c u l a r Portion ( ~ - ( ~ 1 ~

= C i r c u l a r Portion

P o s i t i o n

L e n g t h i

Fig. 1. Schema ['or topographic analysis of ciliary muscle. By digitization ol" ciliary muscle drawings, measurements were made of ciliary muscle length (anterior-posterior distance along outer longitudinal edge from posterior tip to anterior insertion at scleral spur), width, position (anterior-posterior distance from inner apex to scleral spur, perpendicular to width of inner apex), and area of entire muscle and longitudinal, reticular and circular components.

were e v a l u a t e d separately. T h e g r a d i n g was 0, if no c o n n e c t i v e tissue was present between the muscle b u n d l e s , +, if the c o n n e c t i v e tissue comprised _< 20% o f the area o f the muscle p o r t i o n , + + for < 50% a n d + + + for >_ 50%.

RESULTS

Differences in the circumfi, rence

C o m p a r i s o n of the m e a s u r e m e n t s o f the temporal q u a d r a n t a n d the nasal q u a d r a n t of the h o r i z o n t a l l y sectioned eyes showed that the differences between the two were n o t significant (for each p a r a m e t e r t-test: P > 0.05). The same was the case for the m e a s u r e m e n t s of the u p p e r a n d lower q u a d r a n t of the vertically sectioned eyes ( P > 0.05). T h e data from both sides of each i n d i v i d u a l eye were therefore treated together a n d the m e a n values were calculated.

W h e n the m e a n values of b o t h h o r i z o n t a l l y a n d vertically sectioned eyes were similarly c o m p a r e d , the differences between both groups o f eyes was again not significant (for each p a r a m e t e r , P > 0.05). Therefore, for the final e v a l u a t i o n of each parameter, the m e a n values of all i n d i v i d u a l eyes were treated together.

T h e total area of the ciliary muscle m e a s u r e d on histological m e r i d i o n a l sections shows a c o n t i n u o u s a n d highly significant decrease with increasing age (correlation coefficient (r) = - 0 . 7 4 , P > 0.001, Fig. 2). This is c o n c o m i t a n t with a m a r k e d decrease in the length of the muscle (r = - 0 . 9 0 , P _< 0.001, Fig. 3). T h u s the mean length of the ciliary muscle, which measures approx. 4 m m in the 4th decade of life.

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l ~ I l l I i

I I I I I I i L I ~ I

i

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~ o 4 0 5 0 6 0 ~ o . o 9 0

a g e ( y e a r s )

Fig. 2. T o t a l m e r i d i o n a l sectional a r e a o f the h u m a n ciliary muscle as a f u n c t i o n o f age. T h e total a r e a s h o w s a significant d e c r e a s e with i n c r e a s i n g age (y = 1.36 - 0.0095x, r = - 0 . 7 4 , P <: 0.001).

shortens through age 70-80 years by approx, one half. In contrast, the width of the muscle does not show a significant correlation with age (r = -0.27, P _< 0.05, Fig.

4). Regarding the decrease in muscle area, differences between the different portions of the muscle were found. While the reduction in area of the longitudinal portion was highly correlated with age (r = -0.83, P _< 0.001, Fig. 5), this was not the case for the reduction in area of the reticular portion (r = -0.53, P _< 0.001, Fig. 6). In marked contrast to the rest of the muscle, the area of the circular portion showed a significant increase with age (r = 0.77, P _< 0.001, Fig. 7). This circular portion forms the inner apex of the muscle. In the younger eyes, the inner apex was obtusely

4.5

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Fig. 3. L e n g t h o f the ciliary m u s c l e as a f u n c t i o n o f age. Ciliary muscle s h o r t e n s significantly with age (v = 5.24 - 0.037x, r = - 0 . 9 0 , P - 0.0011.

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F i g . 4. W i d t h o f t h e c i l i a r y m u s c l e as a f u n c t i o n o f a g e . T h e w i d t h d o e s n o l s h o w a s i g n i f i c a n t c o r r e l a t i o n ( ",

w i t h a g e ()' = 0.62 - 0 . 0 0 1 4 x . r = - )._7, P _< 0.05).

angled and showed only a small a m o u n t o f circularly oriented muscle cells. In these eyes, the inner apex was located approx. 0.4 m m behind the scleral spur (Figs. 8.9A).

With increasing age, an acutely angled inner apex was formed, which in the oldest eyes was located nearly as forward as (and in some sections anterior to) the scleral spur (Figs. 8, 9B, 9C). T h u s the distance between the inner apex o f the muscle and its insertion to the scleral spur, ('inner apical position'), showed a significant inverse correlation with age (r = - 0 . 7 4 , P _< 0,001 ). In these old eyes, with an acutely angled inner apex and a short inner apical position, well developed circular muscle bundles were invariably seen (Fig. 9C).

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F i g . 5, S e c t i o n a l a r e a o f t h e l o n g i t u d i n a l p o r t i o n o f t h e c i l i a r y m u s c l e a , a f u n c t i o n o l age. f h c l o n g i t u d i n a l p o r t i o n s h o w s a r e d u c t i o n in a r e a , w h i c h is h i g h l y c o r r e l a t e d w i t h a g e ( I = 0.~1 - t l . 0 0 7 0 x , r = - 0 . 8 3 . P _< 0.001}.

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30 40 50 60 70 80 90

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Fig. 6. Sectional a r e a o f the r e t i c u l a r p o r t i o n o f the ciliary m u s c l e as a f u n c t i o n o f age. T h e a g e - r e l a t e d r e d u c t i o n in a r e a o f the r e t i c u l a r p o r t i o n is significant ( r = 0.56 - 0. 0028x, r -- - 0 . 5 3 , P _< 0.001 but less p r o n o u n c e d t h a n t h a t o f the l o n g i t u d i n a l p o r t i o n area.

With increasing age, ciliary muscle also showed a marked increase in intramuscular connective tissue (Table I). The increase in connective tissue was, however, not evenly distributed throughout the muscle, but showed differences between the different portions of the muscle. In eyes of humans younger than 50 years, there were only slight amounts of connective tissue fibers present between the muscle bundles of the longitudinal portion of the ciliary muscle. Even in the eyes of humans aged 50-85 years, the amount o f connective tissue in the longitudinal portion never

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Fig. 7. Sectional a r e a o f the c i r c u l a r p o r t i o n o f the ciliary m u s c l e as a f u n c t i o n o f age. In c o n t r a s t to the o t h e r p o r t i o n s o f the muscle, the a r e a o f the c i r c u l a r p o r t i o n shows a significant increase with age (y = - 0 . 0 0 1 6 + 0.00032x, r = 0.77, P ~< 0.001).

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30 40 50 60 70 80 90

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Fig. 8. Inner apical position of the ciliary muscle as a function of age. The distance between the inner apex of the muscle and its insertion to the scleral spur shows a significant inverse correlation with age (y = 0.67 - 0.0077x, r = -0.74, P _< 0.001).

c o n s t i t u t e d m o r e t h a n a p p r o x . 20(¼, o f t h e t o t a l a r e a o f t h e l o n g i t u d i n a l p o r t i o n . T h i s w a s in c o n t r a s t to t h e r e t i c u l a r p o r t i o n o f t h e m u s c l e . In t h e eyes o f h u m a n s b e t w e e n a g e 30 a n d 40 years, t h e c o n n e c t i v e t i s s u e o f t h e r e t i c u l a r p o r t i o n c o n s t i t u t e d a p p r o x . 20°/,, o f t h e t o t a l a r e a o f t h e r e t i c u l a r p o r t i o n . T h e r a t i o b e t w e e n t h e a r e a o f c o n n e c - tive tissue a n d t h e a r e a o f r e t i c u l a r m u s c l e b u n d l e s w a s a p p r o x . 1:1 in eyes o f h u m a n s a g e d 5 0 - 6 0 years. I n h u m a n s o l d e r t h a n 60 years, t h e c o n n e c t i v e tissue o f t h e r e t i c u l a r p o r t i o n u s u a l l y e n c o m p a s s e d m o r e t h a n h a l f o f t h e t o t a l a r e a o f t h e r e t i c u l a r m u s c l e p o r t i o n . T h e l a r g e b l o o d vessels a n d n e r v e s w e r e s u r r o u n d e d by a t h i c k c o n n e c t i v e t i s s u e s h e a t h . A d d i t i o n a l l y , all m u s c l e f i b e r b u n d l e s a p p e a r e d t h i n n - ed a n d w e r e s e p a r a t e d b y d e n s e c o n n e c t i v e tissue b a n d s . F r o m a g e 50 a n d o l d e r , the b u n d l e s o f t h e c i r c u l a r p o r t i o n w e r e s e p a r a t e d f r o m t h e r e t i c u l a r p o r t i o n by a large m a s s o f c o n n e c t i v e tissue, w h i c h h y a l i n i z e d w i t h i n c r e a s i n g age. T h e a r e a s o I h y a l i n i z a t i o n w e r e c o n t i n u o u s w i t h t h e s i m i l a r l y h y a l i n i z e d c o n n e c t i v e tissue o f the s t r o m a o f t h e c i l i a r y p r o c e s s e s . In c o n t r a s t , t h e s t r o m a o f t h e iris r o o t , w h i c h is s i t u a t e d a n t e r i o r - i n w a r d l y to t h e c i r c u l a r p o r t i o n , w a s n o t h y a l i n i z e d a n d s h o w e d n o m a r k e d i n c r e a s e in c o n n e c t i v e tissue w i t h age.

Fig. 9. Ciliary muscle of 34- (A), 59- (B) and 80-year-old (C) human donors. "File inner apex of the muscle.

which consists mainly of the muscle's circular portion, changes its position throughout lifetime. (A) In the ciliary muscle of the 34-year-old donor, the inner apex (arrow) is located well posterior to the scleral spur (arrowhead). (B) In the eye of the 59-year-old donor, the inner apex of the muscle is located nearly as forward as the scleral spur. (C) In the 80-year-old donor, the inner apex of the muscle is located anterior to the seleral spur (paraffin sections, Masson's stain, × 50).

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T A B L E 1

S E M I Q U A N T I T A F I V E F . V A L t i A T I O N O F I H E P E R ( ' E N T A G E O F I N T R A M t r S ( ' U I ~ A R ( ' ( ) N - N E C T I V E T I S S U E A R E A I N T H E S I ' ~ C T I O N A I . A R E A OF L O N ( H T L D I N A I . A N I ) R E H ( ' [ I I A R M U S C L E P O R T I O N S

0. n o c o n n e c t i v e t i s s u e s t a i n e d . +, p e r c e n t a g e o f c o n n e c t i v e t i s s u e _< 2(1'~,: + ~. ~ 50" : ~ + + , ~, .~i)':

Age Longitudinal Reticular

(year,s) porliotl porliotl

3 0 - 4 0 0 +

4 0 - 50 0 + +

5 0 - 6 0 0 + +

6 0 - 7 0 0 - + + + +

7 0 - 8 0 + + ~ +

_>80 + ~ + +

D I S C U S S I O N

Our morphometric study shows that ciliary muscle continuously atrophies from age 30-80. Age-related atrophy of the ciliary muscle was also investigated by Stievc [9] who, however, described that this process starts later in life, beginning with age 55-60 years. The a t r o p h y of the muscular elements is even more pronounced as a large concomitant increase in intramuscular connective tissue takes place with age, which has also been reported by other authors [8,9,13-15]. Findings of Stieve [9]

and Rother et al. [16], that the ciliary muscle of women is more prone to atrophy cannot be confirmed.

The loss of contractile elements might cause a weakening of the ciliary muscle with increasing age. As the time course of these muscular changes is in marked correlation with the age-related loss of accommodative amplitude [17-19], weakening of the ciliary muscle might contribute to presbyopia. Swegmark [20] and Fisher [21] stated that ciliary muscle power does not decline with age. However, these studies utilized very indirect methods such as impedance cyclography or in vitro passive stretch and lens deformation, to obtain information about ciliary muscle function. Moreover, forces on the lens during accommodation are determined less by the contractile strength of the ciliary muscle, but more by its position and configuration. I)uring contraction, ciliary muscle shortens and moves anterior-internally. In meridional sections, the area of the longitudinal portion decreases, while the area of the circular portion increases, giving the muscle a sharp and prominent inner edge [6,22-24[

These changes in muscle configuration cause the relaxation of the zonule and allow the lens to assume a more spherical shape. Interestingly, our study shows that the same changes in muscle configuration during contraction occur also with increasing age.

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artefacts induced by fixation and tissue processing. It has been shown, however, that pharmacologically induced changes in ciliary muscle configuration and position can be preserved to some extend by fixation with aldehydes [6,24-26]. Most of the eyes used in the present study were treated before fixation with tropicamide, which is known to exert a weak cycloplegic action. Some of the eyes were treated with atropine before fixation, but several hours post mortem. However, the pupils of the eyes became mydriatic, indicating that active drug entered the anterior chamber. We do not know to what extent the ciliary muscle of the eyes investigated was relaxed, but it seems reasonable to assume that it was not contracted. Moreover, all eyes were fixed and processed similarly regardless of their age. We therefore assume that in a given eye, ciliary muscle had been fixed in a relatively relaxed, disaccommodated position and configuration. With age, the relaxed ciliary muscle adopts more and more a position anterior-inwardly. A similar position is seen in young eyes after ciliary muscle contraction only.

These findings are in marked contrast to findings in the ciliary muscle of presbyopic rhesus monkeys. In these animals, ciliary muscle becomes fixed in a position far posteriorly with increasing age, as seen in young eyes after relaxation of the muscle.

Moreover, the presbyopic muscle loses its anterior inward movement in response to pilocarpine [6]. it has been shown that this is probably due to an increased stiff- ness of its posterior tendons, which insert to Bruch's m e m b r a n e [27]. However, there are also other differences in ageing of the accommodative apparatus between humans and monkeys. In monkeys, the age-related increase in intramuscular connective tissue is minimal c o m p a r e d to that of humans [28]. Also differences were found between monkeys and humans in the ageing of the lens [29]. Thus, although the ac- c o m m o d a t i v e system of the two species is very similar, the factors contributing to presbyopia might be different.

What causes the age-related changes in position and configuration of the human ciliary muscle, and how does it relate to presbyopia? The remodelling of the ciliary muscle might bring the muscle in a more favorable position to induce a c c o m m o d a - tion and to overcome lenticular factors hindering accommodation. The pronounced increase in connective tissue, which is mainly confined to the reticular portion of the muscle, might serve as a kind of internal skeleton to keep the muscle in this more advantageous position. It has been shown that the attachment site of the zonules on the front surface of the lens change as the lens ages and grows [30]. With age the attachment site shifts from the equator onto the anterior lens surface. The zonules might become unable to relax if the front o f the enlarged lens is so far from the ciliary muscle that the lens pulls the zonules taut. This might be prevented, at least for a time, by the anterior inward shift of the ciliary muscle position. It might also be the case that the remodelling o f the ciliary muscle happens to counteract an age- related decrease in refractive index of the lens mass. A relaxed ciliary muscle, which

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is positioned more anterior-internally, should cause a more spherical shape of the disaccommodated lens. Donders [17] and Fincham [31] both concluded that the sur- face o f the lens flattens with age, but Brown [32] established in a careful work, thal in humans the anterior and posterior curvatures indeed become steeper with age.

This finding was called the qens paradox" as a steepening o f the lens curvature im- plies rather an increase in refractive power than a decrease as in presbyopia. It has been suggested based on computer simulation experiments that the overall sharpen- ing of lens curvature happens to counteract the concomitant reduction in the index of refraction of the lens mass [2]. Thus the age-related remodelling of the ciliary mus- cle might be important to maintain emmetropia.

In summary, the age related decline in accommodation seems to be a multifac- torial event involving both the ageing of the lens and the ciliary muscle. Although the age processes in lens and muscle are spatially and qualitatively different, they still take place in functional relation with each other. This relationship might be an im- portant factor to guarantee that emmetropia is maintained throughout the whole human life span.

A C K N O W L E D G E M E N T S

We would like to thank Carmen Rummelt for her expert assistance in histology and Marco G613wein for his excellent preparation o f the photographs. This study was supported by the Academy of Science and Literature, Mainz, F.R.G. and by the Deutsche Forschungsgemeinschaft (Dre 124/6-1 ).

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