Crystalline Lens Optical Dysfunction

through Aging
Jorge L. Ali, MD, PhD,1,2 Patricia Schimchak, MD,1 Herminio P. Negri, MD,1
Robert Monts-Mic, OD, MPhil1
Purpose: To evaluate the optical and densitometric changes that take place in the crystalline lens with aging.
Design: Cross-sectional study.
Participants: Seventy-two eyes of 72 patients of different ages (8 80 years) with a clear lens, a visual acuity
of 20/25 or better, and no ocular disease.
Methods: In each case, the lens thickness, optical density, modulation transfer function (MTF), and intraocular aberrations were measured.
Main Outcome Measures: Embryonic and fetal nucleus density, lens thickness, intraocular high-order
aberration (HOA), and 0.1 MTF.
Results: Embryonic, anterior, and posterior fetal nucleus densities show a positive correlation with age
(P0.0001, P0.0001, and P0.0001, respectively). Lens thickness also shows a positive correlation with age
(P0.0001). Total ocular and corneal HOAs for a 6-mm pupil show a positive correlation with age (P 0.036 and
P0.0001, respectively). Ocular and corneal Zernike polynomials Z4iZ6i and intraocular spherical aberration
(Z40) also show a positive correlation with age (P 0.001, P 0.039, and P 0.001, respectively). Intraocular
coma aberration (Z31) shows a negative linear correlation with age (P0.0001). In addition, 0.1 MTF decreased
with age from 18.557 to 10.100 cycles per degree.
Conclusion: There is a degradation of the optical quality of the crystalline lens with aging that is associated with
morphological changes (thickness and density). These results are important for the consideration of lens replacement
in the absence of evident cataract. Ophthalmology 2005;112:20222029 2005 by the American Academy of
Ophthalmology.

Visual function is affected by environmental light conditions, the optical quality of the eye, and neural processing of
visual information. The quality of the image on the retina is
degraded because of scattering, diffraction at the pupil,
defocus due to accommodation or ametropia, and aberrations of the eye.15 Scattering is not as important in young
subjects as it is in older subjects. As a person ages, scattering becomes an important contributor of image degradation.3 6 The aforementioned changes result in a degradation
of the optical performance of the human eye.
The crystalline lens undergoes changes with age. The lens
grows in size and weight throughout life.7 It has been estimated
that the thickness of a human lens increases about 0.02 mm per
Originally received: October 19, 2004.
Accepted: April 20, 2005.
Manuscript no. 2004-201.
1
Research, Development, and Innovation Department, VISSUM, Instituto
Oftalmolgico de Alicante, Alicante, Spain.
2
School of Medicine, Miguel Hernndez University, Alicante, Spain.
This study has been supported in part by a grant of the Spanish Ministry of
Health, Instituto Carlos III, Red Temtica de Investigacin en Oftalmologa,
Subproyecto de Ciruga Refractiva y Calidad Visual, Madrid, Spain (grant no.:
C03/13).
The authors have no proprietary interest in any of the materials or methods
described herein.
Correspondence to Prof Jorge L. Ali, MD, PhD, VISSUM, Instituto Oftalmolgico de Alicante, Universidad Miguel Hernndez, Avda. Denia s/n,
Edificio VISSUM, 03016, Alicante, Spain. E-mail: jlalio@vissum.com.

2022

2005 by the American Academy of Ophthalmology

Published by Elsevier Inc.

year.8,9 As new fiber cells are formed, older cells are displaced
towards the center of the lens, or lens nucleus, which becomes
denser. The most superficial area of the lens, formed by
younger fiber cells, is called the lens cortex. With aging, the
molecular changes that take place in the crystalline lens should
contribute to a gradual reduction in transparency. In many
cases, the aging process of the crystalline lens reaches a point
where vision is impaired. The clinical condition of cataract is
defined at that point. The molecular changes that increase the
density of the lens result in an increase in the scattering and
aberration of light waves and a degradation of the optical
quality of the eye. Until now, the correlation between optical
(high-order aberrations [HOAs] and modulation transfer function [MTF]) and densitometric changes of the crystalline lens
that take place during the aging process has not been studied.
We present here a comprehensive study in which these
optical and densitometric changes have been measured in
different age groups of patients without cataract, to evaluate
ways in which morphology and optical performance of the
human crystalline lens degrade with aging.

Patients and Methods

Population
In this cross-sectional observational study, 72 patients were
examined. Subjects were recruited consecutively between JanISSN 0161-6420/05/$see front matter
doi:10.1016/j.ophtha.2005.04.034

Ali et al Crystalline Lens through Aging

Figure 1. Photographs using a flash intensity of 200 Wseconds in a Scheimpflug slit lamp. a, Eight-year-old subject. b, Eighty-year-old subject. Linear
densitometric analysis to quantify nuclear density. 1, 2, 3 densities at the embryonic nucleus, anterior fetal nucleus, and posterior fetal nucleus,
respectively.

uary and May 2003 at VISSUM, Instituto Oftalmolgico de

Alicante, Spain. Only one eye from each subject was studied.
The male to female ratio was 26/46, and the age of the subjects
ranged from 8 to 80 years (4121 [mean standard deviation
(SD)]). The spherical equivalent (SE) refraction ranged from
3.00 to 2.75 diopters (D) (0.401.25 [mean SD]).
The tenets of the Declaration of Helsinki were followed in this
study. After the nature and possible consequences of the study had
been explained, informed consent was obtained from all patients or
from a parent when children were involved in the study.10
Inclusion criteria included best-corrected distance visual acuity
(Snellen chart) of 20/25 or better; a transparent crystalline lens, as
assessed by the Lens Opacities Classification System III,11 with a
pupil mydriasis of at least 6 mm; and an otherwise normal eye, as

determined by slit-lamp biomicroscopy and fundoscopy. Because

ametropia within 3.50 D from emmetropia has been shown to
have a minimal effect on the root mean square wavefront error, SE
refractions from 3.00 to 3.00 D were included in the study
(Invest Ophthalmol Vis Sci 40:ARVO Abstract 2361, 1999). Subjects with opacification of the ocular media, corneal surface problems, retinal disease, or a history of ocular surgery were excluded.
Once the patient entered the study, the pupil was dilated with
tropicamide 1%, which was allowed to act for at least 15 minutes
before any measurement, to allow full dilation and cycloplegia.
Accommodation is known to induce optical aberrations. In
younger subjects, despite precautions, accommodation could not
be paralyzed, and as a result, intraocular aberrations could not be
completely ruled out. All the measurements used were simple,

Figure 2. Photographs using a flash intensity of 200 Wseconds in a Scheimpflug slit lamp. a, Eight-year-old subject. A. anterior; R radius. b,
Eighty-year-old subject. Axial biometric analysis to quantify lens thickness. 1, 2, 3 densities at the embryonic nucleus, anterior fetal nucleus, and
posterior fetal nucleus, respectively.

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Ophthalmology Volume 112, Number 11, November 2005

Figure 3. Curves of spatial frequency and modulation transfer function (MTF) obtained using the Optical Quality Analysis System in (a) an 8-year-old
subject, (b) a 30-year-old subject, and (c) an 80-year-old subject. c/d cycles per degree.

objective, and performed quickly, requiring minimum cooperation

from the subject. Moreover, all measurements were made by the
same observer.

Scheimpflug Photography
To evaluate lens morphology and densitometric data more objectively, a Scheimpflug slit lamp (EAS 1000, Nidek, Japan) was
used.12 In this technique, slit-lamp photography measures light
that is reflected anteriorly from the lens to the camera. To record
a slit image, an alignment system is coupled to a television monitor
and a fixation light is placed to lie along the optical axis of the slit
projection lens. A photograph is taken using a flash intensity of
200 Wseconds. Density is measured by optical density units that
are EAS 1000 specific. The resulting cross-sectional image of the
anterior chamber and lens is displayed on a monitor for evaluation
by the operator. If satisfactory, the image can be transferred to the
computer for analysis. To quantify nuclear lens density, linear
densitometric analysis of the image was performed. Density was
measured at the embryonic, anterior, and posterior fetal nuclei (Fig
1). The embryonic nucleus is composed solely of primary fiber
cells. The fetal nucleus consists of the embryonic nucleus and all
the secondary fiber cells added onto it until birth. To quantify lens
thickness, an axial biometric analysis of the image was performed
(Fig 2). This analysis was performed in a masked fashion by one
of the observers (PS).

Modulation Transfer Function

Optical quality was studied using the MTF for monochromatic
light. The image at the retina is a mixture of waves. The image of
a single wave has the same frequency and orientation as the
original wave (object), but the contrast is always decreased. The
ratio of the image wave contrast to the object wave contrast is the
MTF.
The MTF was measured with the Optical Quality Analysis System
(Visiometrics S.L., Terrassa, Spain), a new instrument based on the
double-pass technique and developed to perform an objective optical
quality-of-vision evaluation. The double-pass technique is based on
recording images of a point source after reflection in the retina and a
double pass through the ocular media.13 The design of the Optical
Quality Analysis System is based on the asymmetric scheme of a
double-pass technique layout incorporating new and improved features adapted for routine measurements in clinical practice. Therefore,
with this configuration the ocular point-spread function can be obtained. From the point-spread function images, the MTF that yields

2024

the relationship between the contrast of an object and its associated

image as a function of spatial frequency was obtained, computing the
modulus of the 2-dimensional Fourier transformations of the pointspread function. The 1-dimensional MTF was calculated as the radial
projection (averaging over all orientations) of the 2-dimensional
MTF. The Imax/Imed is a single parameter that provides information on
the overall image quality. Vol.D-P and Vol. D-P0,5 allow us to
compare the part of the double-pass image corresponding to high
irradiance with the part corresponding to low irradiance. From this
comparison, it is possible, for example, to prove the existence of an
increment in dim light on the retina.
Measurements were done with a 5-mm pupil. Different curves
of MTF were not compared; instead, spatial frequencies at 0.5 and
0.1 MTF were analyzed. Data at 0.5 MTF represent the spatial
frequency (cycles per degree) in which the image contrast is
degraded 50% relative to the object contrast. Data at 0.1 MTF
represent the spatial frequency in which the image contrast is
degraded 90% relative to the object contrast, and correspond to the
maximum resolution of the optical system (Fig 3).

Wavefront Analyzer
Ocular and corneal wavefront errors were measured with a HartmannShack aberrometer (Wavefront Analyzer, Topcon, Tokyo,
Japan). For each eye, measurements were repeated at least 3 times
to obtain a well-focused properly aligned image of the eye. Measurements were taken for 4- and 6-mm pupils. The Wavefront
Analyzer gives us the total ocular and corneal aberrations for 4and 6-mm pupils, comalike Zernike polynomials (Z3iZ5i) and
Z4iZ6i for a 6-mm pupil, and ocular and corneal Zs for 4- and
6-mm pupils. Zernike mode Z33 through Z33 plus a fifth-order Z
(Z55 through Z55) corresponds to comalike aberrations. From
ocular and corneal aberrations, intraocular aberrations can be obtained. Intraocular aberration is the difference between ocular and
corneal aberrations. Intraocular aberrations are due more to the
crystalline lens and less to the posterior corneal surface.
Total ocular and corneal HOAs for a 6-mm pupil and ocular
and corneal comalike, ocular and corneal Z4iZ6i, and intraocular
spherical (Z40) and coma (Z31) aberrations were studied.

Data Analysis
Analyses were performed using SPSS 11.0 for Windows software
(SPSS Inc., Chicago, IL). Values are presented as means SDs.
The relationship between all variables and age was modeled using
the bivariate correlation model and Pearson correlation (r).

Ali et al Crystalline Lens through Aging

Figure 4. a, Embryonic nucleus (flash intensity, 200 Wseconds) as a function of age. A positive correlation was found after the age of 40 years (r 0.762,
P0.0001). b, Embryonic nucleus (flash intensity, 200 Wseconds) in 4 age groups. The mean difference using Bonferroni multiple comparison is
statistically significant for groups 2 and 3 (P 0.002) and for groups 3 and 4 (P0.0001). Error bars, minimum and maximum of the 95% confidence
interval.

A level of significance of 0.05 (2 tailed) was used in this

study.
The statistical significance between different age groups was
obtained by using a 1-way analysis of variance with Bonferroni
adjustment for multiple comparisons.

Results
Results were first analyzed for the entire population, then subjects
were arbitrarily divided into 4 age groups: group 1 included
subjects from 8 to 20 years old (n 15); group 2, subjects from
21 to 40 (n 20); group 3, subjects from 41 to 60 (n 21); and
group 4, subjects from 61 to 80 (n 16).

Nucleus density is represented in Figures 4 to 6. Densities of

embryonic, anterior fetal, and posterior fetal nuclei show a
positive correlation with aging after the age of 40 (r 0.762,
P0.0001; r 0.764, P0.0001; and r 0.756, P0.0001,
respectively). When different age groups and densities are
compared by multiple comparison, groups 1 and 2 do not show
a statistically significant difference in the densities of the embryonic (P 1.000), anterior fetal (P 1.000), and posterior
fetal (P 0.075) nuclei. Between groups 2 and 3 and between
groups 3 and 4, there is a statistically significant difference for
the embryonic nucleus (P 0.002 and P0.0001, respectively), the anterior fetal nucleus (P0.0001 and P0.0001,
respectively), and the posterior fetal nucleus (P0.0001 and
P0.0001, respectively).

Figure 5. a, Anterior fetal nucleus (flash intensity, 200 Wseconds) as a function of age. A positive correlation was found after the age of 40 years (r
0.764, P0.0001). b, Anterior fetal nucleus (flash intensity, 200 Wseconds) in 4 age groups. The mean difference using Bonferroni multiple comparison
is statistically significant for groups 2 and 3 (P0.0001) and for groups 3 and 4 (P0.0001). Error bars, minimum and maximum of the 95% confidence
interval.

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Ophthalmology Volume 112, Number 11, November 2005

Figure 6. a, Posterior fetal nucleus (flash intensity, 200 Wseconds) as a function of age. A positive correlation was found after the age of 40 years (r
0.756, P0.0001). b, Posterior fetal nucleus (flash intensity, 200 Wseconds) in 4 age groups. The mean difference using Bonferroni multiple comparison
is statistically significant for groups 2 and 3 (P0.0001) and for groups 3 and 4 (P0.0001). Error bars, minimum and maximum of the 95% confidence
interval.

The scatterplots of embryonic and anterior fetal nuclei

clearly show a turning point around the age of 40 years, after
which densities of the nuclei show an increase with age. This
turning point is not so evident on the scatterplot that shows the
changes in the density of the posterior fetal nucleus with age.
The relationship between age and crystalline lens thickness is
shown in Figure 7. Crystalline lens thickness increases significantly with age in a linear mode (r 0.679, P0.0001). When
different age groups are analyzed, there are statistically significant
differences between groups 1 and 2 (P 0.002) and also between
groups 2 and 3 (P 0.004). No significant difference is seen,
however, between groups 3 and 4 (P 1.000).
Total ocular and corneal HOAs as a function of age for a 6-mm
pupil are shown in Figure 8. Corneal HOA shows a weak statistically significant variation with age (r 0.248, P 0.036).
Ocular HOA increases linearly with age (r 0.511, P0.0001).

As shown in the scatterplot, ocular HOA until 30 to 40 years of age

is smaller than corneal HOA. In the 40s, ocular HOA is similar to
corneal HOA, and it increases in older subjects.
The same result can be seen for ocular and corneal Z4iZ6i
aberrations (Fig 9; r 0.368, P 0.001, and r 0.244, P 0.039,
respectively). Corneal comalike aberrations were not statistically significant (r 0.201, P 0.090), and ocular comalike aberrations show
a positive linear correlation with age (r 0.507, P0.0001).
Intraocular spherical aberration (Z40) for a 6-mm pupil (Fig 10)
shows a positive linear correlation with age (r 0.382, P
0.001). Intraocular coma aberration (Z31), on the contrary, shows
a negative linear correlation with age (Fig 11; r 0.459,
P0.0001).
The error bar graphs shown in Figure 12 represent 0.1 and 0.5
MTFs in different age groups. The 0.1 MTFs are 15.673 for group 1,
18.557 for group 2, 12.404 for group 3, and 10.100 for group 4.

Figure 7. a, Crystalline lens thickness as a function of age. A positive linear correlation was found (r 0.679, P0.0001). b, Crystalline lens thickness
in 4 age groups. The mean difference using Bonferroni multiple comparison is statistically significant for groups 1 and 2 (P 0.002) and for groups 2 and
3 (P 0.004). Error bars, minimum and maximum of the 95% confidence interval.

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Ali et al Crystalline Lens through Aging

Figure 8. Total ocular and corneal high-order aberrations (HOAs) as a

function of age for a 6-mm pupil. For ocular HOA, a positive linear
correlation was found (r 0.511, P0.0001). For corneal HOA, a weakly
positive correlation was found (r 0.248, P 0.036).

The 0.5 MTFs are 4.317 for group 1, 5.384 for group 2, 3.501 for
group 3, and 3.046 for group 4. A significant difference is seen
between groups 2 and 3 for 0.1 and 0.5 MTFs (P 0.009 and P
0.004, respectively).

Figure 9. Ocular and corneal Z4iZ6i (Zernike polynomials) aberration as

a function of age for a 6-mm pupil. For ocular aberration, a positive linear
correlation was found (r 0.368, P 0.001). For corneal aberration, a
weakly positive correlation was found (r 0.244, P 0.039).

Figure 10. Intraocular spherical aberration (Z40) as a function of age for

a 6-mm pupil. A positive linear correlation was found (r 0.382, P
0.001).

Discussion
In the present study, we analyzed the densitometric changes
that take place in the crystalline lens with aging and how
these changes affect the optical quality of the eye. Densi-

Figure 11. Intraocular coma aberration (Z31) as a function of age for a

6-mm pupil. A negative linear correlation was found (r 0.459,
P0.0001).

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Ophthalmology Volume 112, Number 11, November 2005

Figure 12. a, Spatial frequency for 0.1 modulation transfer function (MTF) in 4 age groups for a 5-mm pupil. The mean difference with Bonferroni
multiple comparison is statistically significant for groups 2 and 3 (P 0.009). b, Spatial frequency for 0.5 MTF in 4 age groups for a 5-mm pupil. The
mean difference using Bonferroni multiple comparison is statistically significant for groups 2 and 3 (P 0.004). c/d cycles per degree. Error bars,
minimum and maximum of the 95% confidence interval.

tometric changes were studied on the lens nucleus, which is

the oldest anatomical region of the crystalline lens.
In our study, nucleus density showed a positive correlation with age, after 40 years, for embryonic, anterior fetal,
and posterior fetal nuclei. When different age groups are
analyzed, we can see that nucleus density does not increase
before the age of 40, after which nucleus density increases
linearly with age.
As a result of the continuous production of new fibers,
the aging lens becomes thicker. We found a correlation
between age and overall lens thickness, as was found by
Kashima et al.14 In our study, crystalline lens thickness
increases from the age of 8 years to the age of 40, after
which the increase in lens thickness is not statistically
significant. Whether or not gender has any effect on optical
and densiometric changes cannot be concluded from this
study, due to the sample including significantly more males
than females. No previous evidence of such an effect has
been found in the literature.
Due to the anatomical changes that take place with aging,
scattering and aberrations of the crystalline lens are expected to increase.
The main contributors to the overall aberrations in the
eye are the tears, anterior and posterior surfaces of the
cornea, and crystalline lens. So, if the aberrations of the
crystalline lens increase, total ocular aberrations will increase as well.
Several previous studies have reported an increase in
overall eye aberrations with aging.1,2,15,16 In our study,
overall eye HOAs increased linearly with aging, as previously reported in the literature. This increment in overall
ocular HOAs is not due to corneal HOA, which shows a
very weak correlation with age (for corneal HOA, r
0.248, P 0.036, and for ocular HOA, r 0.511,
P0.0001).
Before the age of 30 years, overall HOA and Z4iZ6i
were significantly larger for the cornea than for the entire

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eye, which suggests that the lens compensates for part of the
corneal aberrations. The corneal and lens aberrations show
a trend to compensate each other.17 In our study, we found
that this mechanism is disrupted in the older eye as a
consequence of normal aging. According to our data, the
turning point for the coupling of these 2 optical systems
(cornea and the entire eye) seems to appear around 40 years
of age. The changes in the optical performance of the
crystalline lens with aging should be related to the anatomical changes (nucleus density and thickness) found.
With previous studies, authors have investigated the correlation that the development of aberrometric changes has
with aging.1,2,15,16 In such studies, the Zernike polynomials
that were used differed from those analyzed in this study.
We found a linear correlation between intraocular spherical aberration and age. Because the main contributor to
intraocular aberration is the crystalline lens, we can assume
that spherical crystalline lens aberration increases with age.
On the other hand, intraocular coma aberration (Z31) decreases with age.
McLellan et al studied Z5i to Z7i and found a positive
correlation with age.1 Oshika et al studied corneal Z3iZ5i
and corneal Z4iZ6i. For Z3iZ5i, they found a positive
correlation with age, but for Z4iZ6i, no correlation was
found.16 Amano et al studied coma (Z31, Z31, Z51, Z51)
and spherical aberration (Z40, Z60).18 Brunette et al studied
ocular Z3iZ5iZ7i and ocular Z4iZ6i and found a secondorder regression for all aberrations.2 Artal et al studied Z4i
and Z3i and reported that corneal aberrations increased moderately with age. In addition, they reported that internal
surface aberrations showed a larger variability and a tendency to increase in middle-age and older subjects.19
Glasser and Campbell found in vitro that spherical aberration of excised older lenses changed.3 In this study, we
investigated corneal, ocular, and intraocular HOAs in the
same patient. We studied the overall corneal and ocular
HOAs, corneal and ocular Z4iZ6i, intraocular spherical

Ali et al Crystalline Lens through Aging

aberration (Z40), and intraocular Z31. We found a positive
linear correlation for all the aberrations studied except for
intraocular Z31, which shows a negative linear correlation.
Even with such differences, our results confirm that the
increase in corneal aberration is too small to account for the
increase in ocular aberrations and support the theory that the
crystalline lens must be responsible for the increase in the
ocular aberrations that take place with aging.
To the best of our knowledge, the correlation found
between crystalline lens aberration changes and the increase
in the densitometric values and thickness of the lens has not
been previous reported.
Changes in crystalline lens morphology are responsible
for the degradation of the optical performance of the human
eye through aging. Such anatomical changes are also related
to the degradation of the MTF with age, as shown by
double-pass imaging in the present study, in agreement with
other previous reports on the subject.4,5 We observed a
degradation in the MTF in different age groups. The highest
MTF is observed in group 2 and corresponds to subjects
between 21 and 40 years old. Between 41 and 60 years, the
MTF declines. The turning point for crystalline lens
changes seems to be around the age of 40, when presbyopia
appears. Nuclear crystalline lens density increases around
the age of 40, and this anatomical change implies an increase in intraocular aberrations. The increase in scattering
and aberrations around the age of 40 decreases the optical
quality of the eye, which we measure in our study using the
MTF.
We can conclude that there is a degradation of the optical
function of the crystalline lens measured as changes in the
MTF and in the aberration pattern through aging and, also,
that such changes are associated with morphological
changes in the thickness and density of the lens. The turning
point for these changes is shown to be around the age of 40
years. Morphological changes in the crystalline lens and the
consequent degradation in the eyes optical quality should
decrease the normal performance of the human eye before
the development of evident cataract. Such visual deterioration would continue further with the development of cataract that is evident at a clinical level.6
The decrease in the eyes optical performance through
aging shown as a continuous process related to morphological changes at the level of the crystalline lens may have
clinical implications in the future. New intraocular lens
(IOL) technology is being used to try to improve the optical
performance of the eye using customized lens optical design.20 The increase in spherical aberrations observed by us
through aging can be compensated for either by the induction of negative spherical aberration at the corneal level, as
in hyperopic excimer laser procedures, or by an adequately
designed customized IOL.21 If the optical performance of an
eye that is implanted with a customized IOL reaches a level
that is superior to that of an aged eye, crystalline lens
substitution may have a clinical indication, especially if
improvements in other lens functions such as accommodation can also be implemented and the complication rates for
the surgery are minimal and acceptable. Future research in
this area seems to be of utmost importance.

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