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ABSTRACT PURPOSE MicroRNA 34a (miR-34a) is involved in regulating tissue senescence. However, the role of miR-34a in age-related cataracts is unclear. In this study, we evaluated the

correlations among the severity of lens opacity, patient age, and miR-34a expression level in the lens epithelium of age-related cataracts for clarifying the role of miR-34a in the lens

senescence. METHODS This study was carried as a case control study in the Department of Ophthalmology, Taipei Veterans General Hospital, Taiwan. We recorded age of each patient at the time

of their cataract surgery and information regarding lens opacity according to a modified version of the Lens Opacities Classification System III. Correlations among age, lens opacity, and

miR-34a expression levels were evaluated. RESULTS This study evaluated 110 patients with a mean age of 73.19 years (SD±10.2). Older patients had higher nuclear cataract (NC), cortical (C),

and posterior subcapsular cataract (P) scores (one-way analysis of variance (ANOVA), _P_<0.05). miR-34a expression levels were significantly different between each age group (ANOVA _post

hoc_ Bonferroni’s test, _P_<0.001), and there were moderate correlations between high NC, C, and P cataract scores and high miR-34a levels (Pearson correlation coefficient; _R_=0.606,

0.575, and 0.515, respectively). CONCLUSIONS The current study demonstrated positive correlations between high miR-34a levels and high lens opacity severity in NC, C, or P cataracts. These

results suggest that miR-34a expression has a role in lens senescence. SIMILAR CONTENT BEING VIEWED BY OTHERS LNCRNA GAS5 REGULATES MIGRATION AND EPITHELIAL-TO-MESENCHYMAL TRANSITION IN LENS

EPITHELIAL CELLS VIA THE MIR-204-3P/_TGFBR1_ AXIS Article 16 December 2021 MIR-204-5P MAY REGULATE OXIDATIVE STRESS IN MYOPIA Article Open access 29 April 2024 URIC ACID–DRIVEN NLRP3

INFLAMMASOME ACTIVATION TRIGGERS LENS EPITHELIAL CELL SENESCENCE AND CATARACT FORMATION Article Open access 09 March 2024 INTRODUCTION Studies have provided many evidences of the

participation of microRNAs in multiple cellular functions, such as cell proliferation,1 cell apoptosis,2 stress response,3 and senescence,4 mainly through post-transcriptional mRNA silencing

and subsequent protein translation inhibition. MicroRNAs, which are groups of endogenous and small noncoding RNAs, have also been found to be biological modulators at the post-translational

level through complementary or partial complementary binding with the 3′ untranslated region (UTR) of target mRNA.5, 6 MicroRNAs are also involved in DNA damage response-induced senescence,

which is mainly governed by the p53 pathway.7 The microRNA-34a (miR-34a), the most apparent of the p53-induced microRNAs, has a role in senescence through the upregulation of acetylated p53

and activation of apoptosis in a positive feedback loop.2 However, very less information is available regarding miR-34a in ocular aging processes, such as cataracts. Cataracts, the most

common cause of blindness worldwide,8 are significantly related to the aging process. Currently, many factors such as diabetes mellitus, ultraviolet exposure, systemic drugs, and other

ocular diseases are known to be related to cataract formation. Among these disorders, oxidative stress with the subsequent formation of reactive oxygen species reactive oxygen species (ROS)

is thought to be a major predisposing factor in age-related cataracts.9 Recently, a biological factor, silent information regulator T1 (SirT1), was proposed as an element involved in

delaying the aging process and lifespan extension by suppressing NF-_κ_B signaling. We have found that decreased expression of the _SirT1_ gene is associated with higher cataract severity

and patient age in our prior study,10 but miR-34a expression in age-related cataracts has not been understood well. The aim of this study was to investigate the expression of miR-34a in the

lens epithelium of patients with age-related cataracts. To further evaluate the correlations among patient age, cataract severity, and miR-34a expression, the Lens Opacities Classification

System III (LOC III)11 was conducted to stratify the patients according to cataract type and severity. MATERIALS AND METHODS Lens epithelium samples were obtained from 110 eyes between

January 2008 and December 2010. This study followed the tenets of the Declaration of Helsinki. All patients underwent a complete preoperative ophthalmologic examination and only those who

had no ocular diseases other than age-related cataracts were included. Patients who had previously undergone ocular surgery or those with diabetes were not included from this study. All

samples were collected after obtaining informed consent from the patient. Lens epithelium samples were obtained by intact continuous curvilinear capsulorhexis, with care taken to avoid

vascular contact or damage to the iris or other intraocular structures. Cataract type and severity were graded and recorded on the basis of a modified version of the LOCSIII by using six

silt-lamp images for grading nuclear color and nuclear retro-illumination images for grading posterior subcapsular (P) cataracts. Each scale on the LOCSIII is a decimalized scale ranging

from 0.1 (a completely clear or colorless lens) to 5.9 (upper value on the C and P scales indicating complete opacification of the cortex or posterior capsule) and 6.9 on the NC scales

(indicating advanced opacification and brunescence of the nucleus). All LOCSIII scorings among subjects was carried out and consisted up to at least three ophthalmologists. The control lens

epithelium samples with a LOCSIII score of C1, NC1, and P1 were obtained from the vitrectomy operation for epiretinal membranes (_N_=13). MICRORNA ISOLATION AND MICRORNA QUANTITATIVE

REAL-TIME REVERSE TRANSCRIPTASE (RT-PCR) The expression levels of miR-34a microRNA were determined by quantitative real-time RT-PCR (qRT-PCR) as previously described.12 Briefly, a mirVana

PARIS kit (Ambion, Grand Island, NY, USA) was used to isolate small RNAs from total RNA according to the manufacturer’s instructions. The mature miR-34a sequence is (5′–3′)

UGGCAGUGUCUUAGCUGGUUGUU. For microRNA quantitation, qRT-PCR was performed using TaqMan miRNA assays (Applied Biosystems, Grand Island, NY, USA) with specific primer sets. All reagents and

protocols were obtained from (Applied Biosystems) and detection was performed using a 7900HT fast real-time PCR system (Applied Biosystems) with RNU6B as an internal control. The conditions

for amplification were as follows: one cycle of 94 °C for 2 min, followed by 50 cycles of 94 °C for 20 s, 57 °C for 20 s, and 70 °C for 20 s. MicroRNA-specific qRT-PCR was performed in

triplicate and repeated three times, the expression ratio of miR-34a/RUN6B in control patients was defined as 1. STATISTICAL METHODS For statistical analysis, patient age was expressed as

mean±SD and miR-34a mRNA levels were expressed as mean±SE. The correlations among LOCSIII score, age, and levels of miR-34a mRNA were analyzed using one-way analysis of variance (ANOVA),

followed by _post hoc_ Bonferroni’s test. The correlation between LOCSIII score and age, and LOCSIII score and levels of miR-34a mRNA expression were analyzed using the Pearson correlation

coefficient and unpaired Student’s _t_-test. A _P_-value of <0.05 was considered statistically significant. All analyses were performed using SPSS 12.0 (IBM, Armonk, NY, USA). RESULTS At

the end of enrollment, 110 patients were included in this study. Patient ages ranged from 55–92 years with an average of 73.19 years (SD 10.2). We further stratified patients according to

age into four groups: between 55 and 64 years (25; 22.7%), between 65 and 74 years (35; 31.8%), between 75 and 84 years (28; 25.5%), and older than 85 years (22; 20%). Considering the entire

patient cohort, the age at the time of cataract surgery showed significant differences with respect to the grading of nuclear cataracts (NCs) (one-way ANOVA, _P_<0.05) (Figure 1). In

addition, the age at the time of cataract surgery showed significant differences with respect to the grading of cortical cataracts (C) (one-way ANOVA, _P_<0.05) and the grading of P

cataract (one-way ANOVA, _P_<0.05) (Figure 1). There were correlations among older ages at the time of cataract surgery and higher NC, C, and P LOCSIII scores (Pearson correlation

coefficient; _R_=0.399; _P_<0.001; _R_=0.479; _P_<0.001; _R_=0.410; _P_<0.001, respectively). We compared miR-34a levels between each age group and found that the older the patient,

the greater the miR-34a level. The mean miR-34a level of all patients was 1.18 (SE±0.01) and the mean miR-34a levels in patients older than 85 years (mean±SE, 1.30±0.03) was significantly

different from those in patients whose age was between 75 and 84 years (mean±SE, 1.24±0.03) (ANOVA _post hoc_ Bonferroni’s test, _P_<0.001). In addition, the mean miR-34a levels of the

patients between the age of 75 and 84 years were significantly different from those of the patients aged between 65 and 74 years (mean±SE, 1.15±0.02) (ANOVA _post hoc_ Bonferroni’s test,

_P_<0.001). There was also a significant difference between the mean miR-34a levels of patients aged 65–74 years and those of patients aged 55–64 years (mean±SE, 1.03±0.02) (ANOVA _post

hoc_ Bonferroni’s test, _P_<0.001) (data not shown). A scatter plot showed a moderate correlation between age at the time of cataract surgery and miR-34a levels in the lens epithelium

(Pearson correlation coefficient _R_=0.683; _P_<0.001, Figure 2). In NC cataracts, there was a moderate correlation between miR-34a levels and lens opacity severity (Pearson correlation

coefficient _R_=0.606; _P_<0.001, Figure 3). Moreover, there were moderate correlations between miR-34a levels and severity of C cataracts (Pearson correlation coefficient _R_=0.575;

_P_<0.001) and between miR-34a levels and P cataract severity (Pearson correlation coefficient _R_=0.518; _P_<0.001). To further examine relations among levels of miR-34a expression

levels, age of patients, and different levels of cataracts, we stratified patients into nine subgroups according to their levels of cataracts. It was noted that in each subgroup, miR-34a

expression levels increased as older age of patients (Figure 4a). Then, in each subgroup, we compared miR-34a expression levels between samples from male and female subjects (Figure 4b).

There was no significant difference between different gender samples in any subgroup of our study. DISCUSSION Cataract, the first leading cause of blindness in the world, accounts for 47.8%

of blindness that equals 37 millions blind people in the world.8 Notably, 90% of cataract-related blindness are in the developing countries.8 Most cataracts are age-related; however, there

are several risk factors about cataractogenesis.13, 14 Previous studies focused on prevalence differences of three specific types of lens opacity: nuclear sclerosis, C cataract, and P

cataract. Owing to variation of subject race and age, nuclear sclerosis is most commonly noted in Canadian, Chinese, and American whites,15, 16, 17 while African, Japanese, and Singaporean

present higher prevalence of C cataract than nuclear sclerosis.16 However, there is scant information about certain factors among different types of lens opacity. Our study enrolled Chinese

patients aged 55 and older with age-related cataract, and analyzed detailed information among individual grades of cataracts according to LOC III. We found that cataract in all subtypes of

cataracts got more severe and higher miR-34a expression levels as subjects aged older. Gender is proposed as a risk factor to cataract formation;13 however, we could not find such results

from our study (Figure 4b). We believed a larger scale of further study on miR-34a may be needed to answer the question. Some confirmed risk factors to cataract formation are related to

oxidative stress, such as chronic ultraviolet light exposure, smoking, and diabetes.14, 18 Oxidative stress is proved to cause DNA damage and subsequent cataract formation.19, 20 Blue

Mountain Eye Study proved antioxidants intake, including beta-carotene, zinc, and vitamins A, C, and E, reduced nuclear sclerosis cataract formation.21 Sorte _et al_20 examined DNA damage

amounts in lens epithelial cells right after cataract surgery and found that DNA damage products were noted maximally in C cataract subject samples. Those studies disclosed that oxidative

stress prevention may be related to cataract prevention. Recently, one study on _Caenorhabditis elegans_ with miR-34 loss-of-function mutation showed that subjects extend their lifespan, and

increases resistance to oxidative stress.22 Taken together, we supposed that miR-34a may have their role in age-related catracts and from our study, we proposed that miR-34a is correlated

with age of patients (Figure 2) and severity of cataracts (Figure 4a). MiR-34a is a microRNA that regulates biological processes through complementary binding to its target at the 3′ UTR

site.23 MiR-34a also interferes with the cell cycle and proptosis via the p53 pathway in cancer cells.24, 25, 26 MiR-34a was recently reported to be involved in senescence. Upregulation of

miR-34a was observed in a premature senescence model induced by hydrogen peroxide27 and, alternatively, antisense inhibition of miR-34a hindered the onset of replicative senescence.28 Zhao

_et al_12 studied bone-marrow-derived endothelial progenitor cells (EPCs) from rats and found that overexpression of miR-34a led to the inhibition of EPC-mediated angiogenesis and induction

of senescence by suppressing SirT1. In addition, Ito _et al_29 found that miR-34a increased with age in endothelial cells in senescent human umbilical cord vein endothelial cells and in the

hearts and spleens of older mice. However, there is no study yet about correlation between miR-34a expression and ocular senescent tissues. Our current study focused on miR-34a expression in

the lens epithelium of age-related cataracts for investigating their role in the ocular aging process. There were significant correlations among NC, C, and P cataracts and age at the time

of surgery (Figure 1). We also investigated the association between miR-34a expression in the lens epithelium and cataract subtypes and severity, which was classified according to LOCSIII.

Our results show that the level of miR-34a expression in the lens epithelium increased with aging (Figure 2) and with the increase in the severity of NC, C, and P cataracts. (Figure 3) We

believe that this is the first report describing a role for miR-34a in the senescence of aging lenses. Age-related cataract formation involves several mechanisms, including ROS

accumulation.9 UV exposure and cigarette smoking are two examples of ROS-generating stress resources. Lou _et al_30 used hydrogen peroxide exposure to generate ROS in rat lenses and found

that most of the ROS accumulated in the lens epithelium and this resulted in a cataract. Grape seed proanthocyanidin extract is known to protect lens epithelial cells from ROS damage31 in a

dose-dependent manner and it exerts its effects via nuclear SirT1 expression.32 Recently, microRNAs, such as let-7 members, have been shown to have a role in newt lens regeneration.33, 34

MiR-34a participates in the aging process by suppression of SirT1 expression.2, 35 Ito _et al_29 demonstrated miR-34a regulates endothelial senescene directly through SirT1 that

overexpression of miR-34a can reduce SirT1 expression and increase senescene; conversely, SirT1 expression will increase if miR-34a is knocked down. From our prior study,10 we found that

decreased expression of SirT1 correlated with the severity of age-related cataracts, age at the time of surgery, and with NC, C, and P subtypes. In this study, we found that miR-34a

expression positively correlated with the cataract severity according to LOCSIII classification (Figure 1). In our current study, our results support the hypothesis that miR-34a expression

increases with aging (_R_=0. 683; Figure 2). This result implies that miR-34a expression in the ocular aging process occurs in parallel with the aging process of the entire body through

miR-34a–SirT1 pathway. We also stratified the age-related cataracts into different subtypes according to LOCSIII and found that miR-34a positively correlated with the severity of all

subtypes (Figure 3). Ito _et al_29 used population doubling time as a time course to follow miR-34a expression, whereas our study showed that the LOCSIII system correlated with miR-34a

expression in aging human lenses. In conclusion, in order to understand miR-34a expression specifically in human age-related cataracts, we evaluated miR-34a expression in lens epithelial

cells obtained via cataract surgeries. We discovered that miR-34a expression not only correlated with age at the time of surgery but also correlated with the different severity of aging

cataracts in nuclear, C, or P subtypes. Given these results, it is apparent that miR-34a expression has a role in lens senescence and may be a target for scavengers of oxidative stresses in

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Download references ACKNOWLEDGEMENTS This work was assisted in part by the Division of Experimental Surgery of the Department of Surgery, Taipei Veterans General Hospital. This study was

supported by the National Science Council (98-2314-B-341-001-MY3, 99-2314-B-075-005-MY3 and NSC 101-2314-B-341 -003 -MY3), Taipei Veterans General Hospital (C1-099/ER3-001), Taipei City

Hospital (96/97/98/099XDAA00102/10001-62-042), Shin-Kong Wu Ho-Su Memorial Hospital (SKH-8302-97-DR-25 and SKH-8302-98-DR-26), Zuoying Armed Forces General Hospital (9502/9696/9719),

Cheng-Hsin General Hospital (CHGH-100-01, 100-19, 100-20, 100-22, and 100-40) and Yen-Tjing Ling Medical Foundation (96/97/98), Taiwan. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS *

Department of Ophthalmology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan K-H Chien, C-M Liang & J-T Chen * School of Medicine, National Yang-Ming

University, Taipei, Taiwan S-J Chen, J-H Liu, L-C Woung, S-H Chiou & C-H Peng * Department of Ophthalmology, Taipei Veterans General Hospital, Taipei, Taiwan S-J Chen & S-H Chiou *

Department of Ophthalmology, Cheng-Hsin General Hospital, Taipei, Taiwan J-H Liu * Department of Optics and Photonics, National Central University, Chung-Li, Taiwan H-M Chang * Department of

Ophthalmology, Taipei City Hospital, Taipei, Taiwan L-C Woung * The Graduate Institute of Clinical Medical Sciences, Chang Gung University College of Medicine; Kaohsiung, T-J Lin *

Kaohsiung, Kaohsiung, Taiwan T-J Lin * Department of Ophthalmology, Zuoying Armed Forces General Hospital, Kaohsiung, Taiwan T-J Lin * Institute of Clinical Medicine, National Yang-Ming

University, Taipei, Taiwan S-H Chiou & C-H Peng * Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan S-H Chiou * Department of Ophthalmology,

Shin–Kong Wu Ho-Su Memorial Hospital and Fu-Jen Catholic University, Taipei, Taiwan C-H Peng Authors * K-H Chien View author publications You can also search for this author inPubMed Google

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DECLARATIONS COMPETING INTERESTS The authors declare no conflict of interest. ADDITIONAL INFORMATION This paper is not presented at any conference. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Chien, KH., Chen, SJ., Liu, JH. _et al._ Correlation between microRNA-34a levels and lens opacity severity in age-related cataracts. _Eye_

27, 883–888 (2013). https://doi.org/10.1038/eye.2013.90 Download citation * Received: 28 June 2012 * Accepted: 20 March 2013 * Published: 10 May 2013 * Issue Date: July 2013 * DOI:

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available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * aging * cataract * microRNA * senescence