Aging and the Cornea

814 British Journal of Ophthalmology 1997;81:814–817 Br J Ophthalmol: first published as 10.1136/bjo.81.10.814 on 1 October 1997. Downloaded from BRIEF REVIEWS ON ASPECTS OF AGING AND THE EYE Aging and the cornea RGAFaragher, B Mulholland, S J Tuft, S Sandeman, P T Khaw Aging, the persistent decline in age specific fitness of an also known as contact inhibition. Rather confusingly, both organism as a result of internal physiological deterioration, senescence and quiescence are referred to as the G0 phase is a common process among multicellular organisms.1 In of the cell cycle (sometimes more helpfully distinguished as humans, aging is usually monitored in relation to time, G0Q and G0S).15 Senescence is also distinct from cell which renders it diYcult to diVerentiate between time death, occurring either by apoptosis or necrosis, and it is dependent biological changes and damage from environ- not a form of terminal diVerentiation.16 17 The phenotypes mental insults. There are essentially three types of aging at of growth and senescence are totally distinct cell cycle work in any adult tissue; the aging of long lived proteins, compartments; there is no such thing as a half senescent the aging of dividing cells, and the aging of non-dividing cell. Cells that enter replicative senescence acquire two cells.2 Dividing cells may be derived from renewing popu- phenotypes: they leave the cell cycle with a G1 DNA lations in which the rate of cell loss and division is great. An content,18 and they undergo a characteristic series of example is the corneal epithelium in which complete changes in biology and gene expression that alters the turnover occurs within 5–7 days after terminal function of the cell.13 19 In this latter situation some genes diVerentiation.34 Conditional renewal populations, which are transcriptionally repressed, some gene expression is normally have an extremely low proliferation rate, can also upregulated, and some totally senescent specific genes are produce dividing cells in response to extrinsic stimuli. turned on.20 These changes cover practically every aspect Stromal keratocytes are a prime example of a conditional of cell physiology and occur in a highly selective manner.2 renewing population.5 Corneal endothelial cells retain the As many of the changes occur in genes coding for secreted capacity to undergo mitosis and conditional renewal in products the senescent cell can potentially aVect the humans although they very seldom do so.6–9 Non-dividing surrounding microenvironment. This altered function of cells are those from static cell populations (exemplified by senescent cells may thus be the critical phenotype that cerebral neurons) which never divide during adult life.3 compromises tissue function and integrity. As these Corneal aging produces both structural and functional changes have been largely studied in vitro it is important to changes. These changes in turn can aVect the ability of the examine the means by which cells become senescent and organ to refract light, to repair itself, and to protect itself to question their significance within aged tissue. and the internal structures of the eye.10 A variety of corneal Where could senescent cells come from within the aging changes have been reported. However, as it is http://bjo.bmj.com/ diYcult to distinguish age specific deterioration from cornea? degenerations modified by environmental and genetic fac- There are two main routes by which a cell may become tors, we think it is helpful to consider these alterations senescent; they are explained below. within the broader framework of the aging process. The study over the past 30 years of isolated cells in culture as a CONSTITUTIVE CELL SENESCENCE model system for aging changes has greatly advanced our Replicative failure is often visualised as the cell counting a understanding of these concepts. fixed number of divisions and then entering senescence but, while conceptually straightforward, this is a mislead- on September 28, 2021 by guest. Protected copyright. ing oversimplification. Rather than simply counting its way Cell aging to senescence, each time a cell divides it has a given chance Normal adult cell populations do not divide indefinitely of never dividing again, a chance that increases each time either in the culture dish or in the body.311Cellular senes- the cell replicates until senescence becomes a certainty.21 22 cence or replicative failure is the process that imposes a However, since the process is controlled by chance, a cell limit on their replicative lifespan, and it is thought that cell that has divided only once can still be unlucky and enter senescence acts as a powerful tumour suppression senescence. The constitutive process is thus rather like mechanism which thus lengthens the healthy reproductive playing Russian roulette, the chance of the fatal bullet is lifespan of the organism.12 However, the emergence of fixed, but the outcome is uncertain. Unlike Russian senescent cells also contributes to the aging process in roulette, each time the cell divides extra bullets are loaded mitotically competent tissues. This theory, the cell hypoth- into the revolver. In tissue culture the end result of tens of esis of aging, proposes that the gradual accumulation of thousands of chance decisions are cell populations which senescent cells is the primary event that leads to the devel- have a mixture of growing and senescent cells, the propor- opment of age linked degenerative changes in tissue.13 14 A tions of which shift in the direction of total senescence as key feature of this hypothesis is the presence of senescent the culture is passaged and the cells divide.23 In tissue, even cells, but it says nothing about the mechanism that causes very limited division can thus begin to produce senescent the cells to become senescent in the first place. These cells. The kinetics of constitutive senescence can be mechanisms are considered below. explained in terms of the inheritance of chromosomes with progressively shortened telomeric DNA sequences.24 What are senescent cells? A concept of cell senescence can perhaps best be appreci- REACTIVE CELL SENESCENCE ated after a consideration of what it is not. Senescence is This pathway to the senescent state was demonstrated distinct from quiescence, a transient growth arrest state, recently and provides a fascinating alternative to the Aging and the cornea 815 constitutive route. Current data show that this stage is old donors is also consistent with an elevated fraction of Br J Ophthalmol: first published as 10.1136/bjo.81.10.814 on 1 October 1997. Downloaded from essentially identical to constitutive senescence but happens senescent cells in the biopsy rather than a reduced number in a matter of hours. It has been shown that the induction of starting cells.35 An age related increase in the number of of the activated H-ras oncogene into growing fibroblasts senescent cells in human endothelium has been can trigger senescence.25 This suggests that, rather like observed.36 37 apoptosis, senescence can be induced by mutation or mitogenic overload; this may implicate topical treatment How does cell senescence aVect the cornea? with anticancer drugs in the induction of senescence. In Structural and functional alterations documented in the contrast with the constitutive route, this pathway appears aging cornea are listed in Table 1. Although insuYcient to require little if any cell division. Thus, senescent cells information exists on the senescence of epithelial cells to may appear much more frequently in quiescent tissue than draw more than speculative observations, senescence is previously thought, particularly if that tissue is in a muta- associated with a decreased ability to resist a wide range of genic environment. This may be clinically relevant with the physiological stresses. Changes in the ocular surface render increasing use of potentially mutagenic agents such as the aging cornea more susceptible to infection for various 5-fluorouracil and mitomycin C to prevent scarring after reasons. There is an increase in epithelial permeability with pterygium excision or glaucoma filtration surgery; particu- age that may either represent a breakdown of epithelial larly since mitomycin C has been shown to rapidly induce barrier function47 or an increased tear contact time.46 senescent-like changes in cultured fibroblasts.26 These Changes in the distribution of integrin subunits in the epi- drugs soak into sclera, conjunctiva, and cornea, particu- thelium could also reduce the epithelial barrier function. larly after subconjunctival injection, but probably also after The á6 subunit and the â4 subunit, components of sponge application.27 We have seen prolonged eVects on hemidesmosomes, become discontinuous with age. How- the tissue fibroblasts in the drug treated area that seem ever, the number and distribution of hemidesmosomes unable to divide further despite maximal serum along the basal lamina do not appear to change with age.48 stimulation.28 It is possible that some of this growth arrest A reduced ability of corneal cells to upregulate adhesion is reactive cell senescence although this remains to be molecules and a reduced phagocytic ability of reactive proved. This is an important distinction as senescence is polymorphonucleocytes in response to infection also occur irreversible, unlike prolonged growth arrest seen in vitro with aging,43 44 and this could impair the ability to that may recover.29 30 The clinical importance of these eliminate a bacterial infection. Epithelial

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