**2. Trabecular meshwork and aqueous humor outflow pathway**

Aqueous humor is a colourless and transparent fluid that makes contact with various struc‐ tures in both the anterior and posterior chambers of the eye including the lens, iris, and cornea. The lens and the cornea are clear and avascular, which enables light to be effectively trans‐ mitted to the photoreceptors in the back of the eye. Aqueous humor provides nutrients to the avascular lens and cornea and also removes metabolic waste products. The composition of aqueous humor has been of great interest due to the potential regulatory effects on all the structures to which it makes contact. For example, the presence of antioxidants such as glutathione and ascorbic acid [4,5] in the aqueous humor suggest that this fluid affects the ability of cells to respond and adapt to stress.

Aqueous humor flows from the site of production, which is the non-pigmented ciliary epithelial cells [6,7] in the posterior chamber, to the site of drainage, which is the TM and Schlemm's canal in the anterior chamber (Figure 1). Production and drainage of aqueous humor is a continuous and dynamic process. Diurnal variations in aqueous humor turnover rates occur ranging from 3.0µL/min in the morning to 1.5µL/min at night [8]. The balance between aqueous humor production and drainage is essential for maintaining a healthy IOP of approximately 15mmHg within the eye [9]. Abnormalities in aqueous humor drainage due to increased resistance at the TM are thought to result in elevated IOP, which is a major risk factor for developing glaucoma [10].

extracellular material deposits and accumulates in various ocular tissues, predisposing the

Primary open angle glaucoma (POAG) is a common type of glaucoma where the iridocorneal angle is unobstructed. Although POAG can occur in patients with normal intraocular pressure (IOP), sometimes referred to as normal-tension glaucoma, elevated IOP is a major risk factor of developing POAG. IOP is dependent on proper flow of aqueous humor from the site of production in the posterior chamber to the site of drainage in the anterior chamber of the eye. The anterior chamber structures that function in regulating the drainage of aqueous humor from the eye are the trabecular meshwork (TM) and Schlemm's canal. Disruptions of the

In this chapter, the recent advances in research regarding the contribution of the TM in maintaining proper IOP will be reviewed. An overview of the anterior chamber drainage structures, the TM and Schlemm's canal, and how these structures maintain the aqueous humor outflow pathway will be provided. Also, the changes that occur in the TM during the normal aging process and in the glaucoma phenotype will be compared. Then, the specific types of stresses that TM cells are exposed to, mainly mechanical, oxidative, and phagocytic stresses, and the effects these stresses have on gene expression will be examined. Recent advances in technology have enabled the analysis of global gene expression profiles. These analyses have revealed that signal transduction pathways play an important role in the cellular adaptive response to environmental stresses. Finally, the effect that environmental stresses

aqueous humor flow pathway are predicted to result in elevated IOP.

**2. Trabecular meshwork and aqueous humor outflow pathway**

Aqueous humor is a colourless and transparent fluid that makes contact with various struc‐ tures in both the anterior and posterior chambers of the eye including the lens, iris, and cornea. The lens and the cornea are clear and avascular, which enables light to be effectively trans‐ mitted to the photoreceptors in the back of the eye. Aqueous humor provides nutrients to the avascular lens and cornea and also removes metabolic waste products. The composition of aqueous humor has been of great interest due to the potential regulatory effects on all the structures to which it makes contact. For example, the presence of antioxidants such as glutathione and ascorbic acid [4,5] in the aqueous humor suggest that this fluid affects the

Aqueous humor flows from the site of production, which is the non-pigmented ciliary epithelial cells [6,7] in the posterior chamber, to the site of drainage, which is the TM and Schlemm's canal in the anterior chamber (Figure 1). Production and drainage of aqueous humor is a continuous and dynamic process. Diurnal variations in aqueous humor turnover rates occur ranging from 3.0µL/min in the morning to 1.5µL/min at night [8]. The balance between aqueous humor production and drainage is essential for maintaining a healthy IOP of approximately 15mmHg within the eye [9]. Abnormalities in aqueous humor drainage due

have on glaucoma-associated genes will be considered.

ability of cells to respond and adapt to stress.

patient to developing glaucoma.

28 Glaucoma - Basic and Clinical Aspects

**Figure 1. Schematic diagram of aqueous humor flow pathway**. Aqueous humor is produced by the ciliary body in the posterior chamber and then flows into the anterior chamber. The majority of the aqueous humor will be drained from the eye via the trabecular pathway through the trabecular meshwork (TM) and Schlemm's canal. The rest of the aqueous humor is drained via the uveoscleral pathway. Increased resistance occurs when the TM and Schelmm's canal malfunctions. This disruption in aqueous humor outflow leads to increased intraocular pressure (IOP), which is a major risk factor for developing glaucoma.

Aqueous humor is drained from the eye by two distinct outflow pathways: the trabecular (aka conventional) pathway and the uveoscleral (aka unconventional) pathway. The uveoscleral pathway is an IOP-independent pathway in which the aqueous humor leaves the anterior chamber by passing through the ciliary muscle bundles into the supraciliary and suprachor‐ oidal spaces and eventually into the sclera [11,12]. Direct measurement of the percentage of aqueous humor leaving the human eye via the uveoscleral pathway has proven to be difficult [13]. There appears to be great variation between individuals with values ranging from 36% to 54% in healthy young subjects [14,15]. The percentage of aqueous humor leaving the eye via the uveoscleral pathway decreases with age with values ranging from 4% to 46% in older subjects [15,16]. Thus, as aging progresses, a larger portion of aqueous humor is drained via the trabecular pathway.

Despite the individual variations, it is generally accepted that in humans, the majority of aqueous humor is transported through the TM via the trabecular pathway. Disruption of aqueous humor drainage through the trabecular pathway is thought to be the major contri‐ buting factor to alteration of IOP. The TM is a multi-layered tissue located in the anterior chamber angle. From the anterior chamber the aqueous humor passes through the multiple layers of the TM: the uveal meshwork, the corneoscleral meshwork, and the juxtacanalicular meshwork (also known as the cribriform plexus). Each layer consists of a central connective tissue (aka beam) surrounded by an outer endothelial layer. Connecting fibrils tightly connect the network of elastic fibres in the juxtacanalicular meshwork to the inner endothelial wall of Schlemm's canal [17-20]. As the aqueous humor passes through each layer of the TM, the intercellular space narrows resulting in increased resistance. Then, aqueous humor progresses through the inner endothelial cell layer of Schlemm's canal. The endothelial cells of Schlemm's canal express the tight junction protein Zona occludens-1 (ZO-1), which allows aqueous humor to be transported via the intercellular route [21]. The aqueous humor is also transported via the transcellular route through giant vacuoles [22-24]. Aqueous humor passes through Schlemm's canal and returns to the general circulation via the aqueous and episcleral veins [23,25]. IOP is affected by the episcleral venous pressure and the resistance to aqueous humor flow within the TM. Episcleral venous pressure directly affects IOP because aqueous humor must flow out of the eye against the pressure in the episcleral veins. The main source of resistance to aqueous humor flow is thought to be located in the intercellular (aka subendo‐ thelial) region of the juxtacanalicular network [26-29].

**Figure 2. Trabecular meshwork under normal conditions**. Even under normal conditions, the cells of the tra‐ becular meshwork (TM) are constantly exposed to mechanical and oxidative stresses. TM cells have defense mechanisms including the antioxidant and proteolytic systems to protect the cells from these stresses. Also, spe‐ cific changes in global gene expression occur in response to the specific stress, which enables TM cells to adapt

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Aging is a major risk factor for developing glaucoma. However, at the physiological level, minimal changes in aqueous humor flow dynamics occur in normal healthy subjects as aging progresses (reviewed in reference [37]). Using tonography, many studies have observed that aqueous humor outflow facility decreases with age [15,38-40]. The tonographic procedure measures outflow facility. IOP is first increased by applying force to the cornea using a tonometer probe. The subsequent decrease in IOP over the time of the test is used to determine aqueous humor outflow via the trabecular pathway. However, interpretation of results using the tonographic technique is limited because ocular rigidity is not taken into account. Since ocular rigidity increases with age [39,41], older subjects may appear to have a reduction in aqueous humor outflow facility because the stiffer eyes are less responsive to the tonographic technique, which involves applying force to the cornea. Also, the tonographic measurements do not take into account the change in pseudofacility, which refers to the probe-induced change in aqueous humor flow into the anterior chamber. In contrast to tonography, fluorophotometry is not affected by ocular rigidity and pseudofacility because no force is applied to the cornea. The outflow facility measured by fluorophotometry was 0.23±0.10µL/min/mmHg in 20-30 year old subjects (n=51) and 0.27±0.13µL/min/mmHg in subjects 60 years and older (n=53) [15]. Thus, fluorophotometric measurements indicate that there is in fact no difference in outflow facility as aging progresses [15]. Many studies using tonographic and fluorophotometric measurements have consistently shown that with age, aqueous humor production decreases [15,38,39,42-44]. Although outflow facility remains stable and aqueous humor production decreases, IOP remains stable in normal healthy subjects as aging progresses. Toris *et al.* have recently measured IOP to be 14.7±2.5mmHg in 20-30 year old subjects (n=51] and 14.3±2.6mmHg in subjects 60 years and older (n=53) [15]. A decrease in anterior chamber depth

**3. Change in trabecular meshwork during the normal aging process**

[15,45,46] with aging may account for the lack of change in IOP.

to the environment and survive.

Extracellular matrix (ECM) occupies the intercellular space between the beams of TM cells. The ECM consists of glycosaminoglycans (GAGs), proteoglycans, laminin, various collagens, fibronectin, and vitronectin (reviewed in [30]). The constant turnover of this ECM has been proposed to play a role in maintaining proper aqueous humor resistance. The family of matrix metalloproteinases (MMPs) are secreted zinc proteinases that initiate ECM turnover [31,32]. MMP activity is inhibited by the family of tissue inhibitors of metalloproteinases (TIMPs). MMP activity is suggested to be important in regulating aqueous humor outflow facility by proteolytic alterations. Using perfused human anterior segment, Bradley *et al*. observed that increasing MMP activity increased the outflow rate while inhibiting MMP activity by the addition of TIMP decreased outflow rate [32]. MMP activity is suggested to have various functional consequences including degradation of ECM components, cleavage and modifica‐ tion of signaling molecules, and cleavage of intercellular junctions and basement membrane (reviewed in [33]).

Another factor that affects resistance is the ciliary muscle. The elastic anterior tendons of the ciliary muscle insert into the network of elastic fibres in the juxtacanalicular meshwork and corneoscleral meshwork [19,20,34]. The elastic fibres are surrounded by a collagen-based sheath [20]. Ciliary muscle contractions result in increased aqueous humor outflow facility [35]. Upon ciliary muscle contraction, the connecting fibres straighten. Since the ciliary muscle is connected to the TM and the inner wall of Schlemm's canal by the connecting fibrils, ciliary muscle contraction widens the intercellular space in the juxtacanalicular meshwork allowing aqueous humor to flow against less resistance [35]. In contrast, relaxation of the ciliary muscles results in the opposite effect where there is increased resistance to aqueous flow [36].

As outlined above, the aqueous humor flow pathway is a complex process regulated by structures in both the posterior and anterior chambers of the eye. The TM is a highly specialized tissue that is able to adapt to the dynamic nature of aqueous humor outflow. The ability to adapt is an essential characteristic of the TM, especially because these cells are located in an environment that is constantly changing (Figure 2).

Genetics and Environmental Stress Factor Contributions to Anterior Segment Malformations and Glaucoma http://dx.doi.org/10.5772/54653 31

the network of elastic fibres in the juxtacanalicular meshwork to the inner endothelial wall of Schlemm's canal [17-20]. As the aqueous humor passes through each layer of the TM, the intercellular space narrows resulting in increased resistance. Then, aqueous humor progresses through the inner endothelial cell layer of Schlemm's canal. The endothelial cells of Schlemm's canal express the tight junction protein Zona occludens-1 (ZO-1), which allows aqueous humor to be transported via the intercellular route [21]. The aqueous humor is also transported via the transcellular route through giant vacuoles [22-24]. Aqueous humor passes through Schlemm's canal and returns to the general circulation via the aqueous and episcleral veins [23,25]. IOP is affected by the episcleral venous pressure and the resistance to aqueous humor flow within the TM. Episcleral venous pressure directly affects IOP because aqueous humor must flow out of the eye against the pressure in the episcleral veins. The main source of resistance to aqueous humor flow is thought to be located in the intercellular (aka subendo‐

Extracellular matrix (ECM) occupies the intercellular space between the beams of TM cells. The ECM consists of glycosaminoglycans (GAGs), proteoglycans, laminin, various collagens, fibronectin, and vitronectin (reviewed in [30]). The constant turnover of this ECM has been proposed to play a role in maintaining proper aqueous humor resistance. The family of matrix metalloproteinases (MMPs) are secreted zinc proteinases that initiate ECM turnover [31,32]. MMP activity is inhibited by the family of tissue inhibitors of metalloproteinases (TIMPs). MMP activity is suggested to be important in regulating aqueous humor outflow facility by proteolytic alterations. Using perfused human anterior segment, Bradley *et al*. observed that increasing MMP activity increased the outflow rate while inhibiting MMP activity by the addition of TIMP decreased outflow rate [32]. MMP activity is suggested to have various functional consequences including degradation of ECM components, cleavage and modifica‐ tion of signaling molecules, and cleavage of intercellular junctions and basement membrane

Another factor that affects resistance is the ciliary muscle. The elastic anterior tendons of the ciliary muscle insert into the network of elastic fibres in the juxtacanalicular meshwork and corneoscleral meshwork [19,20,34]. The elastic fibres are surrounded by a collagen-based sheath [20]. Ciliary muscle contractions result in increased aqueous humor outflow facility [35]. Upon ciliary muscle contraction, the connecting fibres straighten. Since the ciliary muscle is connected to the TM and the inner wall of Schlemm's canal by the connecting fibrils, ciliary muscle contraction widens the intercellular space in the juxtacanalicular meshwork allowing aqueous humor to flow against less resistance [35]. In contrast, relaxation of the ciliary muscles

results in the opposite effect where there is increased resistance to aqueous flow [36].

As outlined above, the aqueous humor flow pathway is a complex process regulated by structures in both the posterior and anterior chambers of the eye. The TM is a highly specialized tissue that is able to adapt to the dynamic nature of aqueous humor outflow. The ability to adapt is an essential characteristic of the TM, especially because these cells are located in an

thelial) region of the juxtacanalicular network [26-29].

environment that is constantly changing (Figure 2).

(reviewed in [33]).

30 Glaucoma - Basic and Clinical Aspects

**Figure 2. Trabecular meshwork under normal conditions**. Even under normal conditions, the cells of the tra‐ becular meshwork (TM) are constantly exposed to mechanical and oxidative stresses. TM cells have defense mechanisms including the antioxidant and proteolytic systems to protect the cells from these stresses. Also, spe‐ cific changes in global gene expression occur in response to the specific stress, which enables TM cells to adapt to the environment and survive.

#### **3. Change in trabecular meshwork during the normal aging process**

Aging is a major risk factor for developing glaucoma. However, at the physiological level, minimal changes in aqueous humor flow dynamics occur in normal healthy subjects as aging progresses (reviewed in reference [37]). Using tonography, many studies have observed that aqueous humor outflow facility decreases with age [15,38-40]. The tonographic procedure measures outflow facility. IOP is first increased by applying force to the cornea using a tonometer probe. The subsequent decrease in IOP over the time of the test is used to determine aqueous humor outflow via the trabecular pathway. However, interpretation of results using the tonographic technique is limited because ocular rigidity is not taken into account. Since ocular rigidity increases with age [39,41], older subjects may appear to have a reduction in aqueous humor outflow facility because the stiffer eyes are less responsive to the tonographic technique, which involves applying force to the cornea. Also, the tonographic measurements do not take into account the change in pseudofacility, which refers to the probe-induced change in aqueous humor flow into the anterior chamber. In contrast to tonography, fluorophotometry is not affected by ocular rigidity and pseudofacility because no force is applied to the cornea. The outflow facility measured by fluorophotometry was 0.23±0.10µL/min/mmHg in 20-30 year old subjects (n=51) and 0.27±0.13µL/min/mmHg in subjects 60 years and older (n=53) [15]. Thus, fluorophotometric measurements indicate that there is in fact no difference in outflow facility as aging progresses [15]. Many studies using tonographic and fluorophotometric measurements have consistently shown that with age, aqueous humor production decreases [15,38,39,42-44]. Although outflow facility remains stable and aqueous humor production decreases, IOP remains stable in normal healthy subjects as aging progresses. Toris *et al.* have recently measured IOP to be 14.7±2.5mmHg in 20-30 year old subjects (n=51] and 14.3±2.6mmHg in subjects 60 years and older (n=53) [15]. A decrease in anterior chamber depth [15,45,46] with aging may account for the lack of change in IOP.

Interestingly, prominent changes at the structural and cellular levels occur with age. Connect‐ ing fibrils ensure that contact is maintained between the juxtacanalicular meshwork and the inner endothelial wall of Schlemm's canal [19,20]. The sheath surrounding these elastic fibres thickens with age [47]. The intercellular space narrows due to an increase in the amount of extracellular material from the thickened sheath, resulting in increased resistance [48,49]. Also, as aging progresses, the number of TM cells decrease [50,51]. Grierson and Howes estimate that at age 20, there are approximately 763 000 cells in the TM. By age 80, approximately 403 000 cells remain [51]]. The outer TM layers lose more TM cells while the least number of TM cells are lost from the inner juxtacanalicular layer [51,52]. This decline in TM cells appears to be a continuous and linear process with an estimated 0.58% loss of cells annually [50,52]. The linear decrease in TM cellularity is intriguing because the mechanism of cell loss may be different between the ages [52]. Age-related mechanisms such as accumulation of reactive oxygen species (ROS) and misfolded proteins are likely to contribute to cell loss in older subjects. However, other non-age-related mechanisms, such as exposure to mechanical stress, are likely responsible for cell death in the TM in younger subjects. Interestingly, Alvarado *et al.* noted that TM cells may have a reduced reparative capacity, which would further contribute to the decreased cellularity with age [52]. The loss of TM cells with age could have a more severe consequence in some individuals because there appears to be great variation in the absolute number of TM cells between individuals [53]. Therefore, individuals with less TM cells would be predicted to be less efficient in fulfilling the function of TM cells (Figure 3).

debris from the aqueous humor outflow pathway [54-58]]. Although TM cells have the ability to ingest particulate matters rapidly, the phagocytic process may have detrimental effects on the overall health of the cell, even leading to necrosis [59]. Zhou *et al.* also showed that after phagocytosis, temporary alteration of TM cells occurred including rearrangement of the cytoskeleton and increased migratory activity [60]. These alterations, although temporary, have been speculated to be linked to the age-related loss of TM cells [60]. TM cells also maintain aqueous humor outflow by releasing factors that regulate permeability of the endothelial cells of Schlemm's canal [61]. TM cells release various enzymes and cytokines both in the presence and absence of stimulation such as mechanical stretching and exposure to pro-inflammatory cytokines [61,62]. TM endothelial cells constitutively secrete cytokines such as Interleukin 8 (IL8], Chemokine, CXC motif, ligand 6 (CXCL6), and Monocyte chemotactic protein 1 (MCP1], strengthening the notion that the release of cytokines is important in maintaining aqueous

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**4. Change in trabecular meshwork in glaucoma disease phenotype**

Even with the age-related structural and cellular changes, the TM effectively functions to drain aqueous humor. However, in patients with glaucoma, the structural and cellular changes are more pronounced and as a result, TM function is disrupted. In glaucomataous eyes, there is more prominent and irregular thickening of the sheaths of the elastic fibers. Also, there is increased deposition of sheath-derived plaques compared with normal eyes [47,63]. This increase in extracellular material in the TM is predicted to block aqueous humor outflow [20] contributing to the development of disease. As in normal aging, there is a linear decrease in cellularity as aging progresses in the TM of POAG patients. Moreover, Alvarado *et al.* observed fewer cells in the glaucomatous TM compared with the non-glaucomatous TM over a wide

The risk of developing glaucoma significantly increases after age 40. Despite the fact that glaucoma is an age-related disease, aging in most people does not result in this disease (Figure 3). The changes that occur in the TM during the normal aging process may make the tissue more susceptible to malfunction. However, other unknown factors and even stochas‐ tic factors must be present for the TM to fail to a point that the glaucoma phenotype develops

In order to survive, TM cells must be able to constantly adapt to their continuously changing environment. Similar to any other cell in the body, TM cells are exposed to a variety of environmental stresses. Due to the location of cells of the TM, one of the major types of stress these cells are exposed to is mechanical stress. IOP continuously fluctuates throughout the day with a higher IOP occurring during the nocturnal period. The fluctuation in IOP is part of a normal physiological process and is unavoidable. Fluctuations in IOP occur with blinking, eye

**5. Exposure of trabecular meshwork to mechanical stress**

humor outflow [62].

range of ages [50].

(Figure 4).

**Figure 3. Trabecular meshwork during normal aging**. During normal aging, the cellular defense mechanisms of the trabecular meshwork (TM) cells become less efficient. As in normal conditions (see Figure 2), the TM cells are exposed to a variety of stresses. However, the TM cells will also be exposed to other types of stresses such as chronic oxidative stress because there is an accumulation of reactive oxygen species (ROS) as aging progresses. Since the TM cells are no longer able to adapt to the environment, there will be increased TM cell death (dotted circle). However, the TM tissue still functions, preventing the onset of glaucoma.

Regardless of the individual variation in TM cell number, the consequence of losing TM cells in all aging individuals can be predicted. As avid phagocytes, TM cells are thought to clear debris from the aqueous humor outflow pathway [54-58]]. Although TM cells have the ability to ingest particulate matters rapidly, the phagocytic process may have detrimental effects on the overall health of the cell, even leading to necrosis [59]. Zhou *et al.* also showed that after phagocytosis, temporary alteration of TM cells occurred including rearrangement of the cytoskeleton and increased migratory activity [60]. These alterations, although temporary, have been speculated to be linked to the age-related loss of TM cells [60]. TM cells also maintain aqueous humor outflow by releasing factors that regulate permeability of the endothelial cells of Schlemm's canal [61]. TM cells release various enzymes and cytokines both in the presence and absence of stimulation such as mechanical stretching and exposure to pro-inflammatory cytokines [61,62]. TM endothelial cells constitutively secrete cytokines such as Interleukin 8 (IL8], Chemokine, CXC motif, ligand 6 (CXCL6), and Monocyte chemotactic protein 1 (MCP1], strengthening the notion that the release of cytokines is important in maintaining aqueous humor outflow [62].

Interestingly, prominent changes at the structural and cellular levels occur with age. Connect‐ ing fibrils ensure that contact is maintained between the juxtacanalicular meshwork and the inner endothelial wall of Schlemm's canal [19,20]. The sheath surrounding these elastic fibres thickens with age [47]. The intercellular space narrows due to an increase in the amount of extracellular material from the thickened sheath, resulting in increased resistance [48,49]. Also, as aging progresses, the number of TM cells decrease [50,51]. Grierson and Howes estimate that at age 20, there are approximately 763 000 cells in the TM. By age 80, approximately 403 000 cells remain [51]]. The outer TM layers lose more TM cells while the least number of TM cells are lost from the inner juxtacanalicular layer [51,52]. This decline in TM cells appears to be a continuous and linear process with an estimated 0.58% loss of cells annually [50,52]. The linear decrease in TM cellularity is intriguing because the mechanism of cell loss may be different between the ages [52]. Age-related mechanisms such as accumulation of reactive oxygen species (ROS) and misfolded proteins are likely to contribute to cell loss in older subjects. However, other non-age-related mechanisms, such as exposure to mechanical stress, are likely responsible for cell death in the TM in younger subjects. Interestingly, Alvarado *et al.* noted that TM cells may have a reduced reparative capacity, which would further contribute to the decreased cellularity with age [52]. The loss of TM cells with age could have a more severe consequence in some individuals because there appears to be great variation in the absolute number of TM cells between individuals [53]. Therefore, individuals with less TM cells would be predicted to be less efficient in fulfilling the function of TM cells (Figure 3).

**Figure 3. Trabecular meshwork during normal aging**. During normal aging, the cellular defense mechanisms of the trabecular meshwork (TM) cells become less efficient. As in normal conditions (see Figure 2), the TM cells are exposed to a variety of stresses. However, the TM cells will also be exposed to other types of stresses such as chronic oxidative stress because there is an accumulation of reactive oxygen species (ROS) as aging progresses. Since the TM cells are no longer able to adapt to the environment, there will be increased TM cell death (dotted circle). However, the TM tissue

Regardless of the individual variation in TM cell number, the consequence of losing TM cells in all aging individuals can be predicted. As avid phagocytes, TM cells are thought to clear

still functions, preventing the onset of glaucoma.

32 Glaucoma - Basic and Clinical Aspects
