**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 range of ages [50].

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 (Figure 4).
