Cellular Senescence as a Contributing Cause of Glaucoma

With advancing age an ever greater number of cells in the body linger in a senescent state in which replication is halted rather than destroying themselves after reaching the Hayflick limit. This can be a reaction to cellular damage or potentially damaging tissue environments, and at least initially helps to lower the incidence of cancer by preventing cells that are potentially at risk from continuing to replicate. Unfortunately senescent cells secrete a range of proteins that degrade surrounding tissue and encourage nearby cells to also become senescent. Given large enough numbers of senescent cells this activity leads to meaningful loss of function in important organs and contributes to the development of age-related disease.

In recent years researchers have demonstrated benefits to health and healthy life span resulting from selective clearance of senescent cells in mice, and removing senescent cells is one of the targets of the SENS rejuvenation research program. Here scientists link cellular senescence to mechanisms known to contribute to glaucoma, a form of blindness caused by raised fluid pressure inside the eye and resulting nerve damage:

The most common form of glaucoma, primary open angle glaucoma, is an aging associated disease often characterized by elevated intraocular pressure induced by increased outflow resistance of the aqueous humor. The human trabecular meshwork (HTM), a complex three-dimensional structure comprised of cells, interwoven collagen beams and perforated sheets, is believed to provide the majority of outflow resistance in both normal and glaucomatous eyes. HTM cells, depending on the region of the HTM, either form sheets covering extracellular matrix (ECM) structures or are scattered throughout the ECM. What changes in the HTM resulting in increased resistance is poorly understood, but our recent study showed the HTM is ~20 fold stiffer in glaucoma, suggesting a prominent role of HTM mechanobiology. This tissue-scale stiffening is likely a result of biophysical changes to both the ECM and constituent cells, as structural changes to both the cytoskeleton and ECM have long been associated with glaucoma.

Building upon these findings, further research has led to a growing body of evidence that these biophysical changes are not epiphenomena, but upstream of factors important in the progression of the disease. A prime candidate for this process is cellular senescence, the irreversible arrest of cellular proliferation. Senescence is thought to contribute to many of the physiological changes associated with aging as well as aging associated disease. In this study, primary HTM cells were serially passaged until senescence and atomic force microscopy (AFM) was used to measure the intrinsic mechanical properties of senescent cells compared to normally proliferating controls. We found that stiffness was significantly increased in high passage HTM cells. In aggregate, these data demonstrate that senescence may be a causal factor in HTM stiffening and contribute towards disease progression. These findings provide insight into the etiology of glaucoma and, more broadly, suggest a causal link between senescence and altered tissue biomechanics in aging-associated diseases.

Link: http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=3798&path%5B%5D=8094


Given that there is a collagen matrix I'd bet that the Glucosepane cross links that form everywhere else could also be part of the problem.

It makes me wonder how much aging disease could be avoided or massively delayed just by removing senescent cells and glucosepane extra cellular matrix cross links.

Posted by: Jim at May 5th, 2015 9:59 AM

I was wondering the same thing today Jim, Just by clearing the Senescent cells has been shown to restore function to tissue (presumably as SASP ceases and the Cytokines it creates are reduced) so I wonder just how much effect it would have removing them all?

Posted by: Steve H at May 5th, 2015 11:32 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.