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Senolytics and the Glaucoma Niche: Clearing Old Cells for Longer-Life Signals · Glaucoma, Vision & Longevity: Supplements & Science

• 0:00
  SPEAKER_00: Introduction.
• 0:01
  SPEAKER_00: Glaucoma is an age-related eye disease in which high pressure in the eye, intraocular pressure or IOP, damages retinal nerve cells and leads to vision loss.
• 0:11
  SPEAKER_00: Aging is the single biggest risk factor for glaucoma, and new research suggests this may be because aging eyes accumulate senescent cells, cells that have permanently stopped dividing and secrete inflammatory signals.
• 0:24
  SPEAKER_00: Cellular senescence is a normal response to damage or stress, but when these old cells build up, they release a mix of molecules called the senescence associated secretory phenotype, CSP.
• 0:36
  SPEAKER_00: SASP factors include inflammatory cytokines like interleukin-6, growth factors like TGFB, and enzymes that remodel tissue.
• 0:45
  SPEAKER_00: In eye tissues such as the trabecular mesh work, the drainage canal that controls IOP, and the optic nerve head, ONH, where retinal ganglion cell axons exit the eye, senescent cells and their SASP appear to drive chronic inflammation and scarring.
• 1:00
  SPEAKER_00: For example, one recent review noted that both TM cells and retinal ganglion cells in aging eyes show markers of senescence, and clearing those old cells improved retinal ganglion cell survival in animal models.
• 1:13
  SPEAKER_00: This article reviews the evidence that senescence contributes to glaucoma and explores how senolytic therapies, drugs that specifically kill senescent cells, might help protect the eye.
• 1:25
  SPEAKER_00: Senescence in the glaucoma niche, trabecular meshwork, senescence.
• 1:30
  SPEAKER_00: The trabecular meshwork is a sponge-like tissue that drains fluid from the eye.
• 1:35
  SPEAKER_00: With normal aging, TM cell numbers gradually decline and the meshwork develops thick, stiff extracellular material.
• 1:42
  SPEAKER_00: Histological studies show that older eyes have far fewer TM cells than young eyes, and this loss is much greater in glaucoma patients.
• 1:50
  SPEAKER_00: When TM cells die or senesse and are replaced by scar-like matrix, the drainage channel narrows and IOP rises.
• 1:57
  SPEAKER_00: In fact, Zhang et al.
• 1:59
  SPEAKER_00: describe how an absence of TM cells followed by their replacement with extracellular matrix leads to increased resistance to fluid outflow.
• 2:08
  SPEAKER_00: This fits with clinical observations that the aging outflow pathway becomes fibrotic.
• 2:12
  SPEAKER_00: For example, accumulation of type 6 collagen is seen in glaucomatous TM and raises IOP.
• 2:19
  SPEAKER_00: Laboratory studies of TM cells have identified classic features of senescence in aging or stressed cells, enlarged shape, cell cycle arrest, and expression of markers like P16's ING4A.
• 2:30
  SPEAKER_00: Importantly, senescent TM cells unleash pro-inflammatory SASP factors.
• 2:34
  SPEAKER_00: For example, senescent TM cells have been shown to overproduce interleukin-6, IL6, IL8, and chemokines, CCL2, CXCL3.
• 2:43
  SPEAKER_00: These cytokines can recruit immune cells and drive fibrotic signaling, notably, TGF-BE is also part of the ocular SAS P.
• 2:52
  SPEAKER_00: Such chronic inflammation likely stiffens the TM.
• 2:54
  SPEAKER_00: In short, aged and diseased TM tissue accumulate senescent cells that secrete fibrosis-inducing signals, contributing to outflow obstruction and elevated IOP.
• 3:04
  SPEAKER_00: Optic nerve head and retina senescence glaucoma also damages the optic nerve head, ONH, and retinal ganglion cells, RGCs, that send signals from the eye to the brain.
• 3:14
  SPEAKER_00: Aging affects these tissues too.
• 3:17
  SPEAKER_00: RGCs in older eyes show more oxidative damage and are less able to survive stress.
• 3:22
  SPEAKER_00: Senescent cells in the retina, neurons or retinal support cells, similarly secrete SAF factors that can harm nearby neurons.
• 3:29
  SPEAKER_00: For example, in experimental models of high IOP, the injured retina exhibits increased IL1 BEPA, IL6, IL8, and other SP cytokines.
• 3:39
  SPEAKER_00: These inflammatory factors feed a vicious cycle of damage.
• 3:42
  SPEAKER_00: They reinforce senescence in neighboring cells and provoke chronic inflammation in the ONH region.
• 3:47
  SPEAKER_00: Indeed, multiple studies have found senescence markers in RGCs and optic nerve tissue in glaucoma models.
• 3:54
  SPEAKER_00: Notably, removing those old RGCs has been neuroprotective.
• 3:58
  SPEAKER_00: In a mouse ocular hypertension model, targeting senescent RGCs for removal, a senolytic approach, preserved healthy RGCs and maintained vision.
• 4:08
  SPEAKER_00: Likewise, in an optic nerve crush injury model, desatinib plus quarcetin, a senolytic drug combo, significantly reduced RGC dendrite shrinkage and even promoted axon regeneration.
• 4:19
  SPEAKER_00: These findings suggest that senescent RGCs actively contribute to degeneration and that clearing them spares the remaining neurons.
• 4:26
  SPEAKER_00: Altogether, the TM and ONH in glaucoma form a niche of chronic pro-inflammatory stress, one driven at least in part by accumulating senescent cells and their SASP.
• 4:37
  SPEAKER_00: Senolytic therapies in eye models.
• 4:39
  SPEAKER_00: Researchers have begun testing known senolytic agents in eye disease models to see if clearing senescent cells can improve ocular health.
• 4:47
  SPEAKER_00: Key senolytics include desatinib, a kinase inhibitor, quircetin, a flavonoid, physetin, a plant flavanol, and navatoclax, a BCL2 family inhibitor.
• 4:57
  SPEAKER_00: Most studies so far are preclinical, animal or cell models.
• 5:01
  SPEAKER_00: Dysatinib plus quarsetin, D plus Q, this two drug senolytic cocktail is the most widely studied.
• 5:07
  SPEAKER_00: In mice with optic nerve injury, one study showed that D plus Q treatment preserved RGC structure and function.
• 5:13
  SPEAKER_00: Treated mice had less dendritic shrinkage in their RGCs and showed a trend toward axon regrowth, suggesting neural repair.
• 5:21
  SPEAKER_00: In a model of laser-induced choroidal neovascularization, a retinal disease, direct intravitreal injection of D plus Q into the eye dramatically reduced senescence markers and disease severity.
• 5:33
  SPEAKER_00: The treated rats had far fewer P60 squared uang4A positive cells in the retina and smaller neovascular lesions.
• 5:40
  SPEAKER_00: In fact, the effect was comparable to standard anti-VEGF therapy.
• 5:44
  SPEAKER_00: This highlights that locally delivered senalytics can act within the eye.
• 5:47
  SPEAKER_00: Intravitrial D plus Q limited retinal pathology by clearing senescent cells.
• 5:52
  SPEAKER_00: In glaucoma-specific experiments, D plus Q has shown neuroprotective effects.
• 5:58
  SPEAKER_00: The human retina study of glaucoma patients, a retrospective analysis of those exposed to senolytic drugs, found no harm.
• 6:05
  SPEAKER_00: Patients on senalytics did not have worse vision or higher IOP than controls, setting the stage for safety.
• 6:12
  SPEAKER_00: Meanwhile, animal glaucoma models suggest benefit.
• 6:16
  SPEAKER_00: Besides the optic nerve injury study above, a classic glaucoma-prone mouse strain, treated with D plus Q or with quercetin alone, had better pattern electroretinogram, PERG, and visual-evoked potentials indicating healthier RGC function, Liad al 2019.
• 6:32
  SPEAKER_00: Those treated eyes also retained more RGCs and had less microglial inflammation than untreated controls.
• 6:39
  SPEAKER_00: In short, removing senescent cells with D plus Q preserved vision in glaucoma models while the neurons were still alive, a strong hint of a neuroprotective effect.
• 6:48
  SPEAKER_00: Physetin.
• 6:49
  SPEAKER_00: Phycotin is a dietary flavanol with senolytic properties.
• 6:53
  SPEAKER_00: In aged mice, it potently killed senescent cells in multiple organs and extended lifespan.
• 6:59
  SPEAKER_00: It also reduced inflammation-linked markers in tissues.
• 7:02
  SPEAKER_00: In an experimental glaucoma model, physicin has shown promise.
• 7:06
  SPEAKER_00: DBA2J mice given physin had lower IOP and better retinal signaling than untreated mice.
• 7:12
  SPEAKER_00: E.
• 7:12
  SPEAKER_00: et al.
• 7:14
  SPEAKER_00: Although details are still emerging, these findings imply physicin can protect RGCs, likely by dampening the inflammatory SAS pumilue in the eye.
• 7:24
  SPEAKER_00: Navoclax, Navatoclax, ABT263, is a cancer drug that kills senescent cells by blocking BCL2 survival proteins.
• 7:32
  SPEAKER_00: It works in many lab cell types, including vascular and neural cells, but it has serious side effects.
• 7:38
  SPEAKER_00: In preclinical models, navatoclax effectively cleared senescent cells from heart and brain, slowing atherosclerosis or neurodegeneration, but its use is limited by blood toxicity.
• 7:48
  SPEAKER_00: Specifically, navatoclax causes severe thrombocytopenia, low platelets, neutropenia, and bleeding.
• 7:55
  SPEAKER_00: These hematologic risks have so far prevented clinical trials for aging.
• 8:00
  SPEAKER_00: There are no published reports yet of navatoclax in eye models.
• 8:03
  SPEAKER_00: In principle, it could remove senescent TM or retinal cells, but the bleeding risk is worrisome if given systemically.
• 8:10
  SPEAKER_00: In summary, animal data suggests senolytics can benefit the eye.
• 8:15
  SPEAKER_00: Most evidence so far comes from D plus Q and similar agents in retinal and optic nerve injury models.
• 8:22
  SPEAKER_00: These studies report improved RGC survival and retinal structure function when senescent cells are eliminated.
• 8:29
  SPEAKER_00: Direct IOP effects of synolytics have not been demonstrated yet.
• 8:33
  SPEAKER_00: We don't have a study showing TM senescence clearance actually lowers pressure.
• 8:37
  SPEAKER_00: However, since removal of TM cells was shown to raise IOP, it is reasonable to speculate that clearing old TM cells or preventing their fibrotic SASP might restore some outflow and ease IOP.
• 8:49
  SPEAKER_00: Senolytics and whole body aging senalytics have received attention for extending healthy lifespan.
• 8:55
  SPEAKER_00: In mice, intermittent D plus Q or physetin treatments in late life cleared senescent cells from multiple organs, reduced age-related disease markers, and extended lifespan.
• 9:06
  SPEAKER_00: For example, Yusuf Zade et al.
• 9:08
  SPEAKER_00: found that giving healthy old mice physetin restored tissue homeostasis, reduced age-related pathology, and extended median and maximum lifespan.
• 9:17
  SPEAKER_00: Similarly, SHUE et al.
• 9:20
  SPEAKER_00: showed that periodic D plus Q treatment in old mice improved exercise endurance and significantly increased survival compared to controls.
• 9:28
  SPEAKER_00: Senolytic treatment even improved glucose metabolism, cardiac function, and other aging endpoints in tissue studies.
• 9:35
  SPEAKER_00: These organismal benefits suggest that if cenolytics protect the body generally, they may also protect the eye.
• 9:42
  SPEAKER_00: In other words, keeping mice younger systemically often coincides with healthier eyes.
• 9:48
  SPEAKER_00: For instance, mice treated with phystin or D plus Q later in life have less liver fibrosis, better lung function, less arthritis, and likely better ocular microstructure, though eye measurements were not the focus of those papers.
• 10:01
  SPEAKER_00: By analogy, clearing systemic senescent cells might slow down age-related decline in the TM and retina as well.
• 10:08
  SPEAKER_00: The eye is often termed a window to aging, so improvements in body aging might be reflected in preserved vision.
• 10:16
  SPEAKER_00: Delivery, safety, and clinical considerations.
• 10:19
  SPEAKER_00: One major question is how to deliver senalytics safely to the eye.
• 10:23
  SPEAKER_00: Systemic delivery, oral pills or injections is the simplest route, but it exposes the whole body to the drug.
• 10:30
  SPEAKER_00: Encouragingly, a retrospective study found that glaucoma patients who happen to take senolytics for other reasons had no worsening of vision or IOP.
• 10:39
  SPEAKER_00: In clinical trials of aging, D plus Q pills were generally well tolerated.
• 10:43
  SPEAKER_00: Hickson et al., 2019 noted no severe adverse effects, like organ failure or death in subjects taking disatinib plus quorcidin rounds.
• 10:52
  SPEAKER_00: Physotin is even safer.
• 10:54
  SPEAKER_00: It's a plant compound present in strawberries that caused no significant side effects in human studies.
• 11:00
  SPEAKER_00: In contrast, Navidoclax's risks, bleeding marrow suppression, are a major concern.
• 11:06
  SPEAKER_00: If used systemically, regular blood monitoring would be essential.
• 11:10
  SPEAKER_00: A local ocular strategy could avoid systemic toxicity.
• 11:14
  SPEAKER_00: For example, anti-VGF drugs are routinely injected into the vitreous to treat retinal disease.
• 11:20
  SPEAKER_00: Similarly, one could inject a senolytic agent into the eye.
• 11:23
  SPEAKER_00: This was done in the RAT CNV model described above.
• 11:27
  SPEAKER_00: Intravitrial D plus Q markedly reduced senescent burden and disease lesions.
• 11:32
  SPEAKER_00: In theory, an intracameral injection into the front of the eye could target TM cells specifically.
• 11:38
  SPEAKER_00: Alternatively, specially formulated eye drops or slow-release nanoparticles might carry senolytics into the TM.
• 11:45
  SPEAKER_00: Local delivery would limit exposure to other organs and potentially allow higher doses in the eye.
• 11:51
  SPEAKER_00: However, eye injections carry risks, infection, retinal detachment, and repeated injections may be impractical.
• 11:58
  SPEAKER_00: Topical drops often penetrate poorly to deeper tissues.
• 12:02
  SPEAKER_00: No published studies have yet tested cenolytic in eye drops or intracameral injections.
• 12:07
  SPEAKER_00: In sum, both systemic and local approaches have pros and cons.
• 12:11
  SPEAKER_00: Systemic senalytics are easier to administer pill by pill and might benefit the whole body and eye, but run the risk of general side effects.
• 12:20
  SPEAKER_00: Local delivery would concentrate the drug in the eye, perhaps safer systemically, but may miss relevant cells, for example, blood-derived senescent immune cells, and requires invasive procedures.
• 12:32
  SPEAKER_00: A combined strategy might one day be used, for instance, oral senalytics to refresh the body and eye lens capsule, plus a local eye treatment for posterior tissues.
• 12:42
  SPEAKER_00: More research is needed to find safe formulations and dosing schedules that knock out senescent cells without harming normal ones.
• 12:50
  SPEAKER_00: Conclusion.
• 12:52
  SPEAKER_00: Glaucoma remains incurable by existing treatments, which only lower eye pressure.
• 12:57
  SPEAKER_00: Targeting cellular senescence is a fresh approach that aims to modify disease at a deeper level.
• 13:03
  SPEAKER_00: Evidence is mounting that senescent cells in the trabecular meshwork and optic nerve head fuel chronic inflammation, fibrosis, and retinal neuron death in glaucoma.
• 13:13
  SPEAKER_00: Preclinical studies show that senolytic drugs, especially disatinib quarsetin, and physetin, can protect retinal ganglion cells and preserve vision in animal models.
• 13:24
  SPEAKER_00: There is also reason to hope that ocular benefits will parallel the overall health improvements seen when these agents extend lifespan in mice.
• 13:32
  SPEAKER_00: While human data are so far limited, early reports suggest no obvious harm to eyes from senalytics.
• 13:39
  SPEAKER_00: Moving forward, careful testing of senolytic therapy in glaucoma models and eventually patients is needed.
• 13:46
  SPEAKER_00: Key issues will be ensuring safety, avoiding off-target toxicity, and finding practical delivery methods.
• 13:53
  SPEAKER_00: If successful, senolytic treatment could add a disease-modifying tool to protect the aging optic nerve and outflow system, in effect, clearing out the old cells to restore healthier eye signals and better preserve vision.
• 14:05
  SPEAKER_00: Tags, senolytic, glaucoma, trabecular meshwork, retinal ganglion cell, senescence, intraocular pressure, desatinib, quarsetin, fascitin, nevitoclax.
• 14:18
  SPEAKER_00: All links to sources are available in the text version of this article.
• 14:22
  SPEAKER_00: You can find the full article at VisualFieldtest.com.
• 14:25
  SPEAKER_00: Thanks for listening.
• 14:27
  SPEAKER_00: To check your visual field, click the link at the bottom of this article or visit visualfieldtest.com.