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Helping Eye Cells Take Out Their Trash May Protect the Optic Nerve From Glaucoma · Glaucoma, Vision & Longevity: Supplements & Science

• 0:00
  SPEAKER_00: Helping eye cells take out their trash may protect the optic nerve from glaucoma.
• 0:04
  SPEAKER_00: Evidence review current to September 2nd, 2026.
• 0:09
  SPEAKER_00: Introduction.
• 0:11
  SPEAKER_00: Lowering eye pressure remains the most proven way to slow glaucoma.
• 0:15
  SPEAKER_00: Yet some people continue to lose retinal nerve tissue and vision even when their eye pressure is considered controlled.
• 0:21
  SPEAKER_00: This is especially relevant in normal tension glaucoma, but it can also occur in ordinary open-angle glaucoma after pressure-lowering treatment.
• 0:30
  SPEAKER_00: One possible explanation is that pressure is only the initial stress.
• 0:35
  SPEAKER_00: The lasting damage may also depend on whether retinal ganglion cells can maintain their mitochondria, transport cellular cargo along their axons, control oxidative stress, and remove damaged cell parts.
• 0:48
  SPEAKER_00: A study published in 2026 provides some of the clearest evidence so far for this idea.
• 0:54
  SPEAKER_00: The investigators use torin II, a powerful laboratory inhibitor of the mechanistic target of rapamycin pathway, to increase autophagy and mitophagy, the processes cells use to recycle damaged proteins and mitochondria.
• 1:07
  SPEAKER_00: In mouse glaucoma models, torin II reduced the buildup of abnormal mitochondria and preserved retinal ganglion cells, optic nerve axons, and electrical retinal responses.
• 1:18
  SPEAKER_00: It also increased survival of retinal ganglion cells in human retinal tissue maintained in the laboratory.
• 1:25
  SPEAKER_00: The findings are important, but they do not establish torin II as a treatment.
• 1:30
  SPEAKER_00: The compound was given by injection into the mouse eye at a research concentration.
• 1:35
  SPEAKER_00: It has broad kinase effects.
• 1:37
  SPEAKER_00: Visual behavior was not tested, and the study did not directly measure mitochondrial respiration or energy production.
• 1:44
  SPEAKER_00: The most useful interpretation is narrower.
• 1:47
  SPEAKER_00: Glaucoma may involve a failure of mitochondrial quality control, and selectively restoring mitochondrial clearance could become a form of pressure-independent neuroprotection.
• 1:58
  SPEAKER_00: What the recent Torin II study actually showed, the experimental design.
• 2:04
  SPEAKER_00: The study used several complementary approaches, a glucocorticoid-induced ocular hypertension mouse model, in which eye pressure was elevated for 10 weeks, a mutant myosillin mouse model representing a form of inherited open-angle glaucoma.
• 2:19
  SPEAKER_00: Meat Kema reporter mice, which allow researchers to measure mitophagy flux, the delivery of mitochondria to acidic lysosomes for degradation.
• 2:28
  SPEAKER_00: Retinal ganglion cell-specific deletion of autophagy-related gene 5, testing what happens when autophagy is removed directly from retinal ganglion cells.
• 2:37
  SPEAKER_00: Human retinal explants, cultured outside the body under conditions that normally cause progressive retinal ganglion cell death.
• 2:45
  SPEAKER_00: The investigators found that chronic eye pressure elevation caused abnormal mitochondrial accumulation, oxidative DNA damage, and reduced mitophagy flux.
• 2:56
  SPEAKER_00: Importantly, the mitophagy defect appeared before substantial retinal ganglion cell loss, suggesting that impaired clearance may be an early event rather than merely a consequence of dying neurons.
• 3:07
  SPEAKER_00: Reported effects of torin 2.
• 3:10
  SPEAKER_00: For the full table, please open this article on visualfieldtest.com.
• 3:14
  SPEAKER_00: The pattern electroretinogram result can be expressed in two ways.
• 3:18
  SPEAKER_00: Compared with injured vehicle-treated eyes, the mean response was approximately 83% higher, 31.17.36, 17.36, approx 83%.
• 3:30
  SPEAKER_00: Relative to the entire deficit between injured eyes and non-hypertensive controls, Torrent closed approximately 92% of the electrophysiological gap, 31.82 minus 17.33.46 approximately.
• 4:00
  SPEAKER_00: What happened when autophagy was removed?
• 4:02
  SPEAKER_00: The genetic experiments strengthened the argument that autophagy is not merely an incidental response.
• 4:08
  SPEAKER_00: When autophagy-related gene 5 was selectively removed from retinal ganglion cells, pattern electroretinogram amplitude fell from 21.78 to 8, 61 microvolts, a reduction of approximately 60%.
• 4:22
  SPEAKER_00: Retinal ganglion cell number fell by approximately 39%.
• 4:26
  SPEAKER_00: The number of healthy optic nerve axons fell by approximately 59%.
• 4:30
  SPEAKER_00: Swollen and abnormal mitochondria accumulated in retinal ganglion cell axons.
• 4:35
  SPEAKER_00: Oxidative DNA damage increased.
• 4:37
  SPEAKER_00: A separate 2026 study using autophagy-related gene 7 and autophagy-related gene 5 deletion, progressive retinal ganglion cell, and optic nerve degeneration without inducing high eye pressure.
• 4:51
  SPEAKER_00: The retinal ganglion cell bodies accumulated swollen mitochondria, distended endoplasmic reticulum, abnormal synaptic vesicles, and enlarged Golgi structures.
• 5:01
  SPEAKER_00: This supports the idea that normal, ongoing autophagy is necessary for retinal ganglion cell housekeeping even in the absence of glaucoma-related pressure elevation.
• 5:11
  SPEAKER_00: What did torin II do to mitochondrial function?
• 5:14
  SPEAKER_00: The answer requires precision.
• 5:17
  SPEAKER_00: Torin-2 increased measured mitophagy flux, reduced the accumulation of structurally abnormal mitochondria, improved the apparent pool of healthy mitochondria, reduced oxidative DNA damage, improved axonal transport and electrical retinal function.
• 5:32
  SPEAKER_00: However, the study did not report direct measurements of adenosine triphosphate production, oxygen consumption, respiratory chain complex activity, mitochondrial membrane potential, calcium handling, mitochondrial adenosine triphosphate reserve.
• 5:48
  SPEAKER_00: Therefore, it is safest to say that torin-2 improved mitochondrial quality control and mitochondrial structural health, while direct restoration of mitochondrial bioenergetics remains to be demonstrated.
• 6:00
  SPEAKER_00: Important limitations.
• 6:02
  SPEAKER_00: The study has several important limitations.
• 6:05
  SPEAKER_00: Torin II was administered by intravitreal injection, not as a clinically practical eye drop or tablet.
• 6:12
  SPEAKER_00: The reported concentration, 1 millimolar in mice, cannot be translated directly into a human dose.
• 6:18
  SPEAKER_00: The human experiment involved retinal tissue outside the body, exposed to 100 micromolar torin II under artificial stress conditions.
• 6:27
  SPEAKER_00: The treatment was tested over a relatively short period.
• 6:30
  SPEAKER_00: The mutant myosin model had a fall in eye pressure after torin-2, making it difficult to separate direct neuroprotection from pressure reduction.
• 6:39
  SPEAKER_00: The glucocorticoid model did not show an eye pressure reduction, making that model more persuasive for pressure-independent retinal protection.
• 6:48
  SPEAKER_00: No living human safety data exist for torin II as an eye treatment.
• 6:52
  SPEAKER_00: No behavioral test of vision was performed.
• 6:56
  SPEAKER_00: Why retinal ganglion cells are so dependent on mitochondria?
• 7:00
  SPEAKER_00: Retinal ganglion cells are unusually vulnerable to energy failure for several anatomical and physiological reasons.
• 7:07
  SPEAKER_00: They have long, energy-demanding axons.
• 7:10
  SPEAKER_00: Retinal ganglion cell axons travel from the retina through the optic nerve and eventually to visual centers in the brain.
• 7:17
  SPEAKER_00: Much of the axon within the retina and optic nerve head is unmyelinated.
• 7:21
  SPEAKER_00: Unlike a myelinated nerve, an unmyelinated axon must continuously restore ion gradients along a large length of membrane after each electrical impulse.
• 7:31
  SPEAKER_00: That requires constant activity from sodium-potassium pumps and other energy-consuming transport systems.
• 7:37
  SPEAKER_00: Retinal ganglion cells also maintain large dendritic trees, synapses, and active transport pathways.
• 7:43
  SPEAKER_00: Their energy demand is therefore high even at rest.
• 7:47
  SPEAKER_00: Mitochondria must be positioned throughout the neuron.
• 7:51
  SPEAKER_00: Mitochondria are not useful only in the cell body.
• 7:54
  SPEAKER_00: They must be moved to dendritic synapses, the axon initial segment, the optic nerve head, regions of high calcium influx, distant axonal terminals in the brain.
• 8:05
  SPEAKER_00: The optic nerve head is particularly vulnerable because retinal ganglion cell axons bend sharply and undergo major structural changes as they pass from the retina into the optic nerve.
• 8:16
  SPEAKER_00: Their high mitochondrial density in this region reflects the need to support electrical activity and axonal transport.
• 8:23
  SPEAKER_00: Retinal ganglion cells cannot dilute damaged organelles by dividing.
• 8:27
  SPEAKER_00: Retinal ganglion cells are long-lived postmitotic neurons.
• 8:31
  SPEAKER_00: A dividing cell can distribute damaged proteins and organelles between daughter cells.
• 8:36
  SPEAKER_00: A retinal ganglion cell cannot.
• 8:39
  SPEAKER_00: It must repair, recycle, or remove its own damaged components for decades.
• 8:43
  SPEAKER_00: This makes defective autophagy particularly dangerous.
• 8:46
  SPEAKER_00: If damaged mitochondria are not removed, they can produce excessive reactive oxygen species, release oxidized mitochondrial DNA, impair adenosine triphosphate production, disrupt calcium balance, activate apoptotic pathways, obstruct axonal transport, damage synapses and dendrites.
• 9:05
  SPEAKER_00: The 2026 Autophagy Deficiency Study directly observed this type of intracellular accumulation in retinal ganglion cells.
• 9:13
  SPEAKER_00: Why damage can continue even when eye pressure is controlled?
• 9:17
  SPEAKER_00: Eye pressure remains important, but it is not the only determinant of retinal ganglion cell survival.
• 9:23
  SPEAKER_00: Pressure-related stress can initiate a chain of secondary problems, compression or distortion at the optic nerve head, impaired axonal transport, reduced delivery of target-derived survival factors, mitochondrial transport failure, energy shortage and oxidative stress, synapse and dendrite loss, neuroinflammation and glial dysfunction, irreversible retinal ganglion cell death.
• 9:48
  SPEAKER_00: Once this process becomes self-sustaining, lowering pressure may remove the original trigger without immediately reversing mitochondrial damage, inflammation, or axonal degeneration.
• 9:58
  SPEAKER_00: Human and experimental studies support a metabolic component.
• 10:02
  SPEAKER_00: Human glaucomatous retinas have shown abnormal mitochondrial structure and fragmentation in retinal ganglion cell dendrites, even in areas with limited gross cell loss.
• 10:12
  SPEAKER_00: Reduced labeling for nicotinamide mononucleotide adenyl L transferase II, an axonal survival protein involved in nicotinamide adenine dinucleotide metabolism, has also been reported in human glaucoma tissue.
• 10:26
  SPEAKER_00: This is one reason glaucoma is increasingly viewed as a disorder of mechanical stress plus metabolic susceptibility rather than as a disease caused by eye pressure alone.
• 10:36
  SPEAKER_00: The full mechanistic pathway.
• 10:38
  SPEAKER_00: A simplified model looks like this pressure, aging, vascular stress, inflammation, or genetic susceptibility, mitochondrial injury and energy shortage, abnormal AMP-activated protein kinase, and mechanistic target of rapamycin signaling, impaired or poorly completed autophagy, damaged mitochondria accumulate, reactive oxygen species, and oxidized mitochondrial DNA rise, axonal transport, synapses, and electrical function fail, retinal ganglion cells and optic nerve axons degenerate.
• 11:10
  SPEAKER_00: The model is plausible, but each step is influenced by cell type, disease stage, and the type of stress.
• 11:16
  SPEAKER_00: Mechanistic target of rapamycin.
• 11:19
  SPEAKER_00: The mechanistic target of rapamycin is a nutrient and growth signaling kinase.
• 11:24
  SPEAKER_00: When nutrients and growth factors are abundant, it promotes protein production, cell growth, and anabolic activity.
• 11:30
  SPEAKER_00: When it is inhibited, autophagy is generally released from suppression.
• 11:34
  SPEAKER_00: Rapamycin mainly acts through mechanistic target of rapamycin complex 1.
• 11:39
  SPEAKER_00: Torin-2 is an ATP competitive inhibitor that more directly inhibits the catalytic activity of mechanistic target of rapamycin and can inhibit both mechanistic target of rapamycin complexes 1 and 2.
• 11:52
  SPEAKER_00: It is also capable of inhibiting other kinases, including ataxia telingiectasia mutated, ataxia telingiectasia and rad 3 related, and DNA-dependent protein kinase at higher concentrations.
• 12:05
  SPEAKER_00: This matters because mechanistic target of rapamycin is not simply harmful.
• 12:09
  SPEAKER_00: It also supports protein synthesis, neuronal growth, cytoskeletal maintenance, synaptic function, axonal survival, metabolic adaptation.
• 12:19
  SPEAKER_00: In human stem cell-derived retinal ganglion cells carrying an optineurin mutation, trihelose improved autophagy-related clearance and neurite structure while avoiding broad suppression of mechanistic target of rapamycin.
• 12:31
  SPEAKER_00: This suggests that mTOR-independent or selective autophagy activation may be safer than chronic global mTOR blockade.
• 12:39
  SPEAKER_00: AMP-activated protein kinase.
• 12:41
  SPEAKER_00: AMP-activated protein kinase is an energy sensor.
• 12:44
  SPEAKER_00: When cellular energy falls, it usually activates energy-producing pathways, inhibits energy-consuming synthesis, activates the autophagy-initiating kinase ULK1, suppresses mechanistic target of rapamycin complex 1.
• 12:58
  SPEAKER_00: This makes AMP-activated protein kinase a logical route for enhancing autophagy and mitophagy.
• 13:04
  SPEAKER_00: However, glaucoma research shows that AMP-activated protein kinase may have a Goldilocks problem.
• 13:10
  SPEAKER_00: One study found strong AMP-activated protein kinase activation in retinal ganglion cells from ocular hypertensive mice and from patients with primary open-angle glaucoma.
• 13:20
  SPEAKER_00: Excessive activation was linked to mechanistic target of rapamycin complex 1 inhibition, dendritic retraction, synapse loss, and neuronal dysfunction.
• 13:30
  SPEAKER_00: Reducing AMP-activated protein kinase activity restored mechanistic target of rapamycin signaling and improved retinal ganglion cell structure.
• 13:39
  SPEAKER_00: Other studies have reported the opposite.
• 13:42
  SPEAKER_00: In retinal ischemia reperfusion models, activating AMP-activated protein kinase reduced apoptosis through mechanistic target of rapamycin inhibition.
• 13:51
  SPEAKER_00: A 2026 study concluded that AMP-activated protein kinase activation protected retinal ganglion cells in that acute injury model.
• 14:00
  SPEAKER_00: The apparently conflicting results may reflect acute versus chronic injury, retinal ganglion cells versus glial cells, moderate versus extreme energy stress, transient versus sustained activation, different disease models, different amounts of residual mitochondrial reserve.
• 14:17
  SPEAKER_00: AMP-activated protein kinase activation may be helpful when it restores energy balance, but harmful when it becomes a persistent marker of severe energy failure.
• 14:26
  SPEAKER_00: Mitophagy and the P10-induced putative kinase 1 parkin system.
• 14:31
  SPEAKER_00: Mitophagy is selective autophagy directed at mitochondria.
• 14:35
  SPEAKER_00: When a mitochondrion loses its membrane potential, P10-induced putative kinase 1 accumulates on its outer membrane.
• 14:43
  SPEAKER_00: It then phosphorylates ubiquitin and helps recruit the ubiquitin ligase parkin.
• 14:48
  SPEAKER_00: Parkin labels the damaged mitochondrion for removal.
• 14:52
  SPEAKER_00: Autophagy receptors such as optineurin help connect the tagged mitochondrion to the autophagy machinery.
• 14:58
  SPEAKER_00: This pathway is particularly relevant to glaucoma because Parkin overexpression has protected retinal ganglion cells in experimental glaucoma.
• 15:07
  SPEAKER_00: It improved mitochondrial health and partially restored abnormal mitophagy responses after pressure elevation.
• 15:14
  SPEAKER_00: Mitochondrial quality control may also be shared between retinal ganglion cells and optic nerve glia.
• 15:20
  SPEAKER_00: Damaged mitochondria shed from retinal ganglion cell axons can be transferred to astrocytes for degradation, a process sometimes called transmitophagy.
• 15:30
  SPEAKER_00: Mitophagy in astrocytes appears necessary for optic nerve health, and the mitochondrial compound urolithin A has rescued some astrocyte mitophagy defects in experimental systems.
• 15:40
  SPEAKER_00: This means that a future therapy may need to target not only retinal ganglion cells, but also astrocytes, microglia, optic nerve head support cells, lysosomal function, mitochondrial transport.
• 15:52
  SPEAKER_00: Nicotinamide adenine dinucleotide metabolism.
• 15:55
  SPEAKER_00: Nicotinamide adenine dinucleotide is required for mitochondrial energy production, redox reactions, DNA repair, sertuin activity, mitochondrial biogenesis, stress responses.
• 16:08
  SPEAKER_00: Nicotinamide adenine dinucleotide availability can fall with age, inflammation, DNA damage, and increased activity of enzymes such as polyadenosine diphosphate ribose polymerase and CD38.
• 16:19
  SPEAKER_00: Some glaucoma research suggests that reduced nicotinamide adenine dinucleotide metabolism contributes to retinal ganglion cell vulnerability.
• 16:28
  SPEAKER_00: Nicotinamide and related precursors may therefore help in a different way from torin-2.
• 16:34
  SPEAKER_00: Torin II attempts to remove damaged mitochondria.
• 16:37
  SPEAKER_00: Nicotinamide attempts to improve the metabolic environment in which mitochondria operate.
• 16:42
  SPEAKER_00: This distinction is important.
• 16:44
  SPEAKER_00: A cell may need both disposal of defective mitochondria and replacement with healthier mitochondria.
• 16:51
  SPEAKER_00: Oxidative stress.
• 16:52
  SPEAKER_00: Damaged mitochondria can become both a consequence and a source of oxidative stress.
• 16:57
  SPEAKER_00: They may generate excess reactive oxygen species while producing less energy.
• 17:01
  SPEAKER_00: Oxidative damage can affect mitochondrial DNA, respiratory chain proteins, axonal microtubules, membrane lipids, synaptic proteins, nuclear DNA.
• 17:12
  SPEAKER_00: In the Torin II study, improved autophagy was accompanied by reduced accumulation of abnormal mitochondria and reduced oxidative DNA damage.
• 17:20
  SPEAKER_00: This supports a mechanistic link, although it does not prove that oxidative stress is the only reason the cells survived.
• 17:26
  SPEAKER_00: Mitochondrial biogenesis.
• 17:29
  SPEAKER_00: Mitophagy removes defective mitochondria.
• 17:32
  SPEAKER_00: Mitochondrial biogenesis builds new ones.
• 17:35
  SPEAKER_00: A healthy neuron needs a balance between the two.
• 17:38
  SPEAKER_00: Important regulators include sertuin1 and sertuin 3, peroxisome proliferator activated receptor Gamma Coactivator 1 Alpha, nuclear respiratory factors, mitochondrial transcription factor A, AMP-activated protein kinase, nicotinamide adenine dinucleotide availability.
• 17:56
  SPEAKER_00: A therapy that only accelerates mitochondrial destruction could worsen energy failure if new mitochondria are not produced.
• 18:03
  SPEAKER_00: Conversely, increasing mitochondrial biogenesis without clearing damaged mitochondria could expand the pool of dysfunctional organelles.
• 18:11
  SPEAKER_00: What independent glaucoma research says The broader glaucoma literature supports several parts of the Torin-2 model, but it does not yet establish a universal rule that more autophagy is always better.
• 18:24
  SPEAKER_00: Evidence supporting the model.
• 18:26
  SPEAKER_00: Independent or partially independent findings include human glaucoma tissue shows abnormal mitochondrial structure and fragmentation.
• 18:34
  SPEAKER_00: Retinal ganglion cells and optic nerve axons have unusually high energy demands.
• 18:39
  SPEAKER_00: Parkin overexpression protects retinal ganglion cells in experimental glaucoma.
• 18:44
  SPEAKER_00: Optic atrophy type 1, a mitochondrial-shaping protein, can protect retinal ganglion cells and increase parkin expression in experimental glaucoma.
• 18:53
  SPEAKER_00: Glaucoma-associated optineurin and tank-binding kinase 1 mutations affect autophagy or mitophagy-related biology.
• 19:01
  SPEAKER_00: Urolithin A and nicotinamide riboside improved mitochondrial bioenergetics and reduced reactive oxygen species in cells derived from people with exfoliation glaucoma.
• 19:12
  SPEAKER_00: Fucoxanthin protected retinal ganglion cells in an experimental glaucoma model while increasing Parkin-related mitophagy markers.
• 19:21
  SPEAKER_00: Together, these findings support the general biological model.
• 19:24
  SPEAKER_00: Mitochondrial quality control is relevant to glaucoma, and strengthening selective mitochondrial maintenance may be protective.
• 19:32
  SPEAKER_00: Evidence that complicates the model, older and more recent studies have also found potentially harmful effects of autophagy activation.
• 19:40
  SPEAKER_00: A 2012 chronic hypertensive RAT study found that autophagasomes accumulated in retinal ganglion cells, autophagy markers increased, and blocking autophagy with 3-methyl adenine reduced apoptosis.
• 19:54
  SPEAKER_00: The authors concluded that autophagy contributed to retinal ganglion cell death in that model.
• 20:00
  SPEAKER_00: A 2023 study found that reducing autophagy-related gene 4B activity protected against eye pressure elevation and optic nerve damage in several mouse glaucoma models.
• 20:11
  SPEAKER_00: Even mice with partial autophagy reduction developed high eye pressure but had better retinal ganglion cell and optic nerve preservation than controls.
• 20:21
  SPEAKER_00: These results do not necessarily disprove the Torin II findings.
• 20:24
  SPEAKER_00: They may be showing different biological situations.
• 20:27
  SPEAKER_00: For the full table, please open this article on VisualFieldtest.com.
• 20:32
  SPEAKER_00: The key question is therefore not simply should autophagy be increased?
• 20:36
  SPEAKER_00: It is.
• 20:37
  SPEAKER_00: Can mitochondrial clearance be restored selectively at the correct stage without suppressing the survival and repair functions that retinal ganglion cells still need?
• 20:47
  SPEAKER_00: Autophagy, age, metabolic state, and glaucoma stage early disease.
• 20:52
  SPEAKER_00: Early in glaucoma, many retinal ganglion cells may be dysfunctional but not yet dead.
• 20:57
  SPEAKER_00: Their mitochondria may be damaged, their dendrites simplified, and their axonal transport impaired.
• 21:03
  SPEAKER_00: This is probably the most favorable stage for quality control therapy.
• 21:07
  SPEAKER_00: Removing defective mitochondria could theoretically preserve energy production, reduce reactive oxygen species, maintain synapses, improve axonal transport, prevent a reversible stress state from becoming irreversible degeneration.
• 21:22
  SPEAKER_00: Advanced disease.
• 21:24
  SPEAKER_00: In advanced glaucoma, many retinal ganglion cells and axons have already disappeared.
• 21:29
  SPEAKER_00: Autophagy cannot bring dead neurons back.
• 21:32
  SPEAKER_00: In remaining cells, however, the strategy might still be useful if it preserves surviving tissue.
• 21:37
  SPEAKER_00: The expected benefit would be slowing further loss, not restoring the visual field already gone.
• 21:44
  SPEAKER_00: Aging.
• 21:44
  SPEAKER_00: Aging is associated with reduced autophagy and declining lysosomal efficiency.
• 21:49
  SPEAKER_00: Older retinal ganglion cells may therefore benefit from restoring a weakened quality control system.
• 21:55
  SPEAKER_00: An autophagy reporter study found that older mouse retinas had poor.
• 22:00
  SPEAKER_00: Basal and stress-induced autophagy and were more vulnerable to pressure elevation.
• 22:04
  SPEAKER_00: But older cells may also have poorer lysosomal function, less mitochondrial reserve, more accumulated damaged proteins, more inflammation, slower recovery from cellular stress.
• 22:16
  SPEAKER_00: In that situation, forcing more autophagy initiation without improving lysosomal completion could increase the number of stalled autophagosomes rather than improve clearance.
• 22:27
  SPEAKER_00: Metabolic state, diabetes, insulin resistance, undernutrition, vascular disease, and severe caloric restriction may change the response.
• 22:36
  SPEAKER_00: Caloric restriction and every other day fasting protected retinal ganglion cells and improved visual impairment in a mouse model resembling normal tension glaucoma.
• 22:46
  SPEAKER_00: The benefits were associated with lower oxidative stress and increased neurotrophic signaling, but the protection was not proven to result solely from autophagy.
• 22:56
  SPEAKER_00: Intermittent fasting also protected retinal ganglion cells in a newer immune-mediated mouse model and reduced inflammatory cytokines.
• 23:04
  SPEAKER_00: Again, the study supports a metabolic and inflammatory mechanism more strongly than a specific mitophagy mechanism.
• 23:12
  SPEAKER_00: Treatment intensity.
• 23:13
  SPEAKER_00: The safest future approach is unlikely to be permanent, high-level autophagy activation.
• 23:19
  SPEAKER_00: More plausible strategies include intermittent dosing, selective mitophagy activation, retinal ganglion cell-targeted delivery, improving lysosomal function, combining mitochondrial clearance with mitochondrial replacement, preserving appropriate mechanistic target of rapamycin signaling, using biomarkers to confirm that damaged mitochondria are actually being removed.
• 23:42
  SPEAKER_00: Could anything available today affect the same pathway?
• 23:46
  SPEAKER_00: The following interventions affect overlapping biology.
• 23:49
  SPEAKER_00: None should be interpreted as a recommendation to self-treat glaucoma or replace pressure-lowering therapy.
• 23:55
  SPEAKER_00: For the full table, please open this article on VisualFieldTest.com.
• 24:00
  SPEAKER_00: Metformin is the closest approved drug repurposing candidate for the direct autophagy-mitophagy concept.
• 24:07
  SPEAKER_00: The 2025 study found retinal ganglion cell protection in an ischemia reperfusion model, increased autophagy-related structures, and increased optineurin and parkin.
• 24:18
  SPEAKER_00: However, the authors acknowledged that they did not establish a causal role for AMP-activated protein kinase and did not demonstrate enhanced bulk autophagy flux through changes in P62.
• 24:30
  SPEAKER_00: Nicotinamide is currently closer to practical clinical action for a different reason.
• 24:35
  SPEAKER_00: It already has randomized human glaucoma data and registered phase 3 research.
• 24:40
  SPEAKER_00: In a 2020 crossover trial, 57 glaucoma participants received six weeks of 1.5 grams daily, followed by six weeks of three grams daily.
• 24:50
  SPEAKER_00: The saturated photopic negative response improved by 14.8% with nicotinamide versus 5.2% with placebo, while the photopic negative response to B wave ratio improved by 12.6% versus 3.6%.
• 25:04
  SPEAKER_00: A more recent normal tension glaucoma trial using 1 to 2 grams daily also found improvement in photopic negative response measures, but did not find a significant difference in visual field mean deviation after 12 weeks.
• 25:18
  SPEAKER_00: High dose nicotinamide should not be treated as an ordinary vitamin supplement.
• 25:24
  SPEAKER_00: The American Glaucoma Society and American Academy of Ophthalmology have advised that doses of approximately 3 grams daily or more should not be used outside clinical trials with liver monitoring because of reported drug-induced liver injury.
• 25:40
  SPEAKER_00: What about nicotinamide ribicide and nicotinamide mononucleotide?
• 25:44
  SPEAKER_00: Nicotinamide ribicide and nicotinamide mononucleotide are attractive because they may raise nicotinamide adenine dinucleotide with lower amounts of nicotinamide itself.
• 25:54
  SPEAKER_00: But this is not yet proof that they will protect retinal ganglion cells.
• 25:58
  SPEAKER_00: A registered trial is comparing nicotinamide, nicotinamide ribicide, nicotinamide mononucleotide, nicotinic acid, and placebo in adults with primary open-angle glaucoma.
• 26:09
  SPEAKER_00: The record reports no results posted.
• 26:12
  SPEAKER_00: A separate 24-month nicotinamide ribicide glaucoma trial protocol planned to test 300 mg daily against placebo.
• 26:21
  SPEAKER_00: Torrin II compared with nicotinamide-based neuroprotection.
• 26:25
  SPEAKER_00: These strategies may be complementary, but that remains an inference rather than a demonstrated treatment combination.
• 26:31
  SPEAKER_00: For the full table, please open this article on VisualFieldtest.com.
• 26:36
  SPEAKER_00: A combined strategy is biologically plausible.
• 26:39
  SPEAKER_00: Nicotinamide could improve the energy and redox environment.
• 26:42
  SPEAKER_00: Selective mitophagy could remove the most damaged mitochondria.
• 26:46
  SPEAKER_00: Mitochondrial biogenesis could replace what was removed.
• 26:50
  SPEAKER_00: Pressure lowering would reduce the initiating mechanical stress.
• 26:54
  SPEAKER_00: However, excessive mitochondrial clearance without adequate replacement could worsen energy failure.
• 27:00
  SPEAKER_00: Conversely, raising nicotinamide adenine dinucleotide without removing severely damaged mitochondria could improve the function of an unhealthy mitochondrial population only temporarily.
• 27:11
  SPEAKER_00: This combination should therefore be tested in a controlled preclinical study before human use.
• 27:17
  SPEAKER_00: How convincing is the animal evidence?
• 27:20
  SPEAKER_00: My assessment?
• 27:22
  SPEAKER_00: 7 out of 10.
• 27:23
  SPEAKER_00: The evidence is stronger than a single positive drug experiment because it includes two glaucoma-related mouse models, a direct mitophagy reporter, retinal ganglion cell-specific genetic disruption, electron microscopy, retinal ganglion cell counts, optic nerve axon analysis, axonal transport, pattern electroretinography, human retinal explants.
• 27:46
  SPEAKER_00: The evidence loses points because most torin-2 experiments had small sample sizes, direct mitochondrial respiration and adenosine triphosphate measurements were absent.
• 27:55
  SPEAKER_00: Visual behavior was not tested.
• 27:57
  SPEAKER_00: Torrin-2 has broad pharmacology.
• 27:59
  SPEAKER_00: The mutant myosin model had a pressure lowering confound.
• 28:03
  SPEAKER_00: The strongest recent studies come from a closely related research program.
• 28:08
  SPEAKER_00: Other glaucoma studies have found that reducing autophagy can be protective.
• 28:13
  SPEAKER_00: The animal evidence is therefore compelling for further investigation, but not yet sufficient to justify clinical use.
• 28:20
  SPEAKER_00: How likely is it to work in humans?
• 28:23
  SPEAKER_00: These are judgment-based estimates, not formally calculated probabilities.
• 28:27
  SPEAKER_00: Torin II itself estimated probability that torin II itself becomes a human glaucoma treatment, less than 5%.
• 28:34
  SPEAKER_00: Its broad inhibition of mechanistic target of rapamycin, ataxia telangiectasia mutated, ataxia telangiectasia and rad 3-related, and DNA-dependent protein kinase makes chronic ocular use difficult.
• 28:48
  SPEAKER_00: The compound is best viewed as a proof-of-mechanism tool that identifies a therapeutic direction.
• 28:53
  SPEAKER_00: Some targeted autophagy or mitophagy intervention.
• 28:57
  SPEAKER_00: Estimated probability that a safer, more selective autophagy or mitophagy intervention eventually shows a reproducible human glaucoma benefit, approximately 30% to 40%.
• 29:07
  SPEAKER_00: Reasons for optimism include strong mitochondrial vulnerability in retinal ganglion cells, human evidence of mitochondrial abnormalities, protective effects of Parkin and related mitochondrial interventions, recent evidence that mitophagy impairment can precede retinal ganglion cell death, a growing pipeline of metabolic and mitochondrial clinical trials.
• 29:30
  SPEAKER_00: Reasons for caution include glaucoma is biologically heterogeneous, autophagy is not uniformly protective, the correct dose and treatment window are unknown.
• 29:40
  SPEAKER_00: Retinal ganglion cells may need selective mitophagy rather than global autophagy.
• 29:45
  SPEAKER_00: Clinical trials must demonstrate slowed visual field loss over years, not merely short-term electrical improvement.
• 29:52
  SPEAKER_00: Which existing intervention is closest to making the biology actionable?
• 29:57
  SPEAKER_00: There are two reasonable answers.
• 29:59
  SPEAKER_00: Nicotinamide is closest to clinical action overall because it has randomized human glaucoma data and phase 3 research.
• 30:07
  SPEAKER_00: Metformin is closest to an autophagy-related repurposing strategy because it is already approved, has preclinical retinal ganglion cell data, and has observational human glaucoma evidence.
• 30:19
  SPEAKER_00: Neither should currently be considered proven neuroprotective treatment for glaucoma.
• 30:24
  SPEAKER_00: Plausible clinical timeline.
• 30:26
  SPEAKER_00: If a repurposed drug such as metformin were selected for a glaucoma trial, an investigator-led mechanistic study could plausibly begin around 2029 to 2032.
• 30:37
  SPEAKER_00: A selective mitophagy activator designed for retinal ganglion cell or optic nerve head delivery would more realistically require two to four years of additional preclinical work, a first-in-human safety study, a phase one or phase two glaucoma trial, several years of structural and visual field follow-up.
• 30:56
  SPEAKER_00: A realistic timeline for a first clinical trial of a purpose-built mitophagy therapy is approximately 2031 to 2035, with evidence of long-term visual field benefit potentially taking until the mid to late 2030s.
• 31:12
  SPEAKER_00: Conclusion.
• 31:12
  SPEAKER_00: The Torin II research strengthens an emerging view of glaucoma as a disease of mitochondrial stress and failed cellular quality control, not simply excessive eye pressure.
• 31:23
  SPEAKER_00: Retinal ganglion cells are unusually dependent on mitochondrial health because they have long, energy-demanding axons, complex dendrites, active synapses, and limited ability to dilute damaged organelles.
• 31:36
  SPEAKER_00: When mitochondrial clearance fails, abnormal mitochondria may accumulate and contribute to oxidative stress, impaired axonal transport, synaptic dysfunction, and eventual cell death, even after eye pressure has been lowered.
• 31:50
  SPEAKER_00: The most promising therapeutic concept is not indiscriminate activation of autophagy.
• 31:55
  SPEAKER_00: It is more precise.
• 31:56
  SPEAKER_00: Restore the completed clearance of damaged mitochondria while preserving the mechanistic target of rapamycin, lysosomal, metabolic, and mitochondrial biogenesis functions that healthy neurons need.
• 32:08
  SPEAKER_00: Nicotinamide may support this strategy by improving nicotinamide adenine dinucleotide metabolism.
• 32:14
  SPEAKER_00: Metformin may influence overlapping AMP-activated protein kinase autophagy and mitophagy pathways.
• 32:22
  SPEAKER_00: Exercise and carefully designed metabolic interventions may provide lower intensity ways to stimulate related biology, but none has yet demonstrated that it can safely slow glaucoma progression through autophagy manipulation.
• 32:35
  SPEAKER_00: Pressure control remains essential.
• 32:38
  SPEAKER_00: The future, if this approach succeeds, is likely to involve pressure lowering plus targeted metabolic and mitochondrial neuroprotection rather than replacing pressure treatment with an autophagy drug.
• 32:50
  SPEAKER_00: Final ratings, scientific importance, 9 tenths, likelihood of translating to humans, 4 tenths, potential impact if successful, 8 tenth.
• 33:00
  SPEAKER_00: All links to sources are available in the text version of this article.
• 33:04
  SPEAKER_00: You can find the full article at VisualFieldTest.com.
• 33:08
  SPEAKER_00: Thanks for listening.
• 33:09
  SPEAKER_00: To check your visual field, click the link at the bottom of this article or visit visualfieldtest.com.