Table 1.
Summary of age-dependent molecular effects on optic nerve (ON) neurodegeneration.
| Tissue (Broad) | Tissue (Subtype, Process, Age, or Disease) | Summary of Molecular Mechanisms | Citation |
|---|---|---|---|
| Connective tissue ECM |
Elastin | LOX oxidation Decreased quality Further research needed on elastin quantity and relative importance of ECM composition and organization |
[12,13,14,15,16,17,18,19,20,21,22,23] |
| Collagen | Elevated LOX expression AGE accumulation RAGE “two-hit” hypothesis ECM remodeling Calcium and lipid accumulation MMPs Mechanical considerations Thickening, stiffening |
[23,24,25,26,27] | |
| Dura mater | 2nd most ON elastic fibers Calcifications Mechanical considerations Less stiff |
[12,16,17,28,29] | |
| Arachnoid Subarachnoid space | CSFP decreases (linked to normal tension glaucoma) Thickening, more coarse trabeculae, more prominent granulations |
[12,30,31,32,33] | |
| Pia mater Septa |
Thickening, expands into fibrous sleeve | [12] | |
| Lamina Cribrosa (LC) | Most ON elastic fibers Collagen deposition AGE and RAGE ECM remodeling Myofibroblast contraction, TGF-β, mechanotransduction TGF-β1 upregulation MMP-2 Increased cribriform plate rigidity (plastic flow) Unique vascularity (thin and thick beams) Thicker astrocyte basement membranes Integrins α2β1, α3β1, α6β1, and α6β4 |
[12,18,19,34,35,36,37] | |
| Optic (scleral) canal | Sclera | Decreased elastin Increased collagen AGE Mechanical considerations V-shaped PPS CSCR Further research is needed on scleral stiffening and/or thickening |
[31,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59] |
| Optic nerve head (ONH) | Age-dependent structural changes may alter the biochemical environment RGC loss Smaller optic canal area associated with more axons |
[12,20,35,41,60,61,62,63,64,65,66,67] | |
| Retinal ganglion cell (RGC) | Embryonic | Caspase-3 neuronal pruning Histone lysine methylation (H3K9me2, H3K27me3) Histone methyl transferases (G9a (EHMT2) and Ezh2 (EZH2)) Barhl2 (BARHL2) Transcriptional gene control Microglial phagocytosis (complement proteins) |
[60,68,69,70,71,72] |
| Age-dependent loss | Mechanical and biochemical RGC loss RNFL thinning Caspases (inflammatory, apoptotic) HAT HDAC |
[12,60,73,74,75,76,77,78,79,80,81] | |
| Aging and injury | Upregulated DLK CaMKII-CREB signaling interference Caspases HDAC upregulation |
[73,75,76,77,78,79,82,83,84,85,86,87,88,89,90] | |
| Mitochondria | Functional decline ROS Worsened mtDNA repair pathways (lost PARP1, MYH, NTH1) Low NRF2 |
[91,92,93,94] | |
| Autophagy | Age-related decline Decreased Atg7 (ATG7) and Beclin-1 (BECN1) Normal tension glaucoma (Optn, Tbk1, and Opa-1) Autophagy activators (AMPK inducer, mTORC1 inhibitors) may decrease ocular disease severity |
[74,95,96,97,98,99,100] | |
| ipRGC | Decreased density and plexus Lipofuscin accumulation |
[74,97,98,99,100] | |
| Diabetic retinopathy (DR) | Decreased oxygen Abnormal metabolism Polyol and hexosamine pathways DAG-PKC synthesis Free radicals AGE and RAGE Caspases Bax Fas Integrins |
[4,5,6,60,61,101,102,103,104,105,106,107] | |
| Glaucoma | Failed axonal transport Derived neurotrophic factor Pro-neurotrophins Apoptotic signals (intrinsic, extrinsic) Caspases AGE and RAGE Integrins Mitochondrial dysfunction (DRP1, OPA1, CoQ10, SOD2, and Mic60) ECM remodeling Trabecular meshwork stiffening |
[12,25,60,108,109,110,111,112,113,114] | |
| Regeneration | Adult RGCs do not regenerate | [115,116,117] | |
| Axon | Embryonic | Embryonic RGCs regenerate Deletion of PTEN, IL22, or SOCS3 (activate mTOR and STAT3 pathways) and Notch, Hh, and mTOR signal pathways (regulate JAK/STAT pathway) propel cell growth and regeneration Caspases |
[60,88,118,119,120,121,122,123,124] |
| Loss of density | ~50–70% of axons eliminated in gestation General (nonlinear) density loss after age 60 May not be associated with visual loss or pathology |
[12] | |
| Swelling | Most notable after age 70 NOS AGE and RAGE |
[2,12,25,102,112,125,126,127] | |
| Metabolic dysfunction | Hypometabolism Decreased respiration, ATP production, spare capacity Altered redox homeostasis Low NRF2 ROS Decreased NAD+ levels may induce senescence |
[3,128,129,130,131,132] | |
| Myelin | Newborn | Newborn ON unmyelinated Oligodendrocytes DNA methylation imperative for myelination (DNMT1, DNMT3A) |
[12,88,133,134,135,136,137,138,139,140] |
| Childhood and adult | Dense myelin sheaths age 2 Remyelination by DNA demethylation, hydroxymethylation (TET1, TET2) |
[12,88,137,141] | |
| After age 70 | Decreased myelin packing density Morphological alterations Ballooning sheaths Separated lamellae Oligodendrocyte degeneration ECM remodeling Decreased growth factors Mitigation of hydroxymethylation Oct4 (Pou5f1), Sox2, and Klf4 (OSK) may contribute |
[88,134,142,143,144,145,146] | |
| Glial cell | Reactive astrocytosis | ROS Decreased ATP production Neurotoxins Classical complement Neurotrophic factors TGF-β1, TNF, CASP3, and p53 “Two-hit” model of injury and neuroinflammatory mediators |
[88,110,111,130,147,148,149,150,151,152,153,154,155] |
| Remodeling | Gap-junction coupling of Cx43 Organizational deterioration Glial coverage increases |
[130,156] | |
| Hypertrophy | Glial filaments in processes Oxidative stress (ROS) Caspases Tau protein Tau dephosphorylation at Ser422 |
[72,157,158] | |
| Inclusions | Corpora amylacea (CA) Myelin debris Lipids |
[12,159,160,161,162,163,164,165,166] | |
| Migration | Integrins | [104,108] | |
| Microglial polarization | M1/M2 polarization imbalance MAPK signaling JNK inactivation Altered cytokine production Increased activation marker expression Abnormal morphologies Dynamic behavior changes |
[86,136,167,168,169,170,171] | |
| Lipofuscin (LF) | May actively induce pro-inflammatory glial cell phenotypes | [12,153,172,173,174,175,176,177] | |
| Vascular degeneration * | Hyalinization of arterioles Integrins α3β1, α6β1, and α6β4, along with α5β1 and αvβ1 |
[12,82,104,125] | |
| Cavernous degeneration * | Common in neurodegeneration Likely due to vascular disease (not glaucoma) |
[12,178] |
* Not explicitly age-dependent changes, but common in elderly individuals.