inflammation theory of aging
The frequency of asymmetric division was significantly reduced upon aging (S1 Table and Fig 2D). Consistent with polarity/apolarity before division, aged CASIN-treated HSCs divided more frequently asymmetrically, while Wnt5a treatment of young HSCs increased the frequency of symmetric divisions (Fig 2E and 2F).Sep 20, 2018
Short take: crank up ROCK/YAP with a stiff ECM and the cell slides into “permanent wound mode.” Identity genes dim, repair/fibrosis genes blare, polarity hardware gets scrambled, and the bioelectric screen saver that keeps tissues ordered starts glitching. Aging just keeps a finger on the “increase tension” key.
How stiffness/ROCK/YAP erode cell identity (aging edition)
1) Set-point drift to hard mode
- Chronic stiff ECM and SASP goo push RhoA/ROCK high → stress fibers → YAP/TAZ nuclear by default.
- That locks a myofibroblast/EMT-flavored program: CTGF, periostin, collagen I, LOX. Cells LARP as repair crews even without real damage.
2) Junctions and polarity stop policing fate
- Tension destabilizes E-cadherin/AMOT/Merlin complexes that normally park YAP at junctions. With fewer “do not proliferate” flags, lineage TFs lose leverage and boundary cues blur.
3) Epigenome gets physically hardened
- Cytoskeletal force transmits through LINC to the nucleus. Lamin A/C rises, pores flatten, chromatin shifts toward heterochromatin (H3K9me3/H3K27me3).
- At the same time, YAP/TEAD recruit p300/BRD4 to pro-mechanical super-enhancers. Net: identity enhancers close; wound/fibrosis enhancers open.
- Mechanics biases DNA chemistry: DNMT1/3A activity and localization increase on stiff substrates, TET/5hmC drops at epithelial/lineage loci. That’s memory. You can move the cell to a soft gel and it still “remembers” it’s supposed to lay rebar.
4) Bad feedback loop
- YAP → LOX/LOXL/TGF-β → more crosslinks → stiffer ECM → more nuclear YAP. Aging accelerates this with AGEs, elastin breakage, and senescent cytokines, so the loop rarely lets go.
5) Developmental signaling tilts
- Stiffness alters Notch/Eph/Wnt gradient handling and receptor clustering. Boundaries that once enforced “you’re a hepatocyte, not a fibroblast” start to smear, supporting dedifferentiation or metaplasia.
How this messes with membrane potential and polarization
1) Direct ion-channel mechanogating
- Stiffer matrices mean more traction and membrane tension. Piezo1/2, TRPV4 open more, Ca²⁺ influx rises, often depolarizing cells and activating NFAT/ERK/YAP. Depolarized baseline correlates with proliferative, less-differentiated states.
2) Trafficking and localization of polarity machinery
- High ROCK tone raises cortical and membrane tension, flattening caveolae and throttling endocytosis. Ion channels and pumps don’t get to the right side of the cell on schedule.
- PAR/Crumbs/Scribble complexes mislocalize when basal traction dominates. Microvilli flatten, tight junctions turn twitchy, and apico-basal polarity degrades.
3) Pump/transport stoichiometry drifts
- Na⁺/K⁺-ATPase and Cl⁻/HCO₃⁻ transporters are polarity-coded. Stiffness-induced trafficking defects and Ca²⁺ spikes alter their surface density, which shifts Vmem set-points and erases local bioelectric gradients that help maintain tissue architecture.
4) Cilia and gap-junction damage = lost coordination
- Excess tension shortens primary cilia and disrupts connexin turnover. Less Shh sensing and poorer electrical coupling mean cells can’t synchronize Vmem or polarity cues across the sheet. Chaos but make it microscopic.
5) Nuclear injury feeds inflammation that feeds depolarization
- Squeezing through rigid pores causes nuclear envelope rupture → cytosolic DNA → cGAS-STING → NF-κB/IFN. Inflammatory signaling alters channel expression and opens nonselective currents. More leak → more depolarization → more YAP. Delightful.
What you’d actually measure if you’re not guessing
- Identity erosion: YAP-nuclear, lamin A/C up; lineage TFs down; ATAC-seq shows global compaction with focal openness at cytoskeleton/ECM genes; increased DNMT1/3A, reduced 5hmC at epithelial loci.
- Polarity/Vmem: TEER down or unstable; DiBAC/ANNINE dyes show depolarized resting Vmem; Piezo/TRPV4 activity up; Na⁺/K⁺-ATPase mislocalized; fewer/shorter cilia; Cx43 plaques patchy.
Knobs that actually move the needle
- LOOSEN THE SYSTEM: soft substrates, ROCK or FAK inhibitors, αv-integrin antagonists.
- CUT THE FEEDBACK: LOX/LOXL inhibition to limit new crosslinks; manage AGEs.
- REOPEN IDENTITY: damp YAP–TEAD coactivation (context-careful), push metabolic cofactors that favor TET/HAT action (α-KG, acetyl-CoA availability, sensible redox).
- STABILIZE BIOELECTRICITY: reduce stretch-current noise (GsMTx4 for stretch channels; TRPV4 blockers in models), hyperpolarize gently (open K⁺ channels, boost pump competency), and rescue trafficking by lowering membrane tension.
- REBUILD POLARITY: support PAR/aPKC retention at the apex and E-cadherin belts; once junctions are solid, YAP naturally vacates the nucleus.
Bottom line: stiffness/ROCK/YAP tilt the whole stack — junctions, epigenome, and ion handling — toward a loud, depolarized, repair-first phenotype. Aging makes that tilt the default. To keep identity and polarity, you have to lower mechanical gain, reopen chromatin at lineage programs, and restore a calm, hyperpolarized baseline. Yes, biology is petty: it remembers every stiff surface it ever stood on.