# Unfolded Protein Response (UPR)

The unfolded protein response (UPR) is a rescue program your cells run when misfolded proteins pile up in the endoplasmic reticulum (ER). Three sensors kick it off: IRE1alpha, PERK, and ATF6. Together they do three things. They pause most protein-making (by tagging eIF2alpha). They ramp up folding helpers (chaperones) in the ER. And they expand the disposal system (ERAD) to clear bad proteins. When the stress is resolved, the UPR switches off and balance returns. But when stress is chronic and cannot be fixed (which gets more common with age), the UPR changes its tune. It then drives NF-kB inflammation and CHOP-dependent cell death, linking protein-folding failure to tissue degeneration.

## Sources

- Walter P, Ron D. (2011). The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation. Science. https://doi.org/10.1126/science.1209038

---

_Canonical: https://longevity-switzerland.com/en/glossary/unfolded-protein-response · Part of Longevity Cities · Updated 2026-06-22_