# p38 MAPK

p38 MAPK (p38 mitogen-activated protein kinase) is a stress-activated enzyme. It has four versions (α, β, γ, δ), with p38α the main, best-studied one. Upstream kinases (MKK3 and MKK6) switch it on in response to inflammatory cytokines, oxidative stress, UV light, and osmotic shock. Once active, it tags many targets, including a downstream kinase (MK2), transcription factors (ATF2 and MEF2), and proteins that stabilize pro-inflammatory mRNAs like TNF-α. In aging, p38α earns its keep as a troublemaker. It drives the SASP in senescent cells (via NF-κB and MK2). It blocks your muscle stem cells' self-renewal (by tagging MyoD and disrupting their dormancy). And it amplifies the inflammation of inflammaging. Blocking p38α with drugs has restored muscle regeneration in aged mice.

## Sources

- Han J, Lee JD, Bibbs L, Ulevitch RJ. (1994). A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science. https://doi.org/10.1126/science.7914033
- Cuadrado A, Nebreda AR. (2010). Mechanisms and functions of p38 MAPK signalling. Biochemical Journal. https://doi.org/10.1042/BJ20100323

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_Canonical: https://longevity-switzerland.com/en/glossary/p38-mapk · Part of Longevity Cities · Updated 2026-06-22_