Pathway

HSF1 / Heat-Shock Response

Last updated Sat May 30 2026 00:00:00 GMT+0000 (Coordinated Universal Time)

Mechanistic— Best-evidenced hormetic pathway

What it is

HSF1 (heat-shock factor 1) is the master transcription factor for the heat-shock response. Under proteotoxic stress (heat, ROS, misfolded proteins) HSF1 trimerises, translocates to the nucleus, and binds heat-shock elements in promoters of chaperone genes: HSP70, HSP90, HSP40, small HSPs, and many others.

Why it matters in aging

HSF1 activity declines with age in most tissues.
Chaperone capacity drops faster than misfolded-protein load rises, pushing the proteostasis network into deficit (Loss of proteostasis).
C. elegans HSF-1 overexpression doubles lifespan.
Mouse HSF1 heterozygotes have accelerated aging phenotypes.

Activators

Heat exposure (sauna therapy).
Exercise — both endurance and resistance.
Caloric restriction and fasting.
HSF1 chemical activators (HSF1A, arimoclomol) — the latter is in trials for inclusion-body myositis and Niemann-Pick C.
Spermidine — partly via HSF1.

Cross-talk

HSF1 and mTOR are inversely regulated — rapamycin boosts the heat-shock response.
Sirtuins deacetylate HSF1, enhancing its activity.

References

Anckar, J. & Sistonen, L. Regulation of HSF1 function in the heat stress response. Annu. Rev. Biochem. 80, 1089–1115 (2011).