Reactive Oxygen Species and Cold Exposure

Reactive oxygen species (ROS) — including superoxide (O₂•⁻), hydrogen peroxide (H₂O₂), and hydroxyl radical (•OH) — are byproducts of normal mitochondrial electron transport. Cold exposure increases ROS production transiently, but the downstream effect is a net increase in antioxidant capacity — a classic hormetic response.

ROS Generation During Cold

Cold exposure increases mitochondrial activity through multiple mechanisms:

Source	Mechanism	ROS Generated
BAT mitochondria	UCP1 uncoupling increases electron transport	Superoxide from ETC Complex I, III
Shivering muscle	Rapid ATP hydrolysis/resynthesis	Mitochondrial ROS
Ischemia-reperfusion analog	Vasoconstriction then vasodilation	Xanthine oxidase-generated ROS
Cold-activated immune cells	NADPH oxidase in activated neutrophils	Superoxide burst

The total ROS generated is a brief pulse during and immediately after cold exposure.

The Nrf2 Pathway — Antioxidant Master Switch

Nrf2 (Nuclear factor erythroid 2-related factor 2) is constitutively expressed but held in the cytoplasm by Keap1 protein, which tags it for proteasomal degradation. When ROS oxidize specific cysteine residues on Keap1:

1. Keap1-Nrf2 interaction weakens
2. Nrf2 is released → translocates to nucleus
3. Nrf2 binds Antioxidant Response Element (ARE) sequences
4. ARE-driven genes are transcribed: SOD1/2, catalase, GPx, HO-1, NQO1, Ferritin
5. Net result: elevated antioxidant enzyme capacity for days

The brief cold-induced ROS burst acts as a signal that upregulates defenses well above the original stimulus level — the hallmark of hormetic benefit.

The Antioxidant Paradox

Ristow & Schmeisser (2011) argued controversially that taking antioxidant supplements (Vitamin C, Vitamin E) blocks the beneficial adaptations from exercise and cold exposure by scavenging the very ROS signals that drive Nrf2 activation. This hypothesis is supported by:

• Antioxidant supplementation blunts exercise-induced insulin sensitivity improvements
• Antioxidant supplementation reduces VO2max improvements from exercise training
• Cold adaptation requires the ROS signal to drive Nrf2 and HSP responses

The practical implication: taking high-dose antioxidant supplements may undermine the hormetic benefits of cold exposure protocols.

Cold ROS vs Chronic Oxidative Stress

Brief, pulsed ROS → adaptive Nrf2 response (beneficial) Chronic, sustained ROS → oxidative damage accumulates → accelerated aging (harmful)

Cold-induced ROS falls into the first category when exposure is properly dosed. Extreme or prolonged cold exposure could shift the balance toward net oxidative damage — another argument for the hormetic dose principle.

Heat Shock Proteins and ROS

Cold-induced ROS also activates heat shock factor 1 (HSF1), the transcription factor for HSP genes. HSP70 and HSP90 are chaperones that:

• Repair partially denatured proteins (restoring function rather than degrading them)
• Prevent protein aggregation that underlies neurodegenerative diseases
• Are positively correlated with longevity in multiple model organisms