Nrf2

Nrf2 regulation: under basal conditions, it is retained in the cytoplasm bound to its inhibitor KEAP1, which directs it to ubiquitin-proteasome degradation. Upon oxidative or electrophilic stress, KEAP1 cysteine residues are modified, releasing Nrf2 to translocate to the nucleus.

Evidence-based natural activators: Sulforaphane (broccoli sprouts, Brassica oleracea): the most potent natural activator known. Therapeutic doses: 20-40 mg/day of glucoraphanin with mustard (which provides myrosinase) to activate sulforaphane. Jed Fahey's studies (Johns Hopkins) show robust Nrf2 activation in humans. Curcumin with piperine: moderate-high Nrf2 activation. Green tea EGCG: moderate activation. Ketones (β-hydroxybutyrate): in nutritional ketosis or fasting, indirectly activate Nrf2. Thermal hormesis: sauna at 80-100°C activates heat shock proteins and Nrf2. Exercise: controlled exercise-induced oxidative stress is the main physiological activator.

Strategic advantage vs exogenous antioxidants: rather than saturating the body with external antioxidants (which can even interfere with physiological ROS signalling of exercise), activating Nrf2 turns on the endogenous antioxidant machinery in a modulated and specific way. It is the preferred modern strategy in longevity medicine.

Chronic Nrf2 hyperactivation also has risks: facilitates survival of pre-existing tumour cells (several cancers hijack constitutive Nrf2). For this reason, pulsatile (cyclic, not continuous) activation is preferable.