The idea that reactive oxygen species make the body “rust” is a familiar metaphor in discussions of health and anti-aging. Yet our cells do not simply allow that damage to proceed unchecked. When they detect oxidative damage, they activate groups of genes needed for defense, initiating antioxidant, detoxification, and anti-inflammatory responses.
At the center of this response is Nrf2, short for nuclear factor erythroid 2-related factor 2, a protein known as a transcription factor1. Since its discovery in the 1990s, Nrf2 has been studied extensively in relation to diseases involving oxidative stress, including cancer, cognitive disorders, diabetes, and cardiovascular disease2.
This article examines how Nrf2 works, why its activity declines with aging, and which everyday habits may influence that activity, drawing on recent scientific literature.
What You Will Learn
- How Nrf2 regulates the expression of defense genes through antioxidant response elements, or AREs
- How Keap1 controls Nrf2 degradation and how this mechanism changes under oxidative stress
- The molecular basis of age-related declines in Nrf2 activity and the diseases associated with this decline
- Everyday factors that may help maintain Nrf2 responsiveness, including diet, exercise, and sleep
What Is Nrf2? A Master Regulator of Cellular Defense
Nrf2 is a type of protein known as a transcription factor. Transcription factors bind to specific regions of DNA and increase or decrease the expression of particular genes. Nrf2 regulates groups of genes that encode antioxidant and detoxification enzymes1.
The DNA regions to which Nrf2 binds are called antioxidant response elements, or AREs. These regions function like a control panel containing switches for defense-related genes. They are located in the promoter and enhancer regions of many such genes. When Nrf2 gains access to AREs, it induces the expression of dozens of defense proteins involved in antioxidant and detoxification processes, including heme oxygenase-1 and enzymes required for glutathione synthesis1, 3.
- Promoter and enhancer regions
- Regions of DNA that regulate gene expression. A promoter lies immediately upstream of a gene and controls the initiation of transcription, whereas an enhancer may be located farther away and increases transcriptional efficiency. The binding of transcription factors to these regions regulates whether a gene is switched on or off and how strongly it is expressed.
- Heme oxygenase-1 (HO-1)
- A representative antioxidant enzyme whose expression is induced by Nrf2. It breaks down heme and produces metabolites with antioxidant and anti-inflammatory properties, including biliverdin and carbon monoxide.
This ability of a single molecule to initiate a coordinated defense response is why Nrf2 is often described as a master regulator of cellular defense.
Keap1-Mediated Degradation Keeps Nrf2 Inactive Under Basal Conditions
Nrf2 is not continuously active. Under normal cellular conditions, a partner protein called Keap1 binds tightly to Nrf2 and promotes its ubiquitination, marking it for degradation. Ubiquitinated Nrf2 is delivered to the proteasome and rapidly broken down. As a result, the half-life of newly produced Nrf2 is only about 10–30 minutes, and very little remains in the cell under basal conditions.
- Ubiquitin
- A small protein that can attach to another protein and mark it for degradation.
This rapid cycle of synthesis and degradation keeps defense genes largely inactive when the cell is not under oxidative stress. It prevents unnecessary activation of the defense response and conserves energy. Keap1 therefore acts as a negative regulator, or molecular brake, that prevents Nrf2 from accumulating under basal conditions.
Nrf2 Under Oxidative Stress: Stabilization, Nuclear Translocation, and ARE Binding
When reactive oxygen species or harmful chemicals known as electrophiles increase in the body, specific sensor sites on Keap1 detect them. These sensors are cysteine residues. When the residues are oxidized or react with electrophilic compounds, the conformation of Keap1 changes.
This change disrupts Keap1-mediated ubiquitination of Nrf2. Nrf2 is no longer degraded and begins to accumulate in the cell.
- Electrophiles
- Chemicals that tend to accept electrons. Many electrophiles in the body are harmful, but some food-derived compounds, including isothiocyanates, also have electrophilic properties and may activate Nrf2 by reacting with cysteine residues on Keap1.
- Cysteine residues
- Cysteine amino acids within a protein. Their sulfur-containing, highly reactive thiol groups readily react with oxidative stress and certain chemicals. In Keap1, these residues act as sensors.
Once stabilized, Nrf2 moves into the nucleus, where DNA is stored. Because Nrf2 cannot bind effectively to DNA on its own, it forms a pair with a partner protein called sMaf. This heterodimer can then bind to AREs1.
- sMaf
- A partner protein that forms a complex with Nrf2 and enables it to bind DNA. Together, Nrf2 and sMaf drive the expression of defense genes.
This sequence—sensor activation, stabilization of Nrf2, nuclear translocation, partnership with sMaf, ARE binding, and activation of defense genes—is known as the Keap1–Nrf2 pathway. It is a central signaling route through which cells respond to oxidative stress and has been studied extensively worldwide.
The Defense Network Regulated by Nrf2
The defenses initiated by Nrf2 are not limited to a single process. Recent research has organized its functions into three broad areas: antioxidant defense, detoxification, and anti-inflammatory regulation3.
Antioxidant Defense Against Reactive Oxygen Species
Enzymes involved in the synthesis of glutathione (GSH) are central to the antioxidant response. Glutathione is the most abundant intracellular antioxidant and helps remove reactive oxygen species and repair oxidized proteins4.
Nrf2 regulates more than the enzymes required for glutathione synthesis. It also controls enzymes that process reactive oxygen species directly and enzymes that repair proteins damaged by oxidation3.
Detoxification and the Elimination of Harmful Substances
Nrf2 also regulates the expression of detoxification enzymes collectively known as phase II enzymes. These enzymes carry out the second stage of the body’s detoxification process. They attach glutathione, sulfate groups, or other molecules to harmful substances that have entered the body—including drugs, environmental pollutants, and carcinogens in food—making them more water-soluble and easier to eliminate1.
- Phase II enzymes
- Enzymes that carry out the second stage of detoxification reactions, following phase I reactions such as oxidation and reduction, primarily in the liver. They attach glutathione, sulfate groups, or other molecules to harmful substances, increasing water solubility and facilitating elimination. Examples include glutathione S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1).
Anti-Inflammatory Regulation and Crosstalk With NF-κB
Whereas Nrf2 coordinates cellular defense, NF-κB is a transcription factor that drives inflammatory responses. Nrf2 has been reported to indirectly suppress NF-κB activity3. NF-κB is essential for immune responses to bacteria and viruses, but chronic activation may contribute to the risk of atherosclerosis and neurodegenerative disease. By strengthening antioxidant defenses, Nrf2 may help limit excessive NF-κB activation and interrupt self-reinforcing cycles of inflammation5.
Aging and Nrf2: Why Cellular Defense Declines
Nrf2 does not necessarily maintain the same level of activity throughout life. An age-related decline in Nrf2 activity has been repeatedly reported in multiple studies6.
Animal studies have shown that older mice have lower Nrf2 expression in the liver and brain than younger mice, along with a weaker response to oxidative stress7. In humans, observational findings indicate that blood markers of oxidative stress tend to rise with age while antioxidant enzyme activity declines. Reduced Nrf2 function is considered one possible contributor to this pattern6.
Recent research also suggests that age-related Nrf2 decline involves another degradation route that cannot be fully explained by the established Keap1 pathway alone.
A Second Degradation Route Beyond Keap1
The enzyme responsible for this second route is GSK-3β, or glycogen synthase kinase-3β. Keap1 promotes the attachment of ubiquitin to Nrf2 and directs it toward proteasomal degradation. GSK-3β, by contrast, phosphorylates Nrf2. The carrier protein β-TrCP recognizes this phosphorylation signal and directs Nrf2 to the proteasome through a Keap1-independent pathway8.
Of particular interest, GSK-3β activity is elevated in chronic conditions associated with aging, including Alzheimer’s disease and type 2 diabetes9. As aging progresses, degradation through the GSK-3β pathway may compound Keap1-mediated regulation, making Nrf2 more difficult to maintain. The simultaneous operation of these two degradation routes has been discussed as one contributor to age-related declines in Nrf2 activity.
Lower Nrf2 Activity and Age-Related Disease
Reduced Nrf2 function has been associated with increased risk of several age-related diseases2.
- Neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease: The brain consumes large amounts of oxygen and is especially vulnerable to oxidative stress. Lower Nrf2 expression has been observed in the brains of people with Alzheimer’s disease and Parkinson’s disease10. This observation does not establish a causal relationship, but reduced Nrf2 activity may contribute to the accumulation of neuronal damage.
- Age-related hearing loss: Cochlear hair cells in the inner ear do not regenerate and are susceptible to cumulative damage from reactive oxygen species. Animal studies have shown that age-related hearing loss progresses more rapidly in Nrf2-deficient animals, while Nrf2 activation may reduce noise- and drug-induced hearing loss. These findings suggest that reduced Nrf2-mediated defense may also contribute to age-related hearing loss11.
- Cardiovascular disease: Oxidative stress is closely involved in the progression of atherosclerosis. Nrf2 is considered to play an important role in the protection of vascular endothelial cells2.
- Vascular endothelial cells
- Cells that form a single layer lining the inside of all blood vessels. They are in direct contact with blood and regulate vascular contraction and dilation, blood coagulation, and inflammatory responses. Oxidative damage to these cells can initiate atherosclerosis, making them important in cardiovascular risk.
- Chronic obstructive pulmonary disease (COPD): The lungs are readily exposed to reactive oxygen species in cigarette smoke, air pollution, and other environmental sources. Lower Nrf2 expression has been observed in lung tissue from people with COPD, and emphysema progresses more rapidly in Nrf2-deficient animals12.
- Type 2 diabetes: Reduced Nrf2 activity is associated with oxidative damage to pancreatic β cells and chronic inflammation and may contribute to worsening insulin resistance2.
- Pancreatic β cells
- Insulin-secreting cells located in the islets of Langerhans in the pancreas.
- Insulin resistance
- A state in which cells in tissues such as muscle and liver do not respond adequately to insulin, making blood glucose more difficult to lower despite insulin secretion. It is a central abnormality in type 2 diabetes and metabolic syndrome.
- Cancer: Nrf2 may have a protective role during the early stages of carcinogenesis. However, excessive Nrf2 activation within cancer cells has also been reported to promote resistance to anticancer drugs. The role of Nrf2 therefore depends on context, and balanced rather than indiscriminate activation is considered important13.
Everyday Factors That May Influence Nrf2 Signaling
Age-related declines in Nrf2 activity cannot be stopped completely. However, recent research suggests that everyday factors such as diet, exercise, and sleep may help maintain Nrf2 responsiveness.
Diet: Foods Containing Isothiocyanates
Among food-derived compounds, isothiocyanates found in cruciferous vegetables have been studied particularly extensively for their effects on Nrf2 signaling. A prominent example is sulforaphane, found in broccoli and broccoli sprouts. Numerous clinical studies have investigated sulforaphane as a compound that reacts with cysteine residues on Keap1 and activates Nrf214.
Hexaraphane/6-MSITC, found in Japanese wasabi, belongs to the same class of isothiocyanates. Although structurally similar to sulforaphane, recent research has reported that hexaraphane/6-MSITC may activate Nrf2 through two routes: inhibition of Keap1 and direct inhibition of GSK-3β9. This mechanism has attracted attention in the context of age-related Nrf2 decline. This article discusses the details, including findings from a human study15.
Other food-derived compounds reported to influence Nrf2 signaling include curcumin from turmeric, EGCG (epigallocatechin gallate) from green tea, and resveratrol from red wine and grapes16. Regularly consuming a variety of these foods may help maintain Nrf2 responsiveness.
Exercise: Moderate Activity May Enhance Nrf2 Responsiveness
Exercise temporarily increases the production of reactive oxygen species. This mild oxidative stress may, in turn, increase Nrf2 responsiveness through a phenomenon known as hormesis17. In a process analogous to muscle fibers becoming stronger after temporary damage from resistance training, regular, moderate exercise may stimulate the Nrf2 pathway and increase the body’s overall antioxidant capacity.
- Hormesis
- A phenomenon in which a low dose of a stressor, such as a toxin or oxidative stress, elicits a beneficial biological response.
The exercise does not need to be strenuous. Habitual activity at a sustainable intensity, such as walking or light jogging, is considered effective for supporting Nrf2 responsiveness17.
Sleep: Insufficient Sleep Increases the Burden on Antioxidant Responses
Sleep quality is also closely related to Nrf2. Sleep deprivation has been reported to increase oxidative stress and place an excessive burden on Nrf2-dependent antioxidant responses18. Adequate sleep is therefore a basic condition for reducing oxidative damage itself and limiting the depletion of Nrf2-dependent defenses.
Calorie Restriction and Intermittent Fasting: Evidence From Animal Studies
Animal studies indicate that calorie restriction and intermittent fasting may activate the Nrf2 pathway. These effects are thought to involve reductions in oxidative stress mediated by improved metabolism, but evidence in humans remains limited19.
- Intermittent fasting
- An eating pattern that includes regular periods without food, such as a 16-hour fasting interval.
Summary
- Nrf2 is a transcription factor that senses oxidative stress and coordinates the expression of antioxidant, detoxification, and anti-inflammatory genes.
- Under basal conditions, Keap1 promotes Nrf2 degradation. During oxidative stress, this suppression is released, allowing Nrf2 to accumulate and undergo nuclear translocation.
- With aging, degradation through the GSK-3β pathway may compound Keap1-mediated regulation, making Nrf2 activity more difficult to maintain.
- Reduced Nrf2 function has been associated with age-related diseases involving oxidative stress, including cognitive disorders, cardiovascular disease, diabetes, hearing loss, and COPD.
- Dietary isothiocyanates, moderate exercise, and sufficient sleep are being studied as everyday factors that may help maintain Nrf2 responsiveness.
Nrf2 is a central component of the body’s intrinsic defense system. Even as we age, everyday choices involving diet, exercise, and sleep may help preserve its ability to respond.
References
- Itoh K, et al. "An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements." Biochemical and Biophysical Research Communications 236(2): 313–322 (1997) ↩
- Ulasov AV, et al. "Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease." Antioxidants 11(12): 2345 (2022) ↩
- He F, et al. "NRF2, a Transcription Factor for Stress Response and Beyond." International Journal of Molecular Sciences 21(13): 4777 (2020) ↩
- Lu SC. "Glutathione synthesis." Biochimica et Biophysica Acta 1830(5): 3143–3153 (2013) ↩
- Wardyn JD, et al. "Dissecting molecular cross-talk between Nrf2 and NF-κB response pathways." Biochemical Society Transactions 43(4): 621–626 (2015) ↩
- Schmidlin CJ, et al. "The KEAP1-NRF2 System in Healthy Aging and Longevity." Antioxidants 10(12): 1929 (2021) ↩
- Suh JH, et al. "Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid." Proceedings of the National Academy of Sciences 101(10): 3381–3386 (2004) ↩
- Rada P, et al. "SCF/β-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner." Molecular and Cellular Biology 31(6): 1121–1133 (2011) ↩
- García-Yagüe AJ, et al. "Dual targeting of Keap1 and Gsk-3 by hexaraphane in the regulation of transcription factor Nrf2." Free Radical Biology and Medicine 239: 579–593 (2025) ↩
- Ramsey CP, et al. "Expression of Nrf2 in neurodegenerative diseases." Journal of Neuropathology & Experimental Neurology 66(1): 75–85 (2007) ↩
- Honkura Y, et al. "NRF2 is a key target for prevention of noise-induced hearing loss by reducing oxidative damage of cochlea." Scientific Reports 6: 19329 (2016) ↩
- Boutten A, et al. "NRF2 targeting: a promising therapeutic strategy in chronic obstructive pulmonary disease." Trends in Molecular Medicine 17(7): 363–371 (2011) ↩
- Rojo de la Vega M, et al. "NRF2 and the Hallmarks of Cancer." Cancer Cell 34(1): 21–43 (2018) ↩
- Houghton CA, et al. "Sulforaphane and Other Nutrigenomic Nrf2 Activators: Can the Clinician's Expectation Be Matched by the Reality?" Oxidative Medicine and Cellular Longevity 2016: 7857186 (2016) ↩
- Nouchi R, et al. "Benefits of Wasabi Supplements with 6-MSITC (6-Methylsulfinyl Hexyl Isothiocyanate) on Memory Functioning in Healthy Adults Aged 60 Years and Older: Evidence from a Double-Blinded Randomized Controlled Trial." Nutrients 15(21): 4608 (2023) ↩
- Cuadrado A, et al. "Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases." Nature Reviews Drug Discovery 18(4): 295–317 (2019) ↩
- Done AJ, Traustadóttir T. "Nrf2 mediates redox adaptations to exercise." Redox Biology 10: 191–199 (2016) ↩
- Trivedi MS, et al. "Short-term sleep deprivation leads to decreased systemic redox metabolites and altered epigenetic status." PLOS ONE 12(7): e0181978 (2017) ↩
- Mattson MP, Arumugam TV. "Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States." Cell Metabolism 27(6): 1176–1199 (2018) ↩
