Nrf2 in Aging and Longevity

The transcription factor nrf2 regulates levels of antioxidant proteins, a part of the response to everyday cellular stress, such as that induced by raised mitochondrial activity and greater generation of reactive oxygen species (ROS) during exercise. Greater nrf2 activity shows up in long-lived species and in the modest slowing of aging that can be achieved via hormesis in some species. Here is an open access review paper on this topic:

The role of Nrf2 in responding to cytotoxic stressors is well defined. However, only within the last few years have studies elucidated how Nrf2 function changes with age and how changes in Nrf2 activity contribute to the aging phenotype. Aged mice show similar losses in cellular redox capacity to those observed in Nrf2 knockout mice, suggesting that Nrf2 dysregulation with age may be responsible for the loss of cellular redox status. Diminished Nrf2 target gene expression with age is accompanied by increased muscle ROS production, glutathione depletion, and increased oxidant damage to proteins, DNA, and lipids in both humans and rodents. Therefore, given that Nrf2 activity decreases with age alongside increased oxidant stress, interventions that activate Nrf2 may impact the aging process and longevity.

Support for the role of Nrf2 in regulation of lifespan comes from Nrf2 gain of function and loss of function studies. For example, experimental deletion of the antielectrophilic gene glutathione transferase (gGsta4) activated Nrf2 and significantly extended lifespan in mice. This mutation increased electrophilic lipid peroxidation products and increased nuclear Nrf2 activity by 43% and 38% in liver and skeletal muscle, respectively. The authors propose that deletion of this glutathione transferase gene resulted in chronic moderate Nrf2 activation and presumably elevated downstream Nrf2 signaling throughout the mouse lifespan. Studies of the Nrf2 homolog SKN-1 in Caenorhabditis elegans (C. elegans) further suggest that Nrf2 may be implicated in longevity processes. Upon activation, SKN-1 upregulates genes involved in the oxidative stress response, including many orthologs to those regulated by mammalian Nrf2. Similar to mouse Nrf2 knockouts, SKN-1 mutants show diminished resistance to oxidative stress and shortened lifespan. On the other hand, moderate overexpression of a constitutively active SKN-1 increases lifespan, alongside increased resistance to oxidative stress.

The naked mole rat is an exceptionally long-lived species, with a lifespan four times longer than similarly sized rodents, thus making the naked mole rat an important model for longevity studies. Naked mole rats do not have typical lifespan curves in which mortality rates increase with age, but rather they experience few of the biological changes typically associated with aging. Naked mole rats also have significantly elevated proteasome quality control mechanisms. The high breakdown and clearance of damaged proteins is suspected to be largely due to increased Nrf2 expression. In support of the hypothesized role of Nrf2 in naked mole rat longevity, under nonstressed conditions, naked mole rats have greater protein levels of Nrf2 and greater expression of Nrf2-regulated enzymes in fibroblasts and liver. These data suggest Nrf2 may be responsible for the heightened quality control mechanisms in naked mole rats and may be associated with their exceptional longevity.