NFE2L2

Also known as NFE2L2, NF-E2-related factor 2 (NRF2) is a transcription factor that is activated by oxidative stress and electrophiles and has a role in inducing a number of antioxidative and carcinogen-detoxifying enzymes. Nrf2-deficient mice develop more tumors in response to carcinogens, and caloric restriction is ineffective in suppressing them in knockout mice. In contrast, caloric restriction remains effective in extending lifespan and increasing insulin sensitivity. In Nrf2-null mice fed a high-fat diet, the levels of hepatic triglycerides and cholesterol in liver were similar to wild type, while the levels of hepatic free fatty acid and malondialdehyde equivalents were higher, suggesting that Nrf2 inhibits lipid accumulation and oxidative stress in the mouse liver. In human fibroblasts, NRF2 shows a declined function in replicative senescence and its silencing leads to premature senescence. NRF2 activation results in the enhanced survival of cells following oxidative stress, whereas continuous treatment leads to lifespan extension of human fibroblasts. NRF2 has been also linked to several human age-related diseases, including atherosclerosis, neurodegenerative diseases, and cancer. It has been shown that progerin, an alternatively spliced product of LMNA involved in Hutchinson-Gilford progeria syndrome, sequesters NRF2, resulting in impaired NRF2 activity and increased oxidative stress. Suppressed NRF2 activity or increased oxidative stress is sufficient to recapitulate some of the accelerated aging effects seen in Hutchinson-Gilford progeria syndrome patients. Thus, NRF2 may play a role in accelerated human aging.