Increase in life-span is commonly related with age-related diseases and with gradual loss of genomic, proteomic and metabolic integrity. Nrf2 (Nuclear factor-erythroid 2-p45 derived factor 2) controls the expression of genes whose products include antioxidant proteins, detoxifying enzymes, drug transporters and numerous cytoprotective proteins. Several experimental approaches have evaluated the potential regulation of the transcription factor Nrf2 to enhance the expression of genes that contend against accumulative oxidative stress and promote healthy aging. Negative regulators of Nrf2 that act preventing it´s binding to DNA-responsive elements, have been identified in young and adult animal models. However, it is not clearly established if Nrf2 decreased activity in several models of aging results from disruption of that regulation. In this review, we present a compilation of evidences showing that changes in the levels or activity of Keap1 (Kelch-like ECH associated protein 1), GSK-3β (glycogen synthase kinase-3), Bach1, p53, Hrd1 (E3 ubiquitin ligase) and miRNAs might impact on Nrf2 activity during elderly. We conclude that understanding Nrf2 regulatory mechanisms is essential to develop a rational strategy to prevent the loss of cellular protection response during aging.