{Reference Type}: Journal Article
{Title}: Nrf2 Plays a Key Role in Erythropoiesis during Aging.
{Author}: Mbiandjeu SCT;Siciliano A;Mattè A;Federti E;Perduca M;Melisi D;Andolfo I;Amoresano A;Iolascon A;Valenti MT;Turrini F;Bovi M;Pisani A;Recchiuti A;Mattoscio D;Riccardi V;Dalle Carbonare L;Brugnara C;Mohandas N;De Franceschi L;
{Journal}: Antioxidants (Basel)
{Volume}: 13
{Issue}: 4
{Year}: 2024 Apr 12
{Factor}: 7.675
{DOI}: 10.3390/antiox13040454
{Abstract}: Aging is characterized by increased oxidation and reduced efficiency of cytoprotective mechanisms. Nuclear factor erythroid-2-related factor (Nrf2) is a key transcription factor, controlling the expression of multiple antioxidant proteins. Here, we show that Nrf2-/- mice displayed an age-dependent anemia, due to the combined contributions of reduced red cell lifespan and ineffective erythropoiesis, suggesting a role of Nrf2 in erythroid biology during aging. Mechanistically, we found that the expression of antioxidants during aging is mediated by activation of Nrf2 function by peroxiredoxin-2. The absence of Nrf2 resulted in persistent oxidation and overactivation of adaptive systems such as the unfolded protein response (UPR) system and autophagy in Nrf2-/- mouse erythroblasts. As Nrf2 is involved in the expression of autophagy-related proteins such as autophagy-related protein (Atg) 4-5 and p62, we found impairment of late phase of autophagy in Nrf2-/- mouse erythroblasts. The overactivation of the UPR system and impaired autophagy drove apoptosis of Nrf2-/- mouse erythroblasts via caspase-3 activation. As a proof of concept for the role of oxidation, we treated Nrf2-/- mice with astaxanthin, an antioxidant, in the form of poly (lactic-co-glycolic acid) (PLGA)-loaded nanoparticles (ATS-NPs) to improve its bioavailability. ATS-NPs ameliorated the age-dependent anemia and decreased ineffective erythropoiesis in Nrf2-/- mice. In summary, we propose that Nrf2 plays a key role in limiting age-related oxidation, ensuring erythroid maturation and growth during aging.