The microRNAs miR-144 and -451 are encoded by a bicistronic gene that is strongly induced during red blood cell formation (erythropoiesis). Ablation of the miR-144/451 gene in mice causes mild anemia under baseline conditions. Here we show that miR-144/451−/− erythroblasts exhibit increased apoptosis during recovery from acute anemia. Mechanistically, miR-144/451 depletion increases the expression of the miR-451 target mRNA Cab39, which encodes a co-factor for the serine-threonine kinase LKB1. During erythropoietic stress, miR-144/451−/− erythroblasts exhibit abnormally increased Cab39 protein, which activates LKB1 and its downstream AMPK/mTOR effector pathway. Suppression of this pathway via drugs or shRNAs enhances survival of the mutant erythroblasts. Thus, miR-144/451 facilitates recovery from acute anemia by repressing Cab39/AMPK/mTOR. Our findings suggest that miR-144/451 is a key protector of erythroblasts during pathological states associated with dramatically increased erythropoietic demand, including acute blood loss and hemolytic anemia.
NAD+ level has been associated with various age-related diseases and its pharmacological modulation emerges as a potential approach for aging intervention. But human NAD+ landscape exhibits large heterogeneity, and the lack of rapid, low-cost assays limits the establishment of NAD+ baseline and the development of personalized therapies, especially for those with poor responses towards conventional NAD+ supplementation. Here, we developed an automated NAD+ analyzer for the rapid measurement of NAD+ with 5 μL of capillary blood using a recombinant bioluminescent sensor protein and an automated optical reader. The minimal invasiveness of the assay allowed a frequent and decentralized mapping of real-world NAD+ dynamics. We showed that sports and NMN supplementation can increase blood NAD+ levels and that male on average has higher NAD+ than female before the age of 50. We further revealed the long-term stability of human NAD+ baseline over 100 days and identified the major real-world NAD+-modulating behaviors.
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