HIF-1α (Hypoxia-Inducible Factor 1α)

HIF-1α (hypoxia-inducible factor 1α) is the oxygen-regulated subunit of the HIF-1 heterodimeric transcription factor that drives the cellular and systemic transcriptional response to low oxygen (hypoxia). Under normoxic conditions, HIF-1α is hydroxylated by prolyl hydroxylase domain enzymes (PHDs), recognised by the VHL E3 ubiquitin ligase, and rapidly proteasomally degraded; hypoxia inhibits PHD activity, allowing HIF-1α to accumulate, heterodimerize with HIF-1β (ARNT), and activate hypoxia response element (HRE)-driven genes for anaerobic glycolysis (GLUT1, LDHA), angiogenesis (VEGF), and erythropoiesis (EPO). In ageing, HIF-1α plays a contextually dual role: in C. elegans, HIF-1 activity in normoxia promotes ageing and its reduction extends lifespan, though some studies report HIF-1-dependent lifespan extension under hypoxic conditions, reflecting a context-dependent dual role; in mammals appropriate HIF-1α activity is required for hypoxic adaptation and ischemic preconditioning, and its dysregulation contributes to tumor progression, pulmonary hypertension, and potentially to age-related metabolic decline.