Systemic long‐term inactivation of hypoxia‐inducible factor prolyl 4‐hydroxylase 2 ameliorates aging‐induced changes in mice without affecting their life span

Hypoxia inactivates hypoxia-inducible factor (HIF) prolyl 4-hydroxylases (HIF-P4Hs), which stabilize HIF and upregulate genes to restore tissue oxygenation. HIF-P4Hs can also be inhibited by small molecules studied in clinical trials for renal anemia. Knowledge of systemic long-term inactivation of HIF-P4Hs is limited but crucial, since HIF overexpression is associated with cancers. We aimed to determine the effects of systemic genetic inhibition of the most abundant isoenzyme HIF pro- lyl 4-hydroxylase-2 (HIF-P4H-2)/PHD2/EglN1 on life span and tissue homeostasis in aged mice. Our data showed no difference between wild-type and HIF-P4H-2- deficient mice in the average age reached. There were several differences, however, in the primary causes of death and comorbidities, the HIF-P4H-2-deficient mice hav- ing less inflammation, liver diseases, including cancer, and myocardial infarctions, and not developing anemia. No increased cancer incidence was observed due to HIF-P4H-2-deficiency. These data suggest that chronic inactivation of HIF-P4H-2 is not harmful but rather improves the quality of life in senescence.