Hypoxia and dehydroepiandrosterone in old age: a mouse survival study

Background: Survival remains an issue in pulmonary hypertension, a chronic disorder that often affects aged human adults. In young adult mice and rats, chronic 50% hypoxia (11% FIO2 or 0.5 atm) induces pulmonary hypertension without threatening life. In this framework, oral dehydroepiandrosterone was recently shown to prevent and reverse pulmonary hypertension in rats within a few weeks. To evaluate dehydroepiandrosterone therapy more globally, in the long term and in old age, we investigated whether hypoxia decreases lifespan and whether dehydroepiandrosterone improves survival under hypoxia. Methods: 240 C57BL/6 mice were treated, from the age of 21 months until death, by normobaric hypoxia ( 11% FIO2) or normoxia, both with and without dehydroepiandrosterone sulfate ( 25 mg/ kg in drinking water) ( 4 groups, N = 60). Survival, pulmonary artery and heart remodeling, weight and blood patterns were assessed. Results: In normoxia, control mice reached the median age of 27 months ( median survival: 184 days). Hypoxia not only induced cardiopulmonary remodeling and polycythemia in old animals but also induced severe weight loss, trembling behavior and high mortality ( p < 0.001, median survival: 38 days). Under hypoxia however, dehydroepiandrosterone not only significantly reduced cardiopulmonary remodeling but also remarkably extended survival ( p < 0.01, median survival: 126 days). Weight loss and trembling behavior at least partially remained, and polycythemia completely, the latter possibly favorably participating in blood oxygenation. Interestingly, at the dose used, dehydroepiandrosterone sulfate was detrimental to long-term survival in normoxia ( p < 0.05, median survival: 147 days). Conclusion: Dehydroepiandrosterone globally reduced what may be called an age-related frailty induced by hypoxic pulmonary hypertension. This interestingly recalls an inverse correlation found in the prospective PAQUID epidemiological study, between dehydroepiandrosterone blood levels and mortality in aged human smokers and former smokers.