Hypoxia and aging.

Eukaryotic cells require sufficient oxygen (O2) for biological activity and survival. When the oxygen demand exceeds its supply, the oxygen levels in local tissues or the whole body decrease (termed hypoxia), leading to a metabolic crisis, threatening physiological functions and viability. Therefore, eukaryotes have developed an efficient and rapid oxygen sensing system: hypoxia-inducible factors (HIFs). The hypoxic responses are controlled by HIFs, which induce the expression of several adaptive genes to increase the oxygen supply and support anaerobic ATP generation in eukaryotic cells. Hypoxia also contributes to a functional decline during the aging process. In this review, we focus on the molecular mechanisms regulating HIF-1α and aging-associated signaling proteins, such as sirtuins, AMP-activated protein kinase, mechanistic target of rapamycin complex 1, UNC-51-like kinase 1, and nuclear factor κB, and their roles in aging and aging-related diseases. In addition, the effects of prenatal hypoxia and obstructive sleep apnea (OSA)-induced intermittent hypoxia have been reviewed due to their involvement in the progression and severity of many diseases, including cancer and other aging-related diseases. The pathophysiological consequences and clinical manifestations of prenatal hypoxia and OSA-induced chronic intermittent hypoxia are discussed in detail.