Healthy Aging at Moderate Altitudes: Hypoxia and Hormesis

Aging is associated with cellular and tissue responses that collectively lead to functional and structural deterioration of tissues. Poor tissue oxygenation, or hypoxia, is involved in such responses and contributes to aging. Consequently, it could be speculated that living at higher altitude, and therefore in hypoxic conditions, accelerates aging. This assumption is indeed supported by evidence from populations residing at very high altitudes (>3,500 m). In contrast, accumulating evidence suggests that living at moderate altitudes (1,500-2,500 m) is protective rather than injurious, at least for some body systems.

In this review, we critically evaluate the hypothesis that the physiological responses to mild hypoxic stress associated to life at moderate altitudes provide protection from many hypoxia-related diseases through hormesis. Hormesis means that a low dose of a stressor (here hypoxia) elicits beneficial outcomes, while a higher dose can be toxic and might explain at least in part the dose-dependent contrasting effects of hypoxia on the aging processes. The lack of well-designed longitudinal studies focusing on the role of the altitude of residence, and difficulties in accounting for potentially confounding factors such as migration, ethnicity/genetics, and socioeconomic and geoclimatic conditions, currently hampers translation of related research into uncontroversial paradigms.

Deeper investigations are required to understand the impact of altitude-related hypoxia on age-related diseases and to develop molecular markers of ageing/senescence in humans that are linked to hypoxia. However, the presented emerging evidence supports the view that hypoxia conditioning has the potential to improve life quality and expectancy.