Response

Dear Editor-in-Chief,

We recently reviewed the influence of aerobic exercise, select anti-aging compounds, and several nutritional interventions on the hallmarks of brain aging (1). As we emphasized, when compared to the alternatives, most evidence suggests that exercise is the most effective strategy for inhibiting brain aging and neurodegeneration, largely because it directly activates energy sensing metabolic pathways in the brain (1). As Dr. Burtscher et al. noted in their comments on our review (2), exercise is a hormetic stimulus, and growing evidence suggests that another hormetic intervention, hypoxia conditioning, could also be a novel/alternative strategy for healthy brain aging.

We agree with Dr. Burtscher and colleagues, and in addition to their points on the potentially protective effects of hypoxia conditioning in neurodegenerative diseases, we also note significant evidence that hypoxia may influence the biology of aging/brain aging. First, moderate hypoxia has been shown to improve healthspan and lifespan (i.e., have ‘anti-aging’ effects) in model organisms including C. elegans (3) and Drosophila (4), whereas extreme (e.g., very low or high) oxygen exposure reduces healthspan and lifespan. This suggests that like exercise, there may be an ‘optimal’ dose of hypoxia for improving health (and perhaps brain health) during aging. Second, like exercise, the hormetic effects of hypoxia are pleiotropic, activating multiple downstream protective mechanisms (5). These effects are mediated largely by hypoxia-inducible factor-1 (HIF-1) transcription factors (6), which influence many genes and pathways implicated not only in the response to hypoxia, but also in healthspan and longevity (7). In fact, a recent large-scale analysis of biological pathways common to established anti-aging interventions identified hypoxic signaling as a potentially novel target for increasing healthspan/lifespan (8). Finally, moderate hypoxia may exert its most beneficial effects on healthspan and lifespan by acting on dysregulated energy metabolism (the main hallmark of brain aging), and improving mitochondrial health through reduced oxidative stress and reactive oxygen species (9). There is also emerging pre-clinical evidence that mild hypoxia can influence several other hallmarks of brain aging, including autophagy (10). Although preliminary, a recent study even showed that intermittent hypoxia may enhance cerebral vasodilation and improve short term memory and attention in older adults (11).

Taken together, the above observations and those by Burtscher et al. (2) do support the idea that hypoxia conditioning could be a promising alternative or complementary strategy for inhibiting brain aging and neurodegenerative diseases. As Burtscher and colleagues have noted elsewhere (12), more pre-clinical and pilot studies are needed to determine the impact of hypoxia on other key hallmarks of brain aging (e.g., dysregulated calcium homeostasis, altered neuronal signaling), as well as the optimal dosing/safety tactics for target populations.