Acute normobaric hypoxia as a reversible probe of oxygen-limitation contributions to cognitive aging.

Chronological age cannot be experimentally manipulated, which limits causal tests of candidate mechanisms in cognitive aging. This focused review evaluates acute, dose-controlled normobaric hypoxia as a reversible probe of whether oxygen-delivery and cerebrovascular-reserve constraints contribute to age-sensitive cognitive phenotypes, particularly associative episodic memory. Evidence from cognitive hypoxia, cerebrovascular aging, and cerebral oxygenation suggests acute hypoxia and later-life cerebrovascular compromise share common mechanisms that reduce the capacity to meet increased neural metabolic demands during high-load cognitive tasks. Associative memory is proposed as a particularly informative target phenotype because it is reliably vulnerable in aging, strongly dependent on hippocampal binding, and theoretically dissociable from more global performance decrements. Emotional effects are considered only insofar as arousal and sustained stress can modify associative binding, with acute hypoxia framed as imposing conditions of vulnerability under sustained and unavoidable stress rather than reproducing age-related positivity. Four conditions are then identified for informative oxygen-limitation inference: dose and capnic (arterial or end-tidal carbon dioxide) characterization, phenotype-specific dissociation tests, coupling to oxygen-sensitive markers, and discriminant validity against non-specific changes in stress, discomfort, or fatigue. Acute normobaric hypoxia is therefore presented as a reversible causal probe, not as a model of aging; its value depends on stringent boundary conditions and careful mechanistic interpretation.