Abstract: Aging neurons do not fail randomly; rather, they enter a self-reinforcing redox spiral, rooted in metabolic responses to their environment, which diminishes their bioenergetic capacity. While pH measures proton donor potential, the redox state reflects electron donor potential, providing oxidative (e.g., NAD+) or reductive (NAD(P)H) power for numerous biochemical reactions. The decline in neuronal energy is orchestrated by mitochondrial checkpoints, transcriptional and post-transcriptional changes (Kumar et al., 2018), and proteostatic stress, all contributing to reduced synaptic resilience. Flux-control experiments highlight bottlenecks in the mitochondrial respiratory chain, particularly substrate-limited complex I and diminished capacity at complex IV (Jones and Brewer, 2010), resulting in increased electron leak, a more oxidized NAD+/nicotinamide adenine dinucleotide (NADH) and glutathione disulfide/glutathione (GSH) state, and a more oxidized quinone pool. Both young and old cortical neurons can increase respiration if provided with excess mitochondrial substrates, but old neurons are more sensitive to inhibition at complex IV. The decreased capacity for adaptive energy generation and electron transport through complex IV compared to young neuronal mitochondria likely results from regulatory nitrosylation by nitric oxide synthase (Torres et al., 1998). Importantly, aged neurons are especially dependent on endogenous substrate availability at complex I, suggesting that a shortage of NADH redox equivalents is a key constraint. This promotes glycolytic and epigenetic compensation (Walker et al., 2013), activating redox-sensitive programs that lock in an oxidative shift. Over time, the ability of the system to revert to a reduced, energy-efficient state narrows, making neurons vulnerable under metabolic stress and priming Alzheimer’s disease (AD)-related pathologies. This constraint is exacerbated in AD by decreased activity of dehydrogenases within the Krebs cycle that would lessen NADH production from NAD (Bubber et al., 2005).