Pulsed Reductive Impulses via Donor Addition or Acceptor Subtraction: A Novel Paradigm for Anti-Cancer and Anti-Aging Metabolic Therapy

Nicotinamide adenine dinucleotide (NAD⁺/NADH) metabolism occupies a central position in both tumour pathogenesis and cellular aging. Current therapeutic strategies pursue apparently contradictory objectives: oncology seeks to deplete NAD⁺ in cancer cells, while anti-aging practice administers NAD⁺ intravenously to restore levels that decline with age. This work proposes the pulsed imposition of a reductive load as an integrated anti-cancer and anti-aging strategy. The core proposition concerns a kinetic condition rather than any specific molecular vehicle: reducing equivalents arising faster than the cell can dispose of them. Where the respiratory chain retains proton-pumping capacity, that load produces a more specific thermodynamic state — over-reduction of the mitochondrial coenzyme Q pool sustained at elevated membrane potential — and because under normoxic operation the pool receives electrons from several dehydrogenases while discharging them through a single oxygen-dependent outlet, that state is reachable in two directions: addition of the electron donor, or subtraction of the terminal acceptor. Where proton-pumping capacity is compromised the same load instead limits free NAD⁺ as electron acceptor, in two compartmentally distinct arms that the two routes do not reach equivalently. NADH is discussed as the illustrative first-line donor because it is the native substrate of the respiratory chain and has an existing clinical precedent for intravenous administration, but it is explicitly not the ideal vehicle, being limited by molecular instability, restricted membrane permeability and stoichiometric consumption. A second class of donor, entering at or below the quinone pool rather than through the pyridine nucleotide pools, is identified; the sulfide couple is the endogenous case, and is notable in performing both directions of intervention with one species. Selectivity is proposed to arise from differential redox buffering capacity between healthy and transformed cells, through two complementary mechanisms: reverse electron transport at Complex I in cells retaining proton-pumping capacity, and limitation of free NAD⁺ in cells that cannot re-oxidise NADH, arresting mitochondrial substrate-level phosphorylation in the matrix and glycolysis in the cytosol. The origin of selectivity differs between routes — metabolic under donor addition, perfusional and spatial under acceptor subtraction — so that the two have largely disjoint zones of resistance and are complementary in domain as well as multiplicative in magnitude. Healthy cells are proposed to escape both by possessing simultaneously the respiratory reserve to dispose of the imposed load and the gradient-discharging flux required to discharge the accumulated proton gradient. A protocol of brief, intense pulses followed by recovery phases (redox press-pulse) is proposed, in combination with glucose restriction and optimisation of intracellular magnesium. The framework generates dissociable experimental signatures, an explicitly predicted zone of resistance, and a candidate predictive biomarker. Principal limitations, including cytosolic lactate dehydrogenase and mitochondrial proton leak as escape routes and the vulnerability of cardiac and neural tissue to the same reverse-electron-transport mechanism, are stated explicitly.