The aging spiral hypothesis: mitochondrial decline, CO2 regulation, and the metabolic collapse of aging

• Mitochondrial loss triggers a self-reinforcing aging spiral via CO 2 decline. • CO 2 acts as a metabolic switch for oxygen delivery via red blood cells. • The Aging Spiral Hypothesis redefines aging as a cascade of energy homeostasis collapse. Aging has conventionally been explained by factors such as oxidative damage, telomere shortening, and epigenetic changes. However, these models fall short in explaining how cellular-level changes lead to systemic aging, particularly the selective vulnerability of high-energy-demanding tissues and the cascading failure of metabolic regulation. In this paper, we propose the “Aging Spiral Hypothesis,” which posits that aging is initiated by a quantitative and functional decline in mitochondria, leading to ATP deficiency. This triggers adaptive metabolic suppression, resulting in reduced CO 2 production. The consequent attenuation of the Bohr effect impairs oxygen delivery, thereby further exacerbating mitochondrial dysfunction in a self-reinforcing metabolic spiral. This hypothesis redefines CO 2 not merely as a metabolic byproduct, but as a metabolic switch regulating oxygen supply, thereby framing aging as a cascade of systemic metabolic collapse. This hypothesis may offer new directions for therapeutic interventions targeting mitochondrial metabolism and CO 2 -mediated oxygen regulation.