The Peripheral Vicious Cycle Hypothesis: Peripheral Origin of Prefrontal Neuroplasticity Decline in Aging and Its Acceleration Under Low-Microgravity

Aging is proposed to be a mechanically driven process originating in the periphery rather than a collection of stochastic molecular damages. According to the Peripheral Vicious Cycle Hypothesis (PVC Hypothesis) [1], accumulated peripheral wear-and-tear after the reproductive peak generates a self-perpetuating upstream vicious cycle. This work demonstrates that the same upstream pathway directly accounts for the progressive decline in prefrontal cortex (PFC) neuroplasticity observed with age, including dendritic atrophy, spine loss, reduced BDNF signaling, and impaired executive function. This work further demonstrates that prolonged low-microgravity (low-g) acts as a natural accelerator of this vicious cycle. Removal of the 1g gravitational field induces rapid sympathetic hyperactivity, fluid shifts, and autonomic imbalance, intensifying peripheral afferent drive and hastening PFC disinhibition. These changes produce accelerated executive deficits — compromised decision-making, cognitive flexibility, and stress resilience — that pose significant risks for long-duration space missions. The Peripheral AI-Symbiont (PAIS) [2], a closed-loop peripheral intervention system, is proposed as an effective upstream countermeasure. By restoring microvascular tone, tissue perfusion, and autonomic balance, PAIS interrupts the peripheral-to-central loop at its origin, thereby preserving adaptive neuroplasticity in both terrestrial aging and microgravity conditions. This framework unifies aging biology and space medicine under a single mechanistic model and generates falsifiable predictions testable in current space analogs. Targeting the peripheral vicious cycle via PAIS may provide a novel strategy to maintain cognitive resilience during human aging and extraterrestrial exploration.