Bioelectric characterization of senescing human keratinocytes

Aging disrupts tissue integrity through the accumulation of senescent cells that impair morphology, signaling, and regeneration. We investigated how bioelectric signaling, specifically resting membrane potential (V_mem), guides the transition to senescence in human keratinocytes. Using voltage-sensitive dyes, we tracked V_mem alongside senescence markers, chromatin state, and senescence-associated secretory phenotype (SASP) cytokines. Senescence was marked by depolarization, increased inter-culture heterogeneity, reduced intra-culture variability, and loss of spatial V_mem organization. SASP activation was partial: depolarization selectively enhanced interleukin-6 (IL-6) but not IL-1α or IL-8, indicating V_mem shapes the senescent secretome. Senescent cells showed reduced responsiveness to hyperpolarizing drug pinacidil and impaired bioelectric resilience. Hyperpolarization attenuated, and depolarization exacerbated, senescence-associated phenotypes. These findings support the morphostatic information loss theory, which posits that aging results from breakdown of bioelectrically encoded cues that preserve tissue structure. V_mem emerges as a low-dimensional integrator of cell state and spatial order, offering a biophysical target to delay senescence and maintain tissue coordination.