Hormetic Stress Encodes Structural Memory via Dynamic Chondroitin Sulfate Sulfation Shifts that Regulate Neuronal Excitability and Senescence

Hypothesis: Intermittent hormetic stimuli trigger a transient increase in chondroitin sulfate C6‑sulfation (C6S) mediated by the sulfotransferase CHST11, which alters the negative charge density of the hippocampal extracellular matrix [1]. This charge shift modulates local electric fields, thereby tuning the voltage‑dependence of nearby Na⁺ and Ca²⁺ channels and adjusting neuronal excitability toward a protective, low‑firing state [2]. Repeated cycles of sulfation increase and subsequent depletion during recovery create a structural memory that sustains improved mitochondrial function and suppresses senescence markers (p16^INK4a, SASP) [3]. With advancing age, basal CHST11 activity declines and the ECM becomes locked in a low‑C6S/high‑C4S state, reducing matrix negative charge, depolarizing resting potentials, and promoting hyperexcitability‑driven calcium overload that feeds into inflammaging [4][5][6]. Thus, the health benefits of hormesis depend on the capacity to remodel ECM sulfation patterns; loss of this plasticity converts a protective signal into a maladaptive, age‑associated ECM signature [7].

Testable predictions: (1) In young mice, intermittent fasting or exercise will raise hippocampal C6S/C4S ratios within 6 h, returning to baseline after 24 h of recovery; (2) Pharmacological inhibition of CHST11 (e.g., with D‑6‑O‑sulfate) will block the hormetic rise in C6S and abolish the associated improvements in spatial memory and mitochondrial respiration; (3) Aged mice supplemented with a CHST11‑activating peptide will show restored C6S enrichment, reduced hippocampal hyperexcitability (measured by in vivo LFP), and delayed onset of p16^INK4a‑positive senescent cells; (4) Conversely, genetic overexpression of CHST11 in young animals should mimic hormetic benefits even without stress exposure, whereas chronic overexpression in aged animals will exacerbate excitotoxic calcium influx if sulfation becomes maladaptively high. Falsification occurs if hormetic interventions extend lifespan or improve cognition without detectable changes in C6S/C4S ratios, or if manipulating CHST11 fails to alter the predicted functional outcomes.