Metabolic-Epigenetic Coupling in Cellular Senescence: In Silico Cristae Remodeling Depletes Alpha-Ketoglutarate to Drive KDM4/6 Inhibition and SASP Amplification

Abstract

Cellular senescence is governed by complex organellar cross-talk, epigenetic remodeling, and non-canonical signaling cascades that drive chronic tissue degeneration. In this work, we formulate a predictive computational systems biology framework to investigate these dynamics. Specifically, Senescence-associated mitochondrial cristae reorganization and metabolic rewiring toward aerobic glycolysis deplete the mitochondrial alpha-ketoglutarate pool relative to 2-hydroxyglutarate and succinate, inhibiting JmjC-domain containing histone demethylases (KDM4/KDM6) and locking chromatin in an open H3K4me3/H3K27ac transcriptional state that autonomously amplifies pro-inflammatory SASP expression independently of persistent DNA damage signaling. By integrating high-dimensional multi-omics cohorts, molecular docking regressions, and dynamic pathway modeling, our results indicate that this signaling axis acts as an autonomous amplification loop of senescence-associated phenotypic decline. Furthermore, targeted in silico screening identifies candidate nodal regulators capable of restoring homeostatic flux. These findings provide an epistemic and computational foundation for selective geroprotective intervention strategies.