Breaking the pH Code: acidification triggers SASP and inflammation in cellular senescence

Cellular senescence is a stress-induced, stable growth arrest accompanied by marked metabolic alterations and acquisition of the senescence-associated secretory phenotype (SASP). While enhanced glycolysis, mitochondrial dysfunction, and lysosomal abnormalities are well-established features, emerging evidence identifies progressive intracellular acidification as an important yet underappreciated regulator of cellular senescence. Acidification results from suppressed Na+/H+ exchanger 1-mediated proton efflux, elevated glycolytic proton production, and lysosomal membrane permeabilization. This lowered pH alters redox balance, inhibits histone deacetylase activity, and promotes transcription of senescence-associated genes. Recent work by Kawakami et al. demonstrates that acidification activates a glycolysis-linked inflammatory circuit through accumulation of glucose-6-phosphate and induction of the MondoA targets TXNIP and ARRDC4, which correlate with SASP induction and define a highly secretory subset of senescent cells. These findings suggest that intracellular pH functions as a key metabolic cue linking altered glycolysis to inflammatory output, offering a conceptual framework that may guide future efforts to modulate age-associated chronic inflammation.