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

Area of Science:

• Cellular and Molecular Biology
• Metabolism and Aging

Background:

• Cellular senescence is a state of stable growth arrest linked to metabolic alterations and the senescence-associated secretory phenotype (SASP).
• While metabolic changes like enhanced glycolysis and mitochondrial dysfunction are known, intracellular acidification's role in senescence is emerging.
• Acidification arises from suppressed proton efflux, increased glycolytic acid production, and lysosomal issues, impacting cellular processes.

Purpose of the Study:

• To investigate the role of intracellular acidification as a regulator of cellular senescence.
• To elucidate the mechanisms linking altered cellular pH to the senescence-associated secretory phenotype (SASP).
• To explore the connection between metabolic shifts, intracellular pH, and inflammatory signaling in senescence.

Main Methods:

• Analysis of cellular pH regulation mechanisms, including NHE1 activity and lysosomal function.
• Assessment of metabolic alterations, such as glycolysis and glucose-6-phosphate accumulation.
• Investigation of gene expression related to senescence and inflammation, including MondoA targets (TXNIP, ARRDC4).

Main Results:

• Intracellular acidification, caused by suppressed proton efflux and altered lysosomal function, is identified as a key regulator of senescence.
• Lowered intracellular pH impacts redox balance, inhibits HDAC activity, and promotes senescence-associated gene transcription.
• Acidification activates a glycolysis-linked inflammatory circuit via glucose-6-phosphate accumulation and MondoA targets, correlating with SASP induction.

Conclusions:

• Intracellular pH acts as a critical metabolic cue linking altered glycolysis to inflammatory output in cellular senescence.
• Acidification promotes a highly secretory senescent cell phenotype through specific molecular pathways.
• Understanding this pH-mediated pathway offers a framework for modulating age-associated chronic inflammation.