Biochemical and biophysical research communicationsNov 1, 2025

Ketotifen restores acidity in cell compartments and improves aging signs in mast cells

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jan 7, 2026

Abstract

Lysosomal acidification in mast cells is progressively lost with age, with restoration observed following chronic ketotifen treatment.

Mast cells from 2-month-old mice exhibited very low lysosomal acidity, indicating immature granules.
As mast cells matured, lysosomal acidity increased, but between 15 to 17 months, a gradual deacidification was noted.
Chronic ketotifen treatment not only restored lysosomal acidity but also enlarged granules and reduced expansion of mast cells in late life.
Ketotifen's effects on lysosomal acidity were linked to the activity of V-ATPase and the process of endocytosis.
Ageing in the brain was associated with hypertrophy of mast cells, yet ketotifen treatment reversed these changes toward a younger profile.

Simplified

Mast-cell (MC) granules are secretory lysosomes whose function depends on a highly acidic lumen. We asked whether lysosomal pH drifts with age and whether this alteration is reversible. Lysosomal acidification was assessed by quinacrine imaging of peritoneal MCs, which revealed very low fluorescence in MCs from 2-month-old mice, consistent with immature granules. As MCs matured, quinacrine signal increased, reflecting expansion of the secretory lysosome pool; however, from 15 to 17 months, fluorescence progressively declined, indicating gradual deacidification. Chronic ketotifen treatment restored and amplified the quinacrine signal, enlarged granules, and reduced late-life MC expansion. Acute pharmacological assays revealed that ketotifen's effect requires V-ATPase activity and dynamin-dependent endocytosis. FM1-43 uptake confirmed enhanced endocytic activity with ketotifen. In the brain, ageing led to hypertrophy of toluidine blue-positive MCs without major changes in cell number; five months of ketotifen treatment reversed these morphometric alterations toward a youthful profile. These findings identify lysosomal deacidification as a hallmark of ageing MCs and demonstrate that ketotifen reacidifies secretory lysosomes via V-ATPase and endocytosis-dependent mechanisms, highlighting lysosomal pH control as a tractable strategy to mitigate MC-driven components of inflammaging.

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Ketotifen restores acidity in cell compartments and improves aging signs in mast cells

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