Disrupted calcium homeostasis triggers a cascade where calcium-binding protein S100A6 accumulates in cell cytoplasm, recruiting CacyBP to degrade PARP1, ultimately causing DNA damage and inflammatory aging signals. The tetracyclic antidepressant mianserin counteracts this process by blocking serotonin receptors HTR2B/2C, reducing cellular calcium concentrations and extending lifespan in both progeria and naturally aging mice. This discovery illuminates calcium dysregulation as a fundamental aging mechanism spanning premature and natural senescence. The therapeutic potential appears significant—mianserin is already FDA-approved for depression, suggesting rapid clinical translation possibilities. However, the mouse model findings require human validation, particularly regarding dosing and long-term safety for longevity applications. The mechanistic pathway from calcium to DNA damage to inflammatory aging represents a potentially targetable aging hallmark. While promising, this represents incremental progress in understanding calcium's role in aging rather than a paradigm shift, building on established knowledge of calcium signaling in cellular senescence.