Common Antidepressant Extends Mouse Lifespan 30% by Fixing Calcium Leaks

Aging researchers have long known that calcium ion balance deteriorates in many age-related diseases, from heart failure to Alzheimer's, but the precise molecular chain linking this disruption to cellular aging had remained unclear. A new study published in Nature Communications by Chinese scientists now maps that chain in detail — and identifies a drug already on pharmacy shelves that can interrupt it.

The team used unbiased proteomics on progeroid mice — animals engineered to age rapidly — and found the calcium pathway and a calcium-binding protein, S100A6, among the most elevated features. Tracing the source of excess cytoplasmic calcium, they identified the IP3R channel on the endoplasmic reticulum as the primary leak. Elevated S100A6 then binds and destabilizes PARP1, a critical DNA-repair enzyme, accelerating DNA damage, cellular senescence, and inflammatory signaling via the cGAS-STING pathway.

The key therapeutic breakthrough came when the researchers identified mianserin — a decades-old antidepressant that blocks serotonin receptors upstream of IP3R — as a tolerable way to shut the calcium leak. Treating progeroid mice with mianserin from four weeks of age extended median survival by approximately 30% and maximum lifespan significantly, while improving cardiac, pulmonary, and muscle function and reducing inflammatory markers.

Critically, the same S100A6 elevation was confirmed in naturally aging mice, not just the rare genetic progeria model, suggesting the calcium-S100A6-PARP1 axis is a general feature of aging rather than a disease-specific artifact.

Caveats remain: all data are from mouse models, and mianserin carries known side effects including sedation and weight gain. Human translation requires clinical trials. Nevertheless, this study provides one of the most complete molecular explanations to date for why calcium dysregulation drives aging — and points to a repurposable drug as a potential intervention.