An antidepressant extends lifespan in aging mice
A long-established antidepressant gave aging mice not just a longer life, but a healthier one. The mechanism behind it is specific and well-studied: how cells handle calcium.
Nearly every cell in the body carefully regulates how much calcium enters and exits. As we age, that balance breaks down. Calcium accumulates in the cytoplasm, triggering a chain of events that drives cellular senescence: cells stop dividing but don’t die. Instead, they release damaging signaling molecules into surrounding tissue, a pattern researchers call SASP (senescence-associated secretory phenotype).
From calcium buildup to cellular damage
Researchers describe in Nature Communications how disrupted calcium regulation leads to accumulation of the protein S100A6. This protein activates another protein (CacyBP), which degrades the DNA repair enzyme PARP1. Without sufficient PARP1, DNA damage accumulates. Chromosome fragments end up outside the cell nucleus, in the cytoplasm. These fragments trigger an alarm response and activate an inflammatory pathway (cGAS-STING-NF-κB), causing the cell to secrete SASP factors.
The entire chain runs from calcium buildup through protein degradation to DNA damage and ultimately to the release of inflammatory signals. The researchers investigated whether a step in that chain could be interrupted.
An old antidepressant as test compound
They chose mianserin, a long-approved antidepressant that blocks serotonin receptors (HTR2B and HTR2C). Through those receptors, calcium concentrations in the cell decrease. In cells from people with a rare premature aging disorder (Hutchinson-Gilford progeria syndrome), mianserin noticeably reduced markers of cellular senescence. An effect was also visible in cells from normally aging humans.
In mice, the results were striking. Both in an accelerated aging model and in normally aging mice, mianserin extended lifespan, by approximately 17 percent in the normally aging group. Measurable aging indicators such as muscle strength and tissue condition also improved. Given that these are animal models, caution is warranted. Whether this effect occurs in humans remains unknown.
From a longevity perspective, it is notable that an already approved drug targets an existing mechanism. The researchers suggest that calcium regulation may represent an intervention point alongside the more common approach of directly eliminating senescent cells.