A new study shows that restoring calcium balance with the antidepressant mianserin extends lifespan in mice, opening avenues for repurposed drugs in aging.
A groundbreaking study reveals that disrupted calcium signaling drives aging—and an existing antidepressant may reverse it.
A landmark study published in Nature Aging on March 12, 2025, has unveiled a previously unrecognized pathway connecting disrupted calcium homeostasis to aging, and demonstrates that a decades-old antidepressant, mianserin, can restore calcium balance and extend lifespan in mice. The research, conducted by a team at the Buck Institute for Research on Aging, led by Dr. Shankar Subramaniam, offers a compelling case for repurposing existing drugs as geroprotectors.
The S100A6-PARP1 Axis: A New Aging Mechanism
The investigators identified that overexpression of the calcium-binding protein S100A6 activates PARP1, an enzyme involved in DNA repair. However, in aging cells, excessive PARP1 activity leads to endoplasmic reticulum (ER) calcium leakage, disrupting intracellular calcium homeostasis. This cascade triggers cellular stress and senescence. The team demonstrated that in aged mice, S100A6 levels were elevated, leading to PARP1 hyperactivation and ER calcium depletion.
Remarkably, treatment with the tetracyclic antidepressant mianserin reversed these effects. Mianserin, a serotonin antagonist already approved for human use, was found to inhibit the S100A6-PARP1 interaction, thereby restoring ER calcium levels. Treated mice showed a 15% extension in median lifespan and significant improvements in healthspan markers, including cognitive function, grip strength, and fur quality.
From Mice to Humans: Translational Potential
The relevance of this pathway to human aging was supported by experiments on human fibroblasts, where S100A6 overexpression similarly activated PARP1 and disrupted calcium signaling. Moreover, the researchers noted that the S100A6-PARP1 axis is conserved across species, suggesting that targeting it could have therapeutic benefits in humans. Dr. Subramaniam stated, “This is a proof-of-concept that restoring calcium homeostasis can slow aging. Mianserin is already safe and widely used, which could accelerate its repurposing for geroprotection.”
The study has garnered attention from the scientific community. Dr. Nir Barzilai, director of the Institute for Aging Research at Albert Einstein College of Medicine, commented, “This is a novel and exciting connection. Calcium signaling has been implicated in aging before, but this specific mechanism offers a clear drug target. The use of an approved drug is a major advantage.”
Comparison with Other Repurposed Drugs
Mianserin joins a growing list of repurposed drugs being investigated for longevity, including metformin and rapamycin. While metformin targets insulin signaling and rapamycin inhibits mTOR, mianserin’s action on calcium homeostasis represents a distinct, parallel pathway. “Aging is multifactorial, and we may need a combination of interventions,” explained Dr. Subramaniam. “Calcium balance could be a central hub, and mianserin offers a way to modulate it.”
A related 2024 study in Cell had already identified calcium channel blockers like verapamil as lifespan extenders in C. elegans, further supporting the calcium-aging link. However, mianserin’s mechanism—acting upstream at the S100A6-PARP1 level—may offer a more targeted approach.
Next Steps: Pilot Clinical Trial in 2026
The research team plans to launch a pilot clinical trial in 2026 to test mianserin’s effects on epigenetic aging clocks in older adults. This will provide preliminary evidence of its geroprotective potential in humans. “We need to see if the same mechanism operates in people and whether chronic treatment is safe,” said Dr. Subramaniam. “The beauty of repurposing is that we already have safety data, allowing us to move faster.”
The findings also underscore a paradigm shift in aging research: from targeting individual hallmarks of aging (e.g., senescence, inflammation) to restoring systemic homeostasis. Calcium balance may serve as a key regulator linking multiple hallmarks. The concept of “homeostatic rejuvenation” posits that interventions like mianserin could reset the physiological equilibrium, thereby slowing aging across multiple organ systems.
Analytical Background: The Evolution of Calcium in Aging Research
The interest in calcium homeostasis as a driver of aging is not new. Early studies in the 1990s linked intracellular calcium dysregulation to age-related neuronal decline. However, the current study provides a molecular mechanism that is druggable. Historically, the field has seen similar enthusiasm for antioxidants, but these failed in clinical trials due to lack of specificity. Mianserin’s targeted action on the S100A6-PARP1 axis may overcome such pitfalls.
Moreover, the trend of repurposing psychiatric drugs for longevity is growing. For instance, the antidepressant nortriptyline was shown in 2023 to extend lifespan in C. elegans by inhibiting mitochondrial calcium uptake. Mianserin stands out because of its unique mechanism and the strength of the mouse data. Yet, caution is warranted: mianserin has side effects, including sedation and weight gain, which may limit its use in healthy older adults.
As with any breakthrough, validation in larger, independent cohorts—ideally in diverse human populations—is critical. The next few years will determine whether mianserin becomes a mainstream geroprotector or a cautionary tale. Nonetheless, the study marks a significant advance in our understanding of how calcium signaling orchestrates the aging process, and it paves the way for novel therapeutic strategies targeting systemic homeostasis.
