Disrupted calcium ion homeostasis accelerates aging through a pathway involving the protein S100A6 and impaired DNA repair. Restoring calcium balance with mianserin, an existing antidepressant, extended median lifespan by approximately 30% in progeroid mice and improved multiple tissue functions.
Key Points
- Calcium leakage from endoplasmic reticulum elevates S100A6 and disrupts DNA repair
- S100A6 overexpression destabilizes PARP1, a critical DNA-repair enzyme central to aging
- Mianserin restores calcium homeostasis and extends lifespan without adverse effects
Longevity Analysis
This work establishes a mechanistic link between a fundamental cellular communication failure and accelerated aging, demonstrating that calcium ion dysregulation is not merely associated with age-related diseases but actively drives the aging process itself. The calcium leak triggers a cascade: elevated cytoplasmic calcium destabilizes PARP1, compromising DNA integrity and triggering inflammatory signaling through escaped nuclear DNA fragments. By restoring calcium homeostasis with a well-tolerated drug, the researchers reversed senescence markers and extended lifespan substantially, suggesting that targeting this single upstream dysregulation addresses multiple downstream consequences of aging simultaneously. This approach illustrates how identifying and correcting specific signal disruption can yield disproportionate gains across tissue function and longevity.
Original published by LifeSpan.io, by Arkadi Mazin.