Ameliorating calcium homeostasis improves longevity and healthspan in progeroid and naturally aged mice

Cellular calcium (Ca²⁺)-regulating systems are compromised during aging-related disorders. Here, we show that disruption of Ca²⁺ homeostasis leads to the cytoplasmic accumulation of Ca²⁺ binding protein S100A6, which promotes Hutchinson-Gilford progeria syndrome (HGPS) and natural aging. S100A6 recruits CacyBP to facilitate the ubiquitination and degradation of PARP1, leading to DNA damage and the formation of cytoplasmic chromatin fragments (CCF), activing cGAS-STING-NF-κB pathway and the secretion of senescence-associated secretory phenotype (SASP) factors. Mianserin (MIA), a tetracyclic antidepressant, attenuates senescence in cells derived from HGPS patients and naturally aging humans by antagonizing serotonin receptors HTR2B/2 C to lower Ca²⁺ concentrations. MIA also improves a range of aging phenotypes and significantly extends the lifespan of both Lmna^G609G/G609G progeroid and naturally aging mice. Together, our findings uncover the mechanism of Ca²⁺ homeostasis disruption during premature and natural aging, and suggest MIA as a potential therapeutic strategy to extend healthy lifespan by augmenting Ca²⁺ homeostasis.