Researchers here identify mechanisms downstream of faulty calcium metabolism that drive the harmful signaling of senescent cells that accumulate in aged tissues. Calcium metabolism is well studied in a number of contexts, and various drugs exist to adjust its operation in one way or another. Applying one of those drugs to aged mice results in a reduction in the harms done by senescent cells, improved health, and a 17% extension of life span. There will be many ways in which the presence of senescent cells in aged tissues could be made less harmful. At present most efforts are focused on the development of new drugs to selectively destroy senescent cells, but it seems likely that these research groups and companies will soon be joined by those seeking to alter the behavior of these cells instead.
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 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.
Link: https://doi.org/10.1038/s41467-026-74021-z
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