Abstract
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 LmnaG609G/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.
Similar content being viewed by others
Funding
This work was supported by the grants from the National Natural Science Foundation of China (grant numbers: 32371216 and 32171163 to Y.Z, 32271207 to J.L), the Scientific Research Innovation Capability Support Project for Young Faculty (SRICSPYF-ZY2025126 to Y.Z), the Development and Reform Commission of Jilin Province (grant numbers: 2024C013-1 to Y.Z), the Natural Science Foundation of Jilin Province (20230101153JC to J.L), and the Foundation Research Funds for Central Universities.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Xiang, W., Hu, Q., Sun, P. et al. Ameliorating calcium homeostasis improves longevity and healthspan in progeroid and naturally aged mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-74021-z
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41467-026-74021-z
