ORIGINAL RESEARCH article
Front. Aging
Sec. Cellular Senescence
Volume 6 - 2025 | doi: 10.3389/fragi.2025.1583288
This article is part of the Research TopicThe Crosstalk Between Metabolism and Inflammation in Aging and LongevityView all 6 articles
Membrane transporter Progressive Ankylosis Protein Homolog (ANKH/Ank) partially mediates senescence-derived extracellular citrate and is regulated by DNA damage, inflammation and ageing
Provisionally accepted
Emma Naomi James1
Muy-Teck Teh1Yufeng Li2Chrisitne Wagner-Bock3
Zahra Al-Khateeb1
Lee Peng Karen-Ng1Terry Roberts4Linnea Synchyshyn1Amy Lewis1
Ana O'Loghlen1
Adina Teodora Michael-Titus1Andrew Silver1Mark H Bennett2
Jake Bundy2
Maria Elzbieta Mycielska3
Eric Kenneth Parkinson1*- 1Queen Mary University of London, London, United Kingdom
- 2Imperial College London, London, England, United Kingdom
- 3University of Regensburg, Regensburg, Bavaria, Germany
- 4Brunel University London, Uxbridge, London, United Kingdom
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A considerable body of recent evidence supports citrate transport as a major regulator of organismal lifespan and healthspan. Citrate accumulates outside senescent cells in vitro and in vivo. However, the detailed mechanism of senescent cell extracellular citrate (EC) accumulation is not clear. We show here that EC is partially mediated by a newly described plasma membrane citrate transporter ANKH/SLC62A1 (progressive human ankylosis -ANKH) in senescent fibroblasts. Analogous to interleukin 6 (IL-6), EC and/or ANKH are regulated by telomere dysfunction, the p38 mitogen-activated kinase axis, transforming growth factor beta and p53, but in contrast not by steroids, sodium butyrate, or Ataxia Telangiectasia Mutated (ATM). ANKH was upregulated in other senescent cell types relevant to ageing but not keratinocytes. In contrast, EC and ANKH were inhibited in dividing and senescent fibroblasts by interleukin 1α (IL-1α) in parallel with increased IL-6 secretion. Loss-and gain of function mutations of ANKH/Ank are associated with disease and interestingly, Ank is also downregulated in both aged mouse liver and brain tissues in parallel with increased senescence markers and several cytokines, suggesting that inflammatory cytokines could inhibit EC production in vivo. These data identify ANKH/Ank as a novel regulator of senescence-derived EC in both humans and mice.
Keywords: ANKH/SLC62A1, Citrate, senescence, Ageing, Inflammation, astrocyte, Telomere, transport
Received: 25 Feb 2025; Accepted: 09 May 2025.
Copyright: © 2025 James, Teh, Li, Wagner-Bock, Al-Khateeb, Karen-Ng, Roberts, Synchyshyn, Lewis, O'Loghlen, Michael-Titus, Silver, Bennett, Bundy, Mycielska and Parkinson. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Eric Kenneth Parkinson, Queen Mary University of London, London, United Kingdom
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