Lifespan extension with preservation of hippocampal function in aged system xc--deficient male mice

Lise Verbruggen, Gamze Ates, Olaya Lara, Jolien De Munck, Agnès Villers, Laura De Pauw, Sigrid Ottestad-Hansen, Sho Kobayashi, Pauline Beckers, Pauline Janssen, Hideyo Sato, Yun Zhou, Emmanuel Hermans, Rose Njemini, Lutgarde Arckens, Niels C Danbolt, Dimitri De Bundel, Joeri L Aerts, Kurt Barbé, Benoit GuillaumeLaurence Ris, Eduard Bentea, Ann Massie

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The cystine/glutamate antiporter system xc- has been identified as the major source of extracellular glutamate in several brain regions as well as a modulator of neuroinflammation, and genetic deletion of its specific subunit xCT (xCT-/-) is protective in mouse models for age-related neurological disorders. However, the previously observed oxidative shift in the plasma cystine/cysteine ratio of adult xCT-/- mice led to the hypothesis that system xc- deletion would negatively affect life- and healthspan. Still, till now the role of system xc- in physiological aging remains unexplored. We therefore studied the effect of xCT deletion on the aging process of mice, with a particular focus on the immune system, hippocampal function, and cognitive aging. We observed that male xCT-/- mice have an extended lifespan, despite an even more increased plasma cystine/cysteine ratio in aged compared to adult mice. This oxidative shift does not negatively impact the general health status of the mice. On the contrary, the age-related priming of the innate immune system, that manifested as increased LPS-induced cytokine levels and hypothermia in xCT+/+ mice, was attenuated in xCT-/- mice. While this was associated with only a very moderate shift towards a more anti-inflammatory state of the aged hippocampus, we observed changes in the hippocampal metabolome that were associated with a preserved hippocampal function and the retention of hippocampus-dependent memory in male aged xCT-/- mice. Targeting system xc- is thus not only a promising strategy to prevent cognitive decline, but also to promote healthy aging.

Original languageEnglish
Pages (from-to)2355-2368
Number of pages14
JournalMolecular Psychiatry
Issue number4
Early online date18 Feb 2022
Publication statusPublished - Apr 2022

Bibliographical note

© 2022. The Author(s).


  • Lifespan extension
  • aged system x c--deficient
  • male mice
  • preservation of hippocampal function


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