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

Tijdschriftbijdrage - Tijdschriftartikel

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.

Tijdschrift: Molecular Psychiatry
ISSN: 1359-4184
Issue: 4
Volume: 27
Pagina's: 2355-2368
Jaar van publicatie:2022
Trefwoorden:Lifespan extension, aged system x c--deficient, male mice, preservation of hippocampal function
  • WoS Id: 000757728300001
  • Institutional Repository URL: https://cris.vub.be/ws/files/81813733/Verbruggen_Ates_2022_1_.pdf
  • DOI: https://doi.org/10.1038/s41380-022-01470-5
  • Scopus Id: 85124764966
  • ORCID: /0000-0002-5695-7202/work/113846500
  • ORCID: /0000-0002-1358-6405/work/113846538
  • ORCID: /0000-0002-6234-9908/work/113846716
  • ORCID: /0000-0002-8418-5879/work/113846801
  • ORCID: /0000-0003-2527-6997/work/113846895
  • ORCID: /0000-0002-7466-3072/work/113846999
  • ORCID: /0000-0002-9323-3465/work/113847107
  • ORCID: /0000-0002-5407-7439/work/113847186
  • ORCID: /0000-0003-4564-5665/work/113847343
  • ORCID: /0000-0002-8853-6031/work/113847488