Purkinje-cell-specific DNA repair-deficient mice reveal that dietary restriction protects neurons by cell-intrinsic preservation of genomic health

María Björk Birkisdóttir, Lisanne J. Van’t Sant, Renata M.C. Brandt, Sander Barnhoorn, Jan H.J. Hoeijmakers, Wilbert P. Vermeij*, Dick Jaarsma*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)
38 Downloads (Pure)

Abstract

Dietary restriction (DR) is a universal anti-aging intervention, which reduces age-related nervous system pathologies and neurological decline. The degree to which the neuroprotective effect of DR operates by attenuating cell intrinsic degradative processes rather than influencing non-cell autonomous factors such as glial and vascular health or systemic inflammatory status is incompletely understood. Following up on our finding that DR has a remarkably large beneficial effect on nervous system pathology in whole-body DNA repair-deficient progeroid mice, we show here that DR also exerts strong neuroprotection in mouse models in which a single neuronal cell type, i.e., cerebellar Purkinje cells, experience genotoxic stress and consequent premature aging-like dysfunction. Purkinje cell specific hypomorphic and knock-out ERCC1 mice on DR retained 40 and 25% more neurons, respectively, with equal protection against P53 activation, and alike results from whole-body ERCC1-deficient mice. Our findings show that DR strongly reduces Purkinje cell death in our Purkinje cell-specific accelerated aging mouse model, indicating that DR protects Purkinje cells from intrinsic DNA-damage-driven neurodegeneration.

Original languageEnglish
Article number1095801
JournalFrontiers in Aging Neuroscience
Volume14
DOIs
Publication statusPublished - 24 Jan 2023

Bibliographical note

Funding Information:
We acknowledge financial support of the National Institute of Health (NIH)/National Institute of Aging (NIA) (AG17242), European Research Council Advanced Grants Dam2Age (to JH), ONCODE supported by the Dutch Cancer Society, ADPS Longevity Research Award (to WV), Memorabel (ZonMW 733050810), BBoL (NWO-ENW 737.016.015), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation—Project-ID 73111208—SFB 829), Regiodeal Foodvalley (162135), and the European Joint Programme Rare Diseases (TC-NER RD20-113).

Publisher Copyright:
Copyright © 2023 Birkisdóttir, Van’t Sant, Brandt, Barnhoorn, Hoeijmakers, Vermeij and Jaarsma.

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