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Life-long Dietary Restrictions have Negligible or Damaging Effects on Late-life Cognitive Performance: A Key Role for Genetics in Outcomes

View ORCID ProfileAndrew R. Ouellette, Niran Hadad, Andrew Deighan, Laura Robinson, View ORCID ProfileKristen O’Connell, Adam Freund, Gary A. Churchill, Catherine C. Kaczorowski
doi: https://doi.org/10.1101/2022.04.09.487742
Andrew R. Ouellette
1The University of Maine, Graduate School of Biomedical Science and Engineering, Orono, ME, 04469, USA
2The Jackson Laboratory, Bar Harbor ME, 04609, USA
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  • ORCID record for Andrew R. Ouellette
Niran Hadad
2The Jackson Laboratory, Bar Harbor ME, 04609, USA
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Andrew Deighan
2The Jackson Laboratory, Bar Harbor ME, 04609, USA
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Laura Robinson
2The Jackson Laboratory, Bar Harbor ME, 04609, USA
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Kristen O’Connell
2The Jackson Laboratory, Bar Harbor ME, 04609, USA
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Adam Freund
3Calico Life Sciences, LLC
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Gary A. Churchill
2The Jackson Laboratory, Bar Harbor ME, 04609, USA
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Catherine C. Kaczorowski
1The University of Maine, Graduate School of Biomedical Science and Engineering, Orono, ME, 04469, USA
2The Jackson Laboratory, Bar Harbor ME, 04609, USA
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  • For correspondence: Catherine.Kaczorowski@jax.org
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Abstract

Several studies report that caloric restriction (CR) or intermittent fasting (IF) can improve cognition, while others report limited or no cognitive benefits. Here, we compare the effects of 20% CR, 40% CR, 1-day IF, and 2-day IF feeding paradigms to ad libitum controls (AL) on Y-maze working memory and contextual fear memory (CFM) in a large population of Diversity Outbred mice that model the genetic diversity of humans. While CR and IF interventions improve lifespan, we observed no enhancement of working memory or CFM in mice on these feeding paradigms, and report 40% CR to be damaging in the context of long-term memory. Using Quantitative Trait Loci mapping, we identified the gene Slc16a7 to be associated with late-life long-term memory outcomes in mice on lifespan promoting feeding paradigms. Limited utility of dieting and fasting on memory in mice that recapitulate genetic diversity in the human population highlights the need for anti-aging therapeutics that promote cognitive function, with a neuronal monocarboxylate transporter encoded by Slc16a7 highlighted as novel target.

Competing Interest Statement

AF is an employee of Calico Life Sciences, LLC, a for-profit biotechnology company focused on aging

  • Abbreviations

    CR
    Caloric Restriction
    IF
    Intermittent Fasting
    DO
    Diversity Outbred
    %SA
    Percent spontaneous Alternations
    CFM
    Contextual Fear Memory
    CFA
    Contextual Fear Acquisition
    LOD
    Log of Odds
    ANOVA
    Analysis of Variance
    SEM
    Standard Error of Mean
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Posted April 10, 2022.
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    Life-long Dietary Restrictions have Negligible or Damaging Effects on Late-life Cognitive Performance: A Key Role for Genetics in Outcomes
    Andrew R. Ouellette, Niran Hadad, Andrew Deighan, Laura Robinson, Kristen O’Connell, Adam Freund, Gary A. Churchill, Catherine C. Kaczorowski
    bioRxiv 2022.04.09.487742; doi: https://doi.org/10.1101/2022.04.09.487742
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    Life-long Dietary Restrictions have Negligible or Damaging Effects on Late-life Cognitive Performance: A Key Role for Genetics in Outcomes
    Andrew R. Ouellette, Niran Hadad, Andrew Deighan, Laura Robinson, Kristen O’Connell, Adam Freund, Gary A. Churchill, Catherine C. Kaczorowski
    bioRxiv 2022.04.09.487742; doi: https://doi.org/10.1101/2022.04.09.487742

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