Abstract
Daily calorie restriction (CR) and intermittent fasting (IF) enhance longevity and cognition but the effects and mechanisms that differentiate these two paradigms are unknown. We examined whether IF in the form of every-other-day feeding enhances cognition and adult hippocampal neurogenesis (AHN) when compared to a matched 10% daily CR intake and ad libitum conditions. After 3 months under IF, female C57BL6 mice exhibited improved long-term memory retention. IF increased the number of BrdU-labeled cells and neuroblasts in the hippocampus, and microarray analysis revealed that the longevity gene Klotho (Kl) was upregulated in the hippocampus by IF only. Furthermore, we found that downregulating Kl in human hippocampal progenitor cells led to decreased neurogenesis, whereas Kl overexpression increased neurogenesis. Finally, histological analysis of Kl knockout mice brains revealed that Kl is required for AHN, particularly in the dorsal hippocampus. These data suggest that IF is superior to 10% CR in enhancing memory and identifies Kl as a novel candidate molecule that regulates the effects of IF on cognition likely via AHN enhancement.
Highlights
These authors contributed : Gisele Pereira Dias, Tytus Murphy, Doris Stangl
This study addressed whether the beneficial effects of intermittent fasting (IF) on cognition are due to a decrease in total amount of calories consumed or to the increased interval between meals
With an overall 10% matched-energy intake, IF in the form of every-other-day feeding is superior to daily calorie restriction (CR) in enhancing long-term memory performance in mice, and we provide evidence that this enhancement is associated with increased adult hippocampal neurogenesis (AHN) and expression of the longevity gene Kl
Summary
Even with these potential limitations, the findings by Anson et al [18] indicate that IF could induce neuroprotection independent of overall calorie intake in the long term. Despite the positive effects of CR and IF in neurodegenerative [19, 20] and affective [21, 22] conditions, the specific behavioral contributions and mechanisms that differentiate both interventions remain largely unknown Answering these questions is pivotal to adapting these regimens to human populations, given the challenges of adhering to a long-term CR regimen when compared to the improved adherence to variations of the IF paradigm [23]. We highlight the potential for IF paradigms in the form of increased meal interval to help bring about improved cognitive performance in human populations
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