Intermittent Fasting Increases Neurogenesis in Mice
Neurogenesis is the process by which neurons are created and then integrated into neural circuits. It is essential to the processes of memory and learning, but also vital to the maintenance of brain tissue over a lifetime. It may or may not take place throughout the brain, versus only in areas connected to memory function, and mice may or may not be a good model for human neurogenesis. Most of the work to date has taken place in mice, as working with human brain tissue is beyond the reach of most research groups.
Neurogenesis declines with age, likely largely because the stem cell populations responsible for generating new neurons become less active, as is the case for stem cells throughout the body. Greater neurogenesis is generally considered to be a good thing, but the research community has yet to produce therapies reliably proven to achieve this outcome in humans. A number of approaches work in mice to varying degrees. Fasting, calorie restriction, and exercise all appear to improve neurogenesis, but a larger effect size than is produced via better lifestyle choices would be desirable.
Dietary restriction (DR) is defined as a decrease in energy consumption without reducing nutritional value. This simple dietary intervention has been shown in a wide range of experimental animals to extend lifespan and decrease the incidence of several age-related diseases. The definition of DR has been expanded from an alternative description of caloric restriction (CR) to also encompass a broader scope of interventions, including short-term starvation, periodic fasting, fasting-mimetic diets, and intermittent fasting (IF).
IF has been proven to be advantageous to various organ systems in the body and acts as a mild metabolic stressor. It has been postulated that IF is able to cause powerful changes in the metabolic pathways in the brain via an increase in stress resistance, and breakdown of ketogenic amino acids and fatty acids. Experimental studies have also shown that IF is neuroprotective against acute brain injuries such as stroke, and neurodegenerative diseases. In addition, recent studies have also shown that IF can lead to an increase in neurogenesis levels in the hippocampus.
We evaluated the impact of 3 months of IF (12, 16, and 24 hr of food deprivation on a daily basis) on hippocampal neurogenesis in mice using immunoblot analysis. We investigated the expression levels of molecular and cellular components of the hippocampal region, focusing specifically on Notch activation and associated proteins that are known to promote hippocampal neurogenesis such as brain-derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB).
Three-month IF significantly increased activation of the Notch signaling pathway, neurotrophic factor BDNF, and downstream cellular transcription factor, cAMP response element-binding protein (p-CREB). The expression of postsynaptic marker, PSD95, and neuronal stem cell marker, Nestin, was also increased in the hippocampus in response to 3-month IF. These findings suggest that IF may increase hippocampal neurogenesis involving the Notch 1 pathway.