In this open access paper the authors present evidence for the practice of calorie restriction, also known as dietary restriction, to enhance learning capacity via mechanisms that are separate from those related to its effects on health and longevity. An evolutionary explanation for lower calorie intake to result in better cognitive function is fairly straightforward; we might suggest that changes improving the odds of obtaining food in times of scarcity are likely to be selected. The calorie restriction response as a phenomenon is near universal in the animal kingdom, though the size of the effect varies widely, with short-lived species having a far greater increase in life span. This appears to have first evolved very early in the development of life, given that the biochemistry controlling nutrient sensing and consequent changes in metabolism is very similar across a spectrum of species ranging from yeast to humans.
Learning capacity is known to decline with age, and similar effects are also associated with several neurodegenerative diseases. Regulation of insulin signaling by dietary restriction (DR) modulates lifespan in many organisms, and it has been also shown to enhance learning and memory. However, the underlying mechanisms of these processes are largely unknown due to the difficulty in disentangling the systemic effects of DR from any potentially brain-specific effects. Here, we have analyzed the molecular effects of dietary restriction in C. elegans and show that associative learning is enhanced by reducing production of the tryptophan metabolite kynurenic acid (KYNA).
KYNA is an antagonist of glutamatergic signaling in neurons, and we find that its depletion in the nervous system upon DR allows for increased activation of an interneuron that is both necessary and sufficient to mediate learning. We investigated the effects of reductions in either insulin or mTOR signaling pathways, as well as the effects of pharmacological and genetic interventions that lead to activations of AMPK and autophagy. We show that DR and these DR mimetics each result in learning enhancements. Despite their wide-ranging cellular and organismal effects, we find that the beneficial effects of each of these interventions on learning are fully dependent on reductions in KYNA.
Finally, we demonstrate that KYNA levels have no effect on organismal lifespan, indicating that the effects of this KYNA-mediated response to dietary restriction is truly specific to brain function and not a secondary consequence of improved health or longevity. As altered KYNA levels are associated with neurodegenerative and psychiatric diseases, our results suggest that this component may be an important modulator of learning and memory in humans as well.