Summary: A PLOS Biology study reports a dietary restriction increases a worm’s ability to form associations.
A new study untangles the further beneficial effects of dietary restriction.
Dietary restriction – the reduction of a specific nutrient or total dietary intake without triggering malnutrition — increases longevity and improves learning, but are these processes regulated separately? A new study publishing on August 1 in the open access journal PLOS Biology by Mihir Vohra, Kaveh Ashrafi and colleagues at the University of California at San Francisco, indicates that the answer is “yes.” The team shows that depletion of a single amino acid metabolite improves learning in an experimental animal, but has no effect on lifespan.
Reducing food intake is thought to improve cellular health in multiple ways, which are believed to contribute to the increase in longevity in animals deprived of calories over long periods. To explore neuron-specific effects of dietary restriction, the authors used the nematode worm Caenorhabditis elegans as a model organism to test how food deprivation affected the ability of these animals to learn an association between a food source and a smelly chemical called butanone.
The authors found that dietary restriction increased the worm’s ability to form associations (a type of learning) with butanone. The neurons responsible for the association are activated by the neurotransmitter glutamate, and the authors showed that kynurenic acid, a metabolic product of the amino acid L-tryptophan which inhibits glutamate signaling, could dampen the learning process. Dietary restriction improves learning by reducing levels of kynurenic acid. Reducing levels of kynurenic acid by knocking out a gene that regulates its production increased learning even in the absence of dietary restriction, and without increasing longevity, indicating that the learning pathway was distinct from the overall longevity effects of dietary restriction. The authors also showed that several molecular pathways known to be involved in diet-induced longevity, including insulin signaling, increased learning by altering the genes that regulate production of kynurenic acid.
According to the model proposed by the authors, restricted access to food limits the production of kynurenic acid, reducing the ability of this metabolite to inhibit glutamate signaling. This increases neuronal activity and increases learning. The results suggest that although dietary restriction exerts its effects on the organism through multiple independent pathways, the learning-specific effects can be separated from those acting on other aspects of cellular and organismic function, such as ageing.
“The kynurenic acid pathway and the inhibitory effects of the compound are also found in mammals,” Ashrafi noted. “But it remains to be determined whether kynurenic acid influences learning in mammals as directly as it does in worms, and whether manipulation of the pathway might offer new opportunities for therapeutic intervention in human disorders.”
Funding: NIH (grant number R01AG011816). KA. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Glenn/AFAR Aging Research Scholarship. MV. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NIH (grant number R01AG046400). KA. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Genentech Foundation Predoctoral Fellowship. MV. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Hillblom Foundation Graduate Student Fellowship. MV. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Image Source: NeuroscienceNews.com image is credited to Hang Ung, Jean-Louis Bessereau laboratory, France.
Original Research: Full open access research for “The beneficial effects of dietary restriction on learning are distinct from its effects on longevity and mediated by depletion of a neuroinhibitory metabolite” by Mihir Vohra, George A. Lemieux, Lin Lin, and Kaveh Ashrafi in PLOS Biology. Published online August 1 2017 doi:10.1371/journal.pbio.2002032
[cbtabs][cbtab title=”MLA”]PLOS “Dietary Restriction Can Improve Learning in Worms.” NeuroscienceNews. NeuroscienceNews, 1 August 2017.
<https://neurosciencenews.com/diet-worm-learning-7217/>.[/cbtab][cbtab title=”APA”]PLOS (2017, August 1). Dietary Restriction Can Improve Learning in Worms. NeuroscienceNew. Retrieved August 1, 2017 from https://neurosciencenews.com/diet-worm-learning-7217/[/cbtab][cbtab title=”Chicago”]PLOS “Dietary Restriction Can Improve Learning in Worms.” https://neurosciencenews.com/diet-worm-learning-7217/ (accessed August 1, 2017).[/cbtab][/cbtabs]
The beneficial effects of dietary restriction on learning are distinct from its effects on longevity and mediated by depletion of a neuroinhibitory metabolite
In species ranging from humans to Caenorhabditis elegans, dietary restriction (DR) grants numerous benefits, including enhanced learning. The precise mechanisms by which DR engenders benefits on processes related to learning remain poorly understood. As a result, it is unclear whether the learning benefits of DR are due to myriad improvements in mechanisms that collectively confer improved cellular health and extension of organismal lifespan or due to specific neural mechanisms. Using an associative learning paradigm in C. elegans, we investigated the effects of DR as well as manipulations of insulin, mechanistic target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and autophagy pathways—processes implicated in longevity—on learning. Despite their effects on a vast number of molecular effectors, we found that the beneficial effects on learning elicited by each of these manipulations are fully dependent on depletion of kynurenic acid (KYNA), a neuroinhibitory metabolite. KYNA depletion then leads, in an N-methyl D-aspartate receptor (NMDAR)-dependent manner, to activation of a specific pair of interneurons with a critical role in learning. Thus, fluctuations in KYNA levels emerge as a previously unidentified molecular mechanism linking longevity and metabolic pathways to neural mechanisms of learning. Importantly, KYNA levels did not alter lifespan in any of the conditions tested. As such, the beneficial effects of DR on learning can be attributed to changes in a nutritionally sensitive metabolite with neuromodulatory activity rather than indirect or secondary consequences of improved health and extended longevity.
“The beneficial effects of dietary restriction on learning are distinct from its effects on longevity and mediated by depletion of a neuroinhibitory metabolite” by Mihir Vohra, George A. Lemieux, Lin Lin, and Kaveh Ashrafi in PLOS Biology. Published online August 1 2017 doi:10.1371/journal.pbio.2002032