A comparative approach to identifying genes linked to successful cognitive aging.

The honey bee is one of the best developed animal models for studies of social behavior, and it also has a long tradition in learning and memory research. Our previous work revealed a stunning social plasticity in how honey bee cognition declines with age. Aging is generally associated with progressive cognitive dysfunction, failure in metabolic (energy) homeostasis and in immune function. Such losses of functions with age have be linked to progressing failures in somatic maintenance systems. In this project, we study factors that contribute to variation in aging. So far, we have resolved that variation in brain mitochondrial DNA (mtDNA) integrity does not explain cognitive differences in old age. General differences in learning ability between honey bees, however, may be associated with different abilities to regulate mitochondrial activity. This may be a central feature of brain metabolic biology. The glial cells of the brain are central regulators of brain metabolic biology, but little was known about anatomical and functional aspects of glia in honey bees. Therefore, we next conducted the first immunohistochemical mapping of glia specific metabolic enzymes that are critical for energy (glycogen) homeostasis and detoxification. We establish that, in honey bees, the division of maintenance tasks between different glia and between glia and nerve cells resembles that of vertebrates. We further show that aging correlates with changing levels of glia-specific metabolic enzymes. While doing this work, we found that glia-specific metabolic enzymes also vary with food intake and food perception. Caloric restriction is one of the most successful aging intervention strategies in model animals. For honey bees, we show that individuals with different social behavior and aging progression differ in starvation stress resilience. Individuals with low food sensitivity, moreover, survive starvation stress better that the individuals that are highly sensitive to food. These results may suggest that some of the variation in honey bee aging progression is influenced by variation in food-related brain circuits. We recently found a considerable number of glia cells in areas that are proximate to the blood-brain barrier of the bees. We are planning to test whether the flexible aging process of these animals also confers flexible changes to the blood-brain barrier, whether the barrier is less functional in old bees that exhibit cognitive decline, and whether barrier function can improve with social interventions that make bees younger. Breakdown of the blood-brain barrier is well-known aging pathology in humans, but was not a focus of the project. We will follow up on this in the future. During the previous reporting period, we did a series of studies on connections between variation in aging and genetic variation, and we provided new data on the immune system of the bee with a focus on trans-generational immune priming (vertical transfer of immunity). In this final reporting period, we have almost completed the work on immunity and aging. The PhD student has submitted her work on the expression of an aging protein in honey bee immune cells, the effect of social role on this gene product, and the effect of immune challenge on individuals from difference social behavioral groups that age at different rates. Some work remains on the PhD thesis work on aging-related gene products that we find in the glial cells, and how these translocate to the nucleus. This translocation is very interesting, since we have been able to capture one of the gene products bound to DNA in a pilot experiment. This DNA binding suggest a role in gene regulation, which can explain how the gene product can regulate the aging process. In this project period, we and collaborators mapped 25 single nucleotide polymorphisms (SNP) in 160 people. These SNP lie within gene candidates for food behavior, and can be considered in the context of the above-mentioned bee studies of variation in food-related behavior, where we conclude that some of the variation in honey bee aging progression is influenced by variation in food-related brain circuits. The interpretation of the SNP results is upcoming, and is particularly interesting in light of other research on connections between appetite, nutrition, health and cognitive function in the elderly. Many elderly experience challenges with eating enough nutritious food. We are now working from a new hypothesis in which we consider that there can be some overlap between genes that promote healthy aging and genes that promote productive food-related behavior in old age. Some of the genetic variation that explain variation in human aging, thereby, may lie in genes that influence food behavior. This is a very exciting possibility that was unforeseen when the project started. We present this hypothesis in the last articles from the project, but a definite answer has to emerge from future experiments.

This project will identify understudied variants in genome and transcriptome that can contribute to differences in cognitive aging. It takes advantage of our unique ability to screen a large number of aged brains from an insect that can be individually te sted for brain function and for genetic and transcript variations with transferability to vertebrates. We recognize that a complete understanding of human traits, including cognitive dysfunction in aging, involves the screening of human cohorts and the me asuring and control of environmental, social, behavioral, physiological and genetic variables. Such studies are resource-demanding and several measurements and controls cannot be performed in humans for practical or ethical reasons. Model systems can meet these challenges and help enhance results. A tractable model for variation in cognitive aging is provided by our insect system: the honey bee (Apis). This is the only invertebrate that currently combines the resources of: a small, sequenced genome (270Mb ); a well-studied brain of reasonable size (1 ul, 1 mill neurons); protocols for individual quantification of complex brain functions; and a social life-style. Sequence homology human/bee is also greater than human/fruit fly (Drosophila) for many genes ex pressed in the brain (cit. 7). Like flies, honey bees can be obtained in large numbers and from known genetic sources. Our team takes full advantage of these resources in an innovative study of aging: Insect and molecular genetic expertise is provided by Amdam (University of Life Sciences, PI), Smith (Arizona State University USA) and Eide (Oslo University Hospital Norway); state-of-art molecular profiling with next generation sequencing and SNP genotyping by Huentelman (Translational Genomics Research In stitute USA); and DNA and cognitive data from human aging cohorts by Alexander, Ryan and Glisky (University of Arizona USA).