Roles of Cdk5 in neurodevelopment and neurodegeneration

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We previously developed a systems-level metric that allows us to infer the physiological age of an experimental sample (as opposed to its chronological age) by employing genome-wide gene expression profiling. We also performed experiments demonstrating the central role of the innate immune system in Cdk5-associated neurodegeneration in Drosophila. In the course of that work, we serendipitously observed that growth of flies under germ-free conditions led to a modest extension of their lifespan. Experiments extending those observations now suggest that our view of the relationship between aging and lifespan requires fundamental reassessment. In brief, we find that 70% of the systematic changes in gene expression that occur over the lifespan of Drosophila are not inherently linked to the program of aging itself, but rather are more accurately considered aspects of the immune system, and reflect the existence of a sequence of strategies that the organism has evolved to support life in a microbe-rich environment. Removal of these immune-centered covariates of aging from our consideration, moreover, reveals the processes that are likely to be bona fide, core components of aging as we mean that term. These are olfaction, epithelial barrier function, mitochondrial function and insulin-like signaling. Ongoing experiments are investigating further the core processes of aging and their role in neurodegeneration, and in determination of lifespan. In other experiments, we are also completing experiments demonstrating that Drosophila Htt, ortholog of the causal gene in Huntingtons Disease, and Appl, the fly homolog of the triggering gene in Alzheimers disease, are antagonistic elements of a single biochemical signaling pathway that regulates growth and branching of axons in the learning and memory center of the Drosophila brain.