The aging population and coincident rise in associated diseases demand a better understanding of the basic mechanisms of aging to design appropriate interventions and prolong human health. Elucidating the molecular mechanisms of the processes that slow aging, such as lifespan extension by caloric or dietary restriction, would provide prime candidates for therapeutic intervention. Model organisms have allowed major advances in defining aging mechanisms due to their exceptionally powerful genetics and analytical tools, and because these processes are evolutionarily conserved from humans to yeasts. We discovered a new pathway in Schizosaccharomyces pombe that both regulates autophagy and extends lifespan. Autophagy is a process that degrades and recycles proteins and organelles, and has been linked to lifespan and diseases associated with human aging. We found that both autophagy and lifespan are regulated through the cyclin-dependent kinase Pef1, an ortholog of human Cdk5. Pef1 acts with its cyclin Clg1 to limit lifespan and autophagy, and is opposed by the effector kinase Cek1 that extends lifespan and increases autophagy levels. The Clg1-Pef1- Cek1 pathway acts independently of TOR, the only other pathway known to regulate both lifespan and autophagy, but how these processes are controlled by the Pef1 pathway is unknown.
Aim 1 will test the hypothesis that the Pef1 pathway senses nutrients to control lifespan and autophagy.
This aim will be significant for testing the linkage between autophagy and lifespan extension by caloric or dietary restriction. Establishing the mechanism by which the Pef1 pathway regulates lifespan and autophagy requires knowing the downstream effectors, and Aim 2 describes a novel chemical genomics approach to identify Pef1 targets. We modified the Pef1 kinase to allow selective binding of ATP analogs that tag kinase substrates to allow their isolation, and used the Pef1 variant to identify the substrates. We identified substrates with predicted roles in autophagy and lifespan, as well as substrates that we hypothesize mediate Pef1 control through signaling pathways.
Aim 2 will validate the substrates and identify substrates of the effector kinase Cek1.
Aim 3 will determine how the phosphorylation of Pef1 and Cek1 substrates affects specific processes in lifespan and autophagy control, and will also use high-throughput functional characterization of substrates to reveal signaling pathways regulated by the Pef1 pathway. The strong functional homology between Pef1 and human Cdk5 indicates that the Clg1-Pef1-Cek1 pathway, its substrates and functions will be conserved in humans, which we will also test in Aim 3. The results of these proposed studies will provide a mechanistic framework for a new, conserved lifespan and autophagy-regulating pathway with important ramifications for healthy human aging.
Interventions that slow aging and aging-related diseases would be of enormous benefit to society. Their design requires a better understanding of aging processes, and we made a major advance in discovering a new lifespan-extending pathway. We will determine how this pathway acts to control lifespan and the onset of aging-related diseases with the goal of identifying therapeutic targets in humans.
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