Lifespan Regulation by Inter-Organellar Heme Signaling - PROJECT SUMMARY The long-term objectives of this proposal are to elucidate heme signaling networks that regulate the metabolic adaption to aging and control lifespan. The canonical function of heme in cell biology is as a protein cofactor. More recent studies indicate that heme may act as a dynamic signaling molecule. Previous studies have shown that there is a decline in heme concentration in several cell and animal models of aging, and this decline is associated with various hallmarks of aging, including mitochondrial dysfunction, oxidative stress, and diminished lifespan. In our recent unpublished studies, we found that limiting cellular heme dramatically increases lifespan in cell (Saccharomyces cerevisiae) and animal (Caenorhabditis elegans) models of aging. However, the mechanisms by which heme regulates lifespan are not known. The current proposal integrates genetically encoded heme sensors, heme chelators, mass spectrometry approaches, and molecular genetics, to probe the role of heme in aging and the mechanisms it acts through to control lifespan. In particular, we seek to identify the targets of heme signaling that control lifespan, the mechanisms that mediate inter-organelle and inter-organ heme transfer to regulate lifespan, and the subcellular and tissue/organ locations where heme signaling operates to respond to aging and control lifespan. Two specific aims are proposed in which the role of heme in cellular and animal aging will be probed in Saccharomyces cerevisiae, a cell model, (Aim 1) and in Caenorhabditis elegans, an animal model (Aim 2). In Aim 1, to elucidate the mechanisms of inter-organelle heme signaling in a yeast cell model of aging, we will (a) identify the targets of heme signaling using complementary genetic and hemoproteomics approaches, (b) determine the subcellular location where heme is sourced for heme signaling, and elucidate inter-organellar heme trafficking pathways using gene-deletion and proteomics screens. In Aim 2, to elucidate the mechanisms of inter-organ heme signaling in a worm animal model of aging, we will (a) determine the role of heme and heme responsive genes (hrgs) in modifying lifespan in long-lived [daf-2] and short-lived [daf-16] worm mutants, (b) identify the sender and receiver cells of heme signaling in control of lifespan using tissue-restricted genetically encoded heme sensors in long-lived and short-lived mutants, (c) assess organ and subcellular labile heme pools that control lifespan, and deploy hemoproteomics to identify novel targets of heme signaling that could control lifespan and assess the impact of these candidate interactors on heme signaling The current proposal will be the first to comprehensively decipher the role of heme in aging and may lead to new heme-based therapeutic interventions that can be used to slow aging or treat age associated diseases.
