Dietary restriction (DR) increases lifespan and delays the onset of age-dependent diseases. The overarching goal of this proposal is to identify the molecular mechanisms underlying the benefits of DR on longevity. The energy-sensing AMP-activated protein kinase (AMPK) is activated in response to decreased cellular energy levels, a direct consequence of DR, raising the possibility that AMPK mediates lifespan extension in response to DR. We recently showed that AMPK is required for DR to extend lifespan in worms and that AMPK phosphorylates and activates FoxO transcription factors, proteins that are known to regulate lifespan in several species. Based on recent work in which we identified genes regulated by FoxO transcription factors in response to AMPK activation, we hypothesize that the energy-sensing AMPK translates DR signals into long-term changes in gene expression programs, at least partly through the activation of FoxO transcription factors. To address the question of how AMPK regulates the extension of lifespan in response to DR, we propose the following specific aims:
Aim 1. To dissect the role of the AMPK family in sensing DR signals Aim 2. To determine the molecular mechanisms by which AMPK extends lifespan A combination of genetics and biochemical approaches in Caenorhabditis elegans (C. elegans) will be used to develop these aims. Deciphering the mechanisms by which AMPK controls longevity in response to DR will increase our knowledge of the genes and the cellular responses that are important to control lifespan. Understanding the role of the AMPK-FoxO pathway in longevity in C. elegans will also provide a molecular foundation for studying the mechanisms underlying DR benefits on lifespan in mammals.
Dietary restriction (DR) extends lifespan and delays the onset of age-dependent diseases, including cancer and neurodegenerative disorders. Identifying the molecular basis by which DR exerts its benefits on lifespan will help uncover the important components of the DR regimen to possibly mimic the effects of DR to make it of practical use for preventing and treating age-dependent pathologies.
|Hardie, D Grahame; Schaffer, Bethany E; Brunet, Anne (2016) AMPK: An Energy-Sensing Pathway with Multiple Inputs and Outputs. Trends Cell Biol 26:190-201|
|Schaffer, Bethany E; Levin, Rebecca S; Hertz, Nicholas T et al. (2015) Identification of AMPK Phosphorylation Sites Reveals a Network of Proteins Involved in Cell Invasion and Facilitates Large-Scale Substrate Prediction. Cell Metab 22:907-21|
|Maures, Travis J; Booth, Lauren N; Benayoun, Berenice A et al. (2014) Males shorten the life span of C. elegans hermaphrodites via secreted compounds. Science 343:541-4|
|Lim, Jana P; Brunet, Anne (2013) Bridging the transgenerational gap with epigenetic memory. Trends Genet 29:176-86|
|Han, Shuo; Brunet, Anne (2012) Histone methylation makes its mark on longevity. Trends Cell Biol 22:42-9|
|Greer, Eric L; Maures, Travis J; Ucar, Duygu et al. (2011) Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature 479:365-71|
|Maures, Travis J; Greer, Eric L; Hauswirth, Anna G et al. (2011) The H3K27 demethylase UTX-1 regulates C.Â elegans lifespan in a germline-independent, insulin-dependent manner. Aging Cell 10:980-90|
|Banko, Max R; Allen, Jasmina J; Schaffer, Bethany E et al. (2011) Chemical genetic screen for AMPKÎ±2 substrates uncovers a network of proteins involved in mitosis. Mol Cell 44:878-92|
|Greer, Eric L; Maures, Travis J; Hauswirth, Anna G et al. (2010) Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature 466:383-7|
|Greer, Eric L; Banko, Max R; Brunet, Anne (2009) AMP-activated protein kinase and FoxO transcription factors in dietary restriction-induced longevity. Ann N Y Acad Sci 1170:688-92|
Showing the most recent 10 out of 11 publications