Honors & Awards


  • Long Term Fellowship, Human Frontiers Science Program (2016-2019)

Professional Education


  • Bachelor of Science, University of Waterloo (2009)
  • Master of Science, Ryerson University (2011)
  • Doctor of Philosophy, McGill University (2016)

Stanford Advisors


All Publications


  • A hormone receptor pathway cell-autonomously delays neuron morphological aging by suppressing endocytosis. PLoS biology Richardson, C. E., Yee, C., Shen, K. 2019; 17 (10): e3000452

    Abstract

    Neurons have a lifespan that parallels that of the organism and are largely irreplaceable. Their unusually long lifespan predisposes neurons to neurodegenerative disease. We sought to identify physiological mechanisms that delay neuron aging in Caenorhabditis elegans by asking how neuron morphological aging is arrested in the long-lived, alternate organismal state, the dauer diapause. We find that a hormone signaling pathway, the abnormal DAuer Formation (DAF) 12 nuclear hormone receptor (NHR) pathway, functions cell-intrinsically in the dauer diapause to arrest neuron morphological aging, and that same pathway can be cell-autonomously manipulated during normal organismal aging to delay neuron morphological aging. This delayed aging is mediated by suppressing constitutive endocytosis, which alters the subcellular localization of the actin regulator T cell lymphoma Invasion And Metastasis 1 (TIAM-1), thereby decreasing age-dependent neurite growth. Intriguingly, we show that suppressed endocytosis appears to be a general feature of cells in diapause, suggestive that this may be a mechanism to halt the growth and other age-related programs supported by most endosome recycling.

    View details for DOI 10.1371/journal.pbio.3000452

    View details for PubMedID 31589601

  • A single biochemical activity underlies the pleiotropy of the aging-related protein CLK-1. Scientific reports Liu, J. L., Yee, C., Wang, Y., Hekimi, S. 2017; 7 (1): 859

    Abstract

    The Caenorhabditis elegans clk-1 gene and the orthologous mouse gene Mclk1 encode a mitochondrial hydroxylase that is necessary for the biosynthesis of ubiquinone (UQ). Mutations in these genes produce broadly pleiotropic phenotypes in both species, including a lengthening of animal lifespan. A number of features of the C. elegans clk-1 mutants, including a maternal effect, particularly extensive pleiotropy, as well as unexplained differences between alleles have suggested that CLK-1/MCLK1 might have additional functions besides that in UQ biosynthesis. In addition, a recent study suggested that a cryptic nuclear localization signal could lead to nuclear localization in cultured mammalian cell lines. Here, by using immunohistochemical techniques in worms and purification techniques in mammalian cells, we failed to detect any nuclear enrichment of the MCLK1 or CLK-1 proteins and any biological activity of a C. elegans CLK-1 protein devoid of a mitochondrial localization sequence. In addition, and most importantly, by pharmacologically restoring UQ biosynthesis in clk-1 null mutants we show that loss of UQ biosynthesis is responsible for all phenotypes resulting from loss of CLK-1, including behavioral phenotypes, altered expression of mitochondrial quality control genes, and lifespan.

    View details for DOI 10.1038/s41598-017-00754-z

    View details for PubMedID 28404998

  • Antioxidants reveal an inverted U-shaped dose-response relationship between reactive oxygen species levels and the rate of aging in Caenorhabditis elegans. Aging cell Desjardins, D., Cacho-Valadez, B., Liu, J. L., Wang, Y., Yee, C., Bernard, K., Khaki, A., Breton, L., Hekimi, S. 2016

    Abstract

    Reactive oxygen species (ROS) are potentially toxic, but they are also signaling molecules that modulate aging. Recent observations that ROS can promote longevity have to be reconciled with the numerous claims about the benefits of antioxidants on lifespan. Here, three antioxidants [N-acetylcysteine (NAC), vitamin C, and resveratrol (RSV)] were tested on Caenorhabditis elegans mutants that alter drug uptake, mitochondrial function, and ROS metabolism. We observed that like pro-oxidants, antioxidants can both lengthen and shorten lifespan, dependent on concentration, genotypes, and conditions. The effects of antioxidants thus reveal an inverted U-shaped dose-response relationship between ROS levels and lifespan. In addition, we observed that RSV can act additively to both NAC and paraquat, to dramatically increase lifespan. This suggests that the effect of compounds that modulate ROS levels can be additive when their loci of action or mechanisms of action are sufficiently distinct.

    View details for DOI 10.1111/acel.12528

    View details for PubMedID 27683245

  • The Intrinsic Apoptosis Pathway Mediates the Pro-Longevity Response to Mitochondrial ROS in C. elegans CELL Yee, C., Yang, W., Hekimi, S. 2014; 157 (4): 897-909

    Abstract

    The increased longevity of the C. elegans electron transport chain mutants isp-1 and nuo-6 is mediated by mitochondrial ROS (mtROS) signaling. Here we show that the mtROS signal is relayed by the conserved, mitochondria-associated, intrinsic apoptosis signaling pathway (CED-9/Bcl2, CED-4/Apaf1, and CED-3/Casp9) triggered by CED-13, an alternative BH3-only protein. Activation of the pathway by an elevation of mtROS does not affect apoptosis but protects from the consequences of mitochondrial dysfunction by triggering a unique pattern of gene expression that modulates stress sensitivity and promotes survival. In vertebrates, mtROS induce apoptosis through the intrinsic pathway to protect from severely damaged cells. Our observations in nematodes demonstrate that sensing of mtROS by the apoptotic pathway can, independently of apoptosis, elicit protective mechanisms that keep the organism alive under stressful conditions. This results in extended longevity when mtROS generation is inappropriately elevated. These findings clarify the relationships between mitochondria, ROS, apoptosis, and aging.

    View details for DOI 10.1016/j.cell.2014.02.055

    View details for Web of Science ID 000335765500017

    View details for PubMedID 24813612

  • ENU-3 Functions in an UNC-6/Netrin Dependent Pathway Parallel to UNC-40/DCC/Frazzled for Outgrowth and Guidance of the Touch Receptor Neurons in C-elegans DEVELOPMENTAL DYNAMICS Yee, C., Florica, R., Fillingham, J., Killeen, M. T. 2014; 243 (3): 459-467

    Abstract

    UNC-6 and SLT-1 guide the migrations of the ventrally directed processes of the AVM and PVM touch receptor neurons and UNC-6 guides the axons of the DA and DB classes of motor neurons in C. elegans. The UNC-6 receptors are UNC-5 and UNC-40. The axon outgrowth defects of a subset of the DB motor neurons in the absence of UNC-5 are enhanced by mutations in enu-3.An enu-3 mutation enhances defects in ventral guidance of the processes of the AVM and PVM touch receptor neurons, the dorsal guidance of the distal tip cell and causes additional architectural defects in axons in unc-40 mutant strains in an UNC-6 dependent manner. These observations suggest that ENU-3 and UNC-40 function in parallel pathways dependent on UNC-6. ENU-3 depends on the presence of UNC-40 for its full effect on motor neuron axon outgrowth.ENU-3 works in an UNC-6 dependent pathway parallel to UNC-40 in ventral guidance of AVM and PVM and in dorsal guidance of the distal tip cells. Motor neuron axon outgrowth defects are caused by the presence of UNC-40 and the absence of functional UNC-5 or UNC-6 and defects are enhanced by the absence of functional ENU-3.

    View details for DOI 10.1002/dvdy.24063

    View details for Web of Science ID 000331374000010

    View details for PubMedID 24123761

  • CEP-1, the Caenorhabditis elegans p53 Homolog, Mediates Opposing Longevity Outcomes in Mitochondrial Electron Transport Chain Mutants PLOS GENETICS Baruah, A., Chang, H., Hall, M., Yuan, J., Gordon, S., Johnson, E., Shtessel, L. L., Yee, C., Hekimi, S., Derry, W. B., Lee, S. S. 2014; 10 (2)

    Abstract

    Caenorhabditis elegans CEP-1 and its mammalian homolog p53 are critical for responding to diverse stress signals. In this study, we found that cep-1 inactivation suppressed the prolonged lifespan of electron transport chain (ETC) mutants, such as isp-1 and nuo-6, but rescued the shortened lifespan of other ETC mutants, such as mev-1 and gas-1. We compared the CEP-1-regulated transcriptional profiles of the long-lived isp-1 and the short-lived mev-1 mutants and, to our surprise, found that CEP-1 regulated largely similar sets of target genes in the two mutants despite exerting opposing effects on their longevity. Further analyses identified a small subset of CEP-1-regulated genes that displayed distinct expression changes between the isp-1 and mev-1 mutants. Interestingly, this small group of differentially regulated genes are enriched for the "aging" Gene Ontology term, consistent with the hypothesis that they might be particularly important for mediating the distinct longevity effects of CEP-1 in isp-1 and mev-1 mutants. We further focused on one of these differentially regulated genes, ftn-1, which encodes ferritin in C. elegans, and demonstrated that it specifically contributed to the extended lifespan of isp-1 mutant worms but did not affect the mev-1 mutant lifespan. We propose that CEP-1 responds to different mitochondrial ETC stress by mounting distinct compensatory responses accordingly to modulate animal physiology and longevity. Our findings provide insights into how mammalian p53 might respond to distinct mitochondrial stressors to influence cellular and organismal responses.

    View details for DOI 10.1371/journal.pgen.1004097

    View details for Web of Science ID 000332021500046

    View details for PubMedID 24586177

  • ENU-3 is a novel motor axon outgrowth and guidance protein in C. elegans DEVELOPMENTAL BIOLOGY Yee, C. S., Sybingco, S. S., Serdetchania, V., Kholkina, G., de Mesquita, M. B., Naqvi, Z., Park, S., Lam, K., Killeen, M. T. 2011; 352 (2): 243-253

    Abstract

    During the development of the nervous system, the migration of many cells and axons is guided by extracellular molecules. These molecules bind to receptors at the tips of the growth cones of migrating axons and trigger intracellular signaling to steer the axons along the correct trajectories. We have identified a novel mutant, enu-3 (enhancer of Unc), that enhances the motor neuron axon outgrowth defects observed in strains of Caenorhabditis elegans that lack either the UNC-5 receptor or its ligand UNC-6/Netrin. Specifically, the double-mutant strains have enhanced axonal outgrowth defects mainly in DB4, DB5 and DB6 motor neurons. enu-3 single mutants have weak motor neuron axon migration defects. Both outgrowth defects of double mutants and axon migration defects of enu-3 mutants were rescued by expression of the H04D03.1 gene product. ENU-3/H04D03.1 encodes a novel predicted putative trans-membrane protein of 204 amino acids. It is a member of a family of highly homologous proteins of previously unknown function in the C. elegans genome. ENU-3 is expressed in the PVT interneuron and is weakly expressed in many cell bodies along the ventral cord, including those of the DA and DB motor neurons. We conclude that ENU-3 is a novel C. elegans protein that affects both motor axon outgrowth and guidance.

    View details for DOI 10.1016/j.ydbio.2011.01.024

    View details for Web of Science ID 000289180200006

    View details for PubMedID 21295567