We study the relationship between stress, aging and metabolism. Environmental stresses are generally considered to accelerate aging and age-associated tissue dysfunction because they damage important cellular macromolecules such as DNA, protein and lipids. However, cells have several stress adaptation mechanisms that can reduce negative impacts on cell and organismal homeostasis. Interestingly, appropriate activation of such adaptive mechanisms could often lead to not only increased stress resistance but also general extension of health and lifespan. We hope that, in the future, we are able to utilize some of these protective mechanisms to generate therapeutics for age-associated degenerative disorders. We have four specific research projects that cover the stress-aging relationship.
(1) Sestrin, a family of stress-inducible proteins that suppress age- and obesity-associated pathologies.
Biochemical and Physiological Roles of Sestrins.
(Center) Janus-faced Sestrins reduce oxidative stress and suppress mTORC1 signalling through their two independent functional motifs that face diametrically opposed directions. (Upper) Many different environmental stress can regulate Sestrins through transcriptional and post-transcriptional mechanisms. (Left) Sestrins reduce oxidative stress through multiple independent mechanisms. (Right) Sestrins regulate multiple cell signaling pathways. (Lower) Through these activities, Sestrins suppress a variety of age- and obesity-associated pathologies.
(2) Molecular mechanisms underlying physiological autophagy regulation and pathogenetic mechanisms of how autophagy is abrogated in human diseases.
Relationship between Obesity and Autophagy
Sophisticated interaction between autophagy and obesity-associated pathologies is schematically illustrated. The image and text are from Mol Cells. 41, 3–10.
(3) Stress-induced alteration of the mRNA transcriptome at subcellular and single cell resolution.
Systematic Characterization of Stress-Induced RNA Granulation
We devised a novel method for characterizing mRNA species sequestered in insoluble RNP granules in normal and stressed cells. Using the method, we showed that endoplasmic reticulum (ER) stress targets only a small subset of translationally suppressed mRNAs into the insoluble RNP granule fraction (RG). This subset, characterized by extended length and adenylate-uridylate (AU)-rich motifs, is highly enriched with genes critical for cell survival and proliferation. This pattern of RG targeting was conserved for two other stress types, heat shock and arsenite toxicity, which induce distinct responses in the total cytoplasmic transcriptome. Nevertheless, stress-specific RG-targeting motifs, such as guanylate-cytidylate (GC)-rich motifs in heat shock, were also identified. Previously underappreciated, transcriptome profiling in the RG may contribute to understanding human diseases associated with RNP dysfunction, such as cancer and neurodegeneration. The image and text are from Mol Cell 70, 175-187.
(4) Seq-Scope: Submicrometer-resolution Spatial Transcriptomics for Single Cell and Subcellular Studies.
Microscopic Examination of Spatial Transcriptome using Seq-Scope
Seq-Scope uses spatial barcoding and the Illumina sequencing platform to achieve sub-micron resolution spatial transcriptomics, enabling the visualization of transcriptomic heterogeneity at the cellular and subcellular level in various tissues. The image and text are from Cell 184, 3559-3572
Previous Research Statements
As of Fall 2011
Previously, the PI investigated genetic programs governing diverse animal physiologies using Drosophila and mice as model organisms. Specifically, he focused on several key signaling pathways that control growth, aging, differentiation, innate immunity, inflammation, apoptosis and cell polarity. For his Ph.D. thesis, he studied the function of p53 and LKB1, two tumor suppressors frequently mutated in human cancers. Using p53-null flies, one of the first models lacking all p53 function, he confirmed the role of p53 in DNA damage-induced apoptosis and maintenance of genomic stability (Lee et al. FEBS lett 550, 5). In addition, through fly genetic screening, he found that JNK mediates LKB1-induced apoptosis (Lee et al. Cell Death Differ 13, 1110). Subsequent studies led him to make a more striking finding that AMPK, a downstream kinase of LKB1, is mediating energy-dependent regulation of cell shape. This work was published in Nature (Lee et al. Nature 447, 1017).
As a postdoc in Dr. Karin’s lab at UC San Diego, he focused on Sestrins, novel stress-inducible molecules regulated by p53. Utilizing his expertise in Drosophila and p53/AMPK/TOR signaling, he was able to reveal the novel role for Sestrin as a feedback regulator of TOR signaling, which attenuates diverse age- and obesity-associated pathologies such as cancerous cell growth, fat accumulation, muscle degeneration and cardiac malfunction. He also suggested that the pathologies partially result from defective ATG1-mediated autophagy and diminished clearance of dysfunctional mitochondria, protein aggregates, and lipids. This work was published in Science as the cover story article (Lee et al. Science 327, 1223). In parallel with the Sestrin project, he was involved in another project that investigates the relationship between obesity and liver cancer, and found that inflammatory cytokine signalings are critical for obesity promotion of liver pathologies, such as hepatosteatosis, steatohepatitis and hepatocellular carcinoma (Park et al. Cell 140, 197). In subsequent studies, he found that mammalian Sestrin 2 is functioning to attenuate the obesity-induced metabolic derangements in mouse liver.
As an independent lab, we will continue focusing on the role of Sestrins in suppressing diverse pathologies that are associated with obesity and aging, using Sestrins-KO and transgenic mice and mouse models of cancer, metabolic diseases, neurodegeneration, cardiac arrhythmia and muscle degeneration. Considering that Sestrins are stress-inducible proteins, these studies may reveal a potential role of Sestrin in mediating hormesis, a paradoxical beneficial effects of low-level stresses.
At the same time, using phospho-proteomics and genome-wide RNAi screening in Drosophila cells, we will identify new genetic components that mediate ATG1-dependent control of autophagy and autophagic removal of damaged mitochondria, which are critical for preventing aging and associated pathologies. Then, using Drosophila genetics, we will characterize the biological roles of newly isolated genetic components. Following these foundation-building experiments, we will embark on long-term mouse experiments on the molecules and related hypotheses. By utilizing both Drosophila and mouse systems, we will be able to conduct the two-pronged approaches for each individual research project, and this dual strategy will increase the effectiveness of our research program and allow us to decipher the fundamental genetic mechanisms of growth and aging that are encoded in our genome.