Multimodal Metabolic Nanoscopy for Studying Aging and Related Diseases
Abstract
Understanding how metabolism functions in multicellular organisms is essential for revealing the fundamental mechanisms of numerous biological processes. Metabolism involves the creation, transformation, and breakdown of biomolecules, acting according to genetic instructions. Traditional imaging techniques like MRI, PET, fluorescence, and mass spectrometry come with limitations. In contrast, stimulated Raman scattering (SRS), a non-linear vibrational imaging microscopy technique, offers chemically specific images with high resolution, deep penetration, and the ability to quantify. Our research has developed and combined deuterium-probed picosecond stimulated Raman scattering (DO SRS), multiphoton fluorescence (MPF), and second harmonic generation (SHG) into a unified nanoscopy. This tool is designed for studying metabolic changes in aging and diseases. The process of enzymatic incorporation of deuterium generates carbon-deuterium (C-D) bonds in newly formed molecules, detectable by DO-SRS within the spectral cell silence region of the Raman spectrum, which identifies them apart from older molecules.
One significant finding is that lipid turnover decreases faster in aged female Drosophila compared to males. Additionally, dietary restrictions, downregulation of the insulin/IGF-1 signaling (IIS) pathway, and AMPK activation significantly alter lipid metabolism in aged or Alzheimer’s-affected brains. The introduction of APoD and PRM algorithms has enhanced our current multimodal metabolic nanoscopy to deliver superresolution with hyperspectral volumetric imaging capabilities. By using deuterated molecules—including glucose, amino acids, fatty acids, and water molecules—as bioorthogonal probes, this technology provides insights into the metabolic heterogeneity of organs such as the brain, adipose tissue, liver, muscle, retina, and kidneys.
Biography
Lingyan Shi is currently an Associate Professor in the Shu Chien Gene Lay Department of Bioengineering at UCSD. She joined UCSD in 2019, following her postdoctoral training in the Department of Chemistry at Columbia University. Her lab at UCSD focuses on developing high-resolution metabolic nanoscopy to study aging processes and related diseases. Notably, she discovered the “Golden Window” for deep tissue imaging and pioneered the “DO-SRS” metabolic imaging platform, which visualizes metabolic dynamics in cells and tissues. At UC San Diego, her group further advanced stimulated Raman scattering (SRS) microscopy into super-resolution multiplex nanoscopy by developing A-PoD and PRM algorithms, revealing various lipid metabolic changes in organ tissues during aging and disease.
Dr. Shi holds 10 awarded patents and 8 pending. She won Blavatnik Regional Award for Young Scientists (2018), Nature Light Science & Applications’ Rising Star Award (2021), the Advancing Bioimaging Scialog Fellow Award 2023, the David L. Williams Lecture Scholarship Award (2023), the Sloan Research Fellowship in Chemistry (2023), the BMES Cellular Molecular Bioengineering Rising Star Faculty Award (2024), the Davos Summit iCANx Young Scientist Award (2024), and Featured in the 2025 Global Woman in Optics notebook.
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