Title: Metabolic Nanoscopy for Studying Aging and Diseases

Abstract: Understanding metabolism in living organisms is crucial for uncovering the fundamental mechanisms underlying various biological processes. We developed the A-PoD and PRM algorithm-assisted multimodal metabolic nanoscopy, which integrates DO-SRS, MPF, FLIM, and SHG into a unified molecular imaging platform for studying metabolic dynamics in living organisms. This approach utilizes various deuterated molecules—including glucose, amino acids, fatty acids, and water etc. as bioorthogonal metabolic probes. The enzymatic incorporation of deuterium results in carbon-deuterium (C-D) bonds in newly synthesized molecules, which can be detected by DO-SRS in the Raman spectrum’s spectral cell-silent region, distinguishing them from older molecules. This nanoscopy provides novel insights into metabolic heterogeneity across different cell types and organ tissues under both physiological and pathological conditions. For example, it revealed that overexpressed tau proteins significantly disrupt lipid metabolism in aged and Alzheimer’s-affected brains, leading to an excessive accumulation of newly formed lipid droplets in glial cells—an effect that can be mitigated by AMPK activation. This advanced nanoscopy imaging platform holds significant potential for disease detection, diagnosis, drug discovery, and evaluating drug efficacy or resistance. It can serve as a tool for understanding the fundamental mechanisms of aging and disease progression.

Bio: Lingyan Shi is currently a tenured 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" (1550nm to 1870nm) for deep tissue imaging and pioneered the "DO-SRS" metabolic imaging platform, which visualizes metabolic dynamics in cellular organelles, and tissues. Her group 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 14 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), ICBME Rising Star Award 2024, and IUPS Young Faculty Award 2024, Featured in the 2025 Optics notebook, women in optics, and selected to be senior member of National Academy of Inventors (NAI).

Title: Metabolic Nanoscopy for Studying Aging and Diseases

Abstract: Understanding metabolism in living organisms is crucial for uncovering the fundamental mechanisms underlying various biological processes. We developed the A-PoD and PRM algorithm-assisted multimodal metabolic nanoscopy, which integrates DO-SRS, MPF, FLIM, and SHG into a unified molecular imaging platform for studying metabolic dynamics in living organisms. This approach utilizes various deuterated molecules—including glucose, amino acids, fatty acids, and water etc. as bioorthogonal metabolic probes. The enzymatic incorporation of deuterium results in carbon-deuterium (C-D) bonds in newly synthesized molecules, which can be detected by DO-SRS in the Raman spectrum’s spectral cell-silent region, distinguishing them from older molecules. This nanoscopy provides novel insights into metabolic heterogeneity across different cell types and organ tissues under both physiological and pathological conditions. For example, it revealed that overexpressed tau proteins significantly disrupt lipid metabolism in aged and Alzheimer’s-affected brains, leading to an excessive accumulation of newly formed lipid droplets in glial cells—an effect that can be mitigated by AMPK activation. This advanced nanoscopy imaging platform holds significant potential for disease detection, diagnosis, drug discovery, and evaluating drug efficacy or resistance. It can serve as a tool for understanding the fundamental mechanisms of aging and disease progression.

Bio: Lingyan Shi is currently a tenured 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" (1550nm to 1870nm) for deep tissue imaging and pioneered the "DO-SRS" metabolic imaging platform, which visualizes metabolic dynamics in cellular organelles, and tissues. Her group 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 14 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), ICBME Rising Star Award 2024, and IUPS Young Faculty Award 2024, Featured in the 2025 Optics notebook, women in optics, and selected to be senior member of National Academy of Inventors (NAI).