News Release

UC San Diego Bioengineers Uncover Lipid Metabolic Dynamics in Drosophila Brain During Aging

The research relies on a new imaging technique called SRS Imaging that allows researchers to peer inside living cells without disturbing cell function. This research demonstrates a new approach for studying brain lipid metabolic activity in live cells. Th

July 26, 2023: 

Aging is an inevitable phenomenon in the process of life, accompanied by the deterioration of physiological functions and increased susceptibility to diseases. Studies have found a connection between lipid metabolism and aging as well as age-related diseases [1]. Lipid droplets, organelles that store fat, are closely linked to lipid metabolism in terms of their size and number. In recent years, researchers have gained a deeper understanding of the important functions of lipid droplets in cellular metabolism and the optimal functioning of organisms more generally [2]. However, the changes in lipid metabolism with age and how nutrient and metabolic pathways regulate lipid metabolism are still under investigation.

Recently, a study on the dynamic changes in lipid droplet metabolism in the Drosophila brain during aging has made significant progress. The research team is led by Lingyan Shi from the Shu Chien-Gene Lay Department of Bioengineering at the University of California San Diego. The team published its findings in the latest issue of the peer-reviewed journal GEN Biotechnology [3].

The researchers employed a novel microscopy imaging technique called deuterium oxide (D2O)-stimulated Raman scattering (DO-SRS) to observe in situ the dynamic changes in lipid droplet metabolism in the Drosophila brain with respect to age, gender, and dietary restriction (Fig. 1 & 2). The study revealed the density, size, membrane, and distribution of lipid droplets in different cell types.

Conceptual illustration considering the interplay between lipid drop 
storage and consumption, diet and aging. Illustration credit: Yuhan (Mary) Li,
who is a student in the Lingyan Shi Lab at UC San Diego. 


The study found that the brains of young flies contain metabolically active small lipid droplets with lipid-rich membranes. However, as flies age, the lipid droplets gradually increase in size and become less metabolically active, resulting in a decrease in the lipid composition of the brain. This finding reveals the interplay between lipid droplet storage and consumption, indicating the presence of functional impairments in the aging brain. Further research showed that downregulation of the insulin/IGF-1 signaling pathway can reverse altered lipid metabolism,   highlighting the crucial role of lipid droplet homeostasis in brain health. Maintaining a balance between lipid synthesis and breakdown is essential for lipid transport between glial cells and neurons. Dietary restriction significantly enhances lipid exchange in the aging fly brain and downregulates the insulin/IGF-1 signaling pathway (Fig. 3), thereby extending lifespan.

In the study of different genders of flies, it was found that the abundance and size of lipid droplets in the female fly brain are consistently higher than those in the male fly brain during the aging process. This finding reflects the possibility of higher detoxification capacity in females, partially explaining the phenomenon of females having longer lifespans than males. It provides clues for further research on the gender-dependent regulation of lipid droplet mechanisms.

The first author-Yajuan Li, MD, PhD-a postdoctoral researcher in Shi Lab in the UC San Diego Jacobs School of Engineering, and the corresponding author -- bioengineering professor Lingyan Shi -- the Principal Investigator, stated that their high-resolution in situ imaging method established for the first time directly observed and quantified lipid metabolism in the Drosophila brain. This technique is not only limited to brain imaging but can also be more widely applied within organisms, providing a reliable platform for future research on lipid droplet metabolism.

Additional authors who participated in this study entitled “Bioorthogonal Stimulated Raman Scattering Imaging Uncovers Lipid Metabolic Dynamics in Drosophila Brain During Aging” and made significant contributions include Phyllis Chang, Shriya Sankaran, Dr. Hongje Jang, Yuhang Nie, Audrey Zeng, Sahran Hussain, Dr. Jane Y. Wu, and Dr. Xu Chen.
 

Metabolic activity of lipid droplets in the brain during the aging process can be observed using DO-SRS imaging technique. DO-SRS imaging shows lipid droplets in the brains of 5-day-old and 35-day-old female and male flies. The images were captured at 2850 cm-1 (CH, total lipids) and 2143 cm-1 (CD, newly synthesized lipids) respectively. The signals are colored in green (CH, total lipids), cyan (CD, newly synthesized lipids), and blue (CD/CH). Columns 1-3: Typical single lipid droplets within dashed boxes; columns 4-5: Enlarged view of the lipid droplets; column 6: Intensity variation curves inside a single lipid droplet showing the distribution of newly synthesized lipids. Scale bar: 10 µm.


Funding: The authors acknowledge support from UC San Diego startup funds, NIH U54 2U54CA132378, NIH 5R01NS111039, NIH R21NS125395, Sloan Research Fellow Award, and Hellman Fellow Award.

The researchers report that no competing financial interests exist.

References:

1. Chung KW. Advances in understanding of the role of lipid metabolism in aging. Cells 2021;10(4):880; doi: 10.3390/cells10040880

2. Zadoorian A, Du X, Yang H. Lipid droplet biogenesis and functions in health and disease. Nat Rev Endocrinol 2023;1-17, doi:10.1038/s41574-023-00845-0

3.      Li Y, Chang P, Sankaran S, Jang H, Nie Y, Zeng A, Hussain S, Wu JY, Chen X, Shi L**, "Bioorthogonal SRS Imaging Uncovers Lipid Metabolic Dynamics in Brain During Aging" GEN Biotechnology, https://doi.org/10.1089/genbio.2023.0017 , 2023

4. Yamazaki Y, Zhao N, Caulfield TR, et al. Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies. Nat Rev Neurol 2019;15(9):501-518, doi:10.1038/s41582-019-0228-7

5. Fanning S, Haque A, Imberdis T, et al. Lipidomic Analysis of alpha-Synuclein Neurotoxicity Identifies Stearoyl CoA Desaturase as a Target for Parkinson Treatment. Mol Cell 2019;73(5):1001-1014 e8, doi:10.1016/j.molcel.2018.11.028

 

Media Contacts

Daniel Kane
Jacobs School of Engineering
858-534-3262
dbkane@ucsd.edu

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