Scientists discover anti-inflammatory molecules that decline in the aging brain: The molecules, called SGDGs, may lead to new ways to treat age-related neurological diseases

Aging involves complicated plot twists and a large cast of characters: inflammation, stress, metabolism changes, and many others. Now, a team of Salk Institute and UC San Diego scientists reveal another factor implicated in the aging process — a class of lipids called SGDGs (3-sulfogalactosyl diacylglycerols) that decline in the brain with age and may have anti-inflammatory effects.

The research, published in Nature Chemical Biology on October 20, 2022, helps unravel the molecular basis of brain aging, reveals new mechanisms underlying age-related neurological diseases, and offers future opportunities for therapeutic intervention.

“These SGDGs clearly play an important role in aging, and this finding opens up the possibility that there are other critical aging pathways we’ve been missing,” says co-corresponding author Alan Saghatelian, professor in Salk’s Clayton Foundation Laboratories for Peptide Biology and holder of the Dr. Frederik Paulsen Chair. “This is a pretty clear case of something that should be dug into more in the future.”

SGDGs are a class of lipids, also called fats. Lipids contribute to the structure, development, and function of healthy brains, while badly regulated lipids are linked to aging and diseased brains. However, lipids, unlike genes and proteins, are not well understood and have often been overlooked in aging research. Saghatelian specializes in discovering new lipids and determining their structures.

His lab, in collaboration with Professor Dionicio Siegel at UC San Diego, made three discoveries involving SGDGs: In the brain, lipid levels are very different in older mice than in younger mice; all SGDG family members and related lipids change significantly with age; and SGDGs may be regulated by processes that are known to regulate aging.

To reach these findings, the team took an unusual, exploratory approach that combined the large-scale study of lipids (lipidomics) with structural chemistry and advanced data analytics. They first obtained lipid profiles of mouse brains at five ages, ranging from one to 18 months, using liquid chromatography-mass spectrometry. Technological advances in this instrumentation vastly expanded the number of data points available to the scientists, and advanced data analysis allowed them to determine age-related patterns in the enormous lipid profiles. The team then constructed SGDG molecules and tested them for biological activity.

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