The brain is comprised of lipids or fats, but the role of these molecules in health and disease remains unknown. The newly identified class of lipids, called SGDGs, decrease with aging, which suggests they may play a role in brain aging. Credit: Salk Institute
Lipids are estimated to make up more than 50% of the adult human brain, and serve an important role in its structure, development and function. Despite this, in comparison to genetics and proteomics, limited research has been focused on the brain lipidome and its role in brain aging. Research by a team of Salk Institute and UC San Diego scientists have now identified a little known class of lipids that decline in the brain with age and may have anti-inflammatory effects, opening up new avenues for studying age-related neurological diseases and exploring potential treatment targets.
The team took an untargeted lipidomics approach to examining the brains of mice at various age stages. Using liquid chromatography-mass spectrometry (LC-MS), the researchers obtained lipid profiles of mouse brains at 4 weeks, 12 weeks, 25 weeks, 48 weeks and 78 weeks. Co-expression network analysis revealed patterns in lipid levels with increasing age; the team identified a progressive decrease in levels of a lipid class called 3-sulfogalactosyl diacylglycerols (SGDGs) as age increased. SGDGs are a class of lipids that were first identified in the 1970s, but “were essentially forgotten and missing from the lipid databases,” said first author Dan Tan, a postdoctoral fellow at the Salk Institute. The bioactivity and role of SGDGs in brain aging have not been previously explored.
To better understand the potential function of SGDGs in the brain, the team studied their chemical structure in order to produce SGDGs in the laboratory. The researchers constructed and tested the lipids for biological activity, and found they exhibited anti-inflammatory properties; specifically, by acting on the NF-κB pathway, these lipids suppressed the release of pro-inflammatory cytokines and lipopolysaccharide (LPS)-induced gene expression, the authors wrote. These findings suggest that the decline of SGDGs in the brain may play a role in neurodegenerative disorders and other neurological conditions that involve increased inflammation in the brain. The researchers found that SGDGs exist in human and primate brains as well, meaning their potential role in human neuroinflammation could be further explored. This study was published in Nature Chemical Biology.
“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,” said co-corresponding author Alan Saghatelian, a professor in Salk’s Clayton Foundation Laboratories for Peptide Biology. “This is a pretty clear case of something that should be dug into more in the future.”
The team plans to further examine how SGDGs are regulated with aging, as well which proteins are responsible for making them and breaking them down, which could open the door to discovering novel genetic activity associated with aging.