Scientists at the Salk Institute find anti-inflammatory molecules that decline with age in the brain
Inflammation, stress, and shifts in metabolism are just a few of the many players in the process of aging. Scientists from the Salk Institute and the University of California, San Diego have discovered a group of lipids known as SGDGs (3-sulfogalactosyl diacylglycerols) that decline in the brain with age and may have anti-inflammatory effects, adding to the list of factors implicated in the aging process.
Published in Nature Chemical Biology on October 20, 2022, the study contributes to the understanding of the molecular foundation of brain aging, sheds light on the mechanisms behind age-related neurological illnesses, and opens up prospects for clinical treatment in the future.
Professor in the Clayton Foundation Laboratories for Peptide Biology at Salk and holder of the Dr. Frederik Paulsen Chair Alan Saghatelian said that these SGDGs clearly play a crucial role in aging, and this finding provides the opportunity that there are additional critical aging mechanisms we’ve been missing. The researchers added that it seems like this is the kind of thing that has to be investigated further down the road.
The lipids, or fats, of which SGDGs are a subclass. However, improper regulation of lipids has been related to accelerated brain aging and neurodegenerative diseases. Lipids play an important role in brain structure, development, and function when they are present in healthy levels. But unlike genes and proteins, lipids are not well understood, and they have been largely ignored in studies of aging. Saghatelian has made a name for himself in the field of lipid structure determination and discovery.
With the help of UC San Diego’s Professor Dionicio Siegel, his lab made three SGDG-related discoveries: Lipid levels in the brain of older mice are drastically different from those of younger mice; SGDGs and all related lipids undergo substantial changes with age; and SGDGs may be regulated by systems known to influence aging.
To get at these results, the researchers utilized a novel, exploratory method by integrating structural chemistry and high-throughput data analytics with the large-scale study of lipids. Lipid profiles of mouse brains were originally collected using liquid chromatography-mass spectrometry at five different ages, spanning from one to eighteen months. The number of measurements that could be taken by this equipment has increased dramatically thanks to technological advancements, and sophisticated data analysis has allowed researchers to identify age-related trends in the massive lipid profiles that have been generated. Afterwards, they built SGDG molecules and examined their biological efficacy.
Since its discovery in the 1970s, however, SGDGs have received little additional research. The lipid databases did not include these compounds because they were practically forgotten. Postdoctoral fellow in Saghatelian’s group at Salk and first author Dan Tan added that nobody realized SGDGs would change or be regulated in aging, let alone that they have bioactivity and, maybe, be therapeutically targetable.
The results of the study demonstrated that SGDGs have anti-inflammatory effects, which may be of importance in the treatment of neurodegenerative illnesses and other neurological ailments characterized by elevated brain inflammation.
SGDGs were also found in the brains of humans and primates, suggesting that they may have vital functions outside of mice. To prove that SGDGs play a role in human neuroinflammation, more study is needed.
To find new genetic activity related with aging, the team plans to investigate how SGDGs are controlled with age and which proteins are responsible for their production and breakdown in the future.
Siegel, co-corresponding author of the paper, explains that they now know the structure of SGDGs and can synthesize them in the lab, the study of these critical lipids is wide open and ripe for exploration.
Tan, D., Konduri, S., Erikci Ertunc, M. et al. A class of anti-inflammatory lipids decrease with aging in the central nervous system. Nat Chem Biol (2022). https://doi.org/10.1038/s41589-022-01165-6