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Researchers discover anti-inflammatory molecules that decline in the aging brain

Researchers discover anti-inflammatory molecules that decline in the aging brain

Summary: SGDGs, a class of lipids that decline in the brain during aging, appear to have anti-inflammatory effects that could have implications for neurodegenerative disorders.

Source: Salk Institute

Aging involves complicated plot twists and a large number of characters: inflammation, stress, metabolic changes and many others.

Now, a team from the Salk Institute and UC San Diego scientists has discovered another factor involved 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 Natural chemical biology Oct 20, 2022, helps unravel the molecular basis of brain aging, uncovers new mechanisms underlying age-related neurological diseases, and offers future opportunities for therapeutic interventions.

“These SGDGs clearly play an important role in aging, and this discovery raises the possibility that there are other critical aging pathways that we’ve been missing,” said co-corresponding author Alan Saghatelian, a professor in the Salk’s Clayton Foundation Laboratories for Peptide Biology and the Ph.D. Frederik Paulsen. “This is a pretty clear case of something that should be explored more in the future.”

SGDGs are a class of lipids, also called fats. Lipids contribute to the structure, development and function of a healthy brain, while poorly regulated lipids are associated with aging and a diseased brain.

However, lipids, unlike genes and proteins, are not well understood and are often neglected in aging research. Saghatelian specializes in discovering new lipids and determining their structure.

His lab, in collaboration with UC San Diego professor Dionicio Siegel, made three discoveries involving SGDG: 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 SGDG can be regulated by processes known to regulate aging.

To arrive at these findings, the team took an unusual, exploratory approach that combined a large-scale study of lipids (lipidomics) with structural chemistry and advanced data analytics.

For the first time, they 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 have greatly expanded the amount of data available to scientists, and advanced data analysis has enabled them to determine age-related patterns in vast lipid profiles.

The team then engineered SGDG molecules and tested them for biological activity.

“SGDGs were first identified in the 1970s, but there have been few subsequent studies. These lipids have essentially been forgotten and disappeared from lipid databases. “No one knew that SGDGs would change or be regulated during aging, let alone have bioactivity and possibly be therapeutically targeted,” says first author Dan Tan, a postdoctoral fellow in Saghatelian’s lab at Salk.

This shows images of the brain
The brain is composed of lipids, or fat, but the role of these molecules in health and disease remains unknown. A newly identified class of lipids, called SGDG, decreases with age, suggesting they may play a role in brain aging. Credit: Salk Institute

The analysis showed that SGDGs possess anti-inflammatory properties, which could have implications for neurodegenerative disorders and other neurological conditions that involve increased inflammation in the brain.

The team also found that SGDGs exist in the brains of humans and primates, suggesting that SGDGs may play an important role in animals other than mice. Further research will be needed to demonstrate whether SGDGs contribute to human neuroinflammation.

In the future, the team will examine how SGDGs are regulated by aging and which proteins are responsible for their formation and degradation, which could open the door to the discovery of new genetic activity associated with aging.

“With an understanding of the structure of SGDGs and our ability to create them in the laboratory, the study of these important lipids is now wide open and ripe for discovery,” says Siegel, co-corresponding author of the study.

Additional authors include Meric Erikci Ertunc, Justin Wang, Tina Chang, Antonio FM Pinto, Andrea Rocha, Cynthia J. Donaldson, Joan M. Vaughan, Peter C. Gray, Pamela Maher, and Nicola J. Allen of Salk; Srihari Konduri of UC San Diego; Pan Zhang of UC Los Angeles; Raissa G. Ludwig and Marcelo A. Mori; Elizabeth Willey and Andrew Dillin of UC Berkeley; Manasi Iyer and Bradley Zuchero of Stanford University; and Steven G. Kohama of Oregon Health and Science University.

funding: This work was funded by Ferring Pharmaceuticals and Frederik Paulsen, the National Institutes of Health (P30 CA014195, R01DK106210, R01NS119823, R01AG069206, and RF1AG061296), the Oregon National Primate All Research Center, the Oregon National Primate All Research Center, and the Oregon National Primate All Research Center (Jouman, 2005). and Clara Tsai Foundation, Anderson Foundation, Bruce Ford and Anne Smith Bundy Foundation, Pioneer Fellowship, Howard Hughes Medical Institute, CZI Neurodegeneration Network, and The Sãn Paulo Research Foundation (2017/01184-9).

See also

This shows the location of the cerebellum in the brain

About this news about aging and neuroscience research

Author: Salk Communications
Source: Salk Institute
Contact: Salk Communications – Salk Institute
picture: Image credited to the Salk Institute

Original Research: Closed access.
A class of anti-inflammatory lipids decreases with aging in the central nervous system” Dionisio Siegel et al. Natural chemical biology


Abstract

A class of anti-inflammatory lipids decreases with aging in the central nervous system

Lipids contribute to the structure, development and function of a healthy brain. Dysregulated lipid metabolism is associated with aging and brain disease. However, our understanding of lipid metabolism in the aging brain remains limited.

Here, we examined the brain lipidome of mice across their lifespan using untargeted lipidomics.

Coexpression network analysis highlighted progressive depletion of 3-sulfogalactosyl diacylglycerol (SGDG) and members of the SGDG pathway, including potential degradation products of lyso-SGDG. SGDGs show an age-related decline, particularly in the central nervous system, and are associated with myelination.

We also found that SGDG dramatically suppressed LPS-induced gene expression and proinflammatory cytokine release from macrophages and microglia by acting on the NF-κB pathway. Detection of SGDGs in human and macaque brains establishes their evolutionary conservation.

This work increases interest in SGDGs in relation to their role in aging and inflammatory diseases and highlights the complexity of the brain lipidome and potential biological functions in aging.



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