Our brain is largely composed of a variety of fats and these are crucial for a healthy, functioning brain. Ageing is often associated with impaired lipid metabolism in the brain, which in turn has been associated with the development of neurodegenerative diseases. But exactly which fats and metabolites are involved is still unclear, because these relatively small molecules are difficult to characterise.    

A large team led by Dionicio Siegel (UC San Diego) and Alan Saghatelian (Salk Institute) has now deployed a combination of techniques to tackle this issue. They used untargeted lipidomics to map the lipidome (the collection of all fats) of mouse brain, then ran co-expression analysis on the results to link gene expression patterns to the presence/absence of certain lipids, and finally synthesised the identified lipids to determine their biological activity.   

Steady decrease

Using this combined approach, they analysed the brains of mice of different ages, ranging from very young to old. This demonstrated a very consistent, steady decrease of sulphogalactosyl glycerolipids during the mice’s lifespan. The decrease of two subgroups, sulfogalactosyl diacylglycerols (SGDGs) and sulfogalactosyl alkylacylglycerols (SGAAGs) occurs specifically in the central nervous system. SGDGs are also structural components of myelin, the protective layer around nerve cells.   

Anti-inflammatory

Since chronic inflammation is a hallmark of various neurodegenerative diseases, including Alzheimer’s and Parkinson’s, the team decided to synthesise and test SGDGs. Assays showed a clear anti-inflammatory effect of the SGDGs. These lipids lower the secretion of interleukin-6 and tumour necrosis factor alpha, two well-known pro-inflammatory cytokines. According to the researchers, these results suggest that there is a clear relationship between the decrease in SGDGs and the occurrence of chronic inflammation in the elderly brain.   

Further research showed that SGDGs are also present in the human and macaque brain; a novel finding. According to the researchers, this points to evolutionary conservation, but whether this means that the decrease in SGDGs is also an important factor in brain ageing and associated disease states in humans - and thus a possible target for therapy - requires further study. In any case, the newly developed workflow will provide much more insight into the exact molecular processes in the brain during ageing.  

Dan Tan, et al., A class of anti-inflammatory lipids decrease with aging in the central nervous system, Nature Chemical Biology (2022)