Lipid Metabolism Drives Immune System Aging

As people age, their immune systems weaken, producing fewer infection-fighting cells, but the underlying reasons remain unclear. A recent study in GeroScience, led by Leslie Crews at UC San Diego in collaboration with UC Irvine, sheds light on this process by focusing on the enzyme ELOVL2, which is critical for synthesizing certain lipids. The researchers found that ELOVL2 levels decline with age, disrupting lipid balance in cells and impairing the development of B cells—the immune cells responsible for producing antibodies. 

The team inactivated the Elovl2 gene in mice and analyzed gene, protein, and lipid profiles in their bone marrow. Mice lacking ELOVL2 showed reduced expression of genes essential for B cell development, with lipid profiles similar to much older control mice. This loss of ELOVL2 led to fewer functional B cells and accelerated immune aging. The enzyme is crucial for synthesizing DHA, an omega-3 fatty acid that helps maintain cell membrane flexibility in B cell precursors.

The findings were mirrored in human samples, where older individuals showed a sharp decline in ELOVL2-expressing blood stem cells and reduced expression of B cell genes. The study also notes that modern diets low in unsaturated fats, including DHA, may further impair immune function in older adults. Notably, dietary intervention alone did not reverse genetic changes in the mice, suggesting that targeted lipid supplementation or gene therapy might be required.

Beyond immune aging, the study highlights links between ELOVL2, lipid metabolism, and blood cancers such as lymphoma and multiple myeloma, where related genes are often mutated. The researchers propose that targeting ELOVL2 could offer new strategies for preventing age-related immune decline and treating blood cancers, underscoring the importance of lipid metabolism in healthy aging.