Systemic deficits in lipid homeostasis promote aging-associated impairments in B cell progenitor development.
Publication Year:
2025
PubMed ID:
40232347
Funding Grants:
Public Summary:
As we age, our immune system gradually weakens, making us more vulnerable to infections, blood disorders, and certain cancers. One major reason for this decline is that the bone marrow—where blood and immune cells are made—undergoes metabolic and functional changes over time. For example, aging bone marrow accumulates more fat and produces fewer healthy stem cells, especially those that develop into lymphoid cells like B cells. These shifts can create conditions that increase the risk of later-life blood cancers.
This study explored how changes in fat metabolism may contribute to aging of the blood and immune system. The researchers focused on a gene called ELOVL2, which helps the body make certain healthy fats known as omega-3 polyunsaturated fatty acids. By studying mice lacking this gene, the team found that their immune systems aged faster: important markers of B cell development were reduced, and a key molecule called CD79B, needed for early B cell formation, was significantly decreased.
The researchers also looked at human bone marrow across different ages. They discovered that only a small group of stem cells in healthy adults produce ELOVL2—and these cells, along with early B cell precursors marked by CD79B, are almost entirely missing in older adults.
Together, these findings reveal a new connection between fat metabolism and immune aging. They suggest that enzymes like ELOVL2 help maintain healthy blood cell development and that disruptions in these pathways may contribute both to normal aging and to age-related blood cancers. Understanding this pathway could open new opportunities for treatments aimed at improving immune health or targeting B-cell–related diseases.
Scientific Abstract:
Organismal aging has been associated with diverse metabolic and functional changes across tissues. Within the immune system, key features of physiological hematopoietic cell aging include increased fat deposition in the bone marrow, impaired hematopoietic stem and progenitor cell (HSPC) function, and a propensity towards myeloid differentiation. This shift in lineage bias can lead to pre-malignant bone marrow conditions such as clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenias of undetermined significance (CCUS), frequently setting the stage for subsequent development of age-related cancers in myeloid or lymphoid lineages. Human aging has also been associated with diverse lipid alterations across tissues, such as decreased phospholipid membrane fluidity that arises as a result of increased saturated fatty acid (FA) accumulation and a decay in n-3 polyunsaturated fatty acid (PUFA) species by the age of 80 years, however the extent to which impaired FA metabolism contributes to hematopoietic aging is less clear. Here, comprehensive multi-omics analyses uncovered a role for a key PUFA biosynthesis gene, ELOVL2, in mouse and human immune cell aging. Whole transcriptome RNA-sequencing studies and complementary flow cytometric analyses of bone marrow from aged Elovl2 mutant (enzyme-deficient) mice compared with age-matched controls revealed global downregulation in lymphoid cell markers and expression of genes involved specifically in B cell development. These studies unveiled CD79B, a vital molecular regulator of lymphoid progenitor development from the pro-B to pre-B cell stage, as a putative surface biomarker whose loss is associated with accelerated immune aging. The lipidome of mutant versus wild-type mice also displayed significant changes in the biophysical properties of cellular membranes. To investigate the relevance of these finding to human bone marrow aging, analyses of a single cell RNA-seq dataset of human HSPCs across the spectrum of human development and aging uncovered a rare subpopulation (< 7%) of CD34(+) HSPCs that expresses ELOVL2 in healthy adult bone marrow. This HSPC subset, along with CD79B-expressing lymphoid-committed cells, were almost completely absent in CD34(+) cells isolated from elderly bone marrow samples. Together, these findings uncover new roles for lipid metabolism enzymes in the molecular regulation of cellular aging and immune cell function in mouse and human hematopoiesis. In addition, because systemic loss of ELOVL2 enzymatic activity resulted in downregulation of B cell genes that are also associated with lymphoproliferative neoplasms, this study sheds light on an intriguing metabolic pathway that could be leveraged in future studies as a novel therapeutic modality to target blood cancers or other age-related conditions involving the B cell lineage.
