Crucial Lipid Metabolism Enzyme Connected to Immune System Aging

As the human body ages, its immune system undergoes a gradual decline, characterized by a reduced capacity to produce infection-fighting cells and a slower recovery from illness and damage. While this phenomenon has long been recognized, the intricate molecular and cellular mechanisms driving immune senescence remain incompletely understood. A groundbreaking study published recently in GeroScience offers compelling insights into how alterations in lipid metabolism, mediated by the critical enzyme ELOVL2, may serve as a key driver of this age-associated immune dysfunction.

This new research, conducted through a collaboration between the University of California San Diego and UC Irvine, focuses on the enzyme ELOVL2—short for “elongation of very long chain fatty acids-like 2”—which is central to the biosynthesis of specific long-chain polyunsaturated fatty acids (PUFAs), particularly the omega-3 fatty acid docosahexaenoic acid (DHA). Notably, ELOVL2 expression is known to decline with age across multiple tissues, but its precise role in the immune system had not been elucidated prior to this study.

Leslie Crews, Ph.D., an assistant professor of medicine and co-leader of the Hematologic Malignancies Research Program at UC San Diego Moores Cancer Center, emphasizes that one of the biggest enigmas in immunology is why elderly individuals have dramatically fewer antibody-producing B cells. Crews and colleagues hypothesized that a disruption in lipid biosynthesis might underpin these changes, and they set out to analyze the molecular consequences of ELOVL2 loss on immune cell populations, particularly focusing on B lymphocyte development.

Using genetically engineered mice whose Elovl2 gene was inactivated, the research team performed comprehensive gene expression profiling, protein quantification, and detailed lipidomic analyses on bone marrow cells. These experiments revealed that in the absence of functional ELOVL2, the lipid composition of hematopoietic stem and progenitor cells was markedly shifted toward saturated fatty acids, with a significant depletion of unsaturated fats, including DHA. This alteration in lipid landscapes was linked to impaired membrane fluidity—a critical biophysical property necessary for proper stem cell function and differentiation.

The consequences of this lipid imbalance were profound. Mice deficient in ELOVL2 at the relatively young age of 18 to 20 months exhibited gene expression signatures in their bone marrow akin to those of considerably older wild-type mice. Crucially, the expression of genes regulating B cell lineage commitment and maturation—such as CD79B, PAX5, and IRF4—was substantially decreased. This genetic dysregulation translated into a diminished capacity to generate functional B cells, which are essential for mounting effective adaptive immune responses through antibody production.

Dorota Skowronska-Krawczyk, Ph.D., from UC Irvine, elucidates the molecular underpinnings of this process by highlighting DHA’s role in maintaining cellular membrane flexibility and resilience. The lack of ELOVL2 disrupts the localized synthesis of DHA, leading to stiffer, less adaptable membranes in the early stem cell progenitors of the B cell lineage—thereby handicapping their ability to develop and proliferate effectively.

The parallels drawn between mouse models and human biology further amplify the study’s significance. By analyzing gene expression data from human hematopoietic stem and progenitor cells (HSPCs) derived from bone marrow samples across a broad age range, the researchers uncovered a similar trend: older individuals over 60 years old exhibited a pronounced reduction in ELOVL2-positive HSPCs, alongside markedly reduced expression of CD79B. This suggests that the mechanistic link between lipid metabolism disruption and impaired B cell genesis is conserved across species and is a bona fide hallmark of immunosenescence.

Beyond the basic science, this research carries important implications for public health and emerging therapeutic strategies. Modern Western diets frequently lack sufficient quantities of unsaturated fats, including critical omega-3 fatty acids like DHA, potentially exacerbating age-related immune decline. The discovery that this form of immune system aging is tightly coupled with lipid metabolism raises the prospect that precision supplementation or pharmacological modulation of fatty acid synthesis pathways could mitigate immunosenescence and enhance infection resistance in the elderly.

However, Crews cautions that simply consuming dietary omega-3 supplements may not suffice to reverse deep-seated genetic and metabolic alterations. The study highlighted a profound “reduced metabolic fitness” in ELOVL2-deficient cells, meaning that dietary inputs alone might not restore proper membrane composition or B cell function. This underscores the need for more refined interventions, potentially involving targeted delivery systems or gene therapy technologies to boost ELOVL2 activity directly within hematopoietic compartments.

Excitingly, insights from previous work by Skowronska-Krawczyk’s group demonstrated that upregulating Elovl2 expression in aging mice improved DHA levels and restored function in retinal tissues, enhancing vision. This paves the way for exploring whether similar gene-based approaches can rejuvenate immune competence by restoring the fatty acid balance necessary for healthy B cell production.

Adding a layer of medical relevance, the researchers noted a potential connection between ELOVL2 activity and hematologic cancers such as lymphoma and multiple myeloma. The B cell-related genes disrupted by low ELOVL2 function—CD79B, PAX5, IRF4—are frequently mutated or aberrantly regulated in these malignancies. Consequently, therapeutic modulation of ELOVL2 pathways may also represent a novel angle for cancer intervention, either by halting tumor progression or restoring normal immune surveillance.

This integrative study represents a landmark advance in our understanding of how cellular lipid metabolism influences immune aging, connecting molecular enzymology to systemic immunity and disease vulnerability. By decoding the biological undercurrents of immunosenescence, the findings open promising avenues for interventions aimed at increasing the healthspan of aging populations through metabolic and genetic precision medicine.

Emphasizing the broader scientific vision, Skowronska-Krawczyk concludes that delving into the fundamental biology of aging is not only an academic exercise but a crucial strategy for discovering therapies that could prevent age-related diseases and improve the quality of life worldwide. As the global population ages, uncovering such molecular keys stands to revolutionize how we sustain human health in later life.

Subject of Research: Role of the ELOVL2 enzyme in lipid metabolism and immune system aging, specifically its impact on B cell development and functionality.

Article Title: Not explicitly provided in the source content.

News Publication Date: Not explicitly stated in the source content.

Web References:

Full study: https://link.springer.com/article/10.1007/s11357-025-01594-w
Related gene aging study: https://today.ucsd.edu/story/researchers-identify-gene-with-functional-role-in-aging-of-eye
Video related to the study: https://www.youtube.com/watch?v=UCFyX3Ww2Fk

References: Details of authors and funding as provided in the article.

Keywords: Stem cell research, Lipids, Cancer stem cells

Tags: aging and immune dysfunctionB cell production in agingcollaborative research in immunologyELOVL2 enzyme functionimmune senescence mechanismsimmune system decline in elderlyinfection-fighting cell productionlipid metabolism and immune aginglong-chain polyunsaturated fatty acidsmolecular insights into immune agingomega-3 fatty acid DHArole of fatty acids in immunity