Clusterin as a Marker of Aging in Hematopoietic Stem Cells

As the global population ages, understanding the biological processes that drive aging and age-related diseases becomes increasingly vital. Hematopoietic stem cells (HSCs), which reside in the bone marrow and are responsible for the production of blood cells, undergo significant phenotypic and functional changes over time. These alterations can lead to an imbalance in blood cell production, contributing to conditions such as anemia, immune deficiencies, and blood cancers.

Recent research has focused on uncovering molecular markers that can identify and track aging in HSCs. A breakthrough study published in the journal Blood on March 25, 2025, by a team from the University of Tokyo, led by Professor Atsushi Iwama and Professor Shuhei Koide, identified Clusterin (Clu), a molecular chaperone, as a key marker of aged HSCs.

Using single-cell RNA sequencing to compare young mice (8–10 weeks old) with aged mice (18–20 months old), the researchers discovered that Clu expression correlates with aging in these stem cells. They developed Clu-GFP transgenic reporter mice, which allowed for the visual identification of aged HSCs via green fluorescence. This method proved to be more efficient than previous techniques using antibody-based markers.

Clu-positive (Clu⁺) HSCs, a minority in fetal mice, increase in number with age and tend to differentiate into myeloid cells and platelets, exhibiting a bias towards these lineages. In contrast, Clu-negative (Clu^–) HSCs maintain a balanced differentiation pattern, characteristic of youthful stem cells. During development, Clu^– HSCs predominate, but their proportion diminishes as animals age.

The shift toward a higher proportion of Clu⁺ HSCs is thought to drive the core aging process in the hematopoietic system, as these cells display reduced self-renewal capacity and increased myeloid bias. Targeting Clu⁺ HSCs could open new avenues for therapies aimed at mitigating age-related hematopoietic decline.

Prof. Iwama emphasized that tracking Clu expression provides a new way to understand cellular aging. "Our findings suggest that Clu⁺ HSCs are integral to age-related changes in blood cell production, and targeting these cells might delay or reverse some aspects of hematopoietic aging," he stated.

Overall, this discovery enhances our understanding of the molecular mechanisms underlying HSC aging and offers promising directions for developing interventions against age-associated blood disorders.