Immunosenescence underlies age-related vulnerability to infections and chronic inflammation. Until now, most attention has focused on the shrinking pool of naive T cells and the accumulation of memory cells. But one question remained open: do the remaining naive T cells retain full function? Most aging atlases were built from peripheral blood or the thymus, while the bone marrow, a stable hematopoietic niche, remained poorly studied. This work fills that gap by analyzing the bone marrow of 15 donors ranging from 3 to 91 years of age.
From the bone marrow of 15 healthy donors across five age groups, CD45+ immune cells were isolated and paired single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing (scTCR-seq) were performed. In addition, flow cytometry was used to assess the fraction of CD8+ naive T cells in the blood of 388 donors. Functional tests included T-cell stimulation with anti-CD3/CD28 antibodies and analysis of activation markers (CD69, CD25), proliferation, and cytotoxicity. To test the role of ANXA1, mice with a knockout of the Anxa1 gene were used along with aging models: doxorubicin-induced, UV-induced, and natural aging.
The main age-related change in the bone marrow T-cell compartment is a decline in the fraction of CD8+ naive T cells (R = -0.91, P < 0.001). Among the remaining naive cells, a subpopulation with surface ANXA1 appears, and its share grows with age. ANXA1+ cells retain a naive phenotype but show signs of senescence: elevated p16INK4a, reduced activation and proliferation, and enrichment of SASP signatures. In mice, Anxa1 knockout enhances activation, IFNγ production, and degranulation of CD8+ T cells, and transfer of Anxa1-/- CD8+ T cells suppresses B16-F10 melanoma growth. ANXA1- CD8+ naive T cells selectively kill senescent fibroblasts in vitro and reduce aging markers in vivo. Monthly transfer of ANXA1- CD8+ naive T cells into 13-month-old mice improved physical performance, lowered aging markers in tissues, rejuvenated the bone marrow immune profile, and increased median survival by more than 30 weeks.
The work shows that immunosenescence is not just quantitative depletion but also a qualitative change in naive T cells: the accumulation of a dysfunctional ANXA1+ subpopulation. This changes the view of the naive compartment as a homogeneous pool of resting cells. The discovery of ANXA1 as an internal brake on cytotoxicity and a marker of senescent T cells provides a new target for diagnosing and treating age-related disorders. Moreover, it demonstrates the principle of an 'endogenous senolytic': the body's own immune cells can selectively remove senescent cells, opening a path to cell therapy for aging.
It is necessary to determine exactly how ANXA1 suppresses T-cell function at the molecular level and which signals control its expression. Studying the TCR repertoire of ANXA1- cells and their behavior under non-sterile conditions closer to real life is promising. Small molecules or antibodies blocking ANXA1 could potentially be developed as an alternative to cell therapy. It is also important to verify the reproducibility of the effects in other aging models and species.
The results could influence gerontology, immunology, oncology, and regenerative medicine by proposing a new class of immune cell-based senolytics and a biomarker of immune aging.
Investigate the mechanism of ANXA1 action in T cells, including signaling pathways and receptor interactions. Conduct preclinical trials in models of age-related diseases and assess the safety of long-term cell transfer.
The work directly addresses the reversibility of immune aging and the search for cellular biomarkers of dysfunction. It also touches on the fundamental question of how senescent cells evade immune surveillance and how to restore that surveillance.
The median lifespan of mice receiving ANXA1- CD8+ naive T cells increased by more than 30 weeks, which translates to roughly 100 human years.
The idea of rejuvenation through transfusion of young immune cells echoes Aldous Huxley's novel Brave New World, where youth is maintained through hormone therapy, and the 2015 film The Immortals, where blood transfusions from young donors halt aging.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.