Menopause Marks a Turning Point in How the Immune System Ages, Study Finds

The immune system does not age the same way in men and women, and a large new study from China suggests that menopause is one of the clearest dividing lines. Analyzing blood samples from more than 4,200 healthy adults, researchers tracked how key lymphocyte subsets shift across the lifespan and found that the peri- to early postmenopausal period in women is marked by a pronounced reconfiguration of T cells, B cells, and immune checkpoint expression. The work, published in Immunity, Inflammation and Disease, offers one of the most detailed population-based portraits to date of how reproductive aging and immune aging intersect.

The study drew on 4,209 volunteers recruited between January 2022 and December 2023 through the First Affiliated Hospital of Guangzhou Medical University (Loudi Hospital), including 2,898 women and 1,311 men. All participants were healthy controls screened to exclude active immune disorders, malignancies, recent infections, and immunosuppressive therapy. Researchers measured ten immune parameters in peripheral blood using flow cytometry, covering total T cells, CD4+ and CD8+ T cell subsets, the CD4/CD8 ratio, B cells, natural killer cells, NKT cells, and expression of the checkpoint molecule PD-1 on several cell types.

Because raw immune measurements rarely follow a normal distribution, the team applied Box-Cox transformations and Tukey’s method to remove outliers before analysis, leaving between 4,123 and 4,204 reference individuals per parameter. Age-related trends were then examined with sex-stratified smooth curves and non-parametric tests, and a 1:1 propensity score matching procedure was used to build age-balanced male and female cohorts for direct comparison.

The headline finding is a sharp sexual dimorphism in B cell dynamics. In women, the proportion of CD19+ B cells rose with age, while in men it fell, producing opposite trajectories that the authors link tentatively to hormonal regulation and X-chromosome-encoded immune genes. After age matching, women had significantly higher B cell percentages than men, but a stratified analysis showed this gap was not significant before age 50 and only emerged after menopause, pointing to the postmenopausal window as the critical period.

T cell subsets told an equally striking story. In women, CD4+ helper T cells and the CD4/CD8 ratio climbed to a peak in the 55-to-59-year age group, while CD8+ cytotoxic T cells declined steadily across the lifespan. The authors describe this as a “scissor-like” pattern that closely parallels the abrupt drop in estrogen levels around menopause. Because hormone levels were not directly measured, they caution that this mechanistic interpretation remains speculative, but the timing of the immune shift aligns closely with the typical age of menopause as defined by the STRAW+10 staging framework.

PD-1, an immune checkpoint molecule best known as the target of modern cancer immunotherapies, showed a complex, cell-type-specific pattern. Women had lower PD-1 expression on CD4+ T cells and NK cells but higher PD-1 on CD8+ T cells, and the proportion of CD8+ PD-1+ cells showed a transient peak in the 60-to-64-year group. The authors suggest this may mark a window of heightened functional dysregulation in cytotoxic immunity, with potential relevance for how immune checkpoint status should be interpreted across demographic groups.

Innate immunity shifted as well. Natural killer cell percentages increased with age in both sexes, but the rise was markedly steeper in men, and the fraction of NK cells expressing PD-1 declined significantly with age in women. NKT cells, by contrast, showed no significant age-related trend. After age matching, women had higher NK cell and NKT cell proportions than men, alongside their higher CD4/CD8 ratios, reinforcing the picture of two distinct immune aging trajectories.

The findings carry practical implications. Because women generally mount stronger vaccine responses but suffer more autoimmune disease, and because PD-1 expression shapes anti-tumor immunity and postoperative infection risk, the authors argue that both sex and reproductive stage should be factored into studies of immune aging and into interventions such as vaccination strategies for middle-aged women. The observed B cell persistence in older women may represent a distinctive adaptive feature of female immunosenescence, though its consequences for humoral immunity remain to be tested.

The study has clear limitations. It is cross-sectional, so it captures age-related differences between individuals rather than tracking immune changes within the same person over time. Without menstrual records or hormone measurements, the researchers could not formally stage participants under STRAW+10 and instead used age groups as an approximation, meaning the 50-to-54-year group inevitably mixes perimenopausal and early postmenopausal women. The authors call for longitudinal studies that pair hormone monitoring with systematic reproductive staging to confirm whether the menopausal transition itself drives the immune shifts observed here.

Even with those caveats, the scale of the cohort and the consistency of the sex differences make a strong case that immunosenescence is not a single process but two, diverging sharply at midlife. For a field in which clinical trial populations and reference ranges have historically skewed male, the message is that middle-aged women may need their own immunological yardsticks, and that menopause deserves a place alongside chronological age as a variable in immune research.

Subject of Research: Sex differences in lymphocyte subset changes during the menopausal transition and immunosenescence

Article Title: Dynamic Shifts in Lymphocyte Subsets During the Menopausal Transition and Sexual Dimorphism in Immunosenescence

Article References: Xuan, C., He, L., Bohan, Z., Junming, X., Qingchao, L., & Junting, H. (2026). Dynamic Shifts in Lymphocyte Subsets During the Menopausal Transition and Sexual Dimorphism in Immunosenescence. Immunity, Inflammation and Disease, 14(10), Article e70558. https://doi.org/10.1002/iid3.70558

Image Credits: AI Generated

DOI: 10.1002/iid3.70558

Keywords: immunosenescence, menopause, lymphocyte subsets, PD-1, T cells, B cells, natural killer cells, sexual dimorphism, flow cytometry, estrogen, immune aging, propensity score matching