Sex-Related Differences in Immune System Aging May Impact Disease Susceptibility

Immune system aging, known as immunosenescence, is associated with changes in immune cell composition and function that increase susceptibility to disease. The results of a study by researchers at the Barcelona Supercomputing Center – Centro Nacional de Supercomputación (BSC–CNS) have now shown that immunological aging follows different dynamics between men and women.

The team analyzed single-cell RNA sequencing data from the peripheral blood mononuclear cells (PBMCs) of 982 female and male donors across adulthood, to identify cells and genes involved in immunosenescence, and potentially provide a molecular explanation for the differences that had previously only been observed globally in the population.

“Until now, most studies analyzed the immune system based on the average of many cells at once, which makes it difficult to capture the progressive effects of aging,” said Maria Sopena-Rios, PhD. “With cell-by-cell analysis and a much larger sample, we were able to detect these patterns and compare them robustly between biological sexes.” Their strategy identified sex-related differences in immunological aging may help to explain why women have an 80% higher incidence of autoimmune diseases than do men, and why men are more likely than women to develop hematological cancers and chronic infections.

Sopena-Rios is co-first author of the team’s published paper in Nature Aging, titled “Single-cell analysis of the human immune system reveals sex-specific dynamics of immunosenescence,” in which the investigators concluded “Together, our findings provide a high-resolution map of sex-specific immune aging and lay the groundwork for tailored sex-specific strategies to monitor and improve immune health across the lifespan.”

Statistics show clear differences in the population’s immune system according to sex: men are more susceptible to infections and cancers, while women have stronger immune responses, which translate, for example, into better responses to vaccines. Even so, with a more reactive immune system, the probability of the body attacking itself also increases, causing 80% of autoimmune disease development to occur in women. In this context, understanding the aging of the immune system is key since, with age, the composition of immune cells changes and their protective functions deteriorate, causing a greater susceptibility to diseases.

Aging of the immune system, or immunosenescence, refers to “… the gradual decline of the immune system, which predisposes to multiple diseases, including infection, cancer, and autoimmune and vascular diseases,” the authors wrote. “Importantly, the age-related decline of the immune system involves both changes in the composition of immune cell populations and molecular alterations.” However, understanding how sex influences this profound transformation was not possible until now. “…how biological sex shapes immune aging at the cellular level remains poorly understood,” the investigators stated.

For their reported study, the team analyzed blood samples from nearly 1,000 people of different ages covering the entire adult life, and carried out single-cell RNA sequencing to analyze the activity of 20,000 genes in more than one million blood cells. This approach allowed them to identify how the immune system changes over the years and detect clear differences between sexes. Although evidence existed that the immune system ages differently according to sex, women have been traditionally underrepresented in studies, the authors comment. This is the first time that large quantities of samples were analyzed with a balance between men and women, a fact that was decisive in obtaining these results.

“Many studies still do not take sex into account in their analyses, or directly only use data from men, so they leave key questions unanswered,” said study director Marta Melé, PhD, leader of the Transcriptomics and Functional Genomics group at BSC. “Our research was born precisely from this need and combines a scientific outlook with a sex perspective, inclusive data, and great computational power.”

The results revealed that women present more pronounced changes in the immune system with age, with an increase in inflammatory immune cells. This finding could help explain why autoimmune diseases are mainly developed by women, especially at advanced ages, as well as the worsening of certain inflammatory pathologies after menopause.

“Female individuals typically mount stronger immune responses, enhancing resistance to infections and vaccine efficacy, but also contributing to an 80% higher incidence of autoimmune diseases,” the authors noted. “Aging further increases autoimmune risk, and we showed that this is accompanied by the female expansion of cell subpopulations with pivotal roles in autoimmunity.”

On the other hand, the study found that changes associated with immune system aging observed in men are globally less extensive, but an increase in certain blood cells presenting pre-leukemia alterations was observed, a fact that could explain why some blood cancers are more frequent in older men. “Male immune aging is less transcriptionally pronounced, with fewer sex-specific signatures and subtler shifts in immune cell abundance,” the investigators wrote. “.… a subset of male participants shows an age-associated expansion of a B cell population linked to an asymptomatic precursor state of chronic lymphocytic leukemia … Our findings suggest that male immune remodeling may contribute to increased vulnerability to hematological malignancies and chronic infections.”

To manage, process, and analyze a volume of data of this magnitude, the scientific team required the use of advanced computational methods that had never been applied to such complex data sets, with the MareNostrum 5 supercomputer as a key piece to make possible a study that would not have been viable without high-performance computing infrastructure.

With these discoveries, the study establishes the bases for incorporating biological sex as a key variable in precision medicine for aging. The identification of sex-specific aging cells and biomarkers opens the door to the development of preventive, diagnostic, and therapeutic strategies better adapted to women and men, contributing to more individualized and equitable healthcare in an increasingly aging population.

“The immune system plays a fundamental role throughout the organism; therefore, the differences we observed have a very important generalized impact on the entire body. Better understanding the aging of the immune system can help us understand processes that go beyond the blood and affect multiple tissues,” noted co-first author Aida Ripoll-Cladellas, PhD.

Treating aging as a homogeneous process in the entire population hides key biological differences, and understanding how it varies between women and men, the authors concluded, will be essential to improve immune health and promote healthy aging within everyone’s reach. “Stratifying analyses according to sex uncovers key sex-specific features of immunosenescence that may otherwise be misinterpreted as shared effects,” they stated. “This underscores the importance of considering sex as a biological variable to ensure biologically accurate conclusions. Ultimately, our findings lay the foundation for sex-tailored strategies to monitor immune aging and mitigate the burden of age-related immune dysfunction.”

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