Study reveals immune aging differs significantly between men and women

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. However, understanding how sex influences this profound transformation was not possible until now.

A new study by the Barcelona Supercomputing Center – Centro Nacional de Supercomputación (BSC-CNS) published today in Nature Aging demonstrated, for the first time, that immunological aging follows different dynamics between men and women, identifying the cells and genes responsible for the process, and providing a molecular explanation for the differences that previously were only observed globally in the population.

Thus, the results reveal 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.

On the other hand, the 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.

Finding these patterns was possible thanks to the analysis of blood samples from nearly 1,000 people of different ages covering the entire adult life, combined with a technology capable of analyzing each cell individually, called single-cell RNA sequencing. In total, the researchers analyzed the activity of 20,000 genes in more than one million blood cells, which allowed them to identify how the immune system changes over the years and detect clear differences between sexes.

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. With cell-by-cell analysis and a much larger sample, we were able to detect these patterns and compare them robustly between biological sexes." 

Maria Sopena-Rios, researcher at BSC and first co-author of the study

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.

Aging with a sex perspective

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. Our research was born precisely from this need and combines a scientific outlook with a sex perspective, inclusive data, and great computational power," highlighted Marta Melé, leader of the Transcriptomics and Functional Genomics group at BSC and director of the study.

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 Aida Ripoll-Cladellas, researcher at BSC and first co-author of the study.

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 conclude, will be essential to improve immune health and promote healthy aging within everyone's reach.