Men and women show striking differences in how their immune systems function and age, influencing susceptibility to infections, cancer, and autoimmune disease. A large-scale, cell-by-cell analysis now reveals that immune aging follows distinct biological paths in each sex, uncovering specific cells and genes behind these shifts. Credit: Shutterstock
Men and women experience immune aging differently, affecting disease risks. New data-driven research identifies key biological differences, supporting more personalized healthcare.
Men and women do not age the same way at the level of the immune system, and those differences may shape who gets sick, when, and why.
Scientists have long known that men are generally more prone to infections and many cancers, while women tend to have stronger immune defenses and respond better to vaccines. But that advantage comes with a tradeoff. A more active immune system is also more likely to misfire, which helps explain why roughly 80% of autoimmune diseases occur in women.
What has remained unclear is how these differences evolve over time. A new study from the Barcelona Supercomputing Center – Centro Nacional de Supercomputación (BSC-CNS), published in Nature Aging, now offers one of the most detailed answers yet. By tracking changes in the immune system across adulthood, researchers found that aging follows distinct biological paths in men and women, down to the level of individual cells and genes.
Women’s Immune Aging vs. Men’s Cancer Risk
The findings show that women experience more pronounced immune changes with age, including a rise in inflammatory immune cells. This may help explain why autoimmune diseases are more common in women, especially later in life, and why some inflammatory conditions worsen after menopause.
Credit: Mario Ejarque / BSC-CNS
In contrast, men show fewer overall changes in immune aging. However, researchers observed an increase in certain blood cells with pre-leukemic alterations, which may help explain why some blood cancers are more common in older men.
These insights came from analyzing blood samples from nearly 1,000 people across the full span of adulthood. Using single-cell RNA sequencing, a method that examines each cell individually, researchers measured the activity of about 20,000 genes in more than one million blood cells. This approach revealed how the immune system evolves and highlighted clear differences between sexes.
In contrast, men show fewer overall changes in immune aging. However, researchers observed an increase in certain blood cells with pre-leukemic alterations, which may help explain why some blood cancers are more common in older men.
These insights came from analyzing blood samples from nearly 1,000 people across the full span of adulthood. Using single-cell RNA sequencing, a method that examines each cell individually, researchers measured the activity of about 20,000 genes in more than one million blood cells. This approach revealed how the immune system evolves and highlighted clear differences between sexes.
Single-Cell Technology and Data Analysis Advances
“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,” explained Maria Sopena-Rios, researcher at BSC and first co-author of the study.
Handling such a massive dataset required advanced computational tools. The team relied on the MareNostrum 5 supercomputer to process and analyze the data, enabling a level of detail that would not have been possible with standard computing resources.
Although earlier research suggested that immune aging differs by sex, women have often been underrepresented in studies. This project is the first to analyze a large number of samples with balanced representation of men and women, which proved essential for uncovering these patterns.
“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,” explained Maria Sopena-Rios, researcher at BSC and first co-author of the study.
Handling such a massive dataset required advanced computational tools. The team relied on the MareNostrum 5 supercomputer to process and analyze the data, enabling a level of detail that would not have been possible with standard computing resources.
Although earlier research suggested that immune aging differs by sex, women have often been underrepresented in studies. This project is the first to analyze a large number of samples with balanced representation of men and women, which proved essential for uncovering these patterns.
Addressing Bias and Advancing Inclusive Research
“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.
“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.
These findings lay the groundwork for treating biological sex as a key factor in precision medicine for aging. By identifying sex-specific immune cells and biomarkers, researchers can begin developing prevention, diagnosis, and treatment strategies tailored to both women and men, helping create more personalized and equitable healthcare as populations age.
“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.
The researchers conclude that treating aging as a uniform process across the population overlooks important biological differences. Recognizing how immune aging varies between men and women will be key to improving immune health and supporting healthier aging for everyone.
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