Women tend to live longer than men, yet they are more likely to develop many age- and immune-related conditions. Why this happens has long puzzled scientists. Now, researchers at Duke-NUS Medical School have uncovered new clues showing that the immune systems of men and women follow different ageing patterns — and that immune ageing may accelerate at particular stages of life.

The study, published in Nature Communications, found that immune cells do not simply deteriorate at a slow, steady pace as people grow older. Instead, they appear to go through periods of more rapid change, with major shifts in gene activity occurring around age 40 and again after 60. Some of the most fundamental processes that keep cells functioning, including genes involved in producing RNA and proteins, showed particularly marked declines during these periods.

T cells — white blood cells that play a central role in coordinating immune responses and fighting infections — showed some of the most striking changes. Researchers found a major shift in T-cell gene activity around the 40s, followed by another wave after age 60. Intriguingly, different types of T cells appeared to drive the changes at each stage, suggesting that different parts of the immune system may be affected as people move through later life.

The patterns also differed between men and women. Certain specialised T cells changed their activity differently across the lifespan depending on sex, potentially offering clues as to why some immune-related diseases affect women and men differently. Autoimmune diseases, for example, are strongly associated with both age and sex and occur when the immune system mistakenly attacks the body’s own tissues.

“We tend to think of ageing as a gradual process, but our findings show that the immune system does not simply decline at a steady rate,” said senior author Associate Professor Jacques Behmoaras of Duke-NUS. He said identifying these periods of rapid immune change could eventually help researchers determine when interventions might be most beneficial and why some autoimmune conditions disproportionately affect women.

The research is among the largest and most diverse studies of its kind. Scientists analysed the genetic activity of 3.8 million individual immune cells collected from nearly 2,000 healthy people between the ages of 19 and 97. The participants included people of Asian ethnicity, including Singaporeans. Data from multiple publicly available studies were combined to create a detailed atlas of immune ageing across the human lifespan.

Professor Antonio Bertoletti, another study author, said the findings reinforce previous evidence that T cells are particularly vulnerable to ageing. Understanding what causes these nonlinear changes could be important because declining or altered T-cell function may help explain why older adults become more susceptible to infections and inflammatory conditions.

Researchers also used the data to develop artificial intelligence models that estimate a person’s biological age, which can differ from their chronological age. The team hopes the models will help identify biological pathways and critical periods when interventions could be tailored according to both age and sex. Ultimately, the findings could help move medicine away from a one-size-fits-all view of ageing towards more personalised strategies for maintaining immune health throughout life.

More information: Harry Park et al, Sex-specific trajectories of nonlinear immune aging at single-cell level, Nature Communications. DOI: 10.1038/s41467-026-76737-4

Journal information: Nature Communications Provided by Duke-NUS Medical School