As flu season approaches and there is a push for vaccination, a study by Allen Institute scientists has uncovered why vaccines can trigger a weaker response in older adults—aged about 65 years—and suggests how these immune responses might be improved. In what they state is the largest study of its kind, the researchers used techniques including single-cell RNA sequencing (scRNA-seq), proteomics, and spectral flow cytometry to profile the immune systems of younger and older individuals over time.
The findings showed that T cells—key players in coordinating immune responses—undergo profound and specific changes as we age. These changes, the results suggest, are not random or a byproduct of chronic disease and inflammation but are a fundamental feature of healthy aging and will happen to all of us as we get older. The changes could also point to why vaccines, including the annual flu shot and COVID-19 boosters, tend to be less effective in older adults. The scientists suggest that their insights, newly reported in Nature, could open the door to designing more effective vaccines.
“We were surprised that inflammation is not driving healthy aging,” said Claire Gustafson, PhD, assistant investigator at the Allen Institute. “We think inflammation is driven by something independent from just the age of a person. This is important because there’s been research showing similar findings that inflammation and aging don’t go hand in hand, and your immune system is just changing with age.”
Gustafson is co-senior and corresponding author of the team’s published paper, which is titled “Multi-omics profiling reveals age-related immune dynamics in healthy adults,” in which they concluded, “The ability to respond to vaccination is critical for protective immunity. By studying the influenza vaccine responses, we were able to identify molecular mechanisms driving reduced protective responses with age.”
Human aging is a “nonlinear” process, the authors wrote. Also, the risk profiles of age-associated disorders, such as cardiovascular or neurodegenerative diseases, do not increase proportionally with age, while autoimmune disorders, such as multiple sclerosis, and inflammatory disorders, also show nonlinear risk trajectories with age. “Understanding the inherent complexities of the immune system over time is essential for elucidating drivers of these age-associated diseases, as well as the healthy aging process,” the team commented.
T cells are a critical part of our immune system that help “train” white blood cells, called B cells, to produce antibodies in response to viruses and vaccines. “…memory T cells and B cells have pivotal roles in long-term immunity, collectively orchestrating responses to pathogens and vaccines and uniquely adapting throughout a lifetime,” the investigators also noted. And while transcriptional changes in human T cells have been “increasingly recognized as a feature of advanced aging” and linked to reduced immune responses and increased vulnerability to infections among older adults, how these changes and their link to age-related immune dysfunction in people, including lower antibody production following vaccination, haven’t yet been completely explained.
For their newly reported study, Gustafson and colleagues, in collaboration with the Benaroya Research Institute, tracked more than 96 healthy adults between the ages of 25 and 65 years for over two years. They pointed out that whereas most studies examine features of what they term advanced age—more than 65 years—the Allen Institute scientists and their colleagues focused on individuals at “the cusp of aging”—55–65 years of age—in comparison with younger adults—aged 25–35 years—”to gain insight into the transition period between functional and diminished immunity.” The researchers then used techniques such as single-cell RNA sequencing, proteomics, and spectral flow cytometry to longitudinally examine the immune system of these individuals over time.
“We longitudinally examined peripheral immune cells in these 96 healthy young adults and older adults over two years, with annual influenza (flu) vaccination and eight to ten time points per donor,” they explained. The scientists then used the data on the immune system to create a detailed Human Immune Health Atlas, an online resource mapping 71 different immune cell types and how they change over time, and why those changes matter. Then, they applied this Atlas to study over 16 million individual immune cells from healthy adults ranging between 25 years to 90+ years of age, offering an unprecedented tool for researchers worldwide to better understand and support the aging immune system. This online resource is the largest of its kind and freely available to researchers worldwide.
The study found that memory T cells in older adults undergo a dramatic shift toward what is known as a Th2-like state, which is a change in gene expression that fundamentally alters how these cells respond to threats. Researchers found this shift directly affects B cells’ ability to generate strong antibody responses. “… we demonstrate robust, nonlinear transcriptional reprogramming in T cell subsets with age that is not driven by systemic inflammation or chronic cytomegalovirus infection,” they reported. “This age-related reprogramming led to a functional T helper 2 (TH2) cell bias in memory T cells that is linked to dysregulated B cell responses against highly boosted antigens in influenza vaccines.”
In other words, the flu shot might still deliver the right viral components, but if the memory T cells aren’t functioning properly, the body struggles to respond effectively. With this insight, doctors may be able to use a person’s immune profile to predict how well they’ll respond to a vaccine. Now that scientists can pinpoint how T cells become less effective with age, they can also start designing new vaccine formulas or immune-boosting treatments to address these issues. “Collectively, this study reveals unique features of the immune aging process that occur prior to advanced age and provides novel targets for age-related immune modulation,” the authors noted. “These studies highlight the importance of considering age in the design of vaccination strategies, cell-based therapies, and clinical immune-focused treatments.”
Since T cells in older adults function differently, scientists could reformulate vaccines to compensate specifically for age-related cellular changes rather than using a one-size-fits-all approach. Gene-editing tools like CRISPR could also be used to reprogram a person’s T cells before vaccination, essentially re-programming older immune cells to make them respond to vaccines like younger cells do—like a CAR-T cell therapy that reprograms immune cells to fight cancer.
Researchers say this work goes beyond just vaccines and reveals how our immune systems change in all of us as we get older and how our bodies fight age-related disease and viruses. It also opens the door to interventions like new therapies to restore key immune cells. “Future studies to identify mediators of age-specific changes at the sites of active immune responses—secondary lymphoid tissues—and on how differing dynamics of antigen-specific exposures (for example, acute but repetitive versus continuous) shape immunity will provide deeper insight into healthy immunity and its regulation during the aging process, and its contribution to health and disease,” the scientists concluded.
“This research illustrates how working collaboratively can make a significant impact on our understanding of the immune system, both now and in the future,” said co-author Jane Buckner, MD, president of the Benaroya Research Institute. “It was made possible through the combined efforts of several Seattle-based research institutions, dedicated scientists, clinicians, and research coordinators, as well as the individuals who generously volunteered their time, samples, and health information.”
The significance of this work extends beyond aging research and provides a roadmap for understanding how immune dysfunction develops over time, offering concrete targets for intervention and potentially transforming how we approach immune health across the entire human lifespan. “There’s so much more information to be gained by looking at this dataset we’ve produced,” said Gustafson. “My hope is that it will be used for a long time to enable other researchers to look more deeply and find more insights into human immunity.”
