ABOVE: Artist’s rendition of T cells © ISTOCK.COM, CGTOOLBOX

A healthy immune response is key to fighting off diseases like COVID-19. As we age, however, our immune systems become less efficient at preventing illnesses, recovering from infection, and responding to vaccines. But not everyone’s immune system ages at the same rate—factors like smoking can accelerate this decline, while exercise can slow it down. 

A study published last week in PNAS reports another contributor to immune aging: social stress. 

“Stress exposure is literally wearing your body down,” says Ryon Cobb, a professor of psychology at the University of Georgia. “It goes along with this idea that the body never forgets.” Cobb wasn’t involved in the research, but study coauthor and University of Southern California (USC) gerontologist Eileen Crimmins was one of his postdoctoral instructors.  

Modeling stress and T cell health

In the study, Crimmins and other USC researchers analyzed data from 5,744 adults over the age of 50 who had answered questions about stress and gave blood samples as part of the Health and Retirement Study (HRS), a large, nationally representative study of older Americans that began in 1990.

Using this data, the team built computational models to determine the link between T cells—white blood cells that fight off infection—and five categories of stressors: everyday discrimination, stressful life events, lifetime discrimination, life trauma, and chronic stress. These five categories are “well-established health-relevant measures of social stress,” the authors write in the paper. 

The researchers examined the percentages of both CD4+ and CD8+ T cells. CD4+ cells (also called helper cells) aid in directing immune responses, while CD8+ cells attack pathogens. The team analyzed cells of both types that were naive and terminally differentiated.

Naive T cells have not yet interacted with an antigen. They’re produced and cycled out of the body quickly and are important for fighting off viruses that the body hasn’t seen before, such as SARS-CoV-2 in the early days of the pandemic. 

On the other end, terminally differentiated T cells are older cells that have already performed their function. They no longer help direct immune responses but may trigger inflammation throughout the body, and age other cells and tissues, explains lead study author Eric Klopack, a gerontology researcher at USC. 

See “Delayed T cell Response Allows Tuberculosis to Gain Foothold in Monkeys

As we age, our body naturally produces fewer naive cells, while at the same time failing to clear out the older terminally differentiated T cells. That results in an immune system with a smaller percentage of naive cells that are ready to fend off pathogens as compared to differentiated cells.

“Younger people tend to have more naive and fewer of these differentiated cells,” Klopack says. “So we think that those are indicators of immune aging.”

Stress’s cellular toll

After controlling for factors including age, race, and gender, the research team found that life trauma and chronic stress were associated with a lower percentage of CD4+ naive cells versus other kinds of CD4+ cells, indicating that fewer of them are being produced. Meanwhile, discrimination and chronic stress were linked with a greater percentage of terminally differentiated CD4+ cells, indicating a worsening ability to clear them out of one’s system.

The team also found that high lifetime discrimination, life trauma, and stressful life events were associated with a lower percentage of CD8+ naive cells and that high lifetime discrimination, chronic stress, and stressful life events were related to a higher percentage of terminally differentiated CD8+ cells. Both high lifetime discrimination and chronic stress were associated with a lower overall ratio of CD4+ cells to CD8+ cells—another indication of immune aging, says Klopack.

The study coauthors only have cell percentage data from the moment blood samples were drawn from each HRS participant, Klopack explains. Without more information about what participants’ immune profiles were like earlier in their lives—especially before and after stressful events—they cannot draw conclusions about a causal relationship.

Why some stressors appeared to affect the body differently is unclear, Klopack says. However, after controlling for lifestyle factors such as education, BMI, smoking, and alcohol consumption, the study authors found that the relationship between stressors and cell percentages was reduced. 

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This suggests that “part of the reason that stress is associated with these different cell type percentages is that people who experience more stress may be more likely to smoke, drink, have poor diet, maybe less exercise,” Klopack explains. 

He and his coauthors also found that after controlling for infection with cytomegalovirus (CMV), a common virus associated with accelerated immune aging, the relationship between stress and immune cell aging was reduced. 

“The findings have really important implications for healthy aging,” says Rebecca Reed, a psychoneuroimmunologist at the University of Pittsburgh. Reed was not involved in the new study but has collaborated with one of its coauthors on another project. 

“We know that these age-related changes in the immune system that they looked at predict important health outcomes. Things like chronic diseases, frailty, how robust of a vaccine response we have,” she adds.

Discrimination is also an important and “unique” stressor associated with higher mortality, chronic diseases, heart diseases, and mental health issues, Klopack says. In this study, participants reported facing different types of discrimination, including on the basis of gender and race, but most commonly for their age. 

From a health equity standpoint, the study “confirms what a lot of us already know, which is that racism is bad for your health; discrimination is bad for your health,” says Bridget Goosby, a sociologist at the University of Texas at Austin who was not involved in the research. 

The paper is the first step toward understanding the biological pathways in the body that are linked to experiencing discrimination, Goosby says. But because it doesn’t look at race specifically, the next step would be examining which racial groups and ethnicities are most vulnerable to immune aging, she says.

The authors write that groups such as residents of retirement communities or care facilities and Indigenous peoples were not well-represented in the HRS. Additionally, respondents with particularly high stress may have died before reaching an age where they could participate in the survey. 

Even with these caveats, Klopack recommends lowering stress—or at least using coping mechanisms like talk therapy. Other studies have shown that making healthier lifestyle choices can boost the immune system. 

“I hate being told at the doctor to eat better, get more exercise, don't drink as much,” he says, laughing. “But honestly, it looks like doing those things might help reduce the effect of stress on your immune aging.”