When patients come to see Michael Osborne, a cardiologist at Massachusetts General Hospital, they’re often at risk of cardiovascular events such as heart attacks. Some have already developed cardiovascular disease, with sticky plaques made of fat and cholesterol beginning to coat their arteries.

Standard prevention guidelines suggest dietary changes, medications, and increased physical activity. But Osborne sees another important piece that many physicians overlook: stress.

“[Stress] is not part of the standard of care in the United States,” Osborne said. " Because stress is unavoidable in modern life, we haven’t paid a lot of attention clinically to it.”

Epidemiological studies reveal that psychological stressors can increase a person’s risk of not only cardiovascular disease, but also cognitive decline, asthma, and gastrointestinal problems.

Yet, stress management has remained peripheral to risk management and treatment plans for these diseases. In part, Osborne said, this is because scientists still haven’t fully connected the dots between day-to-day stress and disease processes happening at the subcellular level. “We haven't really shown how it gets into the body or under the skin,” he said. Without a mechanistic understanding, stress remains on the fringes of treatment plans.

Now, researchers are turning to the lab to investigate how environmental stressors’ effects can reverberate deep within cells, eroding the building blocks of human health.

Good stress and bad stress

Despite its reputation, stress is a good thing in small doses. At its core, stress is a survival instinct. The moment of panic before giving a speech isn’t because the audience is dangerous, but the fight-or-flight sensation it triggers is the same instinct that would have helped early humans survive threats in their environments.

Speed is key. When we perceive dangers, our brains quickly process the threat in an emotional center called the amygdala, triggering a cascade of signals to pump out bursts of hormones including adrenaline and cortisol. These hormones leave almost no part of the body untouched: the heart pumps faster, energy reserves break down to release fuel, and more oxygen wakes up the brain. When the threat disappears, so does this heightened state. 

The problem emerges when the threat lingers. Psychological stress is often tied to more persistent factors such as financial hardship, long work hours, or grief. This leads to a chronic stress response and constant strain on all of the body’s systems. Marie-Ève Tremblay, a neuroscientist at the University of Victoria, studies how chronic stress affects the brain, where it can lead to overactive neurons that trigger a stress response similar to what an infection might elicit. This attracts microglia — the brain’s defense cells — to trim connections between neurons, tamp down the frenetic signaling, and restore balance. “But in the long term, things turn bad when it becomes chronic,” Tremblay said. “Microglia become unable to keep up, and at some point, this becomes maladaptive and can lead to diseases.”

Another piece of the puzzle is inflammation. Chronic stress rallies an immune response that can wear out the body’s organs. In arteries, the barrage of immune cells can promote plaque buildup that weakens cardiovascular function. 

Many of the signs of stress across the body are connected. Osborne and his collaborators scanned people’s brains with positron emission tomography (PET) and found that participants’ perceived stress correlated with activity in their amygdalae (1,2). By scanning other parts of the body as well, they noticed signs of higher immune cell production in the bone marrow and greater inflammation in arteries, providing a potential link between stress and increased risk of cardiovascular events.

“It’s a very complex and tangled network where there’s a lot of interplay between all of these systems,” Osborne said.

Cells under pressure

When stress overstays its welcome in the body, cells are constantly battered by stress hormones and immune molecules. Living in this war zone takes its toll, and cells can change for the worse. Because a wide variety of cells express stress hormone receptors, almost no cell is spared, said Melanie Flint, a cancer researcher at the University of Brighton. 

The microscopic manifestation of the turmoil afoot is known as cellular stress. Just as psychological stress wreaks havoc across the body, cellular stress disrupts the cell’s normal activities. Harmful chemicals called reactive oxygen species roam the cell, damaging DNA and mitochondria so that the cell can no longer produce the energy or proteins that it needs. Cellular stress can siphon the cell’s vitality, accelerating its aging until it resembles a much older cell or dies.

These cells could contribute to maladaptive changes upon stress to pathologically remodel the neural circuits. We're hoping to be able to normalize them to promote stress resilience.
- Marie-Ève Tremblay, University of Victoria

In Tremblay’s studies of mouse brains, chronic stress induces “dark microglia,” named for their dark appearance under an electron microscope (3). In these damaged microglia, the organelles within the cell are misshapen, and they store their DNA in an altered conformation, suggesting that the cell is accessing different instructions from its genome than a normal microglial cell. Dark microglia are overactive and inflammatory, and in their rampages, they can destroy valuable neuronal connections.

“These cells could contribute to maladaptive changes upon stress to pathologically remodel the neural circuits,” Tremblay said. “We're hoping to be able to normalize them to promote stress resilience.”

Flint also has a long-standing interest in how stress transforms cells and how stress hormones affect them. By adding hormones that people often release during psychological stress such as cortisol and adrenaline to cells in a dish, she found that they can damage DNA, interfere with cells’ ability to repair the damage, and can even derail the cell cycle to keep cells from dividing properly (4,5).

A prescription for disease

As a cancer researcher, Flint became interested in stress because of her firsthand observations of family members who had battled cancer. She started to wonder whether the colossal amounts of stress that accompanied the disease affected their prognosis.

It’s not an unprecedented idea. Studies have shown that people with cardiovascular disease who are struggling with higher levels of stress, depression, and anxiety have worse outcomes. In his experience as a cardiologist, Osborne has seen that even some of the medications that physicians prescribe to treat cardiovascular conditions have systemic effects on the body that promote stress, such as erectile dysfunction.

From her work and other studies, Flint is convinced that stress plays a role in cancer progression, but she is also curious about cancer treatments, which can have variable efficacy across patients.

When she treated cells in a dish with stress hormones and paclitaxel, a breast cancer chemotherapy drug, she found that the pantheon of stress hormones all interfered with chemotherapy and kept the cells from dying (5). This startling observation made sense — chemotherapy targets rapidly dividing cells, and if stress hormones interfere with cell division, then they protect cancer cells from the drugs’ effects.

If stress is driving cardiovascular risk factors… it's really working against a lot of the therapies that we're trying to prescribe. 
- Michael Osborne, Massachusetts General Hospital

If stress can run interference on even potent cancer therapies, Flint expects that it may play a role in the effectiveness of therapies for other diseases too. Tremblay has seen similar results with antidepressants: In one study, administering fluoxetine in stressful circumstances actually had negative effects on rats with depression-like symptoms because it increased inflammation (6).

Osborne thinks that it’s something to consider in cardiovascular disease. “If stress is driving cardiovascular risk factors… it's really working against a lot of the therapies that we're trying to prescribe,” he said.

If stress exacerbates disease and counteracts drugs, then mitigating stress might be an important part of treatment plans. There are currently clinical trials testing whether adding drugs that mitigate stress hormones’ effects, such as the beta blocker propranolol or glucocorticoid receptor antagonist mifepristone, can boost chemotherapies. Flint is currently investigating how stress hormone blockers can improve immunotherapies.

Blocking stress pathways comes with risks, though. In the brain, there are promising targets on microglia such as fractalkine receptor CX3CR1 that interact with neurons during periods of stress. Tremblay conducted studies in mice to see how they handle chronic stress simulated through unpredictable disruptions to their routine: for example, inaccessible water or aggressive social interactions. She found that blocking CX3CR1 makes the mice less susceptible to chronic stress (7). While this might be a good short-term solution for stress, she doesn’t think it’s wise in the long term.

“It's deleterious because that would prevent [the microglia] from trying to restore homeostasis,” Tremblay said. “They are essential cells.”

More important than ever

There are other limitations to medicating against stress. For starters, it’s inconvenient.

“People don't want to take a pill to manage their stress,” Osborne said. “The idea of having a lifestyle intervention is so much more attractive to most people.” 

Osborne has been involved in developing stress management training for cardiovascular patients, and early evidence already suggests that incorporating stress reduction techniques into daily life is an effective way to improve cardiovascular symptoms.

Tremblay agreed that lifestyle is critical to managing stress and may synergize with treatments that target stress mechanisms. “Being able to control these stress pathways would be super beneficial in combination with psychosocial support,” she said.

Given how high stress a cancer diagnosis can be, managing stress has general benefits for patients’ quality of life, Flint said. “It’s a good thing to reduce stress in those patients and to recognize that stress is part of the response to the disease,” she said.

Stress’s role in diseases is often downplayed as being “in the head,” Tremblay said, and she hopes that emerging research convinces people of the importance of stress’s physiological effects. In light of the increased stressors introduced by the COVID-19 pandemic, researchers who have long studied stress have noticed that people are more aware of stress’s role in their present and future health.

“It’s more important than ever to work on this,” Tremblay said.

References

1. Osborne, M.T. et al. Multimodality molecular imaging: Gaining insights into the mechanisms linking chronic stress to cardiovascular disease. J Nucl Cardiol  28, 955-966 (2021).
2. Tawakol, A., Ishai, A. et al. Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study. Lancet  389, 834-845 (2017).
3. Bisht, K. et al. Dark microglia: A new phenotype predominantly associated with pathological states. Glia  64, 826-839 (2016).
4. Flint, M.S. et al. Induction of DNA damage, alteration of DNA repair and transcriptional activation by stress hormones. Psychoneuroendocrinology  32, 470-479 (2007).
5. Flint, M.S. et al. Stress hormones mediate drug resistance to paclitaxel in human breast cancer cells through a CDK-1-dependent pathway. Psychoneuroendocrinology  34, 1533-1541 (2009).
6. Alboni, S. et al. Fluoxetine treatment affects the inflammatory response and microglial function according to the quality of the living environment. Brain Behav Immun  58, 1533-1541 (2016).
7. Milior, G. et al. Fractalkine receptor deficiency impairs microglial and neuronal responsiveness to chronic stress. Brain Behav Immun  55, 114-121 (2016).