Author: Mia McDonald Rose
Editor: Altay Shaw
As a primal instinct, the stress response helped our ancestors confront threats like predators and social violence. Whilst you probably won’t encounter a bear on Gower Street, aspects of academic pressure most definetely trigger the ‘fight or flight’ reaction.
Stress is an inherent part of the human experience, the feeling it delivers can be motivating but also overwhelming. Our affinity for it fluctuates, as does the impact it has on our health. Short stress responses enhance our survival prospects, on the other hand, prolonged stress is detrimental. Research has revealed that continuous stress can spark the onset of major depressive disorder (MDD) and cardiovascular disease (CVD).
In 2001, the National Institute of Mental Health published a summary on the co-occurrence of MDD and CVD. Decades later, research now incriminates stress-induced inflammation as a cause linking the degenerative diseases. So how does something as natural as stress drive the development of such complex diseases?
When Stress Goes Awry
The stress response activates a constellation of physiological responses. When a threat is perceived, homeostatic changes occur including an increased heart rate, adrenaline release and boosted immune function. These adjustments serve to maximize our chances of survival but also require a wealth of energy. Cortisol accomplishes this need.
Secreted by the hypothalamic-pituitary-adrenal (HPA) axis, cortisol enhances glucose production whilst also promoting insulin resistance. When the stressful situation is over, cortisol feeds back to the HPA axis, restoring homeostasis and ending the ‘fight or flight’ reaction. Therefore cortisol ensures a short stress response.
That is, unless the stress we experience is continual. Chronic stress is observable when the HPA axis becomes less responsive, and cortisol levels remain elevated—a condition known as hypercortisolemia. This persistent release of cortisol serves as a link between MDD and CVD, with its influence on inflammation emerging as the underlying mechanism.
A Destructive Cadence
In turbulent times, energy demands increase, especially in the brain, which consumes 24 times more energy than other organs. Hence the HPA axis is abundant in mitochondria, and they play a pivotal role in cortisol signalling. However, stress-induced hypercortisolemia overwhelms the mitochondria’s functional capacity, leading to oxidative stress. This imbalance results in the production of reactive oxygen species (ROS), or free radicals, that in turn activate microglia, the immune cells that regulate neuroinflammation. It is evident that chronic stress goes beyond affecting energy production—it kickstarts inflammation.
A major contributor to this process is the pro-inflammatory cytokine interleukin-1 beta (IL-1β), which has been implicated in both MDD and CVD. Cytokines are essential for immune defence, but overproduction can be toxic. Interestingly, there is a correlation between IL-1β that correlates with mitochondrial dysfunction. Considering the concurrence of inflammation, MDD, and CVD, minimal attention has been given to discovering the underlying mechanisms.
The Inflammatory Connection
An estimated 300 million people worldwide live with depression, and the World Health Organisation predicts that it will be the leading cause of disability by 2030. While the exact cause of depression remains elusive, research substantiates that stress-driven neuroinflammation contributes to cognitive decline and neuroinflammation is a consistent feature in brain imaging studies. IL-1β has been found to amplify the activity of indoleamine 2,3-dioxygenase (IDO), an enzyme that impedes serotonin production, by 42 fold. The role of serotonin in depression is more controversial than ever, yet antidepressants continue to show that targeting serotonin depletion can effectively alleviate depressive symptoms. What’s more, IL-1b is extensively associated with the predominant cause of CVD—atherosclerosis.
Cardiovascular disease is responsible for nearly a third of global deaths, and the risk of its inception is increased by 72% in depression. Already implicated in depression, IL-1b via is also significant in progressing heart disease. The potent cytokine contributes to endothelial dysfunction by promoting the adhesion of molecules to blood vessel walls. The atherosclerotic process accelerates the formation of lesions in arteries, which can lead to stroke, heart failure, and ischaemic attacks. Though atherosclerosis is well-established as an inflammatory disease, depression is still painted as a neurologically isolated condition, despite the evidence it is rooted in systemic inflammation.
Conquering Stress: Playing the Long Game
The ‘fight or flight response’ is a remarkable mechanism that sanctions survival. Even so, chronic stress compromises the delicate balance of our immune system, and the stage is set for the development of disease. The complex mechanism outlined has several components: persistent stress, systemic hypercortisolemia, mitochondrial dysfunction, and subsequent inflammation. Yet, by further understanding the connection, we can positively harness the underlying link and conceive a new therapeutic approach for both endemic diseases—major depressive disorder and cardiovascular disease. While the science of stress is still being uncovered, it’s crucial to take steps to reduce daily stress. Simple practices can be profoundly beneficial:
- Ditch your smartphone: Notifications trigger stress, so taking a break can alleviate it.
- Exercise: It activates the immune response like stress but helps recalibrate the system when your heart rate returns to normal.
- Establish a schedule: Aligning with your circadian rhythm and allowing downtime reduces the stress of deadlines.
- Set realistic goals: Avoid frustration by accepting that perfection is unattainable.
Candidly when I undertook this research, I endured anxiety just writing about stress, yet the content confirms that protecting and nurturing our health should be amongst our highest priorities. Stress may be an inevitable part of human experience, except in contemporary society we have the knowledge to ease its effects by embracing resilience. It’s important to recognise that long-term health is too valuable to sacrifice.
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