Thursday, February 20, 2014

Don't Worry, Be Happy. Or Just Try Not to Stress Out too Much

Don't Worry, Be Happy. Or Just Try Not to Stress Out too Much...

By: Joshua Mier

Now this is a song everyone has heard, or at least the face is of someone that we all can recognize. The message Mr. Marley so elegantly declares is also relatively straightforward: "Don't worry about a thing, because every little thing is going to be alright." You say those lines and you can already hear the jingle in your head. So then it seems a simple enough rule to follow right? Well, unfortunately we all know that life isn't always this simple. If we wanted to, we could make an laundry list of all the things that make life difficult, like for instance....Ha! Gotcha, why the hell would anyone want to read that, right? Believe me, my goal here is not to be Jamaican ya crazy:

Did he just throw in both a Cool Runnings and Winter Olympic's Gag?

However, I think everyone can agree that sometimes life just slaps us in the face to let us know we're awake: work continues to pile up, deadlines aren't being met, relationships not panning out the way we had planned. All these negative sentiments can effectively accumulate to the point of anxiety, or the sensation that we all love to loathe: Stress...

This emotion can easily resonate throughout the body: the heart begins to race, your muscles start to twitch, your ventilation rate spikes and it feels as if every neuron in your body is firing all at once. So then have you ever wondered:
  1. What is stress exactly and how or what's causing these feelings in the first place? 
  2. What effects does stress have on the body, what parts of the body are effected?
  3. How do these biological reactions effect overall short or long term health?
Here, I will attempt to answer these questions. But first, I would like to open with a brief quatrain from Walter D. Writle's famous poem "Thinking:"

If you think you are beaten, you are.
If you think you dare not, you don't.
If you like to win, but think you can't.
It's almost certain you won't.

This may seem a little pessimistic, but it's message is clear in being aware of your thoughts. This will make more sense at the conclusion (but please don't cheat and skip to the end!)

I) What is Stress and how does it manifest throughout the body?

First off, stress is a notoriously hard to define for biologists since it covers such a broad spectrum. However, in this instance, we are talking about the physiological stressed strait. That is:
  • Any environmental factor that:
    • Disturbs the normal adaptive responses or
    • Causes disrupts normal physiological functioning to a point where chance of survival is reduced.
Notice: That this definition uses environmental factor. Which makes sense for animals (e.g., temperature, salinity, pH, a big ass predator...)

The normal physiological state is the point when a organism is at homeostasis (your body is basically saying "it's all good."). Stress is an environmental stimulus that causes a disturbance in homeostasis.

So now we know what environmental factors trigger the stress, what exactly is it triggering...
  • Stress triggers hormonal pathways! 
Hormones are "chemical messengers" that are secreted by endocrine gland cells that travel through the bloodstream to exert their effects on distant target cells. Only cells that retain the receptor will elicit the response.

In the stress response (Oh CRAP, it's not all good bro) environmental stimuli activate endocrine pathways that act through the hypothlamus in the brain that eventually stimulates hormone production in the adrenal gland (BOOM...Mind = BLOWN #1)
  1. The 'Fight or flight response' - I'm sure you've all heard of this one (so I'm not going to spend too much time talking about it). But essentially, norepinphrine released from sympathetic neurons stimulates the release of epineprhine (also known as adrenaline) which then goes on to act on multiple different tissues.
Sympathetic neurons converge on the adrenal medulla. Secretion of NE causes release of Epineprhine from the Adrenal Medulla.

But the main pathway I would like to focus this topic on is the Hypothalamic pituitary Adrenal  (HPA axis):

Stress stimuli cause hypothalamic neurons to release corticotropin releasing factor in the anterior pituitary gland (APG). The APG will then release adrenocorticotropin hormone (ACTH) into the bloodstream which acts on the adrenal cortex to release cortisol into the blood

    2. HPA axis = CORTISOL. I wrote out the pathway (which is totally sweet to know by the way..) just to give you an idea of the stimulation and release of the hormone. 
If it was confusing, then please walk away from this section with this:
  • Stress is a environmental stimulus that acts on neurons in the hypothalamus that release hormones into the blood that act on the adrenal gland...
And BOOM goes the dynamite!

 II) Cortisol is a Stress hormone, so what does it effect-

Cortisol why is it important?
  • Corisol's main effect is to prevent hypoglycemia (meaning prevent decreases blood sugar). Cortisol acts on target cells by binding to glucocorticoid receptors.
Note: All nucleated cells have glucocorticoid receptors. If this doesn't trip you out, then consider that basically the only non-nucleated cells are red blood cells (BOOM...Mind = BLOWN #2)

Question? Why would this be important
  • Any environmental stimuli that activates this stress response. Let's say its a second big ass predator (on top of the first big ass predator mentioned earlier) comes at you, your body can synergistically coordinate a single response to get the hell out of dodge (BOOM...Mind = BLOWN #3)
So, what tissues are effected:
  1. Liver - Cortisol acts on the hepatocytes (liver cells) to promote the release of glucose into the blood (through the production of new glucose or gluconeogenesis).    
  2. Skeletal Muscles- Breaks down skeletal muscles to provide substrates . Cortisol causes breakdown of proteins in muscles to amino acids which can then be used by the liver to increase glucose output (BOOM...Mind = BLOWN #4).
  3. Enhanced Lipolysis- Cortisol increases fat breakdown to promote uptake of fats in the liver to increase glucose output.
  4. Suppresses the immune system**- Cortisol acts as an inhibitory signal to promote immunosuppression.

Key point: to reiterate, the main purpose of cortisol production is to prevent hypoglycemia, which makes sense in an environmental context as in the case for animals.

III) Chronic stress- The suburban paradox-

Earlier I noted that stress is associated with environmental stimuli. For animals, the cortisol stimulated stress response makes sense: get the hell out of dodge when I see a big ass predator.

Notice, that in the human context, we don't necessarily have that dilemma. Therefore, stimuli that trigger the stress response in our instance can be triggered psychological manifestations or better yet our emotions.

Remember: cortisol is essential for life! 

However, just like many things in life, too much cortisol (or chronically elevated levels = chronic stress) can be especially dangerous, take these examples:

i) Cortisol suppress the immune response:

Cortisol exerts its effects on the immune system by: a) inhibiting the inflammatory signals (e.g., cytokines such as NF-kB) and up-regulates the expression of anti-inflammatory proteins (e.g., I-Kappa 8).
  • This is actually why cortisol is used as a therapeautic drug to deter inflammations in many sports-related injuries. 

Downside: Excess production of cortisol can inhibit your adaptive immune response 
  • Chronic stress can inhibit and reduce the amount of CD8+ and CD4 lymphocytes (i.e., Cytotoxic and Helper T cells). CD8+ cells will kill viral infected cells to prevent the spread of disease, while CD4+ cells will stimulate alternative immune cells like plasma cells which produce antibodies. Patients with depleted lymphocytes in this instance, also were diagnosed with psychological disorders (e.g., attachement disorder in this case).
Why is this important? Chronic stress can lead to disease progression.

Example: ALS: Amytrophic lateral sclerosis: is a fatal neurodegenerative disease that results in neural and muscle breakdown.

Chronically stressed mice (in this case increased cortisol production over time) exhibited decreased survival rates compared to non-stressed mice. Figure from Fidler et al. 2011.

Chronic stress can also lead to detrimental long-term effects such as reproductive failure, heart disease and alternative neurodegenerative disorders.

Cortisol will continue to be associated with the negative connotation of the stress hormone, however, let us not forget that this conserved hormone has an evolutionary advantage of conferring an adaptive response to evade danger and avoid predation. As we have seen, excess cortisol production can have harmful long term health effect that are directly associated with stress. Denoting both of these aspects, however, we notice that in proper balance the effect of cortisol is negligible. We can essentially think of our bodies then as "perfect  machines." Just like machines, they will respond to external input and respond accordingly. The response in our case (aside from disease associated patterns) can be stimulated from our mindset. This is especially the case if you've ever heard of "The Secret" by Rhonda Byrne outlying the Law of Attraction or the theory of metacognition: how you think is perpetuated into the universe and is reciprocated accordingly. Essentially if you think positively you will get a positive response and vice versa.

Of course, this is easier said then done. Stress is a normal part of life (and an essential one at that). There will always be environmental triggers that elicit the stress response. However, being aware of your emotional status and now having a better understanding of the underlying physiological mechanisms can help elucidate more positive outcomes. Besides, if we were happy all the time, life would be a little dull (imagine a world full of Tony Robbins').

With that in mind, maybe Bob Marley's ideology can be useful. Next time your in a stressful situation, just think about his message to you hoo hoo... Now excuse me while I go stress over studying for another midterm, while I conclude with the ending quatrain from Writle's famous poem:

Life's battles don't always go,
To the stronger or faster man,
For sooner or late the man who wins,
Is simply the man who thinks he can.


Ciriaco, M, P. Ventrice, G. Russo, M. Scicchitano, G. Mazzitello, F. Scicchitano and E. Russo. 2013. Corticosteroid-related central nervous system side effects. Journal of Pharmacology and Pharmacotherapeutics 4: 594-598.

Fidler, J. A., C. M. Treleaven, A. Frakes, T. J. Tamsett, M. McCrate, S. H. Cheng, L. S. Shihabuddin, B. K. Kaspar and J. C. Dodge. 2011. Disease Progression in a mouse model of amyotrophic lateral sclerosis: the influence of chronic stress and corticosterone.

Journal of Federation of American Societies for Experimental Biology 25: 4369-4377

Hill, R. W., G. A. Wyse and M. Anderson. 2004. Animal physiology. In Endorcine and Neuroendocrine Physiology, pp. 400-409. Sunderland, MA: Sinauer Associates, Inc.

Jaremka, L. M., R, Glaser, T. J. Loving, W. B. Malarkey, J. R. Stowell and J. K. Klecolt-Glaser. 2013. Attachment anxiety is linked to alterations in cortisol production and cellular immunity. Psychological Science. 24(3): 272-279.

Kultz, D. 2005. Molecular and evolutionary basis of the cellular stress response. Annual Review of Physiology. 67: 225-257.

Ross, A. P., A. Ben-Zacharia, C. Harris and J. Smrtka. 2013. Multiple sclerosis, relapses, and the mechanism of action of adrenocorticotropin hormone. Frontiers in Neurology 4(21): 1-12

Petes, L. E., B. A. Menge and A. L. Harris. 2008. Intertidal mussels exhibit energetic trade-offs between reproduction and stress resistance. Ecological Monographs 78(3): 387-402.

Images and Videos (Taken in order of appearance):

1) Bob Marley Video "Three Little Birds:"

2) Bobsled jpeg:

3) Dr. Kristin Hardy Lecture slides. Fall 2011. Slide 6, 14_Endocrine.pdf

4) Dr. Kristin Hardy Lecture slides. Fall 2011. Slide 27, 15_Endocrine.pdf

5) Ross et al. 2013.

6) Fidler et al. 2011

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