Tuesday, February 11, 2014

A Cellular Basis for Aging

I was at work yesterday doing some research on mental health and early childhood development, and I came across this awesome article about stress and aging.  But I seriously geeked out because this article linked stress with cell aging and lifespan.  I've always had a bit of an interest in telomere biology since a presentation on the subject in my 4th year microevolution class.

First, some terminology.  Telomeres are the caps at the end of chromosomes.  They are made of bits of DNA that don't encode any genes, and that protect the important parts of chromosomes from shortening. 

The enzyme telomerase adds DNA to telomeres and makes them longer.  

DNA replication starts at the centre of the chromosome, rather than at the ends.  The enzymes that replicate DNA (aka polymerases) can only encode in one direction.  That means that one strand of DNA is copied in one straight shot (this is the leading strand).  But since DNA is double stranded, that leaves the other strand uncopied, which would be a waste.  To solve this problem, DNA polymerase copies the second strand (the lagging strand) in fragments.

Then DNA ligase comes in and seals the ends of the fragments, making a complete strand of DNA.  The ligase can only work if it has two pieces of DNA fragments to seal together, so that means that the last fragment is left with the end missing.  You can see how this would be a problem if the ends of our chromosomes contained important genes.  But it's ok, because telomeres are there to protect our chromosomes, and they progressively get shorter.  When telomeres run out, DNA replication stops and our cells age and die.  Telomere erosion (how fast telomeres shorten) is based on DNA replication rate, exposure to compounds that cause DNA damage (both environmental and physiological), and telomerase activity.  Research in telomere biology shows that the length of telomeres as well as the rate of telomere erosion can actually determine life spans and rate of aging across populations and species.  

This article that I came across is a review article that looks at evidence of different types of stress at different points in our lives, and their effect on telomere length and telomere erosion.  Our aging and susceptibility to disease can be influenced by exposure to stress as fetuses, infants, and children, as well as our mental health and lifestyle choices.  Obviously everyone knows that chronic stress and unhealthy lifestyle can make us age faster, among all kinds of diseases, but this review gives us an idea as to the biological mechanisms for this link.

A lot of very important brain and nervous system developments happen in a fetus, and continues as infants develop.  The researchers who wrote this paper have proposed that telomere length and telomerase activity is plastic during development and can change with different intrauterine and early life conditions.  That means that if a pregnant woman experiences chronic stress, that may trigger some placental-fetal endocrine responses that could influence the rate of telomere erosion in offspring.  The authors of the paper state that there isn't much information available on this process in humans, but there have been some studies in animals that have shown this link.

Stress and mental health in early childhood is becoming a greater public health concern because of its implications on physical, social, and mental development.  Studies of children and adults reporting high levels of stress in childhood have been linked to shortened telomeres.  One recent study that looked at cumulative stress in childhood (on-going family violence, bullying, maltreatment, and neglect) was associated with accelerated telomere erosion, and this effect was magnified with prolonged exposure to multiple stressors.  But other studies were more inconclusive about the link between shorter telomeres and exposure to violence, so the link between the two may not be as straightforward.

The authors also looked at the effect of mental illness on telomere erosion.  The idea is that mental illness causes stress responses in the body, which speeds up cellular aging.  Remember that telomere erosion is dependent on compounds that can damage DNA, among other things.  These compounds can include oxidants and stress hormones, which are heightened during stress.  Chronic stress, like that experienced as a result of mental illness, may therefore be linked to telomere erosion.  The studies that were reviewed in this paper looked at major depressive disorder, anxiety disorder, bipolar disorder, post-traumatic stress disorder, and schizophrenia.  Generally, studies that look at telomere erosion and mental illness have been inconclusive, so it's hard to come to the conclusion that mental illness causes an increased shortening of telomeres.  But one really interesting study looked at telomerase activity in individuals suffering from major depression disorder.  They found that telomerase activity increased in these individuals who were not taking antidepressant medication, and that this activity decreased after subsequent use of antidepressants.  They say that this increase in telomerase activity is likely to protect the cell against heightened stress response.  

What's cool about telomere biology is that all of this is plastic, it is highly influenced by stress levels, lifestyle, and environment.  So even if you were exposed to high stress as a child or you suffer from mental illness, there are other factors that can buffer the effects of these exposures on telomere erosion.  No one experience determines how you age or your susceptibility to disease.  A combination of experiences and exposure, lifestyle choices like healthy diet and exercise, etc. work together to influence your rate of cell replication and telomerase activity.  This paper is especially interesting because it provides a biological basis for how stress causes cellular aging and disease.

Geek on, friends!

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