When they open their eyes in this world, their mind is a blank canvas. From day 1 to early years of childhood everything they experience will matter. And it would matter not only to shape their thought process but also to program their biology.

Childhood - A road to adult life
Image by Greyerbaby | CC0

Recap

In the last article, we explored the mechanisms by which mother's stress affects her fetus. I discussed, how this stress reprograms the epigenetic, metabolic, microbiome, and even the immune response of the child to be born. I mentioned how this reprogramming is then carried on to adulthood and can predict the metabolic, immune and mental disorders the fetus will be prone to later in life. However, the biological reprogramming doesn't stop once the child is born. And, this is what we are going to explore today. How early life sets your health and behaviour as an adult.

The blank canvas

We are all born with certain set of genes. How these genes act in concert with each other, predisposes us to certain kinds of behaviours and even diseases we face as an adult. But no, genes do not explain everything. And, if you follow me you might have noticed that I keep mentioning this fact over and over again. A given gene can be adaptive or maladaptive depending on the environment we encounter. And this environment is not limited to food and air around us; it also includes how our near and dear ones nurture us. Think of a new born child as a blank canvas. Now, every canvas have certain qualitative properties. These are internal to the material of canvas, or genes of the child. However, the child parents, teachers and peers are the artists. They will make strokes on this canvas. The final picture that emerges is a sum of all the strokes made. The better the base coats the better the picture. So if genes are material of paper, how the genes are expressed is controlled by the paints and brushes of the artists.

Early life stress and gene expression.

Early life stress as predictor of cancer and other diseases in adults

An example of epigenetic reprogramming downstream of childhood stressors. Stress can alter the basal state of gene regulation. In this example it shows that it can either methylate a gene promoter and reduce the expression of gene; or it can cause demethylation of normally methylated promoter, leading to overexpression of the gene.
By @scienceblocks

In part 1, we saw that maternal stress changes the dosage of gene products that a child may experience later in life. To see if childhood maltreatment, also affects gene regulation, Yang et al., conducted a study in 2013. They took samples from children who were taken away by social services because they were being abused. They found differential methylation on genes of abused children as compared to normal control. And that's not where the story ends. A lot of genes they found to be deferentially methylated were also the genes that are also implicated in many cancers. And, there is nothing to be surprised here. A lot of previous literature, has already shown that adverse childhood is a risk factor for cancer in adults (Holman et al., 2016). In fact, in 2016, Cecil et al., identified that the kind of maltreatment has unique epigenetic or DNA methylation signatures. These signatures also predict the kind of physical and mental troubles the abused children would face as an adult. For instance they found a link between physical abuse and genes related to cardiovascular risk.

The effect of early life stress on adult health is not just limited to population studies in humans. Take example of studies done in mice. The mice that were exposed to chronic stress starting from either few days after birth or during onset of puberty show perturbed mamammy gland development (see review by Linda and Auger, 2010). The reprogramming of estrogen (sex hormone) and glucocorticoid (stress hormones) receptors seem to play a role here. But is altered development of mammary glands linked to increased risk of cancer? Well, some of the studies they cite in the review hint towards a such a link.

Metabolic disorders - reprogramming mitochondrial responses

The happy motochondria on experiencing psychological stress in early life gets reprogrammed to deal with high stress levels in life.
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In part 1, I also talked how maternal stress, via epigenetic reprogramming, leads to altered metabolism and perturbed immune response in adult life of the fetus. Which made me as ask, if this would also be the case with early postnatal life stress. There is a link between childhood abuse - esp physical abuse and obesity in adulthood (Power et al., 2015). The link is also supported by animal studies, where maternal separation or social isolation stress leads to increased weight gain in mice (Vargas et al., 2016). In fact, the study by Vargas also further establishes evidence for increased insulin resistance as result of early life stress. Well, their study was in line with correlation observed between childhood maltreatment and perturbed regulation of glucose in human adults (Li et al., 2017). But the question remains - how?

At the center of metabolism is mitochondria - the organelle in every cell that makes a the energy for you. In one of a previous post, I talked about how stress increases mitochondrial load and hence Reactive oxygen species(ROS). ROS is known to cause a lot of cellular damage, increases mutations load (and hence risk for cancer), accelerates aging and promotes unwanted inflammation. However, can early life stress alter the mitochondrial dynamics and set stage for diseases in adults? Well, from animal studies we know that proteins involved in mitochondrial activity are decreased in mice hippocampus if exposed to stress in their early life (Wei et al., 2015). Though, mitochondrial dysfunction is not limited to the brain. A study conducted by Bocek et al., 2016 measured markers for oxidative stress in serum of women with history of maltreatment in childhood. Turns out both ROS and inflammation were increased in these women. Given that both ROS and inflammation promote each other it was not that surprising. However, it is not clear which comes first in case of early life stress. Nevertheless, both seem to be acting in concert with each other.

Kicking Immune system off balance

Immune system - Once bitten in childhood, twice shy in adults! (The graph is just hypothetical illustration of what is going on, it is not based on any real data)
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Talking of inflammation, I previous posted about causal relationship between inflammation, obesity and type 2 diabetes, and have also reiterated it in many other posts that followed. Then, I also discussed how chronic low grade inflammation leads to not only metabolic disorders but also psychological disorders such as depression (see my earlier post). Story of cardiovascular diseases follow a similar path, as well(Lopez-Candales et al., 2017). Moreover, in support of link between childhood maltreatment and cancer, there is also evidence to support link between inflammation and cancer. For instance patients with inflammatory bowel disease and Hep C infection have high risk of colon and liver cancer, respectively (Coussens and Werb, 2002). But do childhood abuse change how our immune system will react as an adult?

Turns out, specific inflammatory response profiles in adults can be linked to the kind of abuse or trauma they faced as a child (Baumiester et al., 2016). Moreover, it appears that the threshold for pathogenic threat is lowered in those stressed early in life. For instance, Miguel et al., in 2016 showed that in rats exposed to maternal separation stress early in life - the immune cell proportions remains normal. However, what appears to be happening here is priming of immune response later in life seems a bit towards paranoid side. So, even tiny bit of threat such as that from very small amount bacterial lipopolysaccharide will cause immune system to fire up.

But, how is the immune response profile programmed and primed in early age? We already saw the altered mitochondria function can cause inflammation, so that is there. Then, it can also be programmed via epigenetic mechanism, though more work on that is required to pin point the genes involved. Well, at least we do know the genes for stress hormone receptors (such as NR3C1) are epigenetically regulated in response to early life stress (McGowan et al., 2009). Can altered stress response alter immune responses as well?

The altered stress response

We already know that stress is upstream of inflammatory response in adults and chronic stress throws it off balance (see this blog). And, here we can see that stress response itself can be reprogrammed by childhood stressors. In fact, another gene FKBP5 responds to childhood trauma. FKBP5 is important regulator of steroid hormones, immunoregulatoion and stress response. A specific allele of this gene if demethylayed by childhood trauma alters how we responds to stress and our immune responses during stressed conditions for rest of the life (Klengel et al., 2013).

The fact that demethylation of specific allele of FKBP5 not only leads to the observed response, it also sheds light on something very important. It tells us that people might be genetically predisposed to certain diseases, but we don't have to make sure that they get them. Thinking of which autoimmune disorders also come to mind.

Setting the stage for Autoimmune disorders

Well, because if you have increased unwanted inflammatory responses, and have genetic predisposition to any autoimmune disorder as well, it will be a recipe for disaster. Below are some examples of autoimmune disorders which show significant correlation with childhood maltreatment -

Psoriasis - esp late onset is linked to adverse childhood experiences (Simonic et al., 2010.)

COPD (Shields et al., 2016)

Lupus (Feldman et al., 2018)

Rheumatoid arthritis(RA) (Hellou et al., 2018)

And a lot more (Dube et al., 2009)

In context of psoriasis, RA and ankylosing spondylitis there is a gene variant of Human leukocyte antigen called HLAB27. Now, having this variant does is it makes removing viruses from your body very efficient. For instance, people with this variant of gene are resistant to developing AIDS on getting HIV. But at cost of make self recognition a little less efficient. However, while many people with the diseases mentioned above have this gene variant, only very few people with this gene develop the disease. So having the gene doesn't explain it all. Now add to this childhood trauma and unwanted chronic inflammation. Depending on other gene variants you have you will be at high risk of developing one or the other autoimmune disorder (see previous blog). So, what is to be noted here is the fact that while this gene just predisposes you to risk of an autoimmune disorder; the onset of such disorders may depend on life events - such as early life stress. Now we keep hearing this theme that its both nature and nurture that decides the role of the gene. One may have a general that causes the disease but only if combined with certain stressors in life. The theme is very common in psychological disorders.

You are your connectome - but your connectome is programmed by early life events.

Talking of psychological disorders, the story there is not very different. Metabolism, inflammation, and gene-environment interaction, they all play a role. I already posted, how depression can result from underlying chronic inflammation. While, it is not clear as to which comes first - inflammation or altered cellular metabolism - but mitochondrial dynamics also seem to play a role. Take anxiety disorders for instance. We know that anxiety can result from memories of adverse life events making amygdala in the brain hyperactive. In this regard, mice study showed that stress around puberty in mice increased mitochondrial function in neurons of amygdala (Papilloud et al., 2018). This correlated with aggression displayed by these mice in their adult life. This is probably because if you are exposed to threats early in life, your amygdala better be prepared for threats later in life. So even trivial threats later may cause a hyperactive response from amygdala - leading to generalized fear aka anxiety. In fact the hyperactivity of amygdala has also been noted in human adults who have history of childhood maltreatment (Jedd et al., 2015). So the fact that childhood abuse of any sort increases the risk of anxiety disorders and depression can be attributed to how it primes the amygdala along with other brain regions (Rehan et al., 2017).

Moreover, another gene called Brain derived neurotrophic factor (BDNF), seems to be down regulated esp in amygdala of animals exposed to early life stress Bondar and Merkulova, 2016. The mechanism of BDNF down regulation appears to be result of epigenetic regulation of BDNF gene in response to stress. Similar down regulations of BDNF gene has been observed in humans, as well (Velzen et al., 2016). Also, it appears that the affect of BDNF combined with stress is allele specific. Once again showing the nature and nurture interaction. Apart from BDNF expression explaining many psychiatric and neurodegenerative disorders in these individuals, BDNF is also a gene important in memory and learning. Based on this one would predict that childhood stress also leads to learning disabilities. This prediction is supported by both human population studies and experiments in animals (see Consequences of Child Abuse and Neglect).

Yet another risk, in children who faced childhood maltreatment is altered social behaviour. Now the exact mechanism for this needs to be deciphered, but one good candidate it defective myelination or neurons in children with history of child abuse (Lutz et al., 2017). The myelination of neurons makes the connections between them faster and robust. Though most of our brain is myelinated the prefrontal cortex, the region of the brain that is involved in social conduct, takes about 25 years of our life. So if we prime the kids to have defective myelination regulations , it is not surprising that they will difficult social life as well. In fact, such alteration in myelination program have been reported for prefrontal cortex (Tanti et al., 2017).

The story continues to the grandkids

Passing on the behaviour via behaviour

Now imagine, for whatsoever reason, you thought disciplining a child by physical means was ok. Now maybe they don't develop a full fledged anxiety disorder, but do develop an anxious personality. Now, they go on to have your grandchildren. So what is the risk of a person with anxious personality to treat your grandkids the same way you treated them? Growing up in an anxious environment created by parents would be stressful for your grandkids, as well. So not only you are gambling with your kids, but you are gambling with generations to come (read this article).

Life experiences can be inherited via epigenetics

The story doesn't end at your kids behaviourally influencing the biology of your grandchildren. In an earlier blog, I discussed that parents can pass on their life experiences to their kids via heritable component of epigenome. In the last part of childhood stressors, we saw that a stressed mother can affect the epigenetic of the developing child. But it's not only the mother we have to be concerned about. The childhood maltreatment also causes epigenetic reprogramming in germ cells that form sperms Roberts et al., 2018. The genes regulating fat cells, immune cells and neuronal functions appear to be reprogrammed in sperm of father who underwent adverse childhood.

Altering the initial conditions of microbiome in childhood - and that of grandchildren too.

The third factor, that is altered in stressed mothers is their microbiome. As, I discussed in the previous blog, the microbiome of the mother is important determinant of microbiome of the child. The microbiome in turn can predict both our mental and physical health (see this post). Of many life events that could have altered the gut microbiome of these mothers, crucial one is early life experience. Well, because that's when the microbiome of child is building up. This initial condition is determinant of how it will respond and change with respect to whatever a person experience later in life.

Summary

Graphical summary of discussion
@scienceblocks

So in a nutshell, what we saw in this article was that early life stress plays a crucial role in determining our physical and mental health. We saw a lot of correlative evidence linking childhood maltreatment with various physical and mental diseases, including cancer. We also saw probable mechanisms explaining those correlations. Just like maternal stress experienced in womb, stress during early life can reprogram - microbiome, neuronal connections, gene expression, immune system, and metabolism. Not to mention that all these interact mechanism interact with themselves, as well.

I realise that nurturing a child is not an easy task. This article is not meant to give you any advice on how to go about your business. However, I do believe everybody's actions should be informed. In fact, if parenting style and it's effect on child is what you are interested in you should read more about them here.

With this I would like to close this article. Please comment with suggestions, questions, and information regarding the topic. Anything you can add to knowledge base is much appreciated.

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Signing off

@scienceblocks