Read The Epigenetics Revolution Online
Authors: Nessa Carey
Tags: #Science/Life Sciences/Genetics and Genomics
The Epigenetics Revolution (39 page)
Most breakthroughs in human healthcare up until now have improved both longevity and quality of life. That’s partly because many major advances targeted early childhood deaths. Vaccination against serious diseases such as polio, for example, has hugely improved both childhood mortality figures (fewer children dying) and morbidity in terms of quality of life for survivors (fewer children permanently disabled as a result of polio).
There is a growing debate around the issue sometimes known as human life extension, which deals with extending the far end of life, old age. Human life extension refers to the concept that we can use interventions so that individuals will live to a greater age. But this takes us into difficult territory, both socially and scientifically. To understand why, it’s important to establish what ageing really is, and why it is so much more than just being alive for a long time.
One useful definition of ageing is ‘the progressive functional decline of tissue function that eventually results in mortality’
2
. It’s this functional decline that is the most depressing aspect of ageing for most people, rather than the final destination.
2
. It’s this functional decline that is the most depressing aspect of ageing for most people, rather than the final destination.
Generally speaking, most of us recognise the importance of this quality of life issue. For example, in a survey of 605 Australian adults in 2010, about half said they would not take an anti-ageing pill if one were developed. The rationale behind their choice was based around quality of life. These respondents didn’t believe such a pill would prolong healthy life. Simply living for longer wasn’t attractive, if this was associated with increasing ill-health and disability. These respondents did not wish to prolong their own lives, unless this was associated with improved health in later years
3
.
3
.
There are thus two separate aspects to any scientific discussion of ageing. These are lifespan itself, and the control of late-onset disorders associated with ageing. What isn’t clear is the degree to which it is possible or reasonable to separate the two, at least in humans.
Epigenetics definitely has a role to play in ageing. It’s not the only factor that’s important, but it is significant. This field of epigenetics and ageing has also led to one of the most acrimonious disputes in the pharmaceutical sector in recent years, as we’ll see towards the end of this chapter.
We have to ask why our cells malfunction as we get older, leaving us more at risk of illnesses that include cancer, type 2 diabetes, cardiovascular disease and dementia, amongst a host of other conditions. One reason is because the DNA script in the cells of our body begins to change for the worse. It accumulates random alterations in sequence. These are somatic mutations, which affect the tissue cells of the body, but not the germline. Many cancers have changes in the DNA sequence, often caused by quite large rearrangements between chromosomes, where genetic material is swapped from one chromosome to another.
Guilt by association
But as we’ve seen, our cells contain multiple mechanisms for keeping the DNA blueprint as intact as possible. Wherever possible, a cell’s default setting is to maintain the genome in its original state, as much as it can. But the epigenome is different. By its very nature, this is more flexible and plastic than the genome. Because of this, it is probably not surprising that epigenetic modifications change as animals age. The epigenome may eventually turn out to be far more prone to changes with age than the genome, because the epigenome is more naturally variable than the genome anyway.
We met some examples of this in
Chapter 5
, where we discussed how genetically identical twins become less identical epigenetically as they age. The issue of how the epigenome changes as we age has been examined even more directly. Researchers studied two large groups of people from Iceland and from Utah, who have been part of on-going long-term population studies. DNA was prepared from blood samples that had been taken from these people between eleven and sixteen years apart. Blood contains red and white blood cells. The red blood cells carry oxygen around the body, and are essentially just little bags of haemoglobin. The white blood cells are the cells that generate immune responses to infections. These cells retain their nuclei and contain DNA.
Chapter 5
, where we discussed how genetically identical twins become less identical epigenetically as they age. The issue of how the epigenome changes as we age has been examined even more directly. Researchers studied two large groups of people from Iceland and from Utah, who have been part of on-going long-term population studies. DNA was prepared from blood samples that had been taken from these people between eleven and sixteen years apart. Blood contains red and white blood cells. The red blood cells carry oxygen around the body, and are essentially just little bags of haemoglobin. The white blood cells are the cells that generate immune responses to infections. These cells retain their nuclei and contain DNA.
The researchers found that the overall DNA methylation levels in the white blood cells of some of these individuals changed over time. The change wasn’t always the same. In some individuals, the DNA methylation levels went up with age, in others they dropped. The direction of change seemed to run in families. This may mean that the age-related change in DNA methylation was genetically influenced, or affected by shared environmental factors in a family. The scientists also looked in detail at methylation at over 1,500 specific CpG sites in the genome. These sites were mainly associated with protein-coding genes. They found the same trends at these specific sites as they had seen when looking at overall DNA methylation levels. In some individuals, site-specific DNA methylation was increased whereas in others it fell. DNA methylation levels were increased or decreased by at least 20 per cent in around one tenth of the people in the study.
The authors stated in their conclusion that ‘these data support the idea of age-related loss of normal epigenetic patterns as a mechanism for late onset of common human diseases’
4
. It’s true that the data are consistent with this model of epigenetic mechanisms leading to late onset disease, but there are limitations, which we should bear in mind.
4
. It’s true that the data are consistent with this model of epigenetic mechanisms leading to late onset disease, but there are limitations, which we should bear in mind.
In particular, these types of studies highlight important correlations between epigenetic change and diseases of old age, but they don’t prove that one event causes the other. Deaths through drowning are most common when sales of suntan lotion are highest. From this one could infer that sun tan lotions have some effect on people that makes them more likely to drown. The reality of course is that sales of suntan lotion rise during hot weather, which is also when people are most likely to go swimming. The more people who swim, the greater the number who will drown, on average. There is a correlation between the two factors we have monitored (sales of sun block and deaths by drowning) but this isn’t because one factor causes the other.
So, although we know that epigenetic modifications change over time, this doesn’t prove that these alterations cause the illnesses and degeneration associated with old age. In theory, the changes could just be random variations with no functional consequences. They could just be changes in the epigenetic background noise in a cell. In many cases, we don’t even yet know whether the altered patterns of epigenetic modifications lead to changes in gene expression. Addressing this question is hugely challenging, and particularly difficult to assess in human populations.
Guilt by more than association
Having said that, there are some epigenetic modifications that are definitely involved in disease initiation or progression. The case for these is strongest in cancer, as we saw in
Chapter 11
. The evidence includes the epigenetic drugs which can treat certain specific types of cancer. It also includes the substantial amounts of data from experimental systems. These show that altering epigenetic regulation in a cell increases the likelihood of a cell becoming cancerous, or can make an already cancerous cell more aggressive.
Chapter 11
. The evidence includes the epigenetic drugs which can treat certain specific types of cancer. It also includes the substantial amounts of data from experimental systems. These show that altering epigenetic regulation in a cell increases the likelihood of a cell becoming cancerous, or can make an already cancerous cell more aggressive.
One of the areas that we dealt with in
Chapter 11
was the increase in DNA methylation that frequently occurs at the promoters of tumour suppressor genes. This increased DNA methylation switches off the expression of the tumour suppressor genes. Oddly enough, this increase in DNA methylation at specific sites is often found against an overall background of decreased DNA methylation in many other areas of the genome in the same cancer cell. This decrease in methylation may be caused by a fall in expression or activity of the maintenance DNA methyltransferase, DNMT1. This decrease in global DNA methylation may also contribute to the development of cancer.
Chapter 11
was the increase in DNA methylation that frequently occurs at the promoters of tumour suppressor genes. This increased DNA methylation switches off the expression of the tumour suppressor genes. Oddly enough, this increase in DNA methylation at specific sites is often found against an overall background of decreased DNA methylation in many other areas of the genome in the same cancer cell. This decrease in methylation may be caused by a fall in expression or activity of the maintenance DNA methyltransferase, DNMT1. This decrease in global DNA methylation may also contribute to the development of cancer.
To investigate this, Rudi Jaenisch generated mice which only expressed Dnmt1 protein at about 10 per cent of normal levels in their cells. The levels of DNA methylation in their cells were very low compared with normal mice. In addition to being quite stunted at birth, these
Dnmt1
mutant mice developed aggressive tumours of the immune system (T cell lymphomas) when they were between four and eight months of age. This was associated with rearrangements of certain chromosomes, and especially with an extra copy of chromosome 15 in the cancer cells.
Dnmt1
mutant mice developed aggressive tumours of the immune system (T cell lymphomas) when they were between four and eight months of age. This was associated with rearrangements of certain chromosomes, and especially with an extra copy of chromosome 15 in the cancer cells.
Professor Jaenisch speculated that the low levels of DNA methylation made the chromosomes very unstable and prone to breakages. This put the chromosomes at high risk of joining up in inappropriate ways. It’s like snapping a pink stick of rock and a green stick of rock to create four pieces in total. You can join them back together again using melted sugar, to create two full-length items of tooth-rotting confectionery. But if you do this in the dark, you may find that sometimes you have created ‘hybrid’ rock sticks, where one part is pink and the other is green.
The end result of increased chromosome instability in Rudi Jaensich’s mice was abnormal gene expression. This in turn led to too much proliferation of highly invasive and aggressive cells, resulting in cancer
5
,
6
. These data are one of the reasons why DNMT inhibitors are unlikely to be used as drugs in anything other than cancer. The fear is that the drugs would cause decreased DNA methylation in normal cells, which might predispose some cell types towards cancer.
5
,
6
. These data are one of the reasons why DNMT inhibitors are unlikely to be used as drugs in anything other than cancer. The fear is that the drugs would cause decreased DNA methylation in normal cells, which might predispose some cell types towards cancer.
These data suggest that the DNA methylation level per se is not the critical issue. What matters is
where
the changes in DNA methylation take place in the genome.
where
the changes in DNA methylation take place in the genome.
The generalised decrease in DNA methylation levels that comes with age has also been reported in other species than humans and mice, ranging from rats to humpback salmon
7
. It’s not entirely clear why low levels of DNA methylation are associated with instability of the genome. It may be because high levels of DNA methylation can lead to a very compacted DNA structure, which may be more structurally stable. After all, it’s easy to snip through a single extended wire with a pair of cutters, but much harder if that wire has been squashed down into a dense knot of metal.
7
. It’s not entirely clear why low levels of DNA methylation are associated with instability of the genome. It may be because high levels of DNA methylation can lead to a very compacted DNA structure, which may be more structurally stable. After all, it’s easy to snip through a single extended wire with a pair of cutters, but much harder if that wire has been squashed down into a dense knot of metal.
It’s important to appreciate just how much effort cells put into looking after their chromosomes. If a chromosome breaks, the cell will repair the break if it can. If it can’t, the cell may trigger an auto-destruct mechanism, essentially committing cellular suicide. That’s because damaged chromosomes can be dangerous. It’s better to kill one cell, than for it to survive with damaged genetic material. For instance, imagine one copy of chromosome 9 and one copy of chromosome 22 break in the same cell. They could get repaired properly, but sometimes the repair goes wrong and part of chromosome 9 joins up with part of chromosome 22.
This rearrangement of chromosomes 9 and 22 actually happens relatively frequently in cells of the immune system. In fact it happens so often that this 9:22 hybrid has a specific name. It’s called the Philadelphia chromosome, after the city where it was first described. Ninety-five per cent of people who have a form of cancer called chronic myeloid leukaemia have the Philadelphia chromosome in their cancer cells. This abnormal chromosome causes this cancer in the cells of the immune system because of where the breaking and rejoining happen in the genome. The fusion of the two chromosome regions results in the creation of a hybrid gene called
Bcr-Abl
. The protein encoded by this hybrid gene drives cell proliferation forwards very aggressively.
Bcr-Abl
. The protein encoded by this hybrid gene drives cell proliferation forwards very aggressively.
Our cells have therefore developed very sophisticated and fast-acting pathways to repair chromosome breaks as rapidly as possible, in order to prevent these sorts of fusions. To do this, our cells must be able to recognise loose ends of DNA. These are created when a chromosome breaks in two.
But there’s a problem. Every chromosome in our cell quite naturally has two loose ends of DNA, one at each end. Something must stop the DNA repair machinery from thinking these ends need to be repaired. That something is a specialised structure called the telomere. There is a telomere at each end of every chromosome, making a total of 92 telomeres per cell in humans. They stop the DNA repair machinery from targeting the ends of chromosomes.
The tail ends
Telomeres play a critical role in control of ageing. The more a cell divides, the smaller its telomeres become. Essentially, as we age, the telomeres get shorter. Eventually, they get so small that they don’t function properly anymore. The cells stop dividing and may even activate their self-destruct mechanisms. The only cells where this is different are the germ cells that ultimately give rise to eggs or sperm. In these cells the telomeres always stay long, so the next generation isn’t short-changed when it comes to longevity. In 2009, the Nobel Prize in Physiology or Medicine was awarded to Elizabeth Blackburn, Carol Greider and Jack Szostak for their work showing how telomeres function.
Since telomeres are so important in ageing, it makes sense to consider how they interact with the epigenetic system. The DNA of vertebrate telomeres consists of hundreds of repeats of the sequence TTAGGG. There are no genes at the telomere. We can also see from the sequence that there are no CpG motifs at the telomeres, so there can’t be any DNA methylation. If there are any epigenetic effects that make a difference at the telomeres they will therefore have to be based on histone modifications.
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