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’[237]. 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.
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.
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.
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.
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[238][239]. 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 pre-dispose 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.
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[240]. 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.
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For a useful review of changes in epigenetic modifications during ageing, see Calvanese et al. (2009),