The Epigenetics Revolution

If the telomeres get too short, the cell tends to shut down. But if the telomeres get too long, there’s an increased risk of different chromosomes linking up, and creating new cancer-promoting genes. Cell shut-down is probably a defence mechanism that has evolved to minimise the risk of creating new cancer-inducing genes. This is one of the reasons why it’s likely to be very difficult to create drugs that increase longevity without increasing the risk of cancer as well.

What happens when we create new pluripotent cells? This could be through somatic cell nuclear transfer, as we saw in Chapter 1, or through creation of iPS cells, as we saw in Chapter 2. We may use these techniques to create cloned non-human animals, or human stem cells to treat degenerative diseases. In both cases, we want to create cells with normal longevity. After all, there is little point creating a new prize stallion, or cells to implant into the pancreas of a teenager with diabetes, if the horse or the cells die of telomere ‘old age’ within a short time.

That means we need to create cells with telomeres that are about the same length as the ones in normal embryos. In nature, this occurs because the chromosomes in the germline are protected from telomere shortening. But if we are generating pluripotent cells from relatively adult cells, we are dealing with nuclei where the telomeres are already likely to be relatively short, because the ‘starter’ cells were taken from adults, whose chromosomes are getting shorter with age.

Luckily, something unusual happens when we create pluripotent cells experimentally. When iPS cells are created, they switch on expression of a gene called telomerase. Telomerase normally keeps telomeres at a healthy long length. However, as we get older, the telomerase activity in our cells starts to drop. It’s important to switch on telomerase in iPS cells, or the cells would have very short telomeres and wouldn’t create very many generations of daughter cells. The Yamanaka factors induce the expression of high levels of telomerase in iPS cells.

But we can’t use telomerase to try to reverse or slow human ageing. Even if we could introduce this enzyme into cells, perhaps by using gene therapy, the chances of inducing cancers would be too great. The telomere system is finely balanced, and so is the trade-off between ageing and cancer.

Both histone deacetylase inhibitors and DNA methyltransferase inhibitors improve the efficiency of the Yamanaka factors. This might be partly because these compounds help to remove some of the repressive modifications at the telomeres and sub-telomeric regions. This may make it easier for telomerase to build up the telomeres as the cells are reprogrammed.

The interaction of epigenetic modifications with the telomere system takes us a little further away from a simple correlation between epigenetics and ageing. It moves us closer to a model where we can start to develop confidence that epigenetic mechanisms may actually play a causative role in at least some aspects of ageing.

Is your beer getting old?

To investigate this more fully, scientists have made extensive use of an organism we all encounter every day of our lives, whenever we eat a slice of bread or drink a bottle of beer. The scientific term for this model organism is Saccharomyces cerevisiae, but we generally know it by its more common name of brewer’s yeast. We’ll stick with yeast, for short.

Although yeast is a simple one-celled organism, it is actually very like us in some really fundamental ways. It has a nucleus in its cells (bacteria don’t have this) and contains many of the same proteins and biochemical pathways as higher organisms such as mammals.

Because yeast are such simple organisms, they’re very easy to work with experimentally. A yeast cell (mother) can generate new cells (daughters) in a relatively straightforward way. The mother cell copies its DNA. A new cell buds off from the side of the mother cell. This daughter cell contains the correct amount of DNA, and drifts off to act as a completely independent new single-celled organism. Yeast divide to form new cells really quickly, meaning experiments can be run in a few weeks rather than taking the months or years that are required for some higher organisms, and especially mammals. Yeast can be grown either in a liquid soup, or plated out onto a Petri dish, making them very easy to handle. It’s also fairly straightforward to create mutations in interesting genes.