Telomeres: could we become immortal? Jonas Flohr

Telomeres: could we become immortal?

Jonas Flohr Upper Sixth

I like to think of telomeres a bit like galvanising. In galvanisation, a zinc coating is applied to the surface of a metal object. The zinc acts as a sacrificial material, being exposed to corrosion and rust, hereby protecting the more valuable metal beneath. With telomeres, it is the same principal.

of the strands. The two DNA strands are antiparallel to each other, meaning that the DNA polymerase acting on one strand works in the opposite direction to the DNA polymerase working on the opposite strand. This is because the active site of DNA polymerase is complementary only to the 3’ end of the newly forming strand, and it can therefore only add DNA nucleotides As part of the cell cycle, to this end of the strand. cells must replicate their DNA. This is facilitated by several enzymes, [V]ital genetic material Therefore, while one DNA polymerase can work continuously in one including DNA helicase, DNA polymerase, and DNA ligase. First, DNA would be lost after each direction, the other has to work in segments, known as ‘Okazaki fragments.’ helicase breaks hydrogen replication.bonds between the two DNA polymerase, DNA strands, causing however, cannot just them to separate (Figure 1.1). Each original bind to one strand and begin its work. It DNA strand acts as a template for a new has to have a starting point: the 3’ end of strand. Free DNA nucleotides are attracted a nucleotide that it can bind to. To solve to their exposed complementary bases on this problem, there are primers, ‘startingthe original strands by hydrogen bonding. blocks’ from which DNA polymerase can DNA polymerase then begins to join the add nucleotides. new nucleotides by forming phosphodiester bonds between them (Figure 1.2). As there Primers are single RNA nucleotides, which are two original DNA strands, we have two are later removed by the enzyme RNase DNA polymerase enzymes, acting on each H, and then replaced by DNA nucleotides

Research has found that telomeres of sperm cells in fact lengthen with age - an evolutionary advantage?

by RNA polymerase. The enzyme DNA ligase then joins together the Okazaki fragments by forming phosphodiester bonds between nucleotides. However, when DNA polymerase reaches the last primer, we encounter a problem. As already mentioned, DNA polymerase can only add DNA nucleotides to 3’ ends, yet at the last primer, there is no 3’ end to attach onto, meaning that the RNA primer which is removed cannot be replaced by a DNA nucleotide (Figure 1.3). Therefore, at every DNA replication, some nucleotides are lost, at a rate of around 50-100 nucleotides per replication, so chromosomes become shorter each time a cell divides.

This is where telomeres come into play. If we had no telomeres, then small amounts of vital genetic material would be lost after each replication. This would be hugely damaging to the cell because it would no longer be able to synthesise important proteins such as enzymes, which regulate chemical reactions inside the cell.

Telomeres are the galvanisation of chromosomes: heterochromatic (associated with heterochromatin, tightly packed DNA) domains consisting of repetitive DNA base sequences (TTAGGG repeated many times). They are found at the ends

Figure 1.1

of chromosomes (hence the name telo which is derived from the ancient Greek word for ‘end’ and mere, meaning ‘part’). Telomeres do not code for any proteins, and by sacrificing small amounts of telomeres during each replication, chromosomes are protected from unscheduled DNA repair and degradation. This is, until no more telomere is left at all.

Telomeres are completely degraded after approximately 50-70 cell divisions (this point being referred to as the Hayflick limit). Once the Hayflick limit is reached, cell senescence kicks in, and a cell increasingly loses its ability to proliferate. It is irreversibly locked into the G1 phase of the cell cycle and begins to lose its ability to respond to various external stimuli. In effect, the cell ages, ultimately leading to cell death. The older a person becomes, the more cells enter senescence. The degradation of telomeres is directly associated with cell senescence and therefore the degradation of telomeres can be seen as the cause of ageing, and ultimately, death. So, could telomerase be used to maintain telomeric length in all cells and therefore reduce - or even prevent – ageing?

The link between telomeres and ageing has, in recent years, attracted more and more interest by scientists across the globe. It is suggested that telomere shortening is associated with ageing and age-related diseases in humans, and studies on genetically modified animal models suggest causal links between telomere shortening and ageing. Therefore, if telomeres were to be preserved, or if the shortening process were slowed, hypothetically, ageing in the human body could also be slowed.

One solution may be telomerase, an enzyme that is able to rebuild telomeres. Telomerase is a reverse transcriptase enzyme that contains a sequence of RNA nucleotides which acts as a template for new telomere sequences. A problem, however, is that telomerase is only found in gametes, stem cells, and most tumour cells; not in somatic cells, which make up

Figure 1.3 most of the human body’s tissues. But how significant is telomerase’s role in ageing, and could reactivation of telomerase increase an organism’s lifespan?

In a recent experiment by Harvard scientists, genetically manipulated mice were bred that lacked telomerase. The mice “aged prematurely and suffered ailments, including a poor sense of smell, smaller brain size, infertility and damaged intestines and spleens” (DePinho, R. Nature, 2011) Injections were then given to reactivate telomerase. After four weeks, the mice showed “biological changes indicative of cells returning to a growth state with reversal of tissue degeneration, and increase in size of the spleen, testes, and brain.” Furthermore, “the increase in telomerase revitalized slumbering brain stem cells so they could produce new neurons … the testes produced new sperm cells, and the animals’ fecundity was improved — their mates gave birth to larger litters.” When comparing the lifespan of these mice with those who weren’t given injections to reactivate telomerase, the mice lived longer. They did not, however, exceed the lifespan of a normal mouse. Reactivation of telomerase in studies with a species of nematode worm showed similar findings.

Although the outcomes of these studies are ground-breaking, what is important to know is whether the reactivation

Telomeres are the galvanisation of chromosomes. We could not survive without them

of telomerase could in fact increase reversed. Hibernation, for instance, lowers the lifespan of an organism as well. metabolic activity, which pauses mitosis Furthermore, whether the same effect at lower temperatures and therefore slows that was achieved in mice is possible telomeric degradation. Experiments done in humans is still unclear, and there on hamsters showed that hibernation slows has also been much concern about their ageing process and prolongs their the association between telomeric lifespan. High telomere maintenance in lengthening with cancer. Too short hibernating reptiles such as tortoises may telomeres will lead to cell senescence and be a crucial factor in providing longevity ageing of an organism, yet the inhibition in these species. of telomerase in adult human somatic cells is an evolutionary advantage in the Although our understanding of telomeres sense that it prevents the risk of cancer has improved greatly over the years, there developing. This is because remain many unanswered a cell with maintained telomeric length has the [T]he rate questions. A 2003 study found that telomeres ability to divide indefinitely, of telomere of Leach’s Storm Petrel which increases the risk of cancer. Having cells with shortened telomeres on the decrease varied greatly birds do not shorten but in fact lengthen with age. The birds have an other hand results in an impaired immune system because cell renewal and between individual unusually long lifespan, and despite having high telomerase activity, the clonal selection of T- and species. species does not show B-cell populations is much high susceptibility to more difficult. Activating telomerase to developing cancer. A study on another bird increase telomere length may therefore species, Frageta minor, showed that the provide risks as well as benefits, and rate of telomere shortening decreased with further research needs to be carried out in age, and that the rate of telomere decrease order to fully understand the mechanisms varied greatly between individual species. that are taking place. Telomere length could therefore not be used to accurately determine the bird’s age. But using either drugs or gene Furthermore, telomeric activity does not manipulation are not the only way in which just vary between organisms of different the degradation of telomeres, and therefore species, but also between different cells of the ageing process, could be slowed or even an individual. Whilst a human’s somatic cell telomeres shorten with age, telomeres of sperm cells lengthen with age. This may be an evolutionary advantage in the fact that the child produced is more likely to have longer telomeres and therefore may show signs of greater biological fitness in childhood, for lengthened telomeres strengthen the immune system. However, the older the father, the greater the chances of mutations occurring in a sperm cell’s genetic material, which will counteract the benefits of having long telomeres. Furthermore, a cell with long telomeres that carries a mutation will less likely enter apoptosis (which would have killed the cell and its mutation under normal circumstances), hereby increasing the risk of passing on a mutation to offspring.

It is clear that we are just at the beginning of understanding telomeres and their importance. It is not as simple as concluding ‘the longer the telomeres, the longer an organism will live’ or vice versa. Not only telomere length varies between different species, but also the rate of shortening varies. In some organisms and cells, telomeres in fact lengthen. Will we find methods to cure, or perhaps even prevent cancer through research on telomeres? Will we be able to slow the ageing process in humans? Will humans in centuries, or even decades time be living with eternal youth? For the time being, watch this space…