By Amrita Sule
A legend says that drinking from the “Fountain of Youth” can restore youth. Tempting, indeed. Unfortunately youth doesn’t last forever, as aging is a natural process that all living beings undergo. What comes to your mind when you hear the word ageing? – Wrinkles, becoming weak and more prone to age related ailments. Ever wonder why we age? Let’s take a look at it to see what happens at the molecular level.
Every organ and tissue in our bodies is made up of cells. Inside every cell (except red blood cells) is a compartment called the nucleus. Inside this compartment, all our genetic information (in the form of DNA) is compactly packaged into chromosomes. Humans have 23 pairs of chromosomes. When the cell prepares to divide, these chromosomes become X-shaped and have capped structures on their ends, called telomeres. We can think of telomeres as hats and socks on the chromosomes, which serve to protect the chromosome ends. Chemically, telomeres are made of a short stretch of DNA that is repeated multiple times. But, why do the chromosome ends need protection? If not capped, loose DNA ends on the chromosome will be perceived as broken DNA. The cell will try to fix this situation by sticking together the ends of two chromosomes (chromosome fusion). Also, loose DNA ends are vulnerable to degradation by the DNAse enzyme, which can chew DNA ends like Pacman.
Prior to cell division, chromosomal DNA has to be duplicated into two identical copies by the DNA replication process. The replication process takes place on both strands of DNA. When DNA is being copied, the enzyme DNA polymerase (think of it as a construction worker building a brick wall) cannot copy the ends on the DNA strand. If the DNA ends i.e. the telomeres are not regenerated, a chunk of DNA would be lost after every cell division in the form of telomere shortening. After the cell has divided a few times, there might not be any more telomere sequence left. In subsequent cell divisions, chromosomal DNA containing important genes would start to be lost as well. This, as you can imagine, would be a disaster. This predicament during DNA replication is known as the “End replication problem”.
But worry not; the cell always has a plan. It recruits the enzyme telomerase. This is your superhero coming to rescue the DNA end copying process. Telomerase makes sure that the telomere sequences are regenerated, even though DNA polymerase does not replicate some part of them. So, DNA polymerase can continue to leave out some amount of telomere sequence during replication but the telomerase will build it back. This means that the DNA, which contains important genes, will not be lost due to the end replication problem. This is an extremely important process and in 2009 the Nobel Prize in Physiology or Medicine was awarded for the discovery of telomerase and how telomeres function in protection of chromosomes to Elizabeth H Blackburn, Jack W Szostak, and Carol W Greider. Since then we have come a long way. Telomerase does not work alone but has some friends which together help resolving the end replication problem.
Though telomerase is a saviour, its superpowers are restricted. There is only a very limited amount of telomerase present in somatic cells (all the cells in your body other than stem cells and the cells in reproductive organs). Therefore after every round of cell division, in most cells in the body, chromosomes are less and less protected due to telomere shortening. This effect is similar to the plastic on the tip of your shoelaces that wear out as the laces get old and so cannot protect the lace ends anymore. Telomere shortening can cause the telomeric DNA to lose its protective structure and prevent the binding of proteins that shield the loose DNA ends. This exposes unprotected DNA strands that the cell perceives as damaged DNA. The cell, after sensing this, elicits permanent DNA damage response, which I have discussed here. In cells that have undergone extensive telomere shortening, the DNA damage response causes the cell to enter a state where it cannot divide any more – replicative senescence. This means the cell has reached its Hayflick limit – the number of times a normal human cell divides until it cannot divide any further.
Replicative senescence is protective in nature. Telomere shortening exposes DNA ends, which the cell tries to repair by eliciting a DNA damage response. This can lead to chromosome fusion or chromosome rearrangements, which are the hallmark of cancer. If the cell continues to divide these abnormal chromosomes can be passed on to the daughter cells giving rise to a cancerous cell. Nevertheless, as a particular tissue or an organ acquires more and more senescent cells, their ability to repair and regenerate itself starts dwindling, which is a sign of normal ageing. In case of normal or healthy ageing, the accumulation of senescent cells in various organs causes their wear and tear. Furthermore, increased senescent cells along with additional stressors like cigarette smoking (among others) can lead to age related diseases. For example excessive cigarette smoking can cause pulmonary disorders. Compounds in cigarette smoke cause DNA damage in the cells of lung tissue, leading to cell death. So, these cells have to be replenished much faster than usual thus speeding telomere shortening in this tissue. This leads to increased senescence of cells in lung tissue.
This brings us to an important question: is too much telomerase a good thing? Although telomerase lengthens the telomeres, this is not a good thing in cancer cells. High levels of telomerase can increase the probability of cancer cells becoming immortal. But, having too little telomerase can reduce the normal regenerative potential of tissues and organs. Therefore ideal levels of telomerase are necessary for somatic cells to sustain themselves. On the other hand, stem cells (which we rely on for their regenerative potential) have high levels of telomerase, which allows them to replenish populations of different cell types in the body. For example, the hematopoietic stem cells in the bone marrow can undergo cell division a number of times to make more stem cells or mature into different blood cells.
Telomere shortening is an important event that contributes to normal aging but it is not the only one. Epigenetic modifications, which include alterations on the proteins associated with DNA, act as an ON/OFF switch for many processes in the cell. Age associated epigenetic marks have been identified. Prolonged inflammation (mediated by the immune system) can cause oxidative stress, which in turn can damage DNA and result in cell death. As we get older, levels of stress factors like reaction oxygen species can significantly increase in the body’s cells. This can also contribute to overall cellular damage. Given that ageing is affected by multiple factors, understanding telomerase and how it interplays with these other components in the cell can help us to decipher and treat age related disorders.
Studies are being conducted to use the information on telomerase to develop therapies for patients suffering from age related diseases. For example, the stem cells of patients suffering from Duchenne muscular dystrophy (progressive muscle degeneration) have much smaller telomeres. Also, individuals suffering from the rare premature aging disorders such as Hutchinson-Gilford Progeria Syndrome have smaller telomeres. Presently scientists are working on developing therapies that can lengthen the telomeres in specific cells of these patients. More than any legendary “Fountain of Youth”, the scientific research being conducted on ageing could have immense therapeutic importance.
The author can be contacted on Twitter @DrAmritaSule