Role of Telomeres in ageing

Do the telomeres of the human chromosomes have any role in ageing? the answer is “Yes”.

Telomere and ageing: The human chromosome is made up of a complex network of the protein and DNA which fits DNA inside the cell nucleus. The telomere and ageing process are co-related. In the year 1939, Muller and McClintock concluded that the end of the chromosomes has some specific sequences which prevent chromosomal fusion.

In this article, we will discuss, the structure of the chromosome, the function of the chromosome, the structure of telomere, the role of telomere in cancer, co-relation between telomere and ageing and the role of the telomerase enzyme.

The content of the article:

  • General structure of chromosome
  • Structure of telomere
  • Function of telomeres
  • The end replication problem
  • Telomere and ageing
  • Role of telomere in cancer
  • Telomeres and other disorders

Telomere : Telos = end, meros = part

Telomeres and ageing
The telomere banded chromosomes. Image credit: www.genengnews.com

The general structure of chromosome

The human chromosome is made up of the complex arrangement of DNA and protein. Histones are the protein involved in the process of DNA packaging in eukaryotes. The histone H1, H2A, H2B, H3 and H4 are the backbone of the chromosome.

The thread of the DNA is much longer. It cannot be fixed inside the nucleus if it is not arranged properly. The complex arrangement of histone protein with the DNA makes them fit inside the cell nucleus.

The chromosome helps DNA to replicate properly during each cycle of the DNA replication. Structurally, the chromosome is divided into three different parts: the two arms, centromere and telomeres.

The two arms of the chromosomes are called as a “p” arm and a “q” arm. Different types of genes are arranged on each different arms. Depending upon the type of the chromosome and the location of the centromere, the length of the “p” arm and “q” arm may vary.

For example, in the acrocentric chromosome, the “p” arm is shorter than the “q” arm while in metacentric chromosomes the “p” arm and the “q” arm are almost similar.

The centromere is the central part of the chromosome which helps in the proper arrangement of the chromosome during the process of the replication.

The telomeres are the part of the chromosomes which are located on the tip of the chromosomes. The eukaryotic chromosome is linear while bacteria have circular chromosome. The linearity of the eukaryotic chromosome is due to the presence of the telomeres.

Further, read on DNA topology,

Structure of telomere

Telomere protects a fusion of chromosomal arms and protects it from becoming circular. The special types of repeated sequences present on the telomeres make them unique from other regions of the chromosomes.

The DNA sequences present on the telomeres are made up of the six “repeat” sequences called as “hexa-repeat” which are located one after another throughout the telomere length. The terminal end of the hexarepeat has single-stranded Guanine reach overhang.

This sequence is “ TTAGGG”.  On an average, the TTAGGG repeats may present 2500 times on each human chromosome.

The special Kind of TIP (Telomeric interacting proteins) and the hexa repeats of the telomeres give the structural hierarchy to the telomere. The 6 basepair repeats are tandem repeats which are conserved from the evolution.

Telomeres and ageing
The general structure of telomeres

The DNA is made up of the long chain of A, T, G and C bases, phosphate backbone and the sugar. Read more on the structure of DNA….click here

Function of telomeres

The telomere protects the genetic information of the cell.

Suppose if the telomeres are not present on the edge of the chromosomes, each time when the cell divide, some amount of genetic material will lose. So the telomere present on the top of the chromosomes prevents the loss of genes.

Hence it prevents the loss of genetic information. Also, the telomeric sequences are non-coding junk sequences so the chance of being missing any information is less. The telomeres are generated due to the end replication problem of the cells.

Telomere prevents unnecessary recombination, DNA repair and degradation. Therefore telomere has a crucial role in preserving information in our genome. Ultimately it determines the lifespan of the cell and organism. It is a kind of biological clock.

Telomere also protects the vital coding regions of the chromosomes by capping the end of the chromosomes.

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Telomeres and ageing

The end replication problem

As the worlds suggest, telomeres lengthening occurred due to the problem in DNA replication.

Read further on prokaryotic DNA replication.

The process of replication starts when the single-stranded, short sequences of RNA binds to the single strand of the DNA. This short RNA sequence serves a substrate for DNA polymerase to work. Finally, DNA polymerase binds to the single-stranded DNA-RNA junction and replicate it.

But in the end, the RNA primer is removed and the gap remains as well. A similar problem happens at the lagging strand.

At the lagging strand, each Okazaki fragments are replicated with the help of each dedicated RNA primers, However, the last Okazaki fragment RNA primer creates the single-stranded overhang. This overhand piece of DNA is increased after each cycle of replication.

Now assume that, if some of the important genes may present at the end of the chromosomes, those genes will skip replication and can not inherit into the next generation.

Loss of the DNA sequences from the telomere is called as a telomere shortening and result in the ageing of the cell. After each cycle of the replication, some amount of DNA is lost from the telomere and that induced cell death, resulting in ageing.

Actually, this end replication problem is a reason for eukaryotic mortality. However, it is possible that this problem can be solved by our cell.

The DNA repair pathway of our cell repairs the DNA (which are broken or single-stranded), to prevent the loss of the DNA.

If this DNA repair pathway repairs the DNA of the end of the chromosomes (overhang telomere), the ageing is not possible, to skip the DNA repair, the single-stranded overhang forms the loop and becomes double-stranded by creating hydrogen bonds with the adjacent DNA.

Read further: Different types of inheritance pattern

The cell senescence occurred due to the progressive telomere shorting. “Senescence is a process of loss of a cells growth and division power”.

The telomere shorting is prevented into the germ cells such as eggs and sperms and in stem cells such as pluripotent stem cells. However, telomere shorting is common in somatic cells.

Exceptionally, telomere shortening is not occurred in the pulmonary tissues such as heart muscle, because among the somatic cells these cells are continuously dividing.

In the germ cells, the enzyme called as a telomerase helps to prevent the telomere shortening.

Telomerase enzyme

Telomerase enzyme is an RNA dependent DNA polymerase that prevents the telomere shortening specifically in germ cells and pluripotent stem cells. The short- single-stranded RNA is used as a template for synthesis of new DNA by reverse transcription activity. 

Telomerase is a class of special kind of ribonucleoprotein enzyme that prevents the telomere shortening. The enzyme consists of TERT and TERC sites. The TERT, telomerase reverse transcriptase helps in reverse transcription and TERC, telomerase RNA component serves as a template for the activity of telomerase enzyme.

However, the expression of the TERT gene is highly regulated in stem cells and germ cells. Overall, the telomerase prevents the telomere shorting by adding nucleotides complementary to the overhang.

Mutation in TERC or TERT dysregulates the telomerase activity and leads uncontrolled telomere growth or shorting, the fusion of chromosomes, cancer and ageing, genomic instability and other chromosomal and DNA breakage related syndromes.

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The telomerase activity depends on the shelterin or telosome, the sheltering is a complex of six telomere maintenance protein which is composed of TRF1 and TRF2.

The telomeric repeat binding protein 1 work as a negative regulator for the telomere, promotes telomere shortening while the telomeric binding protein 2 helps in telomere end protection by preventing the telomere shortening.

other shelterin proteins are RAP1, POT1, TIN2 and TPP1 help in telomere maintenance and regulation. Imagine if telomerase is inactive in germ cells such as sperm or egg, what will happen?

In humans, two identical telomerase enzymes are required for the proper function of the telomere. Therefore it is also called as a dimeric enzyme.

Telomeres and ageing
Addition of nucleotide to the telomere by telomerase

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Do you know?

Astragalus membranaceous, a Chinese medicinal plant prevents the telomere shortening. The compound HDTIC enhance the longevity by increasing DNA repair ability and decreasing telomere shortening. Also, the TA- 65 molecule of this plant inhibits DNA damage, elongate telomere by activating telomerase and increasing the life span. This plant has anti ageing properties.

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Telomeres and cancer

Now take a look at cancer,

What is cancer? It is a process of continuous cell division. That means, in a controlled cell division, after each cell division the telomere shorting causes cell death. If telomeres can not shorten, it causes continuous cell division, the cancer.

So the telomere shortening has a definite role in cancer. In general, a normal cell can divide only 50 to 75 times. After that the cell undergoes apoptosis. The apoptosis is a process of cell death.

In cancer, the dysregulation of  p53 and the p16 cell signalling pathway leads to senescence and cell telomere dysfunction causes indefinite cell division.

In some cases of cancer, not overexpression of telomere but the much shorter telomere is involved in the occurrence of cancer. A shorter telomere than the normal range damages the DNA. Mutation in this coding DNA sequences causes cancer.

However, this mechanism is less understood.

Several factors induce telomere shortening such as smoking, stress, several chemical agents, obesity, high oxidative stress, adverse diet and high amount of protein consumption also some of the internal factors such as the epigenetic profile of an individual, genetic makeup and DNA repair pathway also affects telomere activity.

Smoking can cause DNA damage and increases the telomere shortening. Further, lack of physical activity and obesity leads to telomere shortening. Increased telomere shortening at an early age results in premature death.

Our diet has a major role in maintaining our health, consumption of more diet, accumulate more protein in the body and induces the telomere shortening. Studies confirmed that less consumption of dietary intact can increase the age by reducing telomere shortening.

Telomeres and ageing

Also, the consumption of antioxidants such as omega 3 also reduces the telomere shortening. If we restrict protein consumption in younger age, this will helps in growth reduction and increases the biological age of the organism.

In almost 85% of the cancer cases, the telomerase is involved. Telomerase is more active in germ cells and pluripotent cells however the length of the telomere is more shorten in the cancer cells compared to normal cells.

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Telomere and ageing

Progressive reduction in the function of the cell or tissue results in the mortality; is called as an ageing process.

As we age, the functional capability of the cell decreases gradually. The ability of a cell to produce energy, the rate of synthesis of new biomolecules and the rate of replication decreases as well.

“Shorter the telomere, shorter the lifespan of an organism”

As ageing of an organism is depends on the telomere shortening. This means organisms with longer telomeres lives longer (for example human) as compared with short telomere (for example dog and mice). 

Nonetheless, telomere shortening is not the only reason for the ageing. So is it possible to increase lifespan by decreasing the rate of telomere shorting?

Well, theoretically, telomerase enzyme can do so. If we increase the expression of the telomerase gene in somatic tissues, we can live longer.

Practically, it is not possible. Yet, telomerase therapy is one of the options but in this case, the chance of occurring cancer is higher.

As we know, telomerase prevents the shortening of telomeres in a controlled manner and only in the germ cells and stem cells, the effect of telomeres is not significant in somatic cells.

Telomeres and ageing

Telomere and other disorders

Inborn dyskeratosis is the first disorder characterised by the error in telomere activity. However, disturbance in telomere activity is also involved in many other disorders.

Interestingly, telomere shortening is the secondary effect in some of the disease states such as AIDS. AIDS is the acquired immune disease in which telomere shortening observed over a period of time.

Premature ageing and death are occurred by progressive telomere shortening. Further, telomere shortening is involved in cardiovascular disease, diabetes and lung cancer as well.

Conclusion

Telomerase therapy may be one of the best anti-ageing therapy or even the cancer prevention therapy yet it is not proven, extensive research required to establish it. Telomere and ageing are co-related with each other. Telomere shortening is a major reason for ageing.

By taking less, balanced and antioxidants rich food, we can increase the biological age. Now answer to our question: if telomerase is inactive in germ cells such as sperm or egg, what will happen? Answer: we will extinct. 

Comment below and share your thoughts on how this is possible.

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