A telomere is a piece of DNA, non-coding, located at the end of each chromosome. Telomeres serve to protect the ends of chromosomes, including preventing two chromosomes from fusing, causing a degeneration which could make the cell ‘cancer’.
Telomeres shorten with age, becoming shorter and shorter with each cell division. This telomere shortening leads to cell death, they can no longer divide to reproduce.
This is why telomeres are called “biological clock” that determines the end of the life of the organism.
Inflammation and stress accelerate telomere shortening and are therefore make us age faster. This is not necessarily apparent on the outside of the body, but these factors can significantly shorten the life of a person.
Studies have shown that short telomeres are associated with a higher risk of age-related diseases and a shorter life expectancy.
History of telomeres (source Wikipedia):
In 1971, the Russian biologist Alexei Olovnikov issues for the first time the hypothesis that the maximum life span of cells in culture (Hayflick limit) is associated with progressive loss of telomeric sequences.
In fact, during each cell division, telomeres erode until they reache a critical size that triggers entry into cell senescence.
Telomeres act as a biological clock governing the life of cells. This theory is known as the telomere theory of aging.
There is also an enzyme capable of reversing the process of synthesizing new telomeric DNA sequences: it is telomerase.
The identification of telomerase was made in 1985 by Elizabeth Blackburn and Carol Greider. This work was awarded the Nobel Prize in Physiology and Medicine in 2009.
Structure and function of telomeres:
In most prokaryotes, chromosomes are circular and, thus, do not have ends to suffer premature replication termination. A small fraction of bacterial chromosomes (such as those in Streptomyces and Borrelia) are linear and possess telomeres, which are very different from those of the eukaryotic chromosomes in structure and functions. The known structures of bacterial telomeres take the form of proteins bound to the ends of linear chromosomes, or hairpin loops of single-stranded DNA at the ends of the linear chromosomes.
While replicating DNA, the eukaryotic DNA replication enzymes (the DNA polymerase protein complex) cannot replicate the sequences present at the ends of the chromosomes (or more precisely the chromatid fibres). Hence, these sequences and the information they carry may get lost. This is the reason telomeres are so important in context of successful cell division: They “cap” the end-sequences and themselves get lost in the process of DNA replication. But the cell has an enzyme called telomerase, which carries out the task of adding repetitive nucleotide sequences to the ends of the DNA. Telomerase, thus, “replenishes” the telomere “cap” of the DNA. In most multicellular eukaryotic organisms, telomerase is active only in germ cells, stem cells, and certain white blood cells.
Telomere length varies greatly between species, from approximately 300 base pairs in yeast to many kilobases in humans, and usually is composed of arrays of guanine-rich, six- to eight-base-pair-long repeats. Eukaryotic telomeres normally terminate with 3 single-stranded-DNA overhang, which is essential for telomere maintenance and capping. Multiple proteins binding single- and double-stranded telomere DNA have been identified. These function in both telomere maintenance and capping. Telomeres form large loop structures called telomere loops, or T-loops. Here, the single-stranded DNA curls around in a long circle stabilized by telomere-binding proteins. At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop.
Telomere shortening in humans can induce replicative senescence, which blocks cell division. This mechanism appears to prevent genomic instability and development of cancer in human aged cells by limiting the number of cell divisions. However, shortened telomeres impair immune function that might also increase cancer susceptibility.
Telomeres and aging:
Telomeres play a central role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on the basis of previous cell divisions and DNA damage. At least a few hundred nucleotides of telomere repeats must “cap” each chromosome end to avoid activation of DNA repair pathways. Repair of critically short or “uncapped” telomeres by telomerase or recombination is limited in most somatic cells and apoptosis or cellular senescence is triggered when too many “uncapped” telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germline which typically express high levels of telomerase. In somatic cells, telomere length is very heterogeneous but typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal and malignant cells, a process facilitated by the genome instability and aneuploidy triggered by dysfunctional telomeres. The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes.
When the telomere becomes too short, it no longer plays a protective role. The cell will interpret this as a corruption of its DNA, enter senescence and stop its growth. Such shortened telomeres can cause fusion of two chromosomes. As such alterations are not repairable in the ordinary somatic cells, they can cause apoptosis.
Many diseases of aging (including progeria, characterized by a very early age) are caused by excessive telomere shortening. Organs deteriorate even more than their constituent cells die or come into senescence.
A more important shortening of telomeres is a marker for risk of cardiovascular disease in middle-aged men.
Telomerase is an enzyme which, in the DNA replication in eukaryotes, allows to keep the length of the chromosome by adding a specific structure at each end: the telomere (Greek TELOS end or end). Although composed of deoxyribonucleotides as the rest of the chromosome, the telomer is synthesized according to a different mode of replication of the DNA standard.
The telomerase are ribonucleoprotein (RNA and assembly of proteins) that catalyze the addition of a repeated sequence specific to the ends of chromosomes. The nucleotide sequence rich in T and G is (TTAGGG) n among vertebrates (and therefore humans), with a repetition number n of the order of a few hundred to a few thousand. The telomerase RNA component serves as a template for DNA synthesis.
The enzyme was discovered by Elizabeth Blackburn and Carol Greider in 1985, they received the Nobel Prize in Physiology and Medicine in 2009.
The protein composition of human telomerase was identified in 2007 by Dr. Scott Cohen and his team at Children’s Medical Research Institute in Australia. It is composed of two subunits:
– Subunit protein or TERT (Telomerase Reverse Transcriptase). The coding region of the TERT gene is 3396bp, and results in a protein of 1131 amino acids. It is an enzyme with reverse transcriptase, a DNA-dependent RNA polymerase which ensures the synthesis of telomeric sequence using the other subunit RNA as a template.
– Subunit RNA or TERC (Telomerase RNA component). It is a structured RNA with 451 nucleotides and several regions in stem loops and a pseudoknot. One of the loops of this pseudoknot contains the sequence that serves as a template for synthesis of telomeric repeat.
Without the action of telomerase that challenge the party lost with each cell division, after forty divisions, chromosome would lose the information of its last cell genes and become non-viable and die (apoptosis).
Telomerase is expressed only in little or no somatic cells, whereas it is very active in germ cells. This lack of activity in somatic cells induces cell senescence.
Telomerase is also very active during embryonic and fetal development. Its synthesis is dependent on the TERT gene.
A key to eternal life:
We know that telomeres are responsible for the lifespan of a cell, when a cell divides, the telomere shortens, once reached 50 divisions, the telomere is gone, and the DNA of the cell become used in this way, the cell weakens, becomes defective or dies.
This helps to explain many diseases due to age. However, we know that telomerase can rebuild the telomere in its entirety at each cell division, it would allow the human body to remain forever young. However, if telomerase can give eternal life, it can also cause death. Indeed, we found that cancer cells contain high levels of telomerase in cancer cells result can be repeated without dying. However, we are sure that telomerase functions in action on telomeres, as an experiment to make a lobster and a young adult lobsters, showed that the length of their telomeres were identical, and that adult lobsters had all faculties the young lobster without difficulties age. The body of the lobster has a large amount of telomerase in the body.
In 1961, the biologist Leonard Hayflick discovered that certain specialized cells seem to divide about 50 times in succession.
The Hayflick limit (or Hayflick phenomenon) is the number of times a normal human cell population will divide until cell division stops. Empirical evidence shows that the telomeres associated with each cell’s DNA will get slightly shorter with each new cell division until they shorten to a critical length.
The Hayflick limit was discovered by Leonard Hayflick in 1961, at the Wistar Institute in Philadelphia. Hayflick demonstrated that a population of normal human fetal cells in a cell culture will divide between 40 and 60 times. The population will then enter a senescence phase, which refutes the contention by Nobel laureate Alexis Carrel that normal cells are immortal. Each mitosis slightly shortens each of the telomeres on the DNA of the cells. Telomere shortening in humans eventually makes cell division impossible, and this aging of the cell population appears to correlate with the overall physical aging of the human body. Natural maintenance of the length of the telomeric region appears to prevent genomic instability and helps to curb the development of cell mutations that may lead to cancer.