HOW ARE YOUR TELOMERES? COULD THEY DETERMINE HOW FAST YOU AGE?
Getting more sleep helps us get a fresh start for the day, but it can also help keep you young.
A recently conducted research suggested that individuals not having a proper sleep or engaged in stressful activities age six times faster than those who are not. This all comes down to a tool present in our cellular machinery known as ‘Telomeres.’ We are composed of approximately 60 trillion cells, which are constantly splitting into daughter cells. And each of these cells contains DNA present in a highly coiled manner, which we call the ‘Chromosomes.’ Every time a cell divides, the chromosome has to be replicated as one cell splits into two. But, the DNA replication machinery is not as perfect as we think. At the end of a DNA replication process, a little bit of DNA or, say, the chromosome is chopped off at its end, which leads to the shortening of the chromosome, which eventually leads to genomic instability. This is known as the ‘End Replication Problem.’
To prevent this cutting of corners, Telomeres play a significant role. They are present at the tips of the chromosomes and protect them from degradation. The telomeres are just like the plastic tips present on shoelaces to keep them from fraying away. But still, as we age, the length of Telomere keeps reducing significantly. This process- known as ‘Telomere Attrition,’ can eventually lead to genetic disorders, further leading to some neurodegenerative diseases like Alzheimer’s Disease.
(AD). Now we will see precisely how a telomere works, how it gets short after each cell division, the consequences of extensive telomere loss, and what we can do to prevent it.
THE TELOMERE:
The genomes of eukaryotes are composed of linear DNA, which requires a mechanism to protect chromosome ends from being detected as DNA Double-Strand Breaks (DSBs). Therefore, the ends of linear chromosomes in eukaryotes contain caps, called telomeres, that distinguish natural chromosome ends from DSBs. Telomeres prevent chromosome ends from activating DNA damage checkpoints and DSB repair pathways, thereby avoiding the degradation of chromosome ends. Mammalian telomeric DNA is composed of thousands of TTAGGG repeat sequences with a short single-stranded 3' overhang at its end. The single-stranded 3' overhang is tucked back into a proximal complementary telomeric sequence to form a structure called ‘t-loop,’ which essentially hides and protects the free end. A telomere-specific six-subunit protein complex called ‘shelterin’ plays a pivotal role in protecting chromosome ends and facilitating telomere replication and the addition of telomeric repeat sequences. These proteins also help in the recruitment of an enzyme called telomerase.
Telomerase is a reverse transcriptase enzyme that carries an RNA template that aligns with the end of the existing Telomere to add additional telomeric repeat sequences.
THE MECHANISM OF TELOMERE SHORTENING:
Telomeres are actively maintained in human germline cells and embryonic stem cells through the expression of telomerase. However, in the case of human somatic cells’ division, telomere shortening occurs due to insufficient telomerase expression. Out of the 2000–20,000 bases present as telomeric repeat sequences on different chromosomes, approximately 50–200 bases are lost each time a mammalian cell divides. This telomere shortening results from a combination of a failure to completely replicate the ends of linear DNA molecules termed the “end replication problem”; and the processing of DNA that occurs on the ends of linear chromosomes. During DNA replication, the end of the Telomere’s G-rich strand is synthesized by leading strand synthesis. The terminal of the C-rich strand is replicated by lagging strand synthesis.
Following DNA replication, the end of the leading strand will be blunt-ended, and the 5' end must therefore be resurrected to produce the single-stranded 3' overhang. However, the lagging strand is not completely replicated due to the presence of the RNA primer, which does not start at the very end of the chromosome. As a result, telomere shortening occurs with each round of DNA replication.
THE CONSEQUENCES OF EXCESSIVE TELOMERE SHORTENING:
The telomere shortening that occurs during cell division in human somatic cells can eventually result in replicative cell senescence or apoptosis (a programmed cell death) if the telomeres become too short of protecting the end of the chromosome. Studies with human fibroblasts (collagen-producing cells) have shown that senescence occurs when the unprotected chromosome ends are recognized as DSBs (double-stranded breaks), as shown by the presence of DSB repair complexes that co-localize with telomeres, called Telomere dysfunction-Induced Foci (TIFs). The number of dysfunctional telomeres required for senescence may vary between different cell types. In fibroblasts, five different dysfunctional telomeres are required for senescence to occur.
The consequences of telomere shortening are dramatically different in cells with compromised cell cycle regulation. This was first demonstrated in human fibroblasts in which viral proteins inactivated the p16 and p53 proteins involved in the senescence pathway.
These fibroblasts’ failure to senescence results in continued telomere shortening beyond the point that senescence would generally occur, eventually leading to a “crisis,” which involves extensive chromosome fusion and cell death. However, rarely cells can survive the crisis by acquiring the ability to maintain telomeres through reactivation of the enzyme telomerase.
Even though fibroblast surviving crises can maintain telomeres, they typically have highly rearranged chromosomes due to the extensive telomere shortening that occurred before telomerase expression. The importance of the chromosome rearrangements caused by this extensive telomere shortening was demonstrated in mice deficient in the RNA subunit of telomerase, mTERC, and p53 protein. Although mice with knockout of mTERC alone show an increase in cancer, the presence of mutations in p53, which allows for the growth of cells with chromosome instability, accelerates carcinogenesis and shifts the spectrum toward carcinomas. Moreover, the chromosomes in these carcinomas demonstrated rearrangements consistent with chromosome instability resulting from telomere loss. These results demonstrated that telomere loss in telomerase-deficient cells lacking cell cycle regulation results in chromosome rearrangements leading to cancer. However, the cancers in these telomerase/p53-deficient mice were limited in that they did not occur in all tissues and did not fully develop into highly malignant tumors.
THE IMPORTANCE OF TELOMERE LENGTH IN HUMAN DISEASE:
The length of telomeres at birth and the rate of telomere shortening in somatic cells can significantly influence the role of loss of telomere function in human disease. The length of telomeres at birth in humans can be affected by mutations in a variety of proteins involved in telomere maintenance, either by affecting telomere-capping function or by directly affecting telomere elongation by telomerase. Definitive evidence that defects in telomere maintenance are associated with the human genetic disease comes from studies of the genetic disease Dyskeratosis Congenital, which results in early death from bone marrow failure, pulmonary complications, or malignancy. Dyskeratosis Congenita has now been shown to result from mutations in a number of different telomerase components, including dyskerin, TERC, TERT, and the shelterin component TIN2, which result in telomere shortening and reduced proliferative capacity of cells. Genetic diseases other than Dyskeratosis Congenital have now also been attributed to shortened telomeres, some of which have phenotypes that overlap with Dyskeratosis Congenital, including idiopathic pulmonary fibrosis, Coats plus, aplastic anemia, and liver disease. Cardiovascular disease has also correlated with telomere length, although the mechanism involved has yet to be clearly established. In addition to mutations in proteins that affect telomere length, human disease can also be influenced by factors that affect the rate of telomere shortening after birth.
An increased telomere shortening rate can result from either excessive division of adult stem cells, which do not express sufficient telomerase to compensate for telomere loss during cell division. Alternatively, an increased telomere loss rate can also be caused by factors that increase telomere loss during cell division, including inflammation and oxidative stress. The effect of lifestyle on telomere length was first demonstrated by the shortened telomeres in persons under stress. Subsequent studies have found that various lifestyle factors can influence telomere length, including smoking, alcohol abuse, lack of sleep, and exercise. Scott Kelly, an American astronaut, experienced a significant amount of telomere loss due to the stress his body was exposed to for a long period in space.
WHAT WE CAN DO ABOUT IT?:
So, now we must be worried about what we need to do to avoid telomere shortening?
On a certain level, there’s nothing we can do about it. The Telomere’s length and how fast they shorten is highly variable. Estimates say that about 30–80% of our telomeres characteristics could be due to genetic factors and other things that are completely out of our control, like our father’s age when we were conceived.
But there are some factors under our control. Although the telomeres protect our DNA, they are quite susceptible to damage themselves, mostly by stress. Stress includes smoking, obesity, exposure to trauma, and many more. All of these can cause physical effects like higher amounts of stress hormones or the presence of inflammation, which is associated with an increased rate of telomeric shortening.
Exercising, staying away from cigarettes can add years to your life. But, saving your telomeres from excess shortening may not necessarily save you from the things you are genetically predisposed for anyway. It just may happen to you later rather than happening sooner.
CONCLUSION:
Telomere length and its regulation produce many tricky questions for us and are indeed an exciting research topic. Telomeres have very important implications for our future in medicine and other types of innovation. Dolly, the cloned sheep, for example, was born with shortened telomeres and died prematurely, telling us that we need to take telomere science into account when working on some extremely ambitious synthetic organisms. So, now we also have good scientific backing in saying that having some chill time is good for your health.
REFERENCES :
1)Mechanisms of telomere loss and their consequences for chromosome instability
