Hope you all are doing well!!
I am back again with a new series of an interesting topic.Today I will be dealing with the mystery behind ageing in human.Hope it will add something to your pre-existing knowledge about ageing.Let us begin now!!
Human is an eukaryotic organism.Each cell(except Red Blood Cell) has cell nucleus and other organelles enclosed within membranes.Nucleus contains chromosome.There are 23 pairs of chromosomes in each diploid human cells.
Chromosome contains DNA(Deoxy ribo nucleic acid)molecules with histones proteins.These chaperones help to bind the DNA molecules and prevents them from becoming an unmanageable knot.
Human DNA is a double-stranded helical structure.It contains nucleotides, a sugar group, nitrogen bases[Adenine(A), Guanine(G), Cytosine(C), Thymine(T)] and stores biological information and genetic instructions required for growth, development, and reproduction.Two strands of DNA run in opposite direction i.e. 5'—3' and 3'—5'.
image source
(Human DNA, double helical with beta helix type)
During each cell divison, DNA undergoes replication to form two daughters DNA.Each daughter DNA shares half of the character from mother and half from father.This cell division continues and so do the DNA replication until the cells undergo senescence.
But what actually causes the cellular senescence?
The mystery has been revealed.Previously, it was believed that unicellular organism which reproduces through mitosis, resist cellular senescence.It is because of unequal distribution of mitotic debris in between the new cells, as a result, half of the cells are ageless and half with varying degree of senescence.But a recent study has shown that not only the accumulation of mitotic debris in the senescence cells cause cellular aging but rather, there is increased activity of telomeres in the ageless cell.The classical example of an immortal organism is Tetrahymena(Pond scum)[Let us discuss this organism in later part of this post].
So what is this telomere?
A telomere is a region of the repetitive nucleotide sequence at each end of the chromosome.
image source
(In the figure we can see the repetitive nucleotide sequence at each end of a chromosome)
In vertebrates like Human, the sequence of nucleotides in telomere is TTAGGG or GGGATT(also called junk DNA sequences) with its complementary DNA strands being AATCCC or CCCTAA.This repeat sequence of DNA with a protective protein sheath on either side of chromosomes prevent the fusion with neighboring chromosomes inside the nuclei of cells.
Each time replication cycle pass, this human linear chromosome loses some amount of DNA from the terminal region because DNA replication takes place only in 5'—3' direction and at 3' end of DNA, RNA primase can't create primer required for addition of new nucleotides by DNA polymerase.This results in the gradual shortening of the chromosome.
When this activity goes beyond control, the chromosome gradually shortens after each cell cycle resulting in the apoptotic(cell suicide) damage of the cells.
image source
(we can see the progressive loss of telomere on every DNA replication in a normal cell cycle)
But Tetrahymena- an immortal organism, never gets old because there is no shortening of telomere due to plenty of telomerase activity.
image source
(Tetrahymena, an organism with 40,000 chromosomes and showing highest telomere and telomerase activity.So called immortal creature).
How human cells survive then?
Well, thanks to God.We are safe indeed.
Every time DNA replicates, there is addition of some nucleotides on 3' end of the DNA strand with the help of telomerase reverse transcriptase enzyme(TERT) in response to DNA damage.
TERT also called as human TERT(hTERT), the gene encoding this particular protein being present in Chromosome 5, is a catalytic subunit of the enzyme telomerase.This telomerase contains RNA sequence that provides templet for the synthesis of Telomere repeat DNA sequences.It has DNA polymerase activity because of which it can add the junk DNA nucleotides at the 3' end and maintains the structural integrity of cells and prevents cellular damage.This also prevents the shortening of DNA after replication.
image source
(we can see the addition of RNA templet by telomerase on 3' end of DNA so as to replenish the nucleotide loss during cell division and replication).
But despite this, cell undergo ageing..??
Every dividing cells of the human body(except neurons and myocardium, as they rarely divide) can undergo a maximum of 50-60 cell cycles.Thereafter cell attains replication senescence(Telomere shortening) or Hayflick limit i.e. the number of times a normal human cell population will divide until all division stops.
These all changes bring an irresistible cellular senescence which results in human ageing.
Apart from it, there are some more reasons regarding ageing in human.
- genomic instability (mutations accumulated in nuclear DNA, in mtDNA, and in the nuclear lamina)
- epigenetic alterations (including DNA methylation patterns, post-translational modification of histones, and chromatin remodelling)
- loss of proteostasis (protein folding and proteolysis)
- deregulated nutrient sensing (relating to the Growth hormone/Insulin-like growth factor 1 signalling pathway, which is the most conserved ageing-controlling pathway in evolution and among its targets are the FOXO3/Sirtuin transcription factors and the mTOR complexes, probably responsive to caloric restriction)
- mitochondrial dysfunction (the authors point out however that a causal link between ageing and increased mitochondrial production of reactive oxygen species is no longer supported by recent research)
- cellular senescence (accumulation of no longer dividing cells in certain tissues, a process induced especially by p16INK4a/Rb and p19ARF/p53 to stop cancerous cells from proliferating)
- stem cell exhaustion (in the authors' view caused by damage factors such as those listed above)
- altered intercellular communication (encompassing especially inflammation but possibly also other intercellular interactions)
information source
But the evidence and data regarding telomere has been given a great importance, not only because it prevents cellular senescence but rather, it can be one of the reason why human isn’t immortal.
So what do you say now.Are we human really mortal?
Yah it is better to say we aren’t immortal, but we can be immortal.Actually, the activity of telomere can be regulated by manipulating the natural telomerase of a human body with unnatural or synthetic telomerase.Using artificial telomerase with greater half-life and a wide degree of potency and efficacy can prolong the longevity of human life.
Despite being successful in making an alternative to telomerase, a human can’t achieve the immortality.
- Do you know why?
It’s simple I hope.Imagine if you allow your children to spend all of the money you earn throughout your life thinking that "they are my children and I am earning for them and they do deserve to spend and entertain their life, no matter how much it costs, but they do deserve"
Yah you can be right with your thoughts for your children, but did you imagine their future from the moment you allow them their full liberty?didn’t you find you are missing something which you shouldn’t miss??
Yah you are right, it is your control which you gonna lose from your children, they will not care for you when they find a new world where everything is figured out in money and power.
(The above condition is illustrated just to co-relate the body response in cell signaling.Please try to tally it with the reason given below)
Similar is the case inside our body.Our body can ignore some of the stimuli and can work against the normal physiological homeostatic changes.It can help to prolong the cellular longevity by altering the the activity of telomerase.But it isn’t the real way a cell can attain immortality.The body function can't be specific to a particular group of cells only, rather the function is generalized.But if the cell signaling pathway tends to attain some faulty process so as to increase cell’s life, the body will suffer a new problem.
The normal cellular death is required so as to prevent impending DNA damage resulting during replication, transcription, translation.If the impending factors for faulty cell signaling aren’t corrected, the body may develop a tumor(cancer). - How is it so?
Actually Tumor is a condition of abnormal cellular proliferation or decreased cellular senescence or death.It is believed that every tumor cells have increased telomerase activity.As a result, they can easily deceive cellular senescence or death.So if telomerase function is increased, there will be simultaneous increase in tumor activity in the human body and I am damn sure Human will really don't want it to happen.They will prefer dying with cellular aging rather of dying of cancer.
image source
(we can see the increased activity of telomerase in cancer cells which results in their rapid and uncontrolled proliferation)
So human can be immortal but can't survive as immortal.This is what I want our steemians to learn from this post today.Hope you really enjoyed reading this post.Thank you!!
References:-
1.Harper’s Illustrated Biochemistry 29th edition
2.Lippincott’s Illustrated Reviews Biochemistry 4th edition
3.Robbins & Cotrans Pathologic Basis of Disease(South Asia Edition)
4.https://en.m.wikipedia.org/wiki/Senescence#Cellular_senescence
5.https://en.m.wikipedia.org/wiki/Ageing
6.https://en.m.wikipedia.org/wiki/Eukaryote
7.https://en.m.wikipedia.org/wiki/Chromosome
8.https://en.m.wikipedia.org/wiki/Hayflick_limit
9.https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915101/