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AGEING RESEARCH

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The Role of Sirtuin longevity enzyme in the Cell nuclei, Histone and DNA Methylation that cause tissue dysfunction through disruption of epigenetic information

The Role of Senescence cell, Nicotinamide Mononucleotide and Nicotinamide Adenine Dinucleotide as Longevity molecules in Animal kingdoms.

Ectopic expression of Oct4 (Pou5f1), Sox2 and Klf4 genes (OSK) to restores youthful DNA methylation patterns and transcriptomes, promotes demethylation through TET1, TET2 and TET3.

Anatomy of the immortal jellyfish and its life-cycle function. Cell research towards the immortal cell.

Anatomy of the immortal jellyfish and its life-cycle function. Cell research towards the immortal cell.

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WHY WE ARE AGEING?

23 September 2021 -- Jomkhwan Borrirak 

7 min read

 

Why we are aging? This question is among the oldest question in the biologist world that we as human seek for better understanding. In fact, the term 'ageing' is very broad to the point that humans interpret the word differently.  Some may say that it is a disease caused by the body dysfunction and some might say that ageing isn't a disease but natural event.

Before we go and cover that controversial, let us begin the conversation of why do people become older in the first place. What's the indicator to distinguish an old person from young persons. Of course, you might look from one's skin, colour of hair, vision capability and so on, but, what's actually the factor behind those changes. Well, the hallmarks of ageing are consisted of Genome instability, Telomere shortening, Epigenetic alterations, Loss of proteostasis, Mitochondial dysfunction, Senescence cells and Stem cell exhaustion which makes sense. As time goes on, the external factors will cause our body to react or defense those factors which later resulted in loss of energy or incapable of doing the same work.

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Genome instability for instance is the result of having an useless protein in a cell which cause the epigenetic noise to occur. However, our cell defense mechanism contains another useful protein called 'SIRTUIN' (stands for Signal information regulator) to eliminate those unwanted protein and repair DNA damage by gaining cofactor activities from Oxidised form of Nicotinamide Adenine Dinucleotide (NAD+) molecule. The problem is all Sirtuin species in Animal kingdoms (SIR1-7) is constantly needed an energy from NAD molecule which decreases over time. For example, a 50-year old man would have only 1 ng/mg of NAD+ molecules, compared to a 20-year old man with over 5 ng/mg of NAD+. This advantages has caused the reduction of Sirtuin capabilities to tackle the epigenetic noise which later cause the loss of cell identity. The result of this is pretty obvious. This is how a senescence cell is formed and the cell will refuse to divide itself which later caused the dysfunction in the particular tissue. However, this process is considered to be healthy since you really don't want a senescence cell to be divided. That could cause cancer. 

This is raising another question though. As we realised that Sirtuin is doing quite a good job in eliminating the unwanted proteins, where do unwanted proteins comes in the first place? Well, the answer lies inside in our Chromosome where a ribbon of DNA is tightly fasten Histone cells. Biologically, what distinguish the brain cell and a lever cell is the fact that each cell can access to different part of DNA, resulting in distinguish cells in our body with the help of Sirtuin's Histone Deadetylate. Our DNA as we know it, is digital, therefore, losing an information is a big deal. A brain cell could turn into something else that isn't useful to the tissue as a result of epigenetic noise. Therefore, Sirtuin longevity enzyme must prioritise on repairing DNA and leave the histone. The histone without Sirtuin as regulator however caused the DNA to unwrap which give the gene an opportunity to transcribe itself and forms the unwanted proteins. Normally, the protein lasts for only two days, so if the cell has ability to stop producing them, no epigenetic noise would occur. However, it is only if there is Sirtuin to regulate the Histone.


The another strong source of unwanted protein came from the DNA Methylation which is the naturally methylated the unwanted molecules over time. With this fact, the bio scientists nowadays could observe the Methylated components inside the chromosome in order to calculate one's biological clock. Thus, this factors makes up the main source of epigenetic misinformation.

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Therefore, it could be said that all hallmarks of ageing came from the fact that the cell could not function properly due to the loss of cell identity. Tissue dysfunction is the result of it which later create changes in our observable identity and most importantly, the body dysfunction and lack of capabilities to protect itself from diseases.

This is called the informational theory of ageing which completely change the perspective of ageing as we know it. Before 2010s, we tended to believe that DNA damage caused the ageing. To prove this, Harvard PhD David Sinclair has done a research by creating DNA damage through chromosome breaking in mice and the result of it was only the mutation of a mice, not biological ageing. Therefore, it shall be concluded that epigenetic misinformation is the actual cause of ageing whereby the cell failed to maintain its identity.

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Human milestone for extending biological ageing

1 October 2021 -- Jomkhwan Borrirak 

7 min read

 

Previously, we have discussed how one can getting old through time. It is one of the consensus topic that the disruption of epigenetic information is the root cause of senescence cells. Therefore, to extend ageing required the maintain of epigenetic identity in each cells. This can be done by increase the capabilities of Sirtuin longetivity enzyme in order for it to eliminate the unwanted proteins while tackling the DNA digital damage from DNA methylation. In this today's world, there are three main ways to maintain young stem cells and reduce the senescence cells;

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1.) NMN/NR Treatment

The NMN stands for Nicotinamide Mononucleotide. It is a molecule that naturally occurred it is a Ribo-nucleotide, which is a basic structural unit of the nucleic acid RNA. The NMN tends to boost the the metabolic molecules of NAD+ which later provides the an extensive energy for the longevity enzyme. Furthermore, the increase in capability of NAD+ could also repair the Mitochondial dysfunction. NAD+ can be named as an energy carrier as it could carry the protons and electrons to the Mitochondria. NAD+ is extracting Hydrogen's protons and electrons from Sucrose by which it extract 4 hydrogens from C6H12O6 ---> C6H8O6, forming two Pyruvate (C3H4O3) in the process. The NAD+ then turns to NADH with extra H+(NAD+ + 2e- + H+ -----> NADH + H+) for Mitochondria to convert to Adenosine triphosphate (ATP) which powering the entire cell. Mainly the increase in NAD+ is also powering Sirtuin protein to repair the DNA ribbon while also regulate the Histone Deadetylate. 

2.) Stem cell collection

You might have heard the Stem cell collection more often, compared to the NMN treatment since the technology of collecting stem cells from patients and cloning them is already a decade-old technology. The process is simple and yet has been commercialised worldwide while keeping the process affordable for most of the people. The process includes the extraction of 20-40 million stem cells from Abdominal fat where the stem cell will be cloning and collecting in a low-temp freezer. The clone hatching derived from a basic cloning technology by which the process include; Fertilisation ---> Cleavage ---> Compaction ---> Differentiation ---> Cavitation ---> Zona Hatching ---> Implantation which later form into ---> Cell mass differentiation. Stem cells are primitive, unspecialized cells. A 5-day-old human embryo, called a blastocyst, contains an inner cell mass composed of about 12 embryonic stem cells. Adult human bodies contain relatively few stem cells, mostly concentrated in the bone marrow. As time goes on, the collected stem cells will be utilised and injected to the tissue dysfunction as a result of senescence cells. However, this treatment does not solve the main problem of epigenetic misinformation but rather conserve the future stem cells to be divided once the current stem cells could not do. The treatment is not on point but still made up to the list of extending lifespan due to more healthy tissues.

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3.) Anti-Senescent Drug

This non-commercialised treatment however takes different approach in dealing with the epigenetic disrupted senescent cells. Instead of preventing the DNA Methylation, the Anti-Senescent Cells tends to selectively eliminate the senescence cell to prevent any further inflammation. This field of research has been utilising together to tackle Alzheimer as both of them required the attention to the senescence cells.  Senescent cells spew out a panoply of inflammatory molecules (SASP – the senescence-associated secretory phenotype) that can have profound effects on tissue structure and function by promoting chronic low-level inflammation. The SASP is of great interest to researchers who study aging biology; several biotech companies are developing therapeutics aimed at quelling the damaging effects of senescent cells. Buck institute in Nevada is among the first and leading institute to develop therapeutics into drugs. By successfully achieving this type of treatment, we as humans will revolutionise the way we think about ageing where Ageing will be treated as a disease.

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Judy Campisi PhD, A professor at Buck Institute for Ageing

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Different type of senescent cells

 

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Pathway for Age Reversal in Human

3 October 2021 -- Jomkhwan Borrirak 

5 min read

Reprogramming the tissue dysfunction via anti-epigenetic noise treatment and DNA demethylation in mice and other small organism became normalised topic in this new decade . In fact, humanity achieved the age reversal in cells since 2012 by which PhD, Shinya Yamanaka and his notable works proved that any cells could reverse back to the young stem cells by using Four Yamanaka's Factors, right before he got a Noble Prize in Physics or Medicine in 2012. In cell culture, the ectopic expression of the four Yamanaka factors transcription factors OCT4, SOX2, KLF4 and MYC (OSKM Treatment). By utilising three out of four factors (OCT4, SOX2 and KLF4 genes), the OSK genes stimulates axon regeneration and encounter the lose regenerative potentials in the Central Nervous System (CNS). This statement has been proved in 2019 where Professor David A. Sinclair, along with his student, Yuancheng Lu at Harvard Medical School could reprogram the gene to recover youthful epigenetic information and restore vision in old mice. The trail states that, by using three factors of genes, the old mice restore its vision whereby the Retinal Ganglion Cells (RGCs) of the CNS holds axons to the retina to form the optic nerve. 

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To provide those three genes to the crush-injury retina, Tet-Off AAV2s system carry an OSK polycistron were injected into the vireous body, following in DOX-Responsive OSK gene expression in 40% of RGCs. They also introduced tTA in a double-floxed inverse orientation (AAV2-FLEx-tTA) with AAV2-TRE-OSK into two Cre transgenic mouse line, so that OSK was selectively expressed either in RGCS-Vglut2-Cre or Amacrine Cells-Vgat-Cre. However, only OSK expression in RGCs promotes axon regeneration while Amacrine cells do not. Regeneration requires DNA demethylation which can be catalysed by ten-eleven translocation methylcytosine dioxygenases (TET1-TET3). The knockdown of TET1 or TET2 blocks the ability of OSK to increase Stat3 mRNA levels which promote RGC survival and axon regeneration. To get a statistical report, two equal-in-age subjects with glaucomatous eyes are tested whereby either PBS or AAVs with OSK was given to one mice and no OSK to another mice. The mice with OSK treatment receives more axon density

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Not only for vision restoration, another laboratory in Australia, leading by Dr. Michael Bertoldo at the University of New South Wales also achieve the same result with female mice's fertility during reproductive ageing whereby it is an achievement of oocyte quality restoration, promoting higher ovulation rate, higher blastocyst quality, live births and litter size. This trail however also involve SIRT2 treatment and NMN treatment. For better understanding regarding oocyte restoration, the trail report can be accessed publicly in Cell Report Journal. In the 21st century, it could be said that humanity achieved reprogramming in almost all complex tissues in mice. In 2020, we could see an old OSK-treated mice giving birth, more collagen in their skins, energetic mitochondria, restore running ability and most importantly as we speak, the restoration in vision.  

 

Since this is at very edge of biology frontier, more researches for more collectable data are necessary. The wall of effectively reverse ageing rightnow, is the fact that we knows it works only the cells we treated. Humans for example has more than trillion distinctive cells where we still, at my knowledge, have not realised how to implement the reversal treatment to the whole body. Moon Jellyfish for instance knows this exact process whereby the creature is notable as an immortal jellyfish as it can reverse ageing to any form of its lifetime such as the form of Polyps. More accelerate study of them is now in process since 2020. Now, we are arriving at humanity's furthest achievement in Bioengineering capabilities.

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Citation :

Reprogramming to recover youngful epigenetic information and restore vision : https://doi.org/10.1038/s41586-020-2975-4

NAD+ Repletion Rescues Female Fertility during Reproductive Aging : https://doi,org/10.1016/j.celrep.2020.01.058

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Shinya Yamanaka, PhD & Noble Prize 2012

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David Sinclair, PhD, Department of Genetics at Harvard Medical School

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Yuancheng Lu, PhD student, Harvard Medical School

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Michael Bertoldo, Dr., Biologist researcher at New South Wales University

 

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Anatomy of Turritopsis dohrnii

11 October 2021 -- Jomkhwan Borrirak 

5 min read

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Jellyfish are among the bizarre creature on Earth where it floats around for at least 500 Million years. The jellyfish is not really a fish, it is considered to be the gelatinous zooplankton. The distinctive feature about them are the translucent bell as a main body, made out of mesoglea. The mesoglea as the main body contains 95% water whereby the two thin of body helps containing it. The creature utilises a rudimentary nervous system to control the body as the creature contains no brain or spine. Its nervous system is also contains the ability to sense the ocean's current and other animals.  In its epidermis also contain nematocysts cells to act like poisonous harpoons to defend itself and also catch a prey. One remarkable ability though is considered to be the bio fluorescent compound called Green Fluorescent Protein (GFP) by which it helps the creature to create a green light within its body. For human, the GFP from the jelly could then utilised to attach the lightening gene to any cells which allow us to track any cells including the cancer cells or Hela cells or even Alzheimer's cells for further studies. One of its ability though has been amazed by us the human as some of its species, particularly the Turritopsis Dohrnii, could reverse its age by committing cell reversal and therefore creating its own age cycle.

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This raised the question regarding its ability. How did they do such a science fictional ability. Well, the answer lay upon the reverse metamorphosis, cell transdifferentiation and RNA-sequencing. In 2013, Turritopsis Dohrnii group (mainly a medusa form) were gathered in Italy. To contain those newly released medusa, individual colonies were maintained separated in glass containers. Separately, the colony and medusa were kept in RNAlater RNA stabilization solution and stored at freezing temperature for subsequent processing. In July 2015, freshly released medusa from field polyps were separated in glass dishes and starved to induce cysts. For subsequent processing, the cysts were preserved in RNAlater and kept at -80C. A little amount of polyp tissue was saved for DNA barcoding. Total DNA was isolated from polyp tissue before RNA extraction.

 

The transcriptome profiles of the Polyp, Medusa, and Cyst, three life cycle stages of the cnidarian Turritopsis Dohrnii, were characterized using RNA sequencing, de novo assembly, and functional annotation. To discover molecular pathways that may be involved in reverse development and transdifferentiation in the creature, comparative functional gene enrichment analyses were done using the Cyst as the focal stage of comparison. When compared to the Medusa and Polyp stages, their findings reveal that categories related to DNA synthesis, repair mechanisms, telomerase activity, and telomere maintenance are over-expressed in the Cyst. Transcripts, nevertheless, are a different story.  Transcripts associated with specialised functions including lifespan and aging, response to stimuli, cell division, and cell differentiation and development are under-expressed compared to the medusa and polyp stages. The study of life-phase-specific transcriptomes of the creature provides the extensive insight into the network of molecular regulatory genes that controls the stability and reprogramming of differentiated cells, tissue homeostasis, longevity, and the associated potential for rejuvenation. of the organism in a promising in vivo. controlled system. This research has generated a transcriptomic landscape to analyse the extraordinary potential for the reverse development and cell transdifferentiation in the creature. As a sequence, the research proposes the establishment of a new experimental paradigm to obtain new knowledge about regeneration, cellular plasticity, aging and the directionality of ontogeny in a non-model in vivo metazoan system. The research identifies biological processes, for instance, the role of transposable elements, the DNA integrity and repair, cell-to-cell communication, and telomerase activity as processes that occur at the cyst stage.

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Coenzyme - Mechanism Chemistry of NAD+ and NADH

2 August 2021 -- Jomkhwan Borrirak 

5 min read

Jellyfish are among the bizarre creature on Earth where it floats around for at least 500 Million years. The jellyfish is not really a fish, it is considered to be the gelatinous zooplankton. The distinctive feature about them are the translucent bell as a main body, made out of mesoglea. The mesoglea as the main body contains 95% water whereby the two thin of body helps containing it. The creature utilises a rudimentary nervous system to control the body as the creature contains no brain or spine. Its nervous system is also contains the ability to sense the ocean's current and other animals.  In its epidermis also contain nematocysts cells to act like poisonous harpoons to defend itself and also catch a prey. One remarkable ability though is considered to be the bio fluorescent compound called Green Fluorescent Protein (GFP) by which it helps the creature to create a green light within its body. For human, the GFP from the jelly could then utilised to attach the lightening gene to any cells which allow us to track any cells including the cancer cells or Hela cells or even Alzheimer's cells for further studies. One of its ability though has been amazed by us the human as some of its species, particularly the Turritopsis Dohrnii, could reverse its age by committing cell reversal and therefore creating its own age cycle.