AGING CHIPS AWAY IN RUNAWAY FEEDBACK LOOPS

 AGING CHIPS AWAY IN RUNAWAY FEEDBACK LOOPS

 

Why is aging so difficult to prevent or ‘treat’? It chips away at thousands of locations. During millions of years of evolution whenever the cellular processes came across a problem by adaptation one or multiple proteins were designed to resolve that problem. These proteins implement their functions through biomechanical type, biochemical type, bioelectrical type of interactions with its neighbors. Leading to recruitment by activation of other proteins to implement the task/s. When co-activations occur they many times have unintentional consequence as that protein is pulled away from its daily tasks. That consequence leads to other cascade of unwanted consequences. Many of these cascades create feedback loops which slowly expand the scope of consequential damage in small increments with every loop. That’s why even though aging starts just after puberty we begin to notice it only in our sixties. By then the loops are snowballing and the damage gets bigger and bigger with every loop. This basically is the root cause of aging that occurs in mammals. Let me elaborate with an example.

DNA-PK is a fascinating protein designed by Nature to do so many tasks. One of its main tasks is to detect double strand DNA breaks DSDBs and then recruit other proteins to orchestrate its repair. This is a complex task so how does one protein without any brain like neurons or repository of analytical intelligence conduct such complex tasks? So detection for example is done by Ku70/Ku80, the DNA-end recognition component of DNA-PK. Ku70 and Ku80 form a ring-like channel with a positively charged interior that accommodates negatively charged DNA. When DNA is intact, this ring generally cannot thread onto an internal segment of a DNA double helix. When a double-strand break exposes a free DNA end, however, the ring can slide onto that end through thermal molecular motion. This is geometrical detection, not an intelligent assessment of damage. The crucial insight is that the DNA break creates a new physical structure that the protein can bind. So what we see is that it is not done out of any intelligence or embedded memory of tasks but simply by its biomechanical and bioelectrical configuration. Amongst its many tasks it recruits another important protein called HSP90a which then disrupts its usual chaperone support to clients like AMPK. Here is one part of this molecular cascade:

1. DNA Damage and DNA-PK Activation: DNA double strand breaks activates the catalytic subunit of DNA-PK (DNA-PKcs).

2. HSP90α Phosphorylation: Active DNA-PK targets HSP90α in the cytoplasm, phosphorylating it specifically at the Threonine 5 (Thr5) and Threonine 7 (Thr7) residues.

3. Chaperone Function Disruption: Under normal conditions, HSP90α acts as a vital molecular chaperone that binds, folds, and stabilizes both AMPK and its upstream activating kinase, LKB1. Phosphorylation at Thr5/Thr7 by DNA-PK causes HSP90α to lose its affinity for these clients.

4. AMPK Inhibition: Deprived of its chaperone support, the AMPK complex cannot be correctly folded or activated, leading to a down-regulation of metabolic sensing.

This is not a small disruption: Five functions of AMPK:

a)        Energy homeostasis

Prevents energy depletion by matching cellular energy consumption to available ATP production.

b)        Mitochondrial renewal

Coordinates mitochondrial fission, mitophagy and biogenesis, helping maintain a functional mitochondrial population.

c)        Autophagy and cellular cleanup

Regulates degradation and recycling of damaged cellular components, although the response can reverse under extreme energy stress.

d)        Genome and chromatin maintenance

Participates in DNA damage signaling and chromatin regulation. However, AMPK is not established as a universal mechanism for restoring the original epigenomic configuration.

c)       Cellular stress resistance

Coordinates adaptive responses to nutrient deprivation, oxidative stress, mitochondrial dysfunction and other threats to survival.

In younger humans the frequency of DSDBs is much less and so the abandonment of chaperone support during folding of AMPK causes minor disruption in its master regulatory function but as we grow older the number of DSDBs increases causing severe consequences of AMPK misfolding: triggers several systemic declines:

• Mitochondrial Decay: Loss of AMPK suppresses the renewal and function of mitochondria.

• Metabolic Dysfunction: Decreased AMPK activity contributes to weight gain, tissue insulin resistance, and heightened susceptibility to Type 2 diabetes.

• Physical Decline: Animal models demonstrate that this pathway directly correlates with reduced vertical capacity, diminished oxidative muscle fibers, and lower treadmill endurance during aging.

Reference: DNA-PK promotes the mitochondrial, metabolic and physical decline that occurs during aging by Dr. Jay H Chung et.al.

Now going forward on this one loop let us examine the consequences of partial loss of AMPK on mitochondria and autophagy. As mentioned in my previous post Agents of Time: Every day around 450 billion cells die in our body (our body is a collection of avg 33 trillion cells). This huge number of dead cells leave fragments or debris which circulates in our blood. Phagocytes work relentlessly to ‘eat’ this debris and digest it - clear it. These Phagocytes in particular macrophages are hard workers keeping our blood clean of this cellular debris, a single "meal" for them can equal roughly to 3 times the phagocyte's own volume. A single macrophage can clear 60 to 70 whole dead cells every day. On a systemic scale, this high individual capacity allows the body's phagocytes to eliminate 200 to 300 billion dead cells daily across the human body. This intense activity requires huge amounts of ATP from their mitochondria. But as we saw above due to loss of AMPK during DSDBs repair, mitochondria increasingly get disrupted leading to loss of ATP production. Can you see how these runaway loops build up? This results in reduction of the amount of dead cell debris being cleared by macrophages. And this debris circulating in our blood continues to rise as we age. 

A consequence of this is explained by Dr. Indraneel Mittra in his paper ‘Cell-free chromatin particles damage genomic DNA of healthy cells via an ROS-independent mechanism’, he says, “Several hundred billion cells die daily in the human body, releasing cell-free chromatin particles (cfChPs) in the process, which then enter the blood circulation and get taken up by healthy cells. We have previously reported that, these internalized cfChPs damage genomic DNA as well cause physical damage to mitochondria, resulting in increased mitochondrial ROS production.” This is how DSDBs and mitochondrial damage begins to snowball. DSDBs in macrophages activate DNA-PK which recruits HSP90a which leads to partial loss of AMPK which leads to mitochondrial dysfunctions amongst other things which leads to loss of ATP for macrophages which leads to more circulating dead cell debris which causes more DSDBs and mitochondrial damage which results in higher activation of DNA-PK causing the cycle to keep repeating every time increasing the damages some more. There are thousands of such loops that are making thousands of cuts on a continuous basis which manifests as aging. We try to explain how a protein is so important for vital functions and yet also causes so much damage as antagonistic pleiotropy but it may just be a case of competitive recruitment that starts the runaway loop of damage. 

This also shows how futile single interventions like boosting NAD+ patching these cuts inflicted by aging is like trying to apply bandages at thousands of bleeding sites. How can we stop or reverse thousands of these runaway loops? Billions of dollars are being invested in trying to stop or reverse aging but first we need to understand and acknowledge the massive complexity of the problem.

PHAGE WARS

 PHAGE WARS

3.4 billion years of weapon evolution 

As I have brought up before in my previous posts Nature engineers a yin and yang balance to prevent any species from becoming a cancer. The grass eaters would keep foliage in balance and predators would keep grass eaters in balance and so on. Even within us a protein agonist would start a process and another protein antagonist will be there to end it. To maintain equilibrium. If we can stably maintain equilibrium like we see during our youth, we can theoretically live forever. The oldest balancing war has been raging from 3.4 billion years and at a mammoth scale between two of the largest populations on Earth: bacteria and viral bacteriophages or Phages: “There are believed to be 10 million times more phages than stars in the visible universe. They're busy, too. Each day, half of all ocean bacteria are infected and blown apart by these replicating microscopic assassins in a forever war” David McFadden, University of Ottawa.  To give context there are 1 billion bacteria in 1 liter of sea water. This massive amount of dead bacteria feed the planktons which then generate more than half of the oxygen on our planet. Another way to estimate is a trillion phages for every grain of sand on our planet. They have 10s of millions of species of which we have recorded only 1,500 so far. Bacteria can multiply rapidly and even though they are invisible to human eye they can crowd out every other species were it not for the Phages that constantly destroy them. It’s ridiculously unbelievable how a tiny invisible bacteria with a few thousand genes can construct super intelligent engineering weapons like CRISPR to rapidly edit genes of their invading enemy to destroy them before they are destroyed. Phages keep building weapons to outsmart bacterial defense and bacteria keeps generating more novel defenses to protect itself. The Phage than evolves to overcome that defense. Check out Chapter 5 below. This has been going on and on for billions of years. This war is even going on in our bodies: for example Phages occupy our mucosal surfaces like in our nostrils and kill infecting bacteria and become part of our immune response. Bacteria have already gifted us CRISPR in vivo gene editing technology, imagine if we can retrain Phages to attack cancers with the same ferocity and specificity they use to attack bacteria. All living things on our planet share common genes and proteins but majority of the Phages genes and proteins are unknown: they are like invisible alien Zombies hunting, biting, infecting and killing bacteria. 

I want my start up to build unique massive gene insertion technologies inspired from the Phage wars. What genes do I want to insert? Each of the species that have survived on Earth have been gifted unique evolutionary adaptations. Dinosaurs became apex predators and dominated over all other species in their time. Humans, the gift of intelligence which allows us to dominate the planet now. But there are other species that have adaptations that are uniquely superior: like Planar worms can restore and older senescent cell back to youthful configuration or Ginkgo Biloba tree can stabilize their genome/epigenome which permanently keeps them in youth. It may take thousands or even millions of years for us to acquire such adaptations. Instead I want to trigger evolutionary jumps by adopting these rare adaptations into humans. Whether I will succeed or not we have to see. In the meanwhile this is my first post in the age of AI so I have used it to share my wonder of the Phage war. It’s full of fascinating gems and nuggets of information packaged in an easy to read manner. Enjoy: 

BIOLOGICAL MESH NETWORKS

 Biological Mesh Networks

 

We are a collection of cells. We never think about it or probably don’t know that each one of those cells is individual unicellular organism with its own innate intelligence. These cells come together to build a higher life form to improve chances of survival. All evolution is about survival. Individually each cell is much more vulnerable but collectively it can build attributes that would protect it better. But ironically to be part of such collective self it has to sacrifice its own life for the betterment of the whole whereas if it was not part of such collective self it would use its innate intelligence and desire to survive to make itself immortal. We call such cells that break free from the collective self cancer cells. For the higher form to remain operationally and collectively stable the cells are bound together with ‘mesh’ networks. The cell towers that give signal to our millions of cell phones have an interesting architecture where each tower is not just connected to its neighbour but all cell towers are connected to each other like a mesh. This is done to create automatic, intelligent load sharing between them. That way if there is conference or a festival at a certain area it won’t overwhelm the cell towers in its vicinity. Instead the extra load is shared with whichever towers that have much lower utilization regardless of how far or near they are. That way every cell tower helps the other.

 

Mesh Network Topology

 

In our biological mesh networks cell completely changes its persona and priorities to that of the collective organism. This may not be its natural state and so is held tightly on a leash by multiple mesh networks. One of the most recently discovered mesh network is bioelectrical by a brilliant scientist called Professor Michael Levin at Tufts University. I would encourage everyone to see his fascinating videos available on YouTube.

Michael Levin PhD

Another one is a physical mesh network connected by filaments protruding from each cell connecting to each other in a 3D network. The one that my own research works on is Extracellular Messaging Network. Each cell secretes tiny bubbles with various molecules which find another cell and inject that cargo of molecules in the receiving cell. This exchange too is constantly happening amongst and between our more than 30 trillion cells.

Michael Levin has proposed a major change in how we treat diseases. He suggests that the way we currently do so with our obsession with DNA and single molecules and CRISPR gene editing is similar to how programmers changed programs on computers in the 1960s:

By repatching the hardware every time the program needed to be changed. But now it can easily be done systemwide without touching the hardware using only the operating software and recoding it. What we have managed with these manual repatching of hardware is mostly management of symptoms with hardly any full cures of chronic diseases. No wonder 90% of the drugs fail to be approved. It would be much more powerful and effective to reprogram cells through the mesh networks that hold them tightly together. He demonstrates this by taming the most difficult disease ever: cancer. In a young, healthy body the cells are polarized in the bioelectrical network. They are always depolarized in disease and aging. Cancer cells too are depolarized. Michael Levin’s lab hyperpolarized the cancer cells and voila! Like magic they become normal cells. When cells break free from the collective organism all other cells become their host cells and they multiply and proliferate rapidly to ensure survival. They use their innate intelligence to outwit their hosts collective defense networks and tools. But as soon as they are pulled back into the collective self then they lose that independent selfish desire to thrive and survive and become a slave of the collective will. By changing them from depolarized state to hyperpolarized they come back to what we would term as normal behaviour but in reality there is no right or wrong behavior just different personas depending on whether they are part of a collective society or individual single cell organism like an amoeba. Can you imagine us as collection of amoebas? J

What this highlights is the future of medicine: Using any of the mesh networks to resolve a disease state. One can also consider aging as a disease state that we can also resolve in a similar manner.

So there are three levels of intelligence: innate intelligence of each cell, collective intelligence of the mesh networks and neurological intelligence of the higher organism. Although we call multicellular organisms a higher form the distributed innate adaptive intelligence that cells have seems far more superior to the higher form. Without having a central neural network to have the ability to analyze and take complex decisions the cell is able to use its internal, individual bioelectrical, biochemical and genetic/epigenetic networks to become a distributed intelligence. What incredible, incredible engineering in such a tiny, crowded space! Levin showed us through experiments that the bioelectrical network hosts sequential information about spatial organization of a higher form which builds us from a tiny single egg to a complex adult: the program of development.  But where is the sequential information stored on the program of aging? The collective intelligence has a group plan for building a multicellular life form and also a group plan for its operations. Cells that have partial disruption in their mesh network connections manifest into a disease and when they are completely disconnected from the group mesh networks and group identity they become selfish and cancerous.

Professor Michael Levin gives an amazing example of the collective intelligence: He loves to research with Planaria worm because it has evolved some astounding abilities. If it is cut into pieces, each piece is able to grow into a full, exactly same proportioned worm. What is in that cut off piece of that worm that has the distributed memory of its own full architecture and also instructions of how to regenerate exactly the parts needed at exactly the correct location to conform to the original worms architecture. Levin has shown evidence that this information is stored in its bioelectrical mesh network. In another example of collective intelligence: When planaria is inserted in barium its head blows off because it can not survive in barium. In a few days it regrows a head that can survive in barium. How does it activate only those genes that would allow its head to adapt to barium? So not only does it’s collective intelligence design a brand new head and position it correctly but it also changes its tissue material and properties so that it can survive in barium. Think about it: such a tiny worm without its head making decisions about which tissue material would be able to withstand barium! and then which genes to activate and close to produce that tissue as part of the regenerative scaffold! Beyond belief! This same collective intelligence also builds us in correct proportions into a full blown adult starting from a single fertilized egg. Imagine the power we would have if we can code or manipulate this collective intelligence stored in a mesh network? Our current tools like CRISPR seem so advanced and revolutionary but are primitive and unidimensional compared to this tiny worm's collective intelligence. We are so used to intelligence associated with dense neural networks in our brains that it’s very difficult to imagine such brilliant collaborative intelligence without any ‘brain’ or neurons. Where would such analytical computing machine be residing?

This tiny worm's mesh networks are more evolved and more advanced than us humans.

Another mesh network is what I call Extracellular Messaging Network or EMN. YUVAN uses this mesh network to make system wide changes. 

Extracellular vesicles derived from young plasma rejuvenates aging cells through multi-modal improvements by hacking the EMN. It’s like inserting new code to correct operating software errors in a computer. 

Besides bioelectrical network and chemical exchange through physical filament network, cells also communicate with each other via lipid enclosed molecules like proteins and RNAs. Almost all cells constantly secrete these messages in extracellular vesicles (EVs) or in protein conjugates. These EVs naturally do a molecular ‘handshake’ with other cells and inject their cargo of proteins, RNAs and more not only into the recipient cell but also into its nucleus. This cargo then executes their function: for example, a miRNA may bind to a protein and neutralize it or a non coding RNA may make epigenetic change which could affect a gene’s expression. This exchange again is like a mesh, so not just between neighboring cells but across distances with cells in far off locations transported there in circulating plasma. This intercellular messaging is constantly going on from even before we are born till death. Each cell is influencing the epigenome, transcriptome, proteome and gene expression of other cells through this messaging network. Some exchange is targeted to a particular cell through surface proteins called tetraspanins regardless of how far the recipient cells are located.

 

Next generation of medicine will hack into or leverage these intercellular mesh networks to gain system wide results. Levin is developing actuators/switches to manipulate the bioelectrical network to gain Planar worm type of regenerative superpowers. YUVAN has been harvesting EVs and some more plasma constituents from the plasma of the young mammals around puberty. As at that age the messaging cargo is supporting a near homeostatic efficiency in cells. As I have mentioned in my previous posts aging and disease result from ‘epigenetic drift’. A quick recap: all cells have the same DNA then why some cells become a heart cell and another becomes a liver cell – both so different. This is due to epigenetic configuration. Each cell type has its own unique epigenetic template that shuts down around 80% of the genes and keeps open the balance. Which gene is shut and which is left open decides the cells form and function. During embryogenesis these epigenetic marks are wiped clean and a fresh template is installed for each cell type during differentiation. But in almost all multicellular organisms this epigenome begins to lose it’s configuration in some places leading to what some scientists call ‘epigenetic drift’. This can result in partial or full loss of cellular function. As more and more cells progressively get misorganized parts of their epigenome, their tissue or organ can lapse into a disease. Aging is another manifestation of this epigenetic drift. Around puberty such epigenetic drift has not started and body is at its peak to support reproduction. So YUVAN harvests EVs and other plasma constituents around puberty and injects them into older recipients. This basically hacks into the EMN. As per natural process these EVs inject their cargo into older recipients cells. Now the proteins and RNAs circulating in the young influence the epigenome, transcriptome, proteome and gene expression of the older cell. This reverses the epigenetic drift and resets the epigenetic configuration closer to it’s pristine template found around puberty. And voila! the cell begins to function like a young cell.

Modern medicine has been priceless for so many infections and diseases that used to kill us previously but it hardly gives us any full cures. Mostly managing symptoms. Focusing on a single gene or a few genes or a single protein or antibody doesn’t produce a full transformation or regeneration of the diseased tissue or organ. That’s why 90% of the drugs fail to get regulatory approval. Whereas a drug that can influence any of these mesh networks can reprogram the entire network or any part of it to a more efficient form. A tiny worm has adapted its survival mechanism, won during evolution, to regenerate and repair any epigenetic disorganization instantly as we would heal a small wound. This results in a stable epigenome the importance and benefits of which is the subject of my previous blog post titled Stability = Lifespan. A stable epigenome keeps the cells healthy and efficient leading to youthful immortality of the Planar worm. We can see a similar ability to keep its epigenome stable in Ginkgo Biloba tree which is much bigger than the worm. It too has been called immortal. We are a collection of cells. Of all the parts of a cell why is epigenome the most important? Because it is what gives each cell its identity and function. In aging and disease we see a gradual loss of both leading to various painful complications and eventually to death. Reprogramming our biological software to cure epigenetic disorganization is the future of our medicine. Can we learn from the worm and the tree to modulate our endogenous mesh network softwares to stabilize epigenome in each of our cells and then maintain that stability forever?

 

STABILITY 🔀⏩️LIFESPAN

 STABILITY 🔀⏩️LIFESPAN

 

The lifespan of objects in the universe is dependent on the stability of its unit ©2023 akshay Sanghavi 

 

All matter moves towards stability.

 

Atom is more stable when it is in a lower energy state and so it tries to move towards the lesser energy state.

 

 Unstable atom isotopes will spontaneously decay and change to another more stable element. The rate of radioactive decay is inversely proportional to the stability of the isotope. Radon-222 has a half life of just 4 days so every 4 days it will reduce to half. Which creates the spontaneous move towards a more stable form. Universal law of survival: a stable atom can exist for billions of years. Xenon-124’s half life is 18 billion trillion years. Despite its incredible lifespan and stability, it’s not immortal: it will also eventually die and turn to tellurium-124. 

 

Atom of Xenon-124 from Descopera.ro

 

I have been thinking about the different lifespans of biological species on our planet. My fascination and desperate curiosity to unravel the mystery of variable lifespans has obsessed me with constantly researching the potential causes. I have been sharing my findings in some of my previous posts like Mechanism of Aging, Headwaters, Autologous Regulation and Agents of Time. In the last few posts I have shared the realization that a cell’s destiny is strongly linked to regulatory changes enforced by regulators like non coding RNAs. Of course, there is incredible complexity to this process. Nothing else on this planet has brilliant, complex, autonomous engineering like our biology. But can there be one simple factor behind the variance that we see in the lifespans? It’s not size for example as the exceptions demonstrate. My mind is blown by the study by Professor Richard Dixon on Ginkgo Biloba tree. So much that it features in all my longevity related posts since it was published. If these hardcoded transcription plans are making deliberate changes starting after puberty setting off a cascade that ends in death, then how did Ginkgo Biloba make adaptive changes to bypass such a universal recycling mechanism of Nature? Professor Dixon called it almost immortal. The best part is that not only is it almost immortal but it’s almost immortal in a youthful state! Who wants to live a thousand years looking like shrunken bag of bones and crumpled skin? So, what is this one single cause of lifespan variance? We will arrive at that after some more deliberation. 

 

As we read in a paper by Morimoto and Labbadia called ‘Repression of the heat shock response is a programmed event at the onset of reproduction’ that just after puberty there is a change that reduces the ability of chaperones, that are key to the protein production process in our cells, by 60%-70%. This results in higher number of malformed proteins. This starts a cascade of many other drops in important functions in the cell and these drops snowball making us age. For example, as we read in Agents of Time, the debris of the 450 billion cells that die every single day in our body is cleared by phagocytes. But thanks to various regulatory changes and their ensuing cascades their mitochondrial batteries begin to fail them. This leads to accumulating number of sharp debris that enters cells and causes 1 quadrillion double strand DNA breaks everyday! In this chain of events germline cells triggered epigenetic changes that resulted in the fall of efficiency of protein production chaperones. What if these epigenetic changes were not allowed to be made or after they were made they were ‘repaired’ back to their original epigenetic configuration. In order to prioritize reproduction the germline stem cells trigger epigenetic repression of heat shock proteins which act as chaperones to support protein production and as stress response. When we get a hurt while playing sports the injury is repaired over a period of time. What if similarly the epigenetic mark that germline stem cells make after puberty is demethylated or removed to restore back the full strength of heat shock proteins? That would stop the chain of events that eventually cause so many double strand DNA breaks every day. Just to demonstrate how this cascade snowballs when those breaks keep happening in the DNA, even though almost all are repaired, they succeed in creating roadblocks in the hurtling train of transcription in our DNA. This than has serious repercussions as many transcription programs get blunted. In the Agents of Time blog another change causing aging is mentioned wherein our long, coding and noncoding, transcripts begin to fade. The authors of the cited paper also mentioned that these longest transcripts were activating prolongevity genes. Thereby repressing or silencing the genes associated with making us live longer. So when we prevent or significantly reduce the huge number of double strand DNA breaks we restore smooth transcription and thereby prevent the loss of longer transcripts and silencing of longevity genes. Do you see where this is leading us? 

1,400 year old Gingko Biloba Tree

 

The mechanism that Ginkgo Biloba tree has figured out is probably how to keep its epigenome stable! We are a collection of cells and all cells have the same DNA and yet they are transformed into 200 types to form eye and stomach and liver and skin etc. The DNA is the same but each type of cell has its own configuration of epigenetic marks on its DNA. These marks do not change the DNA physically but result in silencing majority of the genes and activating only the10%- 20% that transform it into its type of cell.  Around puberty we achieve our homeostatic peak where all our systems are working at their best. But due to the changes mentioned above we experience what is called as ‘epigenetic’ drift where the beautiful epigenetic configuration found around puberty is slowly changing leading to unwanted genes being activated and wanted genes becoming silent. This epigenetic drift manifests into what we know as aging. The Ginkgo Biloba tree does not seem to succumb to this epigenetic drift which can be seen in almost all multicellular life forms leading to cell nuclear instability that slowly grows into cellular, tissue and organ instability. In a fascinating paper titled ‘Multifeature analyses of vascular cambial cells reveal longevity mechanisms in old Ginkgo biloba trees’ by Professor Richard Dixon and Dr. Jinxing Lin et.al. the authors try to reveal the longevity mechanisms of Ginkgo Biloba trees. The table below shows the miraculous stability of really old Ginkgo Biloba trees:

The authors selected nine trees for further study and divided them into three groups: 20 y (15Y, 20Y, and 22Y, young trees; VC20), 200 y (193Y, 211Y, and 236Y, older trees; VC200), and 600 y (538Y, 553Y, and 667Y, oldest trees; VC600). Below we can see the comparison of the average leaf area, seed germination rates, efficiency of stress resistance, photosynthetic capacity and chlorophyll content of the 3 groups:

 Ginkgo Biloba Trees Comparison of 20 year olds, 200 olds and 600 year olds

 

Unlike almost all plants and trees that grow old and die Ginkgo Biloba’s environmental stress resistance, photosynthesis capacity, autophagy, sexual fertility and immune defense doesn’t drop with age! It’s cambial cells equivalent of our stem cells remain active even in oldest trees in the group but tempered with reduction in cell division, expansion and differentiation allows it to remain young without any uncontrolled growth or senescence. In human aging we begin to lose stability of the epigenome and our transcription track and its machinery leading to loss of beneficial genes and activation of unwanted genes. The exact opposite is happening with Ginkgo Biloba tree. In the same paper authors compared around 27,500 genes of the three groups: 20 year old, 200 year olds and 600 year olds there was only 4.4% difference in gene expression between the young trees and the older trees! How does Ginkgo Biloba tree maintain such stability of its epigenome, transcription, gene and protein expression???

This kind of beneficial stability is quite different then the longer lived species: the latter like Naked Mole Rats or Bowhead whales have some protective genes that are overexpressed even in old age. That does give longer than average life span associated with their species but they do grow old and die. Whereas Gingko Biloba trees seem to live forever in youthful prime. 

 

As I had shared in my post Mechanism of Aging, Nature manages optimum levels of various activities and functions in our biology by the triage of activators and inhibitors and sensors. This works like a tap of hot water and cold water and a thermometer. Equilibrium is when taps are turned just the right amount to create ideal temperature of water. Any disturbance in this ratio can cause either too hot water or too cold water causing damage. In our prime, just after puberty, we enjoy optimum equilibrium or homeostasis between the activators, inhibitors and sensors. But soon after starts the slow offsets in this balance leading to all the accumulation of unrepaired damage and nuclear instability which manifests as age related changes. We can see and feel this happening especially after our 50s but since it’s not overnight and since we see others too showing similar negative changes we accept them. Ginkgo Biloba has been around longer than us: for more than 270 million years. Whereas we humans have been around only 200,000 to 300,000 years. Ginkgo Biloba has had 270 million more years to win the adaptation lottery. We humans too have won another genetic lottery: of higher intelligence that is compounding rapidly like an umbrella curve. We are developing great technologies and tools like CRISPR and AI and will soon figure out how to safely inculcate stability in our epigenome and nucleus. Then we too will have the option to live for thousands of years in the prime of our youth. Every known thing in observable universe seems to be recycled. The stars too die and leave behind a super dense spinning ball with no fusion or light just fading heat. These white dwarfs or neutron/pulsar remnants and planets and their debris all get recycled by black holes. All of the galaxies are probably held together by the gravitational pull of the super massive black hole at their core. This central black hole eventually will eat up the entire galaxy and break it down into fresh units of matter and radiation and spew them out as astrophysical jets long distances into space. So all the different bodies in a galaxy are broken down to sub atomic particles in the intense gravitational crush of the super massive black hole and slowly recycled into basic units of matter and radiation which then forms new stars and planets. So to outwit such a pervasive norm of recycling in the universe is a phenomenal achievement of Ginkgo Biloba. 

Super massive black hole spewing recycled matter and radiation deep into space. By Newsweek. 

 

Has Ginkgo Biloba developed some technology based in the futuristic world of science fiction? No. We see some mindblowing processes in biology all around us. During early embryogenesis there is global epigenetic reprogramming. For example in male embryos 96% of the methylation is wiped out to clear all accumulated errors from parents and later globally re-methylated as per template to create a brand new error free baby. This is the reason why Nature has created a program of aging so that continuous recycling will ensure cleaning out of errors every generation. So such an all encompassing and powerful epigenetic reprogramming technology is already being used in every embryo. Second technology is of self repair. Everyone of us would have got various degrees of hurt as a child while playing and see how over a few days or weeks it’s fully healed. Third technology is seen in some reptiles that regrow limbs even after they are fully severed. So biology already has some incredible engineering technologies to reset and restore any disturbance back to its optimum configuration. Can these technologies be harnessed to restore any erosion in our epigenome so that after every disturbance, whether it is stochastic or programmed, the epigenome is reset back to its optimum, youthful pattern? 

To understand the cause of nuclear and cellular instability further let us borrow from my last post Agents of Time: We read that Aging is associated with loss of longer transcripts including long non coding RNA: https://www.nature.com/articles/s43587-022-00317-6

Plus they found: ‘we find that in humans and mice the genes with the longest transcripts enrich for genes reported to extend lifespan, whereas those with the shortest transcripts enrich for genes reported to shorten lifespan’

This is one of main reasons why longer transcripts fade away with aging:

https://www.nature.com/articles/s41588-022-01279-6

‘The drops were not due to drop in promoter activity or drop in RNAP II activity. Even the launch of transcription was unaffected. The authors postulate that DNA breaks interrupted and stalled transcription – and as longer genes/transcripts have greater chances of being broken somewhere they can be the primary cause of their reduced transcription during aging.’

A recent paper gives us glimpse of one of the ways this loss of long non coding RNAs cause the damage to tissues and organs during aging:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10834948/

“LncREST localises to chromatin (the structure in which DNA is organised in the cell). Its main function is to facilitate the localisation of key proteins in the process of DNA replication and DNA damage repair where they are needed. In fact, the absence of lncREST has been shown to cause impaired stress signalling, leading to the accumulation of severe DNA defects and, ultimately, cell death“

A few deliberate changes like the sudden massive drop in heat shock chaperone efficiency just after puberty start this cascade of errors leading to the instability of epigenome, genome, nuclear architecture and the cell. If these errors can be stopped/repaired as soon as they occur we too can’ live forever’ in youth like the Ginkgo Biloba tree. E5 does this partially by feeding older cells and its nucleus suffering from epigenetic drift with regulatory workers like longer transcripts from a youthful system that fill in some of the gaps or missing pieces in the old cell/nucleus. This restores the broken epigenetic pattern partially back to its original template. The amazing part is that old, damaged cells bounce back to youthful healthy fitness once it’s epigenetic pattern is reversed closer to its optimum design. This is a safer engineering intervention than any that needs the cell to move towards pluripotent state. As it creates a fluid epigenetic state which can lead to tripping into loss of cell identity and loss of controls which can result in development of cancerous growth. The idea is to create stability in the epigenome not fluidity.

We already have the engineering peak around puberty where our biology works beautifully. But there are a thousand negative changes that occur as we age. We have to now learn how not to slip into the epigenetic drift and to keep our cell stable at its homeostatic peak as long as we want. Ultimately, we want to install a Ginkgo Biloba type of mechanism that restores the cell and its nuclear architecture after any disturbance. The secret to long youthful lifespan is achieving long lasting nuclear stability after reaching adult biology. We just have to observe the Universe to unmask this secret. Stability is the difference between a lifespan of 4 days and 18 billion trillion years.