AUTOLOGOUS REGULATION
Our biological destiny is inherited by us in every cell. Our DNA is the repository of this information in every cell. DNA is another incredible wonder of Nature. Todd Smith gives a great description (1): Six billion base pairs of DNA are packaged into 22 pairs of chromosomes, plus two sex chromosomes. Each base pair is 34 angstroms in length (.34 nanometers, or ~0.3 billionths of a meter), so six billion base pairs (all chromosomes laid out head to toe) form a chain that's two meters long. If we could hang this DNA chain from a hook, it would be slightly taller than an average human. But that's just the DNA from one cell. Each of us have around 50 trillion cells (50,000 billion). If we took the DNA from all of those cells and laid it out in a linear fashion, it could wrap around the earth 2.5 million times, or reach to the sun and back 300 times! Yet cells manage to pack all that DNA into a structure so small we can't even see it without a microscope.
This long hard disk is twisted and braided and compressed so amazingly in the tiny nucleus of our tiny cell. Each tiny cell contains all the information to build a complete living organism or human being. Basically it carries two types information: one for autologous regulation- continuously managing itself as per inherited temporal program. This silences most of the genes and activates only those that give it its identity and characteristics. It uses multiple layers of tools and collaborations between those tools to accomplish this as per instructions embedded in it. Second type of information is its mesh like behaviour. Cell functions on its own as per the type of cell it becomes but it also functions collectively with other cells to build as per the design of the organism. On top of this mesh there are non cellular players like bioelectrical networks that influence each cell and also collectively as another language of communication amongst them.
Cells are very crowded places: there are some 42 million protein molecules in a simple cell, revealed a team of researchers led by Grant Brown, a biochemistry professor in the University of Toronto's Donnelly Centre for Cellular and Biomolecular Research. The majority of proteins exist within a narrow range -- between 1000 and 10,000 molecules. Some are outstandingly plentiful at more than half a million copies, while others exist in fewer than 10 molecules in a cell. These molecules move very very fast inside the cell. In a blog by Ken Shiriff where he quotes from the book Molecular Biology of the Cell: You may wonder how things get around inside cells if they are so crowded. It turns out that molecules move unimaginably quickly due to thermal motion. A small molecule such as glucose is cruising around a cell at about 250 miles per hour, while a large protein molecule is moving at 20 miles per hour. Note that these are actual speeds inside the cell, not scaled-up speeds. I'm not talking about driving through a crowded Times Square at 20 miles per hour; to scale this would be more like driving through Times Square at 20 million miles per hour!
Because cells are so crowded, molecules can't get very far without colliding with something. In fact, a molecule will collide with something billions of times a second and bounce off in a different direction. Because of this, molecules are doing a random walk through the cell and diffusing all around. A small molecule can get from one side of a cell to the other in 1/5 of a second.
A rendition of a cross section of a cell and how crowded it is.
In super tiny tightly packed strands of DNA heritable intelligence decides which gene (a segment of the DNA) will be read and which part of the strands will be tightly sealed to avoid being read. The ‘reading’ of the strands is by a process using enzymes and many floppy phase changing proteins as described in previous post. So many things have to come together at the right place for the gene to be read – all inside a tiny tightly packed part of a tiny cell.
From what is not read and what is read in our DNA a cell gets it’s identity and function. Only 10%to 20% of the coding genes are active at any given time in a cell. There is intelligence even in the spatial arrangement of each of the 200 types of cells. It’s like each type of cell is of a particular color and shape in a puzzle and Nature arranges them to form 80 different 3-D organs with incredible functions like our eyes which allow us to see and liver that does complex processing. Cells also form bones and cartilage and tendons and muscles. All of this different things made from the same basic cell. And each cell can be made to turn into any other type of cell. Unbelievably each cell has information on its ‘hard disk’ to build each and every of the organs, bones, muscles and skin. We literally start from a single cell!
As we read in my earlier post Headwaters, this ‘reading’ or transcription of our DNA is quite pervasive and is observed in 85% of our genome. Out of this only 2% is involved in protein coding. Rest is involved in regulating this 2% and it’s translation. The more the complex organism the bigger the ratio between coding and non coding but this tells only one part of the story.
Even in such a crowded cell with such a huge genome Nature maximizes this space by alternatively splicing 95% of the genome. So instead 50,000 genes (coding and non coding) generating 50,000 transcripts not only 85% of the genome transcribes but 98% of this transcriptome undergoes alternative splicing! Creating uncountable isoforms. By alternative splicing we mean that same region of our genome can be ‘read’ in multiple versions. Supposing we mark a region from 1 to 10 and neighbouring region is marked from 11 to 20 as two genes but those genes due to alternative splicing can be transcribed as 5 to 9 or 3 to 6 or 2 to 9 making 3 transcripts from the same gene. This splicing can also include neighbours so it can go 7 to 15 or 3 to 12, etc. to explain it simply. So in the preceding Headwaters post we learnt about how most of the transcription from non coding regions and some proteins create layer upon layer of regulation of the protein coding genes driving the changes that make us from an egg to an adult and after puberty it launches the process of aging. Now in this post we find that that is not all that happens in the genome and it’s housing structures like histones and chromosomes. On top of this there is spliceosome that cuts up the genome into not just linear transcripts across its length but unending variety of isoforms due to rampant alternative splicing. Look at the packaging brilliance of Nature: a 2 meter long DNA 85% of which transcribes into transcripts in a nucleus that is 10 microns (one micron is one millionth of a meter) would be miraculous enough but Nature maximizes this by adding pervasive alternative splicing that creates multiple transcripts from same gene! Thereby multiplying the number of transcripts by multifold that are produced from the 2 meters.
From Universal Alternative Splicing of Non Coding Exons by Tim Mercer et. al
Only a limited number of transcripts whether of a full gene or alternatively spliced gene translates into protein. In my previous post Headwaters we read about how these shapeless, floppy proteins gather near a gene activation site and magically phase change into a condensate that hovers over the site. Similarly a different condensate activates splicingAn article published in Genome Biology Journal on 28th November 2018 by Dr. Steven Salzburg et. Al. states the following: “We assembled the sequences from deep RNA sequencing experiments by the Genotype-Tissue Expression (GTEx) project, to create a new catalog of human genes and transcripts, called CHESS. The new database contains 42,611 genes, of which 20,352 are potentially protein-coding and 22,259 are noncoding, and a total of 323,258 transcripts. These include 224 novel protein-coding genes and 116,156 novel transcripts. We detected over 30 million additional transcripts at more than 650,000 genomic loci, nearly all of which are likely nonfunctional, revealing a heretofore unappreciated amount of transcriptional noise in human cells.”
The interesting thing to note is the huge number of transcripts they found: 30 million! They claim that most of them are non functional but Nature rarely spends resources to construct huge volumes of non-function things. The non protein coding transcripts too have very important roles. In a paper titled ‘Pervasive Transcription of the Human Genome Produces Thousands of Previously Unidentified Long Intergenic Noncoding RNAs’ by Matthew J. Hangaue et. Al. the authors say “It is now becoming more and more clear instead that, far from being genetic “deadwood” these repetitive expanses are actively and deliberately transcribed into non-coding RNAs which play a major role in regulating gene expression and silencing, organizing nuclear architecture, compartmentalizing the nucleus, and modulating protein function.” My previous post explains in detail the various types of non coding transcripts and the regulatory roles they play but here we additionally examined the alternative splicing that generates not only variety of coding transcripts but also as we read above huge number of non coding transcripts.
1. LncRNAs regulate alternative splicing through chromatin modification: An intimate relationship exists between lncRNAs and chromatin conformation. LncRNAs regulate chromatin modifications by recruiting or directly interacting with histone-modifying complexes or enzymes at specific chromosomal loci. A possible lncRNA-mediated crosstalk between histone modifications and the pre-mRNA splicing machinery has also been proposed. Several lncRNAs appear to control important aspects of chromatin organization including chromatin looping, either remaining tethered to the site of transcription or moving over distant loci.
2. LncRNAs regulate pre-mRNA splicing through RNA-DNA interactions: LncRNAs can tether DNA forming an RNA-dsDNA triplex by targeting specific DNA sequences and inserting themselves as a third strand into the major groove of the DNA duplex. These are known as R-loops; three-stranded nucleic acid structures, composed of RNA–DNA hybrids, frequently formed during transcription. Aberrant R-loops are generally associated with DNA damage, transcription elongation defects, hyper-recombination and genome instability. Recent lines of evidence indicate a potential role for R-loops in alternative pre-mRNA splicing. A class of lncRNAs, the so-called circular RNAs (circRNAs) are abundant, conserved transcripts originate from a non-canonical AS process (back-splicing) leading to the formation of head-to-tail splice junctions, joined together to form circular transcripts.
3. LncRNAs regulate pre-mRNA splicing through RNA-RNA interactions: Identified in multiple eukaryotes, Natural Antisense Transcripts (NATs) are a class of long non-coding RNA molecules, transcribed from both coding and non-coding genes on the opposite strand of protein-coding ones. Regardless of their genomic origin, NATs can hybridize with pre-mRNAs and form RNA-RNA duplexes. In some cases, a double function is also possible, and NATs can encode for proteins on one hand, while at the same time working as non-coding molecules modulating the splicing of a neighbouring gene’s transcript.
4. LncRNAs regulate pre-mRNA splicing by modulating the activity of Splicing Factors: lncRNAs interact in a dynamic network with many SFs and their pre-mRNA target sequences to modulate transcriptome reprogramming in eukaryotes. LncRNAs regulate the localization and phosphorylation status of Splicing Factors.
In my preceding post Headwaters we see various ways in which many types of non coding RNAs regulate gene expression not only inside the cell but also through the circulating secretome. Here we saw how alternative splicing leads to protein diversity and non coding transcription by creating alternative transcripts from the same gene. But what is amazing is that non coding RNAs influence the alternative spliceasome. A very interesting paper titled Aging is associated with a systemic length-associated transcriptome imbalance by Dr. Luis Amaral et. Al. in which they find out that as we age longer transcripts reduce and many of them are associated with longevity genes. They cite various possible causes as the source of the origin of these change like heat shock protein leaving translation with truncated protein lengths and spliceosome and splice factors deliberately transcribing shorter transcripts. But the best clue is that they also found in some subset of tissues and cell types exact opposite is seen happening! In these short transcripts are seen reducing and long transcripts are seen increasing. So what is this a dead giveaway of? Temporal program of autologous regulation. The age related changes are not random but are orchestrated by transcription and splicing machinery and their coplayers. In a paper titled Aging associated changes in the expression of LncRNAs in human tissues reflect a transcriptional modulation of ageing pathways by Dr. Joao Pedro de Megalhaes et. Al they observed that LncRNAs are very tissue and lineage specific and typically highly specific spatio-temporal expression patterns. This again shows evidence of an intricately designed regulatory plan that unfolds with timeline of the living organisms. All this intricately complex regulation in such tiny environment is for spatial and temporal organization of a life form:
Spatial organization: Imagine a tiny cell 1/10th the diameter of a human hair has information that it reads which tells it where it should locate itself with respect to other cells in our body. So a cell that is designated to be an eye cell, as it emerges from the multiplication of cells from one single fertilized egg, knows it has to move precisely towards the sockets being formed in the head and then through epigenetic changes it becomes an eye cell! It will not float and land up on the hand or turn into a skin cell in the eye. The precision is mind boggling. Where is that information, that instruction that it must move there to become an eye cell? It’s already labeled in its DNA. Imagine tens of trillions of cells each knowing exactly where it needs to locate itself in a 3 dimensional space of the life form and then what it needs to become to form various organs and tissues and muscles and bones! It must need to coordinate and jostle with its neighbours to land at its physical destination. Dr. Michael Levin says there is Bioelectrical memory which connects all cells in a mesh and guides each cell to where it needs to be. This process is called spatial organization.
Temporal organization: Once a cell takes its place and it’s epigenetic buttons are clicked to transform it into a type of cell a whole different process of organization begins. In this process the 10% or 20% of the coding genes which typically are active begin to print proteins that fulfill their various tasks in line with their cell’s type. So a pancreatic cell with code for insulin for example. These are functional tasks of the cell but parallely as we have read above there is also highly complex regulation that is happening of those protein coding genes and their transcripts. This continuous background regulation creates constant changes in the cell from birth till death. Initially these macro changes are related to development: to make us grow from an egg to an adult and after puberty the main theme of these changes is to dial down important repair and recycling systems so that within a given range the life form dies. These latter changes manifest as aging. These regulatory changes of the spliceosome, alternative splicing, non coding and coding gene transcription all together leading to a particular proteomic configuration which in turn influences the efficiency of all the tasks that are done by those proteins. The changes stop some proteins, change some proteins, reduce some proteins and increase some proteins. This is ongoing all our lives. Ironically these transcriptional and proteomic changes also affect the cells DNA itself as progressively double strand breaks increase as we age and their repair efficiency reduces when it’s needed even more. This brings us to the main observation driving this post:
Autologus Regulation: Nature has created this unit of mind boggling complexity and intricate design: the cell. All life forms on our planet are built from this unit. Incredibly this unit produces regulators that governs itself! It produces transcripts and proteins that regulate the regulators! So basically it writes its own biological destiny. Inherited genetic factors and lifestyle factors do also influence our biological destiny but only in a narrow range. The main driver continues to remain the inherited repository of information in the cell itself. The information it carries enacts it’s spatial organization and the same source of information also enacts it’s temporal organization. It transcribes transcripts that influence the transcriptional machinery and splicing machinery to decide whether to transcribe the entire gene or whether to transcribe an alternate version or whether to silence it. Some of those transcripts along with some of the translated proteins will make further alterations to the transcriptional decisions and splicing decisions in a continuing loop of self regulation driving the two major themes: development before adulthood and aging after adulthood. Besides these two main themes there are also changes that occur due to environmental stimuli. But overall unless they are extreme or fatal these are dominated by the two main themes. Some of these instructions are exchanged between cells through direct connections with neighboring cells or through the secretions of one cell entering another.
This self regulation is a very interesting process created by Nature which we rarely get to witness anywhere else. It’s easy to miss how incredibly remarkable is this technology developed by Nature and evolution. DNA carries information that when read sequentially builds us into an adult starting from a single cell and DNA also carries information that when read sequentially after puberty leads to gradual aging and death. We inherit both, our youth code and our death code, from the moment we are a fertilized egg. Let me try to explain it with an example. Let’s say a branch office is opened (cell) in which there is no manager but only an SOP manual – a standard operating procedure master handbook for the entire year that all the staff has to follow. It gives instructions to the HR dept on what kind of staff to hire. It has various printers that print out instructions daily giving tasks to all the staff. But imagine that only 30% of the employees actually do the tasks that produce the parts that the branch manufactures. 70% of the employees are getting instructions daily from the SOP to manage those 30% employees and what they produce by making changes in the master SOP that is daily giving instructions to those 30%. So the SOP itself has instructions to daily make changes in the SOP and thereby resulting in changes in the production. But those changes and their edits are so complex that it requires 70% of the employees just taking new instructions daily from the SOP and coming over and editing the future chapters of the SOP manual. These self edit instructions flow out sequentially as each new page of the SOP is read each new day of the year. Other branches also exchange data (secretome) and send their employees to also make edits in each other’s SOPs’. In the beginning there is tremendous excitement and new teams are hired and production is going full swing making wonderful products that sell very well (puberty). At its peak the training reaches a point where a team of employees can go and open another branch (reproduction). But once that is done the SOP begins to give out instructions to edit itself (autologous regulation) so that in forthcoming pages the production quality, hiring quality, raw material quality all of it is purposely, gradually brought down (aging). In the beginning it’s hard to notice but after some months of such gradual changes the consequences begin to show and unsold products start piling up. Cash flow is affected, salaries are affected. And what at its peak was a dynamic factory full of enthusiastic, productive workers becomes demoralized and stressed out leading to even further degradation at the branch creating a snowballing stranglehold from which the branch can’t escape and at some point it shuts down which is death. This is done so that there is no over crowding of the branches creating over supply which would destroy the company itself and also to ensure fresh young staff is recruited with every new branch which is enthusiastic and hard working.
Coming back to our biology there are two basic goals of autologous regulation: One is to build an adult from a fertilized egg. Second is to gradually make the adult age that would culminate with sufficient degradation to cause death anywhere between average lifespan to maximum lifespan of that species. One of the key reasons for this regular recycling every generation is because thanks to a paper last year by Dr. Vadim Gladyshev we learnt of this marvelous event occurring during early embryogenesis: all the inherited errors and insults of germline cells is wiped clean to make a brand new error free baby. Have humans outgrown this need to regular recycling? Can our intelligence help us to resolve the challenge of accumulation of biological errors and insults? As mentioned in my previous post I continue to take inspiration from certain life forms which seem to be immortal in permanent youth. I cite the Ginkgo Biloba tree because a researcher Dr. Richard Dixon has studied it. Even after a thousand years the tree that he studied still had photosynthesis efficiency and immune resilience of a 20 year old tree. Question arises as to how it’s able to do this. In almost all other life forms the DNA harbors temporal instructions that, as we read above, make changes to the spliceosome and the splicing factors and the transcription factors and the epigenetic marks which result in gradual collapse of our repair and recycling systems and ultimately death. How is Ginkgo Biloba allowing all the changes related to development to reach adulthood but freezing or blocking or erasing further regulatory changes thereby permanently remaining in youth? Many scientists wonder if we can prolong our youth would we still die when we reach 122 or 125? Ginkgo Biloba tree says no.
Two technologies are moving towards reversing human biological age. One of them is partial reprogramming of the cell using some of the yamanaka factors. This will in effect reverse the epigenetic signature, the gene expression and the proteome back to an earlier point closer to our youth. Question is does it also change the transcriptome? If not, aging related changes would again bring the cell back to an impaired state. If it does also turn back the temporal needle of the transcription program to where it was in our twenties then it would again take decades for the cell to get impaired again. The only catch is that this is the same path that cell would take if it were reverting back to embryogenic cell state and that state can lead to cancer. So does partial reprogramming fully protect against cancer? One can never know till many years later. Second technology is an arbitrage. Signaling and regulatory molecules circulating in the plasma of the young are injected into the circulatory system of the old. As those molecules enter the impaired cells they reset the proteome of that cell back to how it was in youth. Thereby rejuvenating those cells. This does not stop the legacy transcription in the cell which after a point would begin the degradation all over again. The question here is if the pro youth molecules are injected repeatedly would that at some point ‘flip’ the transcriptome to how it was during youth? If yes then it would take decades before the cell would get impaired again.
Human biology is incredibly complex. But does it have to be this complex? The complexity arises to maintain autologous management of the entire body. But can it be improved? Why do we need to generate voltage only from the food we eat? Why can’t we re-engineer so that we need only sunlight for energy like trees and plants do so beautifully? So much of our body’s parts are devoted to eating, digestion and excretion. If we did not need to eat to generate electrical energy we could reduce 50% of of our organs. Also why can’t we store electrical energy in our body/cell? We humans have created batteries to store electrical power so are we now ahead of evolution? Can we create alternate source of electrical energy in our cells? We have the intelligence to do it. Can we obviate the need for oxygen? We will also be able to edit the embryogenic process safely to alter our human organs and systems and form. I guess all of this is possible in the distant future. It will all start with our control over biological age.
58 comments:
Amazing! Thanks for giving the time to share this with the world. It is a fine summary, and it taught me a lot, and refreshed my inspiration.
Thank you, so kind.
Excellent summary, raising intriguing questions.
I never get tired reading your amazing articles. You are outstanding!
Thank you Leo! Very kind of you.
How all this regulatory factors are connected to the faster/slower growth of the species and mTOR in long lived large mammals?
Hi if you referring to variance in the rate of aging and lifespan between different species -especially long lived species and the role these regulatory factors play, here is what I think: Each species undergoes various adaptations during their evolution to survive as a species. These adaptations create heritable changes in time to maturity, maximum lifespan, etc. long lived species have adapted better. We too have received a great gift from our evolutionary journey: higher intelligence. This adaptation may have been arrived at out of improving chances of survival but see where it’s taken us. I haven’t seen any long lived species where a more resilient mTOR homeostasis is the sole cause of their above average lifespan. From the works of Dr. Gorbunova we see systems like resilient autophagy and DNA repair as some of the discovered advantages giving them the longer lifespans. The autologous regulation acts as a primary operating system that runs us and also effects aging to kill us.
Thanks. But are the regulatory factors made and changed as per cell growth/dividing and then quiescence/senescence? I mean why their ratio changes at first?
It’s not just the ratio that changes even the factors itself - some transcripts stop and some new ones begin. Cell division or senescence are not the causes of these changes. They are cellular processes or forms as you know. There is a heritable ‘program’ in our DNA that decides which portion of itself will be transcribed. A minority of the transcribed would go on to produce proteins but majority have the function to regulate the epigenetic framework, histones, gene expression, protein production and transcription itself. That’s what I pointed by the title of this essay that they self regulate. Some of the transcripts and proteins decide what gets transcribed next and that resulting transcription decides what are the next round of transcripts and proteins and their resulting changes. So it’s a constant self regulating process from birth till death. What causes the changes? A small portion is reactive to environmental factors but majority of the changes are caused by our inherited program in our DNA which unspools throughout our lifestages. Hope that answers your question.
Thank you. Only question left to me is why you still think death too is programmed? Okay, development is programmed and after reproduction age is over, the system is out of work because of the ongoing processes. Is there any proof that it’s not just an error and is an intentional one?
Yes there is evidence of deliberate changes that come in patterns for every life form. The bioage clocks for example: Horvath’s clock measures changes in methylation over lifespan. These changes are so predictable that he could build an accurate clock. So if he received an anonymous saliva sample from the DNA methylation pattern his clock would accurately predict the age of the person. Is this possible without a predictable pattern of changes occurring regularly? Then there are papers. I will cite two of my favourites: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546525/
Here Dr. Morimoto shows us that just after puberty there is deliberate collapse of protein production support machinery by 70%! Everyone knows that protein quality and viability keeps dropping as we age with unfolded aggregates causing neurodegenerative diseases for example. If it was accumulation of errors then it’s support can’t suddenly collapse after puberty for everyone. Proteins are what run our biological systems and their undoing leads to tissues and organs losing their viability over time and ultimately reaching a point of death. Second paper: https://www.nature.com/articles/s41591-019-0673-2
This is by Dr. Tony Wyss-Coray of Stanford. He shows us that through out our life there are groups of changes occurring at similar ages for all of us. Such changes can’t occur for all at similar time points unless it’s a program. And what do these changes progressively do? Bring down viability of proteins, DNA, cells, tissues, organs and all our repair systems ultimately reaching an unviable point of death. Hope this gives you the evidence you were asking about.
Thank you. That makes sense, however, even if it’s not strictly a program inserted into us to death sentence, it’s still possible to have such an identical maximum lifespan in species. Let’s say whales develop slowly. Their machinery also deteriorates slowly and therefore, death happens slowly. Do all whales die at the age of 100? Do all humans die at the age of 122? Some die 40 years earlier, at the age of 70-80, because their machinery could deteriorate sooner and cause any of the hyperfunction you call selfish gene(programmed death).
I am glad you have such interest in aging. Lifespan variance amongst different species is due to unique evolutionary adaptations that each species ended up for proliferation and survival of the species. But almost all the life forms inherit a program for a want of a better word that enacts changes at approximately similar lifestage points that initially lead to development and later death. Within that range there differences for two basic reasons as each individual in the species has inherited minor unique genetic characteristics and due to lifestyle differences. On the former for example some of us get puberty at 13 and some as early as 11. Or some have inherited a predisposition towards weight gain or cardiovascular disease in the family. With regards to the latter Nature has created a system that rewards productivity and reproduction and penalizes the opposite for the survival of the species. So those that exercise regularly may have longer lifespan than those that avoid it at all costs. But even the one that has wonderful lifestyle still eventually dies as the program continues to chip away.
I think we both mean the same thing. You call it intentional program and I call it program like autopilot that finally crashes. Only thing is that you think we age and reproduce to adapt and save the species while I consider that Earth is critically tough and based on the environment-food, air, oxygen, predation, infection-species have to reproduce sooner or later and therefore, age sooner or later, since an individual can die of any of the causes above.
If environmental factors on Earth cause aging and death then it should apply to all living lifeforms on Earth right? But there are species that are nearly immortal due to fortunate adaptation that also prove aging program from another perspective. Citing these 3 papers for your reading pleasure: https://www.karger.com/Article/Pdf/215589
https://www.pnas.org/doi/10.1073/pnas.1521002112
https://www.pnas.org/doi/10.1073/pnas.1916548117
The last one is about a tree that lives thousands of years in youth. The photosynthesis efficiency, immune resilience of a 667 year old tree is same as 15 year old tree as studies by Dr. Richard Dixon and colleagues. So amongst the evolutionary adaptations that gift longer lifespan to some species
some very rare species win the lottery and do not age or age so slowly that it’s negligible. Our biology and it’s potential are fascinating. Human intelligence is another evolutionary adaption that is a lottery win.
Thank you for the papers, appreciate. If environment had no influence and if it were strictly a program, then I do not think we would see lifespan doubling in the animals in captivity. Why there are some reported cases of dogs living up to 29Y if their fixed programmed lifespan is 12-16 years? Why a wolf lives twice as much in captivity as in the wild? I think in safer environment, hyperfunction happens later. If it were about the species survival and adaptation, why would nature give that much different lifespan possibilities to almost the identical organisms?
Environmental factors and in humans lifestyle factors do influence lifespan but it’s smaller versus our inherited lifecycle program. Basically in captivity many predation, accident or infection related events are prevented. For 5,000 years of recorded history humans had an average lifespan of 35 to 45 years. But after living in urban enclosures and especially after the discovery of antibiotics our average lifespan has doubled too. That does not change our program to deteriorate and die and our maximum lifespan hasn’t been breached in those 5,000 years. What captivity or urban enclosures change our the infections and deaths due to wild animal encounters, etc.
Thank you. Seems like we are taking about the adaptive hitchhike model, a pepper by Vadim Gladyshev. The adaptive hitchhike model suggests that the selective constraint acting on the genomic region associated with adaptation and fitness is largely responsible for non-random beneficial pro-longevity effects. For example, patterns of selective sweep across loci of close proximities were reported for adaptation to altitude among the Tibetan population and a further association was found between longevity and hypoxia response in this same population. In other cases, natural selection might act on an already existing but neutral mutation through a sweeping selection, therefore, if neutral alleles responsible for lifespan extension are close enough to other alleles under selection, the chances of recombination are slim, and together, they become fixed in the population.
I just do not understand, why nature would want lion to evolve more years like 14-16 years and give the lifespan for 14-16 years and why a tiger just 8-10 years? They are super closely related.
Yes agree with you on adaptation 👍 Regarding Lion and Tiger it may not be direct action of Nature. Over millions of years there has been incredible evolution of the tools used by cells to collectively organize. If you have seen Dr. Michael Levin’s video presentations the Bioelectrical memory that helps organize a 3D life form can have errors that can lead to different life form. Genetic mutations with survival of the fittest too has all contributed to a huge variety of different life forms with different characteristics. So although Lion and Tiger may share most of their genes their evolutionary journey allowed different max lifespans for each of them. What I want to study when we have more financial resources are the life forms that through mutational and adaptation lottery have been able to opt out of aging to live for thousands of years in youth. Studying those mutations and adaptations may change the future of humanity.
Thanks!!! Where do you think all these regulatory elements are born? Are they controlled by mTOR and other cell growth kinases or by oskm and other transcription factors?
mTOR is a very important protein kinase and acts as a modulator between growth and repair/recycling. It is more like a sensor and does not give birth to regulatory elements. OSKM are powerful transcription factors that can revert a cell to its pluripotent state. Regulation is conducted by non coding RNAs that are transcribed from majority of our genome. They regulate at all levels in the cell: before gene expression, during gene expression, after gene expression but before translation, after translation, they modify histones, etc. This essay is about the incredible fact that they also regulate themselves: non coding RNAs and some proteins regulate transcription and spliceosome which decides which coding and non coding RNAs are transcribed next!
Wow. Incredibly complex. Thank you.
You are welcome! And thank you for such interest in aging biology making us both co-compatriots of the same community :)
I have just read a very interesting paper on PA vs Non-PA. It’s obvious how self destructive all the organisms are. Akshay do you know how the program and pre installed death is connected to molecular hallmarks of aging? There was mentioned that endogenous total tissue antioxidant systems and nuclear DNA base excision repair (BER) correlate negatively (or not), with longevity across species, meaning that there is less or similar defense and repair in most cell compartments of long-lived species, likely because decreasing the rate of generation of endogenous damage (less mitROSp), reducing cell membrane sensitivity to oxidation (e.g. less membrane fatty acid double bond index, DBI), and various other endogenous aging mechanisms are a strategy to increase longevity. However, it seems that specific adaptations at the mitochondrial level to this general strategy of defense have been added in endogenous organs. Thus, the mitochondrial form of the superoxide dismutase antioxidant enzyme (MnSOD) activity and protein amount, while not the cytosolic form CuZnSOD, shows a positive correlation with longevity in mammalian tissues and fibroblasts. Does it mean that aging hallmarks like mitochondrial function affect how soon the individual matures and ages or are these just connected to the self running program?
If you read my previous posts on this blog on Mechanism of Aging and Update on Mechanism of Aging it will give a detailed answer to your question. But basically as Professor Hayashi of Tsukuba University shared with us: rate of damage is more or less the same between young and the old what changes as we grow older is rate of repair. Both ROS and Double Strand DNA breaks occur when we are young but are easily neutralized or repaired respectively. Mitochondria too is a victim of this same program and so will face the consequences of rising mtROS for example. The program of aging or the transcriptional changes of regulatory non coding RNA manipulate proteins needed to activate repair to dial down their production progressively. This begins our journey of snowballing unrepaired damage till we die. On top of this highly conserved recycling code or death code in almost all living forms there are individual adaptations and mutations that change the fall of the rate of repair. This is the reason for varied maximum lifespan between species. 99.99% still die but some very very rare life forms win the lottery of adaptations and mutations to figure out a way to allow the inherited program of development but stop the program of aging. We humans did not win this lottery through evolutionary adaptation but are gifted with another very very rare advantage: superior intelligence. We can use this to replicate the youthful immortality of those rare life forms that won evolutionary adaptation lottery. Is our intelligence capable of such a complex task? Yes it is.
Many thanks Akshay. I will read your previous essays thoroughly.
Amazing!! Thanks for sharing your thoughts! It’s incredible how all this information is unspooling and becomes an organism. There is one thing: As Levin says, DNA information is not enough and there is a bio electro memory. May I ask you if you agree? If this is right, we may need to stop all the research experiments we are doing today and start looking for the information memory software.
Hi I am a big fan of Levin’s research. He opened up a whole new layer of biology we did not know existed. Research on epigenetics and cell secretome etc. must go an as that’s complimentary to the research on bioelectric memory. It would be interesting to see where they converge. I absolutely want to know more about bioelectric software so best wishes to Levin.
Thanks for your reply. It may be an interesting avenue for the regeneration field but how would it reverse aging itself? He is too much into physics and thinks genome even if completely messed up does not matter while a new paper just came out of bowhead whale and DNA repair.
High rates of apoptosis are likely to accelerate age-related decline through permanent cell loss, especially in post-mitotic and irreplaceable cell populations in tissues such as brain and heart. Because excessive cell death or arrest is incompatible with organismal survival, baseline levels of DNA damage must be repaired. Given that most cells in mammalian bodies experience multiple endogenous DSBs per day, faithful repair of these breaks is critical. Tumor suppressors, apoptosis, and senescence all appear to pose costs to the organism and represent tradeoffs between cancer and stem cell depletion leading to age-related degeneration. Simply shifting the balance from apoptosis/senescence to survival and repair could be detrimental if not also coupled with increased fidelity, as evidenced by the frequent upregulation of DNA repair pathways in cancer cells. However, evolutionary improvements that couple high efficiency with high fidelity, as found in the bowhead whale, would promote long-term tissue function and maintenance at both the cellular and genomic levels. Efficient repair could reduce loss of valuable post-mitotic cells with age and reduce mutations in dividing cells.
Bowhead whale has really a superbly accurate and efficient repair, almost no deletions and insertions. Plus a retroduplication of CDKN2C, resulting in significantly lower population doubling time. If DSB’s, causing the destabilization of both-Genome/Epigenome is really an upstream cause of aging, then bhWhale like CIRBP or inhibition of DREAM complex should fix everything, but I still do not know any study showing a significantly enhanced DNA repair extending maximum lifespan dramatically. Not even doubling. Maybe Akshay will answer it better.
We lose cell polarity during aging (and also in cancer). Michael Levin is researching using ion channels and Bioelectrical signals to reinstate cell polarity which may have major implications. But he does not dismiss the role of genomic instability and other causes of aging. Whatever I have read and heard from him he says loss of bioelectrical memory is a major cause of aging but not the only cause.
Leo what a brilliant analysis! There are multiple cracks in the glass pane and unrepaired double strand DNA breaks is one of major cracks but not the only one. It’s a very significant cause of damage because genomic instability will lead to loss of cell identity, cell death or worse even senescence or cancer. But that is also true for other causes of damage: inefficient protein production machinery, autophagy, antioxidant defense, etc. Nature kills by hundreds of cuts.
Thank you Akshay, exactly what I think. Generally, if I may say that I do understand some aspects of systemic aging, it’s the deserve of yours only! I am reading tens of papers a day, I am aware of the concepts of the scientists considered pioneers today, however, I do not think anyone is even closer to your understanding in biology. Maybe Tony Wyss-Coray, thanks to his later paper on “Characterizing expression changes in noncoding RNAs during aging and heterochronic parabiosis across mouse tissues”. Some people think aging as an antagonistic pleiotropy, some do it intentionally for the financial strengthens. These include mitochondrial ROS production, DNA modification and repair, lipid peroxidation-induced membrane fatty acid unsaturation, autophagy, telomere shortening rate, apoptosis, proteostasis, senescent cells, and most likely there are many others waiting to be discovered. However, all these well-known mechanisms work only or mainly at the cellular level. Although it is known that organs within a single individual do not age at exactly the same rate, there is a well-defined species longevity and thanks to your Autologous Regulation, I am more than amazed when I think how the body coordinates every detail and knows its biological age.
Leo you are too kind. Yes I get the same feeling: totally awestruck and bewildered at the intelligent complexity and fidelity of our biology.
Akshay, Interesting info on the aging process as usual. I hope your work on E5 is progressing. Did the skin trial results end up being good? Thanks
Hi who is this? Thank you. Skin trial wasn’t conducted as per protocol. So now we are planning to conduct with a reputed dermatology CRO.
Ok Thanks. Its Mike Best someone who comments on Mittledorf's blog sometimes with reference to E5.
Got it. Thank you Mike.
Akshay, may I ask how you are conducting the trial? Lubrication once (As Dr Katcher did) or multiple times? Also, mix of females and males or just males? Also, I would guess speed to market is key to secure more funding for the E5 injection research (if successful that would easily fund your other research). Any timings you can disclose in terms of when you expect the new E5 topical trial to be finilized? Thx, Carl
Hi Carl, We will be trying various combinations so applied once, applied everyday for 3 weeks and in between. It has to show dramatic results for us to invest in production and marketing. We have to wait for the results and then decide. We hope to launch it by August. Thank you for your interest.
OK, thanks. Given the confidence that Dr Katcher expresses I am sure you will find the magic blend. Good luck with the trials.
Even Dr. Katcher believes that unless we have definite human clinical trial evidence he wouldn’t want to sell that product. So yes fingers crossed. Thank you Carl for your best wishes.
Hi, Akshay. Fantastic post!
I'm SO glad that I thought to Google your name today. I din't know that you had a blog!
I didn't care for Mittledorf's most recent post on your and Harold's work. So I'm glad that I found a more direct source on your progress.
I both practice and teach meditation, Tai Chi Quan, Qigong, Neigong, and Neidan aka Chinese Internal Alchemy, and have done so for the past 27 years. I know that aging can be both slowed down and even reversed.
The work that you, Harold, Vince Giuliano, Dr. Sandra Kaufmann, Dr. Kara Fitzgerald, William C. Bushell, Mikhail Blagosklonny, Dr. Alan Green, Konstantin Pavlovich Buteyko, Borut Poljsak, and Jeff T Bowles have done dovetails with everything that I've learned over the decades. The aging process can be slowed and reversed. Taoists, Buddhists, and Yogis have done it for centuries. We can reprogram our epigenetic expression through a combination of meditation, behavioral modification, diet, exercise, alteration of our breathing pattern, and supplements.
What you and Harold have come up with is a faster way of doing this process, which usually takes 18 to 20 years, according to Taoists texts on Neidan aka Chinese Internal Alchemy.
I look forward to reading about your continuing research. I also look forward to the day when E5 will be available for all.
In the meantime, I'm ordering a couple of bottles of Neel! :D
Cheers!
Derrick
Hi Derrick, thank you so much for your kind words of encouragement. I am fascinated by your devotion to Chinese Internal Alchemy! 27 years! Wow. I wish I can enroll in your class. Where do you teach? Some of Indian/Chinese ancients texts are so profound and even scientific. Thank you so much for purchasing NEEL! If you do not mind please leave a review after you have used it daily for a few weeks.
Okay, I will!
I'm based in Philadelphia, PA. Do you have an email that I can send my info to?
atomicblissventures at gmail dot com
COOL! I'll reach out today! Cheers!
Watched the recent 3 epsiode interview with Dr Katcher on Modern Healthspan just now. He seemed not be be fully updated on the progress of the trial of E5 topical (more focused on the theory as I understood it). Any news you can share Akshay?
Hi Carl, Harold is quite intrigued and excited by what happened with his right hand. He is aware and guides the human clinical trial we are preparing for at the same CRO led by the Professor of Dermatology at McGill University. We are hoping to schedule it as soon as we launch our upcoming trial on old dogs.
Hi Akshay, I hope you and Harold are doing well. I wanted to reach out and share my concern regarding the difficulties I've been facing when trying to post on Josh Mittledorf's science blog. It seems that many of us are experiencing this recurring Google verification error message. The blog has always been my go-to source for updates on your groundbreaking work.
Given the circumstances, I was wondering if there's an alternative platform or any other way I can stay updated on your work and progress. It's important to me because my parents are getting older, and I truly believe that E5 could be their only hope for longevity. Other approaches I've come across seem to be considerably less effective.
Thank you for taking the time to read my message, and I genuinely appreciate any guidance or suggestions you can provide.
Hi William thank you for following our research. I too am facing this problem while trying to post replies at Mitteldorf but it seems the problem is with Wordpress and there is little he could do to help resolve it. Yuvan will be making press releases for every major scientific development. Our next should be on our 10-11 year old Beagle dogs trial. Wishing good health to your parents.
Hi Akshay, I stay on the lookout for anything that comes out of here, Josh Mitteldorf's blog and LinkedIn, I also occasionally check out Yuvan's website and Youtube channel; is there any other place where some fresh info could be posted and that I've missed, or is it fair to assume that I'll see every public news with my current sources? And as always, thank you for being so transparent about the research and "available" to random people like me.
Hi UnUtilisateur yes you are well covered with those sources. Next news will be about results of our dog trial. Thanks for your support.
Hi Akshay, is the E5 topical trial running in parallel with the dog trial?
No
Any more color to that possibly? E5 topical no longer anything we should hope for?
Sorry Carl nothing more to add at this point. But we will have some exciting news to share in April/May on E5 trials.
Looking forward to that!
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