The selection as cause of decay/aging hypothesis
I'm not sure if someone has stated this hypothesis in the past, but this is a summary of one of the possible keys towards undoing decay, that I've thought may work, based on the substantial quantities of information I've absorbed in the related fields. These ideas will be refined further as more information, suggestions and data that validates or invalidates portions of it is gathered, but I want to share it now, even though it may be in an unelegant unfinished state, and not explained in as graceful enough a manner as could be(I often mix and match information, and go mostly from memory, so there's no citations, though it's obviously thanks to the work of countless researchers and their sharing of said work that I've come up with these ideas, there may be some mistakes as a result of writing from memory, and some of my explanations may not be clear enough, so bare with me.).
It is a rather long read, so again bare with me, but I'm sure some may find it interesting and amidst the ideas presented, even if some turn out to be flawed, some useful ideas may remain and be of benefit.
The selection as cause of decay/aging hypothesis
The key to immortality, I believe, is selection. The germ line is immortal, that is a fact proved time and again by the persistence of complex life for countless hundreds of millions of years, by carefully examining it we can finally see what evidently bestows it with such immortality, the long sought out key factor towards immortality. It has seemingly been right in front of our noses all this time, we just didn't seem to notice it, despite basically describing it time and again. Natural selection is what prunes the ever occuring defects, and allows the viable progeny to remain, allowing for the species itself to persist, it is that which grants immortality to the species by culling the defects and allowing the functional to prosper.
The human body, and those of all organisms are in effect like small genetically crafted ecosystems. The various cells perform various defined roles in this ecosystem, and together their efforts allow for the persistence of the organism. Nature itself found the way to tap into the enormous power of cellular machinery, to bring about unheard of lvls of order, multicellular organisms, and the pinnacle of it all, the most complex object in the known universe, the human brain. In the uphill war agaisnt the tides of entropy one more battle was won by nature, from unicellular to multicellular, a greater lvl of order and complexity came to be.
What did nature do? How did it manage to organize and bring about complex persisting order? It did so, it unleashed but a portion of the immense power of the cell, with a counterintuitive solution, by crippling it. The evolutionary potential of many cells was hindered, the cells were limited to particular roles or functions, and their potential to survive outside those crafted niches where they performed their roles diminished(even the germ line cells have trouble surviving outside of their niche in the reproductive organs, through which they move while performing their functional role in reproduction.). Even the replicative potential of vast numbers of cells became limited to a set number of divisions, all to carry their function of increasing the probability that their sisters, carrying faithfull copies of the same genetic code would prosper. The cells were crippled by vast and ever more powerful regulatory mechanisms, that went so far as to destruct the cells themselves if they became damaged and began malfunctioning or attempted to escape their assigned function.The cells worked with one another to ensure this regulation was enforced, certain factors even had to be there or delivered for proper functions.
But alas this regulatory cascade stopped short, nature need not preserve the organism indefinitely, just long enough to reproduce, thus the power of immortality was bestowed to the species but not to the individual organisms composing it, selection would occur but at the organism lvl, so that evolution would occur at the group lvl as particular traits became more or less common through the population. Cells could malfunction and persist, cells could even escape their role and wreak havoc on the small well crafted ecosystem known as the organism. Defective cells and defects would persist, nature only brought the power of natural selection inside the organism, into the tissue lvl to a limited degree. The immortality that existed at the species lvl, and in larger ecosystems was not brought about to the organism itself, it left the job half done.
Let me give an example of the power of selection, bacterial populations in the wild are composed of exponentially simpler cells, yet bacteria as a whole can continue to exist indefinitely. Can the individual cell exist indefinitely? Well alone, if we think about it enough, no it cannot dmg would eventually and inevitably occur in the genetic program, such dmg would accumulate, most would be neutral or negative with little positive dmg, and it would eventually destroy the viability of this single lone cell. But a population of cells need not suffer this fate, it would be like a population of replicating nanomachines(actually, that is what most in the know, would say it is.), dmg would occur in all, but even though most dmg would tend to be neutral or negative, a small portion of the dmg would actually be positive(aka confer beneficial change at the genetic lvl.), an inevitable statistical truth. While defects accumulated rendering many defective, the portion of still viable replicating machines would replace the defective ones, in effect taking their place, time and again, this would continue to take place, and the population would remain viable. Aha, you say!!! But aren't each of those cells individually and each of their progeny individually with this beneficial dmg, mutations, subject to the same statistical laws, aka most of the dmg they'd get would be negative or neutral and each of them too would eventually lose viability along with its progeny. Well, actually yes it is true, if you think about it too most of the dmg is neutral or detrimental, the population will decrease in fitness and get screwed, as all individuals composing it are subject to this and we'd assume each will tend to lose more order at the genetic lvl than it gains over time(Think about it EACH individual cell is receiving more negative dmg than possitive dmg, this is inevitably increasing its lvl of entropy, disrupting the carefully orchaestrated molecular order needed for life. And each individual progeny of this cell is also subject to this same effect. Eventually, could take a long time, viability should inevitably be compromised in the entire group given a certain rate of dmg.).
Hmmm... but wait, wait a minute, that can't be right, you might say. I just said life itself is immortal and I've just said natural selection confered this immortality, HOW CAN WHAT I SAY BE TRUE, if there seems to be a logical contradiction. That contradiction arises, because I've purposely left something out of the equation, I've left out a very simple fact whose magnificient effects have been somewhat long overlooked. That little fact is genetic exchange. Genetic exchange between cells would bring about an even more complex interplay, genes with beneficial mutations would not be stuck in a sinking ship, that is amidst an ever deteriorating group of genes. Genes could spread about, and as they did so, the marvelous miracle of extropy would take hold.
Genes which'd received beneficial dmg and those with detrimental dmg would be moving throughout the population. While once beneficial mutations may've been stuck amidst a sea of mostly detrimental and neutral mutations to nearby information, with the latter two exceding the former in occurrence, now they would be free. These pieces of information would spread, and while the proportion of genes with novel beneficial mutations would initially be smaller than those with novel negative mutations, it would not remain SO FOR LONG. These genes, or pieces of information, with the rare beneficial mutation, as they spread throughout the population, they would increase the fitness of the cell in which they land, the detrimental ones would not they'd do the opposite. This would lead to the increase in order, due to the increased efficiency they conferred to their replication vessels, over the long term any gene with beneficial dmg which may've initially been rare, would become ever more common due to receiving the exponential benefits conferred to it by the enhanced replication of their hosts. While those with detrimental dmg diminished in replication efficiency, and these despite been constantly created in greater numbers than genes with beneficial dmg, would be outcompeted by these latter genes[with beneficial dmg] over the long term, due to said effects on replication potential.
An even greater miracle occurs as multiple genes with beneficial dmg happen to congregate. When more than one gene with beneficial dmg managed to land in the same replication vessel/cell, the cell's replication would be further enhanced maybe even synergistically by the effects of these two or more genes, and the combination itself would become more common as it outcompeted those with just one beneficial gene or the other. While the event itself was random and it would initially be rare for any novel beneficial mutations to come together, and more likely that detrimental ones would come, the situation would change over the long term. The initially rare beneficial mutations would spread becoming more common due to enhanced replication, as stated, and while the unceasing torrent of genes with negative/neutral mutations moving about would continue indefinitely, another rare novel beneficial mutation would have a greater likelyhood of landing on one of these cells with the now more common beneficial gene than it would have when that one was novel too, and thus this once rare event becomes more likely.
Whilst all the cells continue to each individually accrue mostly negative and neutral dmg with little beneficial dmg over time, and thus most genes they've tend to either remain the same or deteriorate with few genes improving in performance(again, causing entropy to increase in each individual cell and in each and every individual progeny cell), the proportion of the genes in the gene pool with beneficial dmg/increased function continues to increase, by the aforementioned effects any single beneficial mutation or combination of such has of ever increasing replication potential/efficiency, something brought about by the freedom of movement the genes get through genetic exchange. Which make novel and rare beneficial mutations eventually common in the population and thus more likely to group with other newer rare beneficial mutations that happen to arise in the population, that is brought about by the movement of genes throughout the population. This movement of genes, of information, is essential even for unicellular organisms, it is essential for the continued existence of life, it is the process that grants life its immortality through selection. Information like all else in this world is subject to increased disorder within a closed system, only in an open system, can order increase.
So as said natural selection occurs due to the exponential spreading of each and every individual beneficial gene or aggregation of such throughout the population due to genetic exchange. As this beneficial gene or gene group enhances the replicative potential of every host it happens to land on causing it to outcompete those organisms without it, which make it more likely any other newer rare beneficial gene jumping around will get together with this prior originally rare but now common gene or gene group, and so on ever more increasing the proportion of beneficial genes within a population and countering the ever present and more commonly occuring(in each and every organism) dmging mutations. Detrimental mutations while ever arising any novel such reduce the replication potential of their original host, the progeny of such and any organism it happens to jump to, and so novel detrimental mutations tend to eventually become exponentially[ due to reduced replication efficiency over the longterm] rarer, especially the worse its effects are, they remain only as they manage to persist due to not being detrimental enough to outright dissapear or simply arise again after dissapearing.
So how can we use this knowledge to make an organism immortal. Recall that life itself is immortal, and as we've seen barring any catastrophic change, ecosystems can persist pretty much indefinitely. As said the organism itself can be considered as a smaller ecosystem, a small community of diverse cells, so it too should hypothetically be able to persist indefinitely. We know, as I've said in the past, that even small populations of individuals with large generation times and few progeny can persist pretty much indefinitely. The only way they can do this, given that genetic damage is inevitable and most of it is negative and little is positive, is to greatly diminish the potential of mutations to occur(obviously this can't be stopped by natural selection in an ever changing world, as without change in such an ever changing world the particular species would be screwed.) and more thoroughly limit the capacity for negative mutations to spread, while still keeping the exchange of genetical information(without which the species' indefinite viability is compromised.) occuring to allow for the rare novel beneficial mutations to mix with other older and more common groups of beneficial mutations.
Exchange of genetical information is necessary between individual organisms, due to the fact that species need to adapt to an ever changing world, and thus a certain rate of variance in functionality must be allowed to persist in the population by allowing functional deviations of any kind, due to dmg to spread about, selection will cause mutations that increase fitness to be spread, to persist and those that decrease fitness will simply be culled by selection. But the rate of dmg must be controlled under certain circumstances, the greater the generation time and the smaller the number of offsprings, the lower the dmg rate must be such that the progeny itself receives very few mutations, such that selection whose power has been partially limited by reduced population and progeny size can still manage to cull out detrimental mutations, as they've become fewer/rarer, if populations become excesively too small selection's power of sustaining species immortality will be compromised too much and defects will begin to spread more easily reducing the viability of the group*(inbreeding). Thus by limitting the rate of dmg enough even decreasing the ability to exchange information, and the number of offspring, the power of selection to maintain indefinite fitness throughout the generations can be maintained. While once dmg to the genetic information was likely to accrue faster requiring smaller groups of genes to move about, which themselves were likely to receive only a portion of this faster occuring dmg, now that the entire genetic material is better protected larger groups of genes can viably perform the same function, of moving about, smaller groups did in the past, since they were unlikely to be dmg'ed thanks to the enhanced maintainance and repair mechanisms that had been developed.
With a reduced enough rate of dmg, the need for information exchange can be greatly reduced, that is why large rather than small chunks of information can be exchanged safely(since the large chunks haven't sustained significant dmg), a need reduced from one of preserving functional capacity to one of allowing for new combinations of variations to occur that are advantageous to the species. Thus even clonal reproducing organism with little if any gene exchange are viable, if limited in ability to adapt, due to most of their information being preserved long enough for viable copies to be made. The rate of dmg is low enough that a portion of the organisms will retain nigh perfect functional capacity long enough to replicate, thus creating at least another faithful functional copy of most of the information. The rate of copying/creating more faithful information will exceed the rate of information corruption, thanks to the limited rate of dmg. Even organisms with nigh perfect functional copies will themselves have their information corrupted over a long enough period of time, but it will have made enough faithful copies prior to that event that it wont matter at the species lvl. The newer organisms with faithful copies will continue to replenish the group indefinitely as they manage to copy their information faithfully before their own copies are corrupted too much, the more functional/fitter amongst their offspring will prosper and replicate more than their less fit offspring thanks to selection, sustaining fitness indefinitely(assuming no drastic change occurs as the ability to adapt to change is compromised due to a state of low or no genetic information exchange. Increasing the rate of information exchange in these circumstances can allow for adaptation in the face of changing environments.).
Individual cells are extremely versatile, yet by working alone they cannot easily achieve immortality due to the inability to carry thorough selection mechanisms at the lvl of the molecular parts that compose them, defects could accumulate(particularly the genetic information in the molecular tape... though with multiple internal copies of such information and thorough error correction mechanisms carried with such, this hypothetically might be delayed indefinitely. Though more than two copies of any particular piece of information would probably be needed to allow for thorough enough error correction to allow for indefinite delay of detrimental dmg accumulation. In any case adaptation would be compromised and such cells are unlikely to occur naturally in an ever changing world.). That is while it can constantly recycle the molecular machinery, the instructions for making and recycling such would eventually accrue dmg, mostly detrimental dmg, without some very thorough error correction mechanisms(which'd more probably than not require more than two copies), but working together they can achieve immortality even without exchanging genetic information. They can do this in the same way clonal organisms can persist for prolonged or indefinite amounts of time in their particular niche, while the environment is stable, without resorting to substantial information exchange during such periods of stability. Like some organisms fullfilling their roles in their niche in a particular ecosystem indefinitely, organisms that reproduce clonally, cells too can fullfill their roles within the tissues/niche of the organism/genetical-blueprint-crafted ecosystems indefinitely.
Selection can be used as the means to carry about what is effectively error correction at the cellular lvl. By substantially increasing the robustness of the internal regulatory mechanisms it should be possible to ensure that the cells are crippled enough that they can't escape whatever function they're assigned(be it as stem-cells in regenerative pools or carrying about particular functions in a particular organ). It should be possible to modify the cells so that there is no statistically significant way they can survive should they accrue any form of dmg that compromises their function substantially. Once this is accomplished any cell that accrues any substantial form of detrimental dmg in any gene related to its function will simply decrease in replication potential and will eventually self-destruct as it decreases in functionality. The ways to accomplish this is by making all of the components work more tightly with each other, by tightening regulation mechanisms, and thus by limitting the evolvability of the machine, which should make the cell die rather than hang on should it deteriorate in function.
A tissue can be engineered such that the factors it receives along with the interactions that take place within it promote the proliferation of the more functional cells within that tissue above those cells which may've become less functional, while causing the latter to self destruct if they deteriorate enough. By doing this the more able to carry about its function the cell is the more it will outcompete lesser more defective cells. Cells that have accrued too much dmg and have become too defective will simply self destruct(any other action such less functional cells take and it will probably interfere with any such function preserving mechanics and will probably negatively affect the whole organ and such throughout the organism will affect it as a whole.). This is possible if the cells have such repair and maintenance mechanisms that dmg accumulation is delayed enough to at least allow some highly functional cells to replicate allowing for two daughter cells that maintain function(the same thing that allows for persistence of clonal reproducing organisms, and organisms with reduced genetic exchange due to reduced number of offsprings and population size). So long as functional cells are being manufactured with little if any defect, faster than cells are deteriorating(which would occur slowly with a slow enough rate of avg. dmg), the intra-tissue selective factors/pressure will allow the more functional cells or those whose dmg has been neutral or with the rare beneficial mutation to their function to outcompete the less functional cells, as time goes on the cells that have lost the most function are culled by the selection process purifying the tissue from defects that may impair tissue function, and overall cell population fitness is maintained indefinitely as it is with cell or organism populations in the wild. This creates the same positive selection mentioned to occur with beneficial genes and organisms with slow rate of dmg but at the cellular lvl, due to the aforementioned diminishing of the rates of dmg, to the point that most genes in the cells are undamaged before a particular replication event, such low rates of dmg allow at least one of the daughters to remain as functional as the original, and so too some of the descendant progeny, those cells that retain function or have enhanced function will replicate more and replenish the cell pool with functional cells while at the same time selection culls the pool of cells that have accrued to much dmg and've exceeded a certain threshold. Information is being faithfully copied again and again, preserved, faster than any individual copy is deteriorating. Genetically orchaestrated forces within a tissue will perform the same function limited resources perform at the species lvl, creating a selection force that allows for sustained fitness within a particular niche/tissue by the proliferation of the fitter/more-functional organisms/cells and the culling of the less fit/less-functional organisms/cells.(Something that I believe already happens but to a limited degree in multicellular organism, to a greater degree the larger and more complex the organism.)
A similar mechanism may or may not occur even at the mitochondria lvl. IIRC, a recent study(which most here read.) suggested dmg to mito-dna repair mechanisms resulted in increased apoptosis, an increase in defect culling as more cells are exceeding the defect threshold. But an even more recent and highly controversial study(which will require further studies to confirm or invalidate it.) suggested mitochondria might migrate from cell to cell. If this turns out to be the case mitochondria selection can take place akin to the aforementioned event occuring with regards to genetic exchange in a particular cell population. Mitochondria would spread throughout the tissue from cell to cell, and any cell with less effective mitochondria would be less able to replicate, if too much dmg was accrued that particular group of mitochondria would be eliminated from the tissue. As the mitochondria moved about those cells with greater number of functional mitos would outcompete those with less functional mitos when it came to proliferating in the tissue and performing their functions well enough to persist in the tissue, thus they'd be able to spread even more. Those cells with less functional mitos would be less effective at replicating and performing their function and thus more likely to self destruct cleansing the tissues from any high in defective mito haven/cell. The replication and function benefits warranted by functional mitos would ensure these aided survival and replication(which would make them more common in the tissue and more likely to spread about than defective mitos that would continually arise but with time any such novel defect would also continually be culled from the mito population.) of their host cells, while the less functional the mito became the more it'd do the opposite until eventually the mito would cause destruction of cells harboring it, culling the cells with the most defective mitos. By tightening or loosening such regulation relating to mito selection the avg lvls of mito fitness sustained in organisms throughout their lifespan, and the lvl of mito efficiency in a particular species could be sustained at a particular lvl, and could be moved up or down to the lvl that's just enough, the lvl required throughout the generations for effective function and replication of the organism and no more(as there'd be no pressure to do so.). Again any less functional cell that avoided the self destruct culling mechanism would interfere with this beautiful hypothetical selection mechanism creating havens for defective mitos to survive the culling and persist in the mito population of the tissue spreading about ever more as such havens increased, and disrupting mito selection ever more, decreasing the fitness of the mito populations throughout the whole tissue. Defective mitos would as a result become ever more common throughout the tissue than they would otherwise be, even a small proportion of such havens/cells might be enough to disrupt the selection mechanism, and cause slowly increasing loss of function at the tissue and eventually whole organism lvl.
The problem, as said, is that the selection hasn't evolved to be thorough enough at containing the cells ability to escape the program(aka cancer), and there seems to be an inbuilt mechanism to disrupt selection ever more(senescent cells), it should be possible to make it so any event that increases the likelihood the cell will become deviant also exponentially increases the likelyhood it will self-destruct. Right now from what I've heard this is the case in most scenarios, in order for cancer to arise either a.) a certain sequence of mutations or epigenetic changes that frees the cell from its functional role has to occur, freeing it slowly ever more without causing it to selfdestruct, something that would happen if it started behaving deviantly under most other cases. b.) Drastic alterations to genetic material, aka duplications, losses or rearrengements of substantial chunks of regulatory information. The former can probably be stopped by closing the regulatory-loop holes that can arise should any single regulatory element be lost, produced less or in excess, making the regulatory functions more thorough, thus making cells self-destruct under pretty much any scenario where it starts to escape the program. For the latter the cells should also be made to be more sensitive to more types of such events so that more of them result in selfdestruction, and the few that don't are exponentially less likely to occur. Immunity can also be enhanced by making both the immune cells more apt at spotting deviants and most deviants more likely to display overt signs as the cells receive changes in the direction of escaping the regulatory death/culling signals. This is what I believe may've been done by nature to ensure more massive organism could better contain deviant cell formation, the regulatory mechanisms become ever more thorough making any particular sequence of mutations or epigenetic changes required for cancer exponentially less likely to occur as it'd have to be more specific or a longer sequence and making cells more sensitive to more kinds of rearrangements, loss, duplications of larger quantities of regulatory information, and tightening the organisms' defenses against such.
As for defective protein accumulation, another recent study recently suggested that one form of defective protein accumulation(amyloid) might actually accumulate due to a defect in the natural recycling of such. The choroid plexus was postulated to continually receive the ever forming defective protein aggregates in the brain and hypothesized to poses the enzymes necessary to degrade these defective molecular aggregates, declining function of such process resulting in the accumulation of defective proteins and Alzheimers. IT is not confirmed, but if such a mechanism for recycling defective protein aggregates is latter confirmed to exist in the brain, similar ones may exist elsewhere, and declining function of such cell populations at performing their functions may be behind at least some of the accumulation of certain defective protein aggregates. OF course should that be, that does not mean there aren't several kinds of defective protein accumulations for which no effective recycling occurs anywhere, for such new capabilities may've to be introduced into the body.
Temporary measures can probably be taken while we develop the more advanced knowledge required to enhance and increase the robustness of these hypothetical naturally occuring selection regulatory mechanisms. But once developed, the cells in a particular tissue should maintain function indefinitely thanks to robust regulatory mechanisms based selection, just as clonal populations in the wild are kept fit(assuming stable environment) indefinitely by limited resources selection,thanks to the sequence of events required to escape the cells programming being made so unlikely to occur as to pretty much be a statistical impossibility and as other cells that lose function will slowly be replaced by the more functional cells within that particular cellular population. As in ecosystems at large where particular roles are under most cases indefinitely fullfilled by functioning organisms, so too will happen within the organism, as the full power of selection will have been brought inside the organism. Like a group of replicating machines, increasing problems with replication or function will result in eventual total failure of the particular replicating unit and so too for each and everyone of its descendants that had less functionality, while the more effective units at replication and function will become ever more common and continue replenishing the tissue thanks to inbuilt robust regulatory selection mechanisms favoring them. The crippling of the cell will've been complete, it's evolvability compromised even further to the point its probability of escaping its particular role is a nigh statistical impossibility. The evolutionary force will have been grabbed by the throat and used to maintain optimal function of the cell populations in the body and nothing more. By defining cell fitness as functionality within the tissue, through robust regulatory mechanisms that'll cull defects and allow functional replicating units to create more viable faithful copies faster than any single/particular copy can be damaged. It's molecular machinery so tightly interwoven and regulated that it is more like a traditional machine than a living cell and exponentially more likely to simply breakdown/selfdestruct if its functions change to become less effective or diverges from them, thus being replaced by the replicating units that continue to function properly within the tissue. The newer mutations would constitute new information arriving in the system, an exchange of information, an open system, but the spread of these pieces of information would be controlled so as to stop detrimental information from spreading while allowing beneficial or neutral information to spread. It will be as it happens at the lvl of the species with inevitable selection altering the spread of novel information in favor of beneficial information over detrimental information, making the former which is initially rare eventually exponentially more common and the novel latter which more commonly and constantly arises exponentially less likely to spread with time throughout the population. So the organism's tissues will be immortal, as cell populations are in the wild, the selection regulatory mechanisms will cause crippled traditional-machine like behavior of the cell, as stated, such that deviation from optimal function either by lossing functional efficiency or by most sequences of events leading to escape from its role result in detrimental effects on the cell itself and eventually selfdestruction under most any statistically significant case, as selection happens in the wild, culling the less fit organisms so too will it happen as thoroughly within the tissues themselves. The immortality of the species will have been conferred to the organism itself, the genes will have crafted an organism/ecosystem so well, that it can persist indefinitely as do the naturally occuring ecosystems under normal circumstances.
