DNA, In My Opinion, Is The Cause Of Aging

Although I believe Aging is both caused by Internal influence (DNA structures) and External influences (Viruses, Bacterium, Fungi, Oxygenation, Radiation etc.); Overall DNA is responsible for the Limited Biological Lifespan of an Individual. DNA has shown to have its flaws; such as carrying excess genetic material which causes various diseases in individuals. DNA also dictates how well a cell fights External Influences. Saying that; make no mistake, Biological immortality, as a Unit is possible and will be achieved. Question is; How long will research take and do we have the technology and sufficient funding for this honorable cause?

One way to speed up research in this field is to collect genetic material from distinct parts of the body (bone, Organs etc.) compare and contrast the specialized cells; examining which DNA structures are coated with the protein that makes them dormant. This method will greatly speed up research to map out what genes are responsible for what.



For Skeptics And Interested Individuals.

Various plant life such as trees can live for centuries. Ah, but you may be questioning this; saying along the lines of, that is a plant, humans are animals, we are so different. Wrong! The genetical material is basically the same Adenine ( C5H5N5 ), Thymine ( C5H6N2O2 ), Cytosine ( C4H5N3O ), Guanine ( C5H5ON5 ) are the basis of all living matter. Well, here is another fact, which may be more convincing; Tortoises, which are animals such as us, can also live for centuries. Lobsters can regenerate broken off limbs. Having the benefits, especially form the latter, will give a blind child the ability of sight. A person with missing limbs the ability to be a physically normal human being.

Feedback would be appreciated. Thanks.

DNA causes maturation and phase shifting, but I would hazard that it is the failure of DNA that results in senescence rather than the *programed intent*.

DNA is self preserving and that it doesn't always succeed is only a recognition of mortality but reading into that lost struggle an intentional failure is a trap that may not be a part of the actual program.

DNA doesn't require death it simply till now has run out of options for overcoming cumulative operating flaws, in other words we wear out. I do think DNA does govern the stages of life and I also think that to a certain extent this is the tricky question about creating therapeutic approaches to *reversal*.

For example lets say we could trick all the bodies cells into somehow resetting to a prepubescent state (obviously for this exercise without trigger tumor growth and other malignancies from unregulated cellular reproduction) then effectively you could be given a chance to rejuvenate into more supple tissues, faster more resilient tissue growth hormonal surges that alter how our progress forward from that point as you would grow young for a period instead of older.

But understand that the triggering of *growth stages* doesn't mean the body's cells could actually handle the reversal because of the reality of cumulative cellular damage. In other words hormonally (for example) tricking the body into believing it was young could instead backfire by accelerating the actual rate of aging or induce malignancy. In one sense like causing a candle to burn faster by exposing more wick, in another by causing the candle to just meltdown and deform into a disorganized mass from the overload.

I am presenting this simple analogy to distinguish the idea of *aging* as maturational stages from aging as cellular senescence and cumulative damage to not only Mitochondria but many general metabolic systems, insulin production of the pancreas, or complex structures of the eyes for another.

Also you raise an important distinction on the aspect of immunity resulting from DNA programming as the DNA based immune system also requires a tolerable and continuous level of stress to it to develop and best sustain viable defensives against many environmental threats. Strengthening immunity is not the result of avoiding all threat but instead controlled systematic exposure.

I guess what I am trying to say to people that think DNA is the *cause* of aging is that in a way they are blaming the victim of senescence from cumulative damage both to the host DNA and mDNA. Our job is the find a manner to protect two things, the DNA and the *self*, they began as one thing but are not necessarily only one thing.

I have asked this question many times and we have whole fora dedicated to the issue under other topic names but:

Does the *self* depend on DNA?

BTW everyone let's not belabor the chicken/egg issue. I grant a priori that DNA begot the self; then what?

DNA causes maturation and phase shifting, but I would hazard that it is the failure of DNA that results in senescence rather than the *programed intent*.

I disagree, to an extent. I happen to go with the side of the debate that argues that there are several very strong evolutional reasons that aging exists. I also agree to an extent, because as you pointed out, errors do occur, and damage accumulates.

DNA doesn't require death it simply till now has run out of options for overcoming cumulative operating flaws

That CR and its mimetics are so (primitively) effective implies quite the opposite. DNA does have other options, but the process of Evolution has "decided" that other things are more important than sheer longevity.

Also, evolvability to survive conditions that change on geological timeframes requires genetic mutations, so it has been theorized that we are programmed to tolerate more nDNA damage than we otherwise would have to.

That said, I think that, given a set of DNA that was tailored towards individial maximum lifespan, as opposed to high evolvability and species preservations, a human being could live to at least in the high 100's, and probably even well into the 200's with enough fine tuning. We don't and can't know for sure yet where the limits of genetic-only interventions will take us; perhaps 500?

But yes, there is a limit, and we're not going to achieve "immortality", or anything approaching it, by "dumb" genetic manipulations alone. It will take intelligently controlled damage cleanup systems. Nanobots? Maybe, maybe not. Will these nanobots resemble the diamond/other non-organic designs fancied today? Perhaps, perhaps not. But some form of decision-making intelligence will be needed.

Unless of course, all forms of cellular biochemical damage are repairable as long as the DNA is programmed sufficiently and is intact. In which case, a periodic replacement/repair of the nDNA might be all that's necessary. This only addresses aging, of course. Even drastically reduced accident and viral/bacterial/fungal disease/infection rates will cap our lives at a few millenia, a few tens of millenia at most. But by then, our bodies will be engineered to withstand far more than they can today, in terms of both blunt trauma as well as hypoxia, radiation, toxins, etc.

Jay Fox

I am pressed for time but I would like to address one thing.

That CR and its mimetics are so (primitively) effective implies quite the opposite. DNA does have other options, but the process of Evolution has "decided" that other things are more important than sheer longevity.

Also, evolvability to survive conditions that change on geological time frames requires genetic mutations, so it has been theorized that we are programmed to tolerate more nDNA damage than we otherwise would have to.

I, like others are skeptical of the claims of CR and I do not find them to be all that hard to explain from an Evolutionary Biology perspective. They are the result of some preprogrammed subroutines of the DNA that address the adaptive selection process for coping with the adaptation to feast/famine cycling for life sustaining resources.

From this perspective there is a net positive result from withholding excess caloric intake basically for a similar logic to why the immune system requires stress in order to function. By activating the genes for going into a *diminished capacity mode* (surviving famine) it is slowing the decay clock down but it is not stopping or reversing it. It is like saying that if we could slow our heartbeat down a constant ten percent we would live ten percent longer.

Humans do not hibernate and I suspect the results of CR to be the alternative genetic strategy we see in other species to greater or lesser extent, for coping with dry/wet seasonal, temperate climactic, or even the dependence on migratory behaviors of feeder species. We have a biologically based strategy of switching to a back up *Limp Along* mode that depends on far less caloric intake to sustain essential life support. BUT no one can argue that people who are fully immersed in CR are capable of the same level of sustained physical stress as someone that has a balanced caloric intake to work output in tune with a higher stress(fuel input/expenditure rate) and this is reflected across the board with respect to various subsystems as well, like the immune response.

The point of *stress* in this sense is that speeding the process up (higher caloric intake combined with increased physical labor) simply results in overall faster cumulative damage IMO, slowing it down past a critical threshold only activates a genetic switch to a fall back strategy we are programmed through adaptation for or we wouldn't have gotten this far. It is the effects of the shift to the *Go-Slow Mode* that are providing the result and in that sense CR may be seen as of very limited benefit in and of itself. It also doesn't integrate as a primary explanation for the whole aging process IMO.

DNA causes maturation and phase shifting, but I would hazard that it is the failure of DNA that results in senescence rather the the *programed intent*.

DNA is self preserving and that it doesn't always succeed is only a recognition of mortality but reading into that lost struggle intentional failure is a trap that may not be a part of the actual program.

I believe it's most likely actually programed.

And as for her recent work on infertile worms, which lived six times as long as normal following the removal of their entire reproductive systems, she says: “If we could intervene in the hormone signalling pathways directly, we think the animals would still live six times as long as normal, but would be fertile as well.”

Posit why would systems that reduce an animal's lifespan 6 fold be in place, systems that according to said researcher should most likely be possibly nullified without compromising fertility? The evidence that regulation exists is there, as has been seen in many published studies. The question now is are there other parallel or similar mechanisms in place? The fact that some cells selectively promote proliferation of nearby cancer cells(and those alone, not others, as said selectively) in their senescent state, that with aging an alteration in gene expression that favors loose cellular growth regulation is taking place(allowing for cells to ignore the state of the telomere and keep on dividing when they should've stopped, and become ever more unstable as it changes/shortens) are quite suggestive. Many of these changes are in fact reversed by CR, what posit be the reason for this? Why are reversible negative changes taking place.

Why are there mechanisms that seem to fight of some of the strongest most malignant cancers turned off at later ages? Why are these immune responses more active in some aging organisms without compromising longevity, yet not spread throughout the whole population? Why're auto-immune responses increasing at the same time immune responses against cancer diminish?

"Since the late 1990s, there is a new paradigm in aging research. We think there are key regulators of aging and aging can be regulated," says David Sinclair, PhD, assistant professor of pathology at Harvard Medical School, Cambridge, Mass., and the study's coauthor. "The best thing about this new paradigm is that we don't need to figure out the causes of aging to slow it down; we just need to affect the regulators."

This tantalizing interconnectedness - that all the lab models share a significant number of genes with people, and that such small amounts of genetic meddling can so drastically lengthen a worm's life - has led Richard Miller, the University of Michigan gerontologist, to believe that "aging is a single, fairly tightly controlled process that has a relatively small number of genes timing it."

Programmed aging or error catastrophe? An examination by two-dimensional polyacrylamide gel electrophoresis....
These data are inconsistent with predictions by any one of several, so called, "error catastrophe" models of senescence and also show that modulation of the highest abundancy classes of proteins are also not involved in senescence.

programed or error catastrophe?( this one's kinda old)

From this perspective there is a net positive result from withholding excess caloric intake basically for a similar logic to why the immune system requires stress in order to function. By activating the genes for going into a *diminished capacity mode* (surviving famine) it is slowing the decay clock down but it is not stopping or reversing it. It is like saying that if we could slow our heartbeat down a constant ten percent we would live ten percent longer.

If I'm not mistaken it's no longer believed that Metabolism is slowed in CR. Yet it is not just CR, alternate fasting while still consuming THE SAME QUANTITY, or SLIGHTLY more food, DOES THE SAME THING, actually it's even superior in some parameters(note: given that this requires more info, I don't recommend it for now. But, note that the strength weight is pretty much maintained, though a tiny bit of less fat is seen, thus the same strength and capabilities are retained, but with enhanced toxin resistance, better muscle preservation and mental capability preservation and more endurance/performance IIRC.). There's also the CR mimetics, they achieve similar. Centenarian physiology shows(see my post in the Methuselah prize), that the benefits bestowed to their kin, and the changes that take place in their body are akin to those of an animal IN CR.

PS note also that gene expression changes are actually SEEN in CR, reversal of changes that occur with age is taking place. A large portion of the changes that take place with aging in g-expression are being changed back to a more youthful state.

Edited by apocalypse, 18 August 2004 - 04:34 PM.

If I'm not mistaken it's no longer believed that Metabolism is slowed in CR. Yet it is not just CR, alternate fasting while still consuming THE SAME QUANTITY, or SLIGHTLY more food, DOES THE SAME THING, actually it's even superior in some parameters(note: given that this requires more info, I don't recommend it for now.). There's also the CR mimetics, they achieve similar. Centenarian physiology shows(see my post in the Methuselah prize), that the benefits bestowed to their kin, and the changes that take place in their body are akin to those of an animal IN CR.

Here we must be careful about the semantics for what we mean by metabolism. If you don't agree that at some point (and there is room to disagree) in CR there is also experienced reduced fertility, pseudo menopause, reduced physical output ability, reduced endurance, reduced immunity, and even reduced rates of tissue repair and bone growth then I suspect we mean different things whe we say *metabolism* because all the descriptors I have mentioned are at issue with CR.

The question I am still concerned with is not whether some form of CR and (generally better nutrition) is valuable, it is when is not enough, too much?

Clearly in a society plagued by obesity I am not attempting to protect the opposite POV. I think that is important to suggest as some degree of CR IMO is valuable if for no other reason than we have gone too far the other way.

Famine and CR share many similar characteristics defining the fine line of distinction here is important but also may get confounded by the genetic diversity of the human population and a one size fits all definition here may simply be the result of competing interpretations of Evolutionary Biology I suspect.

Ironically I just as posted under a different thread a response to some of the other points you raise about DNA Apocalypse here:
http://www.imminst.o...048

Rather than simply agreing to disagreeing I think we should continue on two different parallel tracks. On the one hand we can examine biological survival strategies and how these might evolve in relation to specific environmental stress and competition.

That CR and its mimetics are so (primitively) effective implies quite the opposite. DNA does have other options, but the process of Evolution has "decided" that other things are more important than sheer longevity.

As a separate and quite relevant tact we can also look at the growing body of evidence in respect to the genetics specifically. I do not think DNA has a specific self destruct imperative and you would have to see evolution as *self directive for progression* to justify this assumption I suspect.

Evolution does not possess an *imperative to progress*. It possesses an *imperative to survive* the competition for resources and promote one's own genes. (Dawkins)

The transistion from Natural Selection to Human Selection as I understand in fact incorpoprates that specific characteristic of creating an *imperative to progress* as Humans define such progress. Are you not applying a subtle variation of Intelligent Design into your understanding of Natural Selection in order to explain a mechanism of DNA that intentionally ends (programmed senescence) each specific copy of itself in favor of gene pool progression?

I am still reading the article you provided but I find it hardly conclusive though its language comes off as such and I am comparing it to these more recent studies.

Protein turnover plays a key role in aging
http://www2.umdnj.ed...catastrophe.pdf

Abstract
Although the molecular mechanism of aging is unknown, a progressive increase with age in the concentration of damaged macromolecules, especially proteins, is likely to play a central role in senescent decline. In this paper, we discuss evidence that the progressive decrease in protein synthesis and turnover can be the primary cause of the increase in the concentration of damaged proteins with age. Conversely, protein damage itself is likely to be the cause of the decrease in protein turnover.

This could establish a positive feedback loop where the increase in protein damage decreases the protein turnover rate, leading to a further increase in the concentration of damaged proteins. The establishment of such a feedback loop should result in an exponential increase in the amount of protein damage—a protein damage catastrophe—that could be the basis of the general deterioration observed in senescent organisms.
© 2002 Published by Elsevier Science Ireland Ltd

Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans
http://seroudelab.bi...pdf/herndon.pdf

In C. elegans, many single-gene mutations confer significant extensions of lifespan1. Life-prolonging mutations affect several aspects of nematode biology, including insulin-like signalling for dauer larvae development, the development and function of sensory
neurons, the consumption of food, and biochemical defences against stresses such as heat shock and reactive oxygen species (reviewed in refs 2, 3).

However, a detailed understanding of the molecular and cellular events influencing longevity remains a central mystery in the biology of ageing. Similarly, factors that regulate healthspan (the adult period of unimpaired activity and function that precedes age-related decline) have not been well defined, despite their potential as targets for forestalling the deleterious consequences of ageing.

A major gap in our understanding of C. elegans ageing is the question of what happens to cell and organ systems over time. The paucity of information regarding the cellular consequences of ageing is striking, given that each of the 959 somatic cells in the mature C. elegans hermaphrodite is an identified cell of known ancestry4,...

One striking aspect of the biology of the ageing of C. elegans is the wide variability in both the time of onset and the rate of apparent deterioration within an isogenic population reared under uniform environmental conditions9,22.

Although factors in the microenvironment or life histories of individuals (for example, the amount of time spent in food as opposed to near it) could profoundly affect ageing rates, we repeatedly observed a stochastic occurrence of cellular demise within the same cell types of individual animals. The marked variation in cellular decline is probably attributed to random damage or failures. In providing evidence for significant stochastic influences on both the overall senescent decline of the organism and the degeneration of individual cells within a single C. elegans (an organism in which there is virtually no genetic or developmental variation between animals), our data support a key premise of the ‘disposable soma’ theory of ageing, which postulates that damage caused by chance events is a major contributor to ageing soma23–25.

Another premise of this theory is that the genes that influence ageing and lifespan should primarily be involved in maintenance and repair of the soma23–25, and all characterized C. elegans increased-longevity mutations tested increase resistance to various stresses3,26. Given that stochastic contributions also affect ageing in other animals27,28, we emphasize that an understanding of stochastic components will be required for a full description of ageing in both C. elegans and higher organisms27,29.

Evolution does not possess an imperative to progress, it possesses an imperative to survive the competition for resources and promote one's own genes.

But in a world of change, the rate of change, the rate of evolvability, confers itself a fitness advantage. Why would a male after metamorphosis, lack a digestive system? Why would others toss themselves to be killed by the female? Why would the number of teeth replacements be limited in animals that would die without these? Why would salmon, die so quickly after reproduction? Some insects last more than a decade , metamorphose reproduce and then die quickly, why? Why would some animals experience an increase in hormones near the time of reproduction that would in effect kill them quickly after reproducing? In othe words why would animals have a self-destruct switch in so many cases? Seeing this, why would a slow more gradual form of such, which would carry some advantages, be implausible?

The reason, is most likely that which is said, to increase evolvability of species.

I am still reading the article you provided but I find it hardly conclusive though its language comes off as such and I am comparing it to these more recent studies.

Interesting from what I've heard protein turnover is increased in CR.

data support a key premise of the ‘disposable soma’ theory of ageing, which postulates that damage caused by chance events is a major contributor to ageing soma23–25.

Another premise of this theory is that the genes that influence ageing and lifespan should primarily be involved in maintenance and repair of the soma23–25, and all characterized C. elegans increased-longevity mutations tested increase resistance to various stresses3,26.

Yes I agree it is random in nature, but I believe it's most likely set of in motion by genes. As said in aging theory thread, knocking the ability to sense its surroundings, the C-elegans DOUBLES lifespan, clearly whatever was set in motion( changes/alteration in g-expression that would favor unstability, deterioration, random damage/failures to take place.) was regulated in response to environmental stimulus. Clearly the fact that removing the entire reproductive system yielded a six fold increase in lifespan, while allowing mobility, strength, and immunity to remain indicates that something is regulated. The researcher herself indicated that its most likely possible to retain fertility and that simply altering the hormones would most likely yield ridiculous lifespan.

For example if I stop taking my car to the mechanic, and taking care of it, and let it go, the failures that'd take place would indeed be random, but who'd be truly responsible for the failure of the car? If the body did the same thing, and said let's screw it, and hinder the active repair/maintainance/regulation that takes place, it would indeed yield random failures, but in a way who'd be truly responsible?

Dietary restriction has been shown to have several health benefits including increased insulin sensitivity, stress resistance, reduced morbidity, and increased life span. The mechanism remains unknown, but the need for a long-term reduction in caloric intake to achieve these benefits has been assumed. We report that when C57BL/6 mice are maintained on an intermittent fasting (alternate-day fasting) dietary-restriction regimen their overall food intake is not decreased and their body weight is maintained. Nevertheless, intermittent fasting resulted in beneficial effects that met or exceeded those of caloric restriction including reduced serum glucose and insulin levels and increased resistance of neurons in the brain to excitotoxic stress. Intermittent fasting therefore has beneficial effects on glucose regulation and neuronal resistance to injury in these mice that are independent of caloric intake.

However, a previous study did establish a life-span-extending effect of the identical IF[intermitent fasting-apoc] regimen in the identical strain of mice (12). Moreover, a recent study of mice with adipose tissue-selective disruption of the insulin receptor gene showed that the life span of mice can be increased without a reduction in calorie intake (29).

intermitent fasting mice

"Normal rats run maybe a kilometer (.6 mile) every day for a couple of months, and then they do what I do," he says. "They get tired of it and the wheel never turns again.

"Caloric-restricted rats, however, run 5 kilometers (3.1 miles) a day - and I don't mean rat-adjusted kilometers - and they do it until they are very old. Most of the regular rats are dead by 36 months of age. Caloric-restricted rats are still running 5 kilometers a day.

"It's not just that they have a passion for jogging," Miller[probably richard, apoc] says. "These animals have a slow rate of developing cataracts, kidney disease, arthritis, and loss of cognitive function."

Miller is convinced. "The aging process can be slowed. These rats are not immortal, but all of the evidence so far, published in peer-reviewed journals, suggests that what you get is a dramatic extension of the period over which the rats are as healthy as I am."

PS of course the causes of aging are still unknown, as you say. I'm just quoting researchers, and data, showing that it's pointing in one direction. Eventually we will know the true cause(I'd be surprised if it takes more than 30yrs for such, heck I wouldn't be surprised if it were announced this decade), and depending on it will be the time that'll take to cure it.

Edited by apocalypse, 18 August 2004 - 06:02 PM.

QUOTE= LL
Evolution does not possess an imperative to progress, it possesses an imperative to survive the competition for resources and promote one's own genes.

**********
But in a world of change, the rate of change, the rate of evolvability, confers itself a fitness advantage. Why would a male after metamorphosis, lack a digestive system? Why would others toss themselves to be killed by the female? Why would the number of teeth replacements be limited in animals that would die without these? Why would salmon, die so quickly after reproduction? Some insects last more than a decade , metamorphose reproduce and then die quickly, why? Why would some animals experience an increase in hormones near the time of reproduction that would in effect kill them quickly after reproducing? In othe words why would animals have a self-destruct switch in so many cases? Seeing this, why would a slow more gradual form of such, which would carry some advantages, be implausible?

The reason, is most likely that which is said, to increase evolvability of species.

I had just subtly edited that sentence as you were using it. Ironic eh?

Nevertheless it doesn't alter the basic contention and your rebuttal. We are interpreting how strategies develop in terms of evolutionary biology from very different perspective and you insist on reading in an *intentional* aspect. I warn you that is the trap of Intelligent Design proponents and not what is understood by Darwinian Selection.

I am sympathetic to this on a number of levels including that I suspect a mechanism to activate and induce mutation is at work. This is a very different mechanism than one that requires senescence. It does however fulfill the more important but secondary aspect of your conjecture by creating a mechanism for increased rates of mutation and associative possibility of survival for the genes by initiating *divergence*.

There may be a logical explanation for such a mechanism to have evolved and the death of the parent is not at any time necessary for the success of the offspring except in some very interesting cases and the competition for limited resources is when this occurs.

Rates of change then is subject to not only the speed of gestation/maturation (obvious) but the literal physical size (less obvious) and certainly the quantity of offspring. However this strategy is also counter productive to developing more complex lifeforms in terms of divergent adaptation and so can be seen as self limiting (again not the same as programmed senescence). If a more effective strategy then can supersede the more primitive ones and in the process provide adaptive advantages then this strategy comes to take precedence through competition.

As to the various examples of self destructive switches, these almost always have to do with replenishment of food supply or the elimination of a parent from the competition for food. We see this in spiders, salmon, and other species as you allude to but I see the advantages of this strategy differently than you do.

In the case of Salmon for example they die not from a switch being turned off but from exhaustion and lack of feeding ability in the headwaters they have arrived at to spawn. If they could be rescued at that moment theoretically they might be able to recuperate enough to turn on their feeding switches but they basically would have to be feeding on one anther and their own young to meet their physiological demand (a strategy also found in nature).

There is an awful lot we still are learning about what is genetically programmed and what how this occurs. Remember however the confusion also arises because of how *imprinting* works and this too is driven by genetics but the *imprint* is a part of the living experience of the individual not the genetic program. Salmon are programmed to be imprinted with the drive to return to their birthing ground but that imprint is for where ever they are hatched, not some specific headwater.

Metamorphosis is a whole other discussion as well. Clearly there are examples of genetic clocks but also more subtle forms of genetic sensors that depend on temperature or even humidity to trigger growth phase shifts. And also clearly there are examples f strategies that have succeeded by applying a very exploitive numbers game of maximizing the benefit from a fleeting existence (ie. mayflies) but this again doesn't mean that mayflies are programmed to die as much as they lack the ability to *survive* after accomplishing the mission of mating and egg laying.

Am I making the distinction between our positions clear enough?


I have to go right now but I will get back to this later and I encourage others to weigh in on this. We also are separately discussing Evolutionary Biology and Genetic theory in the thread on:
Abiogenesis, DNA, RNA, and Protein Interaction
http://www.imminst.o...&f=44&t=1105&s=

Not to mention Aging Theories:
http://www.imminst.o...&f=44&t=1153&s=

For example if I stop taking my car to the mechanic, and taking care of it, and let it go, the failures that'd take place would indeed be random, but who'd be truly responsible for the failure of the car? If the body did the same thing, and said let's screw it, and hinder the active repair/maintenance/regulation that takes place, it would indeed yield random failures, but in a way who'd be truly responsible?

This is a false comparison but I enjoy it nonetheless because actually your car ages as a consequence of use and cumulative damage not lack of maintenance per se. What you are describing are the *phases* of a car's *life* (New, Used, Junk). What I call the "what next syndrome" is the real culprit in automotive senescence. It is that period when wear and tear combined with sufficient cumulative failures causes systemic failure and your metaphor supports my argument better than yours. )

It isn't the fall that kills, it is the sudden stop. The car is by the way programmed to *die,* to extend the metaphor, and we call that *planned obsolescence* and this *unintelligent design* aspect can be overcome by better programming and redesign. )

Routine maintenance through scheduled inspections and repair are critical for confronting this but just putting your vehicle on blocks and hiding it in a dark garage will not protect it from many forms of degenerative decay, (rust, dry-rot, crazing etc) and what a maintenance schedule requires is for parts, and at times whole systems to be removed and replaced when they are *outside tolerances.*

I am very familiar with this because I not only maintain my personal fleet and have maintained those of others but this is precisely what we must do to keep older aircraft operating and to apply your metaphor in this manner is to also lead to the idea of transplants and whole body replacements as the way of bypassing the problem you present.

However it doesn't follow because if the *genetic program* led to failure you could replace the entire organism with a whole new body and when your *time* was up the organism would die and this is untrue. It would mean that we would be able to reset a specific countdown protein and the body would reset like a clock.

The problem is, and if you go back far enough you will find that I once argued in a similar vein to your own, that while some systems in humans appear to be driven by a variety of chronological mechanisms (menstrual cycles and circadian rhythms for example) it is questionable if these are keeping time in any kind of a longer term calendar sense. What they appear to be regulating are the quantum shifts in physiology associated with maturation for procreation and in this sense are more akin to what drives metamorphosis in insects. For humans these are more like the stages described by the riddle of the sphinx IMHO.

After we reach full maturity we aren't any longer experiencing *phase shifts,* we are simply wearing out.

Am I making the distinction between our positions clear enough?

Well, what do you say about this particular bit:

Intermittent fasting therefore has beneficial effects on glucose regulation and neuronal resistance to injury in these mice that are INDEPENDENT of caloric intake.

However, a previous study did establish a life-span-EXTENDING effect of the identical IF[intermitent fasting-apoc] regimen in the identical strain of mice (12). Moreover, a recent study of mice with adipose tissue-selective disruption of the insulin receptor gene showed that the life span of mice can be increased without a reduction in calorie intake (29).

Not to mention, Miller's quotes, clearly you won't say the CR is iin a lower metabolic state, it's pretty clearly at an equal or higher state.

Nevertheless it doesn't alter the basic contention and your rebuttal. We are interpreting how strategies develop in terms of evolutionary biology from very different perspective and you insist on reading in an *intentional* aspect. I warn you that is the trap of Intelligent Design proponents and not what is understood by Darwinian Selection.

There need be no intention my friend, it's simple if it increases fitness, it will be selected. Evolution is a very nasty process, if you give an organism abundace of something for a long time, even if essential, it'll toss the ability to create it out the window, and grow DEPENDENCE. Even evolved h/w evolves dependece if provided outside resources. It's clear that this is not good in the long run, but it does it anyway, overspecialization and dependence occurs, abilities are tossed out as they're unused. Several animals have what amounts to self-destruct programs going on, it's clear there must be a reason for such, an increase in fitness through improved evolvability would be a plausible reason. No intent is needed here.

I am sympathetic to this on a number of levels including that I suspect a mechanism to activate and induce mutation is at work. This is a very different mechanism than one that requires senescence. It does however fulfill the more important but secondary aspect of your conjecture by creating a mechanism for increased rates of mutation and associative possibility of survival for the genes by initiating *divergence*.

There may be a logical explanation for such a mechanism to have evolved and the death of the parent is not at any time necessary for the success of the offspring except in some very interesting cases and the competition for limited resources is when this occurs.

There is always competition for resources this is one of the drives of selection and evolution. Posit what benefit could there be from promoting(senescent fibros..) the proliferation of cancer cells, and making cellular growth control loose? I see no benefit for loose cell growth control, the cell will become unstable and eventually some will become cancerous, why are these changes there? Why are many of them reverted/undone with CR?

What benefit is there for a senescent fibro to promote pre-malignant and malignant cell proliferation specifically? I see no benefit in doing so, at LEAST no benefit for the individual...

If a more effective strategy then can supersede the more primitive ones and in the process provide adaptive advantages then this strategy comes to take precedence through competition.

Why does a trait that provide immunity to extremely malignant cancer without a decrease in longevity not spread throughout the population? Why, is it rare? Why does it not take precedence in nature? Unless, it made the organism fitter, only if it decreased fitness would it be kept in check, at bay. But what fitness would that be? What benefit for succumbing to cancer? We've seen that an organism may risk its life by protecting its or those of its species offspring, but what benefit for the individual is there? Is it not a benefit for its offspring, for its ability to pass on genes?

After we reach full maturity we aren't any longer experiencing *phase shifts,* we are simply wearing out.

g-expression is changing to one with looser cellular growth control, a reversible change, and it posits no logical benefit. The C-elegans experiments show that a C-elegans that can't sense its environment lives twice as long, why is that? The centenarians show CR esque physiology, why is this? CR alters g-expression why is this?

NOTE: After looking for more info it seems that it's not certain alternate fasting leads to increased lifespan. Still, we've the fat-insulin mutants who do enjoy an increased lifespan without reduced caloric intake.

Clarification, given I can't edit my prior post, and it may yield some misunderstanding.

Posit what benefit could there be from promoting(senescent fibros..) the proliferation of cancer cells, and making cellular growth control loose?

With this sentence I mean the senescent cells promote the malignant/pre-malignant cell proliferation(at least according to some research), and that cellular growth control is lost at later ages, as seen in some other research. I do not mean that the senescent cell is causing the later, because that's not been shown by research that I know, but what I mean is that both things are taking place in the organism.

Edited by apocalypse, 18 August 2004 - 08:09 PM.

There may be a logical explanation for such a mechanism to have evolved and the death of the parent is not at any time necessary for the success of the offspring except in some very interesting cases and the competition for limited resources is when this occurs.

Evolvability is all about the success of the offspring.

If your ill-adapted genes are still out there, using resources and competing with your children for reproductive continuation, then you are doing your offspring, who may be better adapted due to genetic mutations (which were in turn allowed to happen at a higher rate due to the survival fitness of evolvability), a disservice. Die and get out of the way already!

Sure, if you're ill-adapted, you'll probably die sooner than your offspring, but nevertheless, for a longer time than would otherwise have been necessary, you were both using resources, and producing more ill-adapted offspring. And if you're not producing offspring, you're an even bigger threat to the species than if you were, since you're using resources without increasing the total rate of new offspring. (In humans, it is postulated that this line of reasoning became no longer true, vis a vis the "grandmother" advantage of recent Man, allowing lifespans to greatly lengthen.)

Female fruit flies whose lifespans were nearly doubled by genetic manipulation laid an average of over 50% more eggs in their lifetimes: 2000 vs. the usual 1300. Clearly one would expect this to give an advantage in the Evolution department, as 50% more offspring implies that having a 50% higher death rate due to maladaption would be acceptable. The rate of egg production does seem to be a little lower (155% egg production over 180% of the adult lifespan), so that's one disadvantage. Nevertheless, if longer lifespan and greater child output are possible, then Evolution should have picked up on this by now if aging were not a good thing. My contention is, aging is a good thing, and Evolution has figured this out.

By the way, I understand that you dislike it when people anthropomorphize Evolution. Yes, it hints of Intelligent Design. But intelligent design is not necessary when anthropomorphizing Evolution. It is a stochastic mechanism, and even in stochastic mechanisms, the random occurances follow a pattern that can be "explained", indeed "rationalized", and anthropomorphized.

We've come a long way from that basic theory of natural selection, as taught in elementary school. That moths in Great Britain favored a black color over a white color is very interesting, but it doesn't speak to even 1% of what Evolution is capable of. What we anthropomorphize as "intent", Evolution stochastically produced because populations within species that as a whole carried maladapted traits died out, leaving the alternate traits. If long life means gene stagnation and gene pool diminshment, then that population within a species will die out when the next evolutionary pressure comes along. The remainder of the species, with its shorter lifespan and greater evolvability, carries on.

There's no need for intent, and yet we see the logic, and speak of "intent", because it is easier to discuss in human terms than always rehashing the same argument about rates of death, and survival of the individual versus survival of the species, etc. It's easier to in a single word say "intent". It's easier to say that "Evolution has figured this out" than to argue that statistically speaking, Evolution has produced offspring in which Process X is incorporated, because regardless of the individual survival and reproduction (gene survival) benefits, the species as a whole suffers, gene pool diminishes, and the species eventually dies out.

See how much easier it is to just say that "Evolution figured it out"? I know Evolution has no intent, and hopefully so does everyone else here. But I will continue to use the word intent. Intent need not be by an intelligent third party; it can simply be the logical result of the process, all things considered.

Jay Fox

Well, I can see that all who have responded to this topic are much more intelligent and knowledgeable than I am. You all make good points and gave me more insight into the aging process. Still, what I am trying to say is that; DNA, as mentioned before, is responsible for aging, whether human DNA is programmed for a limited lifespan and/or incapable of efficient repair and reproduction of new biological matter, is relatively insignificant from what I see. No doubt, the human genetical coding will have to be manipulated in order for infinite life. Some say the best we can hope for is living a century or two. The law of conservation of matter states; “ Matter cannot be created nor be destroyed”. Space, Time and Matter are eternal, so are we. Ah, it’s just chemical reactions happening in our bodies. Whether a virus is attacking us, oxygenation taking place or radiation passing through the body’s defenses and messing up our genetic code, all are reactions going on. The question is, are we capable of manipulating our DNA so it has a much better repairing system and also programming it to make better defenses against external threats which causes genetic and cellular damage in a whole?


More feedback is appreciate.

Edited by 123456, 14 November 2004 - 03:54 PM.

Evolvability is all about the success of the offspring.

Wrong IMO and this is why the concept gets confused with learning ability and the paradigm shift between genetic driven versus memetic driven evolution. Evolution is about much more than *just* the success of the offspring.

This entire debate is really a confusion of various types of *causality* and the inability to distinguish accurately between the dynamics of consequence and coincidence.

I am going to return to this central theme as it is of paramount importance to the premise for Human Selection but for the moment two things all who read to this point. As you need to be familiar with the serious importance of evolution's relationship to genetic theory I suggest if you haven't already, please read this article by Gavrilov/Gavrilova. I invite them to comment on this subject as well because I believe one or both of them to be present in our membership.

I think there still are many folks reading into Evolution the ideas of Lamarck for a process that was essentially Darwinian. There are many reasons for this and it doesn't mean we can't introduce those ideas but it is important to distinguish when, why, and how we are doing so.

Genetics are essentially Darwinian and virtually all major research from Mendel to today have supported that but as we discuss Dawkins and the Selfish Gene we start, through human intent and social behavior introducing a form of Lamarckian driven selection that is more memetic than genetic.

http://longevity-sci...g/Evolution.pdf

TheScientificWorldJOURNAL (2002) 2, 339–356
ISSN 1537-744X; DOI 10.1100/tsw.2002.96
Corresponding author. E-mail: lagavril@midway.uchicago.edu
website: http://www.src.uchicago.edu/~gavr1/
©2002 with author. 339

Evolutionary Theories of Aging and Longevity
Leonid A. Gavrilov* and Natalia S. Gavrilova
Center on Aging, NORC/University of Chicago, 1155 East 60th Street, Chicago, IL
60637

Received November 1, 2001; Revised December 5, 2001; Accepted December 7, 2001; Published February
7, 2002

The purpose of this article is to provide students and researchers entering the field of aging studies with an introduction to the evolutionary theories of aging, as well as to orient them in the abundant modern scientific literature on evolutionary
gerontology. The following three major evolutionary theories of aging are discussed:

1) the theory of programmed death suggested by August Weismann,
2)the mutation accumulation theory of aging suggested by Peter Medawar, and
3)the antagonistic pleiotropy theory of aging suggested by George Williams.
We also discuss a special case of the antagonistic pleiotropy theory, the disposable soma theory developed by Tom Kirkwood and Robin Holliday.

The theories are compared with each other as well as with recent experimental findings. At present the most viable evolutionary theories are the mutation accumulation theory and the antagonistic pleiotropy theory; these theories are not mutually exclusive, and they both may become a part of a future unifying theory of aging.

Evolutionary theories of aging are useful because they open new opportunities for further research by suggesting testable predictions, but they have also been harmful in the past when they were used to impose limitations on aging studies. At this time, the evolutionary theories of aging are not ultimate completed theories, but rather a set of ideas that themselves require further elaboration and validation. This theoretical review article is written for a wide readership.

The taxonomy of Causality and Chaos theory is very important in and of itself, as well as quintessentially critical to our discussion. The confusion of causality as *intention* or just *derivative* of prior success.

OK why is that important?

Because of the ability to adapt to Catastrophe for example. The genetics of Random Selection are Heisenbergian. Mutation is mostly bad and the result of *scattered* attempts of genetic expression. The shift from Coincidence to Consequence requires intent because mutation as purely random is more than 99 percent ineffectual or even harmful BY NATURE and what alters the relationship of mutation to evolution is its *appropriateness*, or fitness as it is generally understood.

I choose to identify it as appropriateness because of a simple fact of the record, adaptation is driven by the expansion ability of life. Adaption is an expression of *fitness* adjusted for *any* given environmental niche. Fitness at the Birthing Crack for life in the Mid Atlantic Trench where it began as Archaea is not the same defined *fitness* as the peak of Mt. Everest, and certainly not as an adaptive fitness to cohabit human society. Fitness is not a given for any expression of life it is also a coincident of time and space (environment).

Evolving for *everything and anything* is a part of the *reason* humans are becoming the vector species of the paradigm shift from genetic to memetic dominated evolution but when we talk of how we got here a funny happens, if you are deterministic you fall into one of a few simple categories of determinism:

a. Rational Determinism (science)
b. Secular Determinism (law)
c. Theological Determinism (religion)
d. Non Rational Determinism: Chaos Theory, & the Cosmos (nature)

For example one concept central to the discussion, *Natural Determinism,* reflects the core dispute between the prime mover theologians and strict Scientific Rational Determinists. Non Rational Determinists seem more often to side with Theological Determinists and Secular Determinists, depending upon the two for coping with social behavioral norms.

It is necessary to understand that these classifications of determinism are all forms of *Soft* determinism that allow for *randomness* and *choice* to exist counter posed with Hard Determinism.

Back to evolution, when we are looking backward at mutation rates and evolution we have a tendency to know the results of the competition and this has colored our understanding of the process. Look at mutation from the other side of the equation, from before *fitness* (appropriateness really) is proven; how would you anticipate and test for it?

Are all tests automatically fatal to the losers?

This question is important because of the evolution of symbiotic behavior as opposed to parasitic, as well as the parent-child relationship. Symbiosis is the biological expression of *Social* behavior across species distinction. The Parent Child relationship is the fundamental building block of virtually all expressions of social behavior biologically. It is possible for two symbionts BTW to be parasitic with respect to a third and one social group to *parasitize* (exploit) another.

Now specifically when we look at *procreative longevity* we are combining two critical parameters for evolution but *mutation* reflects the introduction of a third element, *Random* as opposed to just *Selected* Change, traditionally only expressed in the offspring as a *coincidence* of haploidal recombination. The Eugenics of cultural determinism and physiological attraction (Mating ritual and instinct) are what makes this process *consequential* of intentional selection.

However a fourth *determinant* and more critical behavior appears logically to be related to the evolution of *strict fitness* as everyone here means it: Cognition and Intelligence.

This last one is most important not only in terms of Human and Scientific Value in terms of Natural Laws. It also reflects *why* we are experiencing the paradigm shift from genetic to memetic evolution as it defines *fitness*. Choice guided by Intelligent Self Awareness is both a product of learned behavior and a form of conceptual mutation (adaptive toolmaking, language, and data retention).

Well most people look at the past in an argument like this and tend to conceptualize evolution as linear in some tenuous web tied to ourselves at one end and all the way back to simple bacteria on the other. But it is more like a matrix and we are the center as a consequence of *Appropriate Fitness.*

Appropriateness is *Pragmatic Fitness*. It is why being adapted for one environment in the best possible manner is not necessarily *appropriate* for any and all environments. Fitness by this measure normally requires eons of procreative mutation to effect a diaspora of life but humans do this through our tool making (technology) ability.

Longevity is an expression of any given species' adaptive choices for biometric expansion and survival. It reflects the *selected strategy* for any given environment but it does not *logically* (rationally) require death, unless that is a *coincidence* of the environmentally demanded choices made for survival.

In humans for example, it is a parents' choice to *sacrifice* themselves for their child and there are numerous examples of this supposedly *instinctive* altruistic behavior but it is NOT the *Selfish* act of the *Parent Gene*, at least by half, because the offspring reflects the re-expressed haploid *recombinant* (the part you say requires death) genes of the parents and this is what drives the process to *recreate* (procreate) itself as the parent.

The experience till now of all life has always, no matter the level of success of the species, been the experience of mortality. Procreation is the prime strategy of continuance; strict mitotic cloning as Hermaphrodism and subtly adapting the offspring through Sexual reproduction (meiotic). Neither possessing a logical requirement of death.

In other words we don't *die* to somehow make room for the offspring, we give birth because we die. Longevity is in direct relationship to Procreativity. Not mutually exclusive but proportional and this chicken/egg aspect is what is being confused IMO because you are looking at the process backward through time as opposed to forward as a *consequence of choice*. BTW even bacteria make choices, in fact that is one of the criteria for how we recognize life.

Another part of adaptation has had to be in relation to catastrophic events, the most common being feast/famine cycling but climate and the cosmos have conspired throughout the eons to *teach* us to adapt to chaos, or cause it.

Self directed mutation is a form learned behavior. It is possible and we have Cancer as a good reason to suspect that a genetic causal factor is at work. BTW, cancer is NOT a disease as most people understand, it is uncontrolled mutation during cell replication/repair and this can be caused by cumulative toxins, radiation, viral phages, *random wrong* cellular replication, and now perhaps by design.

We are taking our *tool making* adaptive behavior to our core substance and simultaneously redefining the rules of environment. The Rules for Selection are right now being written by Humanity. *Natural Selection* in the form of an asteroid, pandemic, or even an alien invasion could change this simple fact at any moment but talk about causality, that rock began homing in on us before humans ever evolved. So adapt to that idea and understand that social competition is also a form of Natural Selection but Darwinism isn't the only way to understand Social Competition.

Yes BTW we are made of star stuff but not all matter is alive or how else do you distinguish life and death?

Is that enough feedback for now?

Edited by Lazarus Long, 22 August 2004 - 02:29 PM.

The question is, are we capable of manipulating our DNA so it has a much better repairing system and also programming it to make better defenses against external threats which causes genetic and cellular damage in a whole?

Yes we are certainly technically capable of up-regulating DNA repair rate.

The reason, is most likely that which is said, to increase evolvability of species.

We are interpreting how strategies develop in terms of evolutionary biology from very different perspective and you insist on reading in an *intentional* aspect. I warn you that is the trap of Intelligent Design proponents and not what is understood by Darwinian Selection.

regardless of the individual survival and reproduction (gene survival) benefits, the species as a whole suffers, gene pool diminishes, and the species eventually dies out.

I think one of the ways to distinguish between the two sides of the debate presented on this thread is to understand that people interpret (and place differing levels of emphasis) on what actual constitutes a "Darwinian Individual", and as such, whether traits observed in organisms can be accounted for by selection pressures other than that manifest in organismal selection (ie; species/group selection). From my perspective, and I could be mistaken, it seems as if this whole debate is an extention of the Dawkins vs. Gould controversy. Im pretty sure this is what Lazarus is alluding to when he states:

if you are deterministic you fall into one of a few simple categories of determinism:

a. Rational Determinism (science) -- [Dawkins, DJS]
b. Secular Determinism (law)
c. Theological Determinism (religion)
d. Non Rational Determinism: Chaos Theory, & the Cosmos (nature) -- [Gould, DJS]

For example one concept central to the discussion, *Natural Determinism,* reflects the core dispute between the prime mover theologians and strict Scientific Rational Determinists. Non Rational Determinists seem more often to side with Theological Determinists and Secular Determinists, depending upon the two for coping with social behavioral norms.

This statement would seem to me to elude to Gould, Chomsky et al and their refusal to consider the exaptation of human culture as an "adaptation by other means" which can be accounted for by the process of natural selection. And additionally, their subsequent rejection of memetics as a legitimate field of scientific inquiry.

Related to the issue of longevity, JD Fox and Apocolypse seem to be utilizing the Gouldian concept of species selection to create the "Super Organism" [a quasi "Darwinian Individual"] in which individual members of the species self destruct (senesce) in much the same way individual cells undergo apoptosis for the good of the organism as a whole.

In contrast, it seems as if Lazarus (correct me if I am wrong) may not view species as "Darwinian Individuals" in the purer sense of the word.

At the end of the day I tend to favor Dawkins and the gene-selectionist approach to evolutionary theory (for a number of reasons which I won't get into here). I will admit that there are qualities which can be selected for distinctly at the species level, however these qualities are not characteristics expressed in individual organisms. An example would be diversity, a characteristic of the species which can be selected for in times of catastophe or mass extinction events. I may be grasping at straws but I think this kind of selection is an example of what Lazarus means by "coincidence" (or "random" selection") and not a "consequence" (or directed selection) In any event, I have yet to see convincing proof of full fledged species selection, and that which has been demonstrated would certainly not constitute the dominant relative frequency under which selection pressures occur in the natural world.

Thank you for the thoughtful reply Don. For the most part you're understanding the direction I am trying to take the discussion and also the way I am shuffling the deck in terms of the basic premises of the overall debate. The idea is an attempt to box-in the core suppositions as promoted by the various theoretical camps.

By doing so I hope to promote an ability to better test for *truth*. But I warn everyone the reason I also assert the critical distinction of Human versus Natural Selection is this is precisely how we are changing the rules and the reason has to do with a fundamental paradigm shift that many *traditional* thinkers are resisting, the paradigm shift from genetic to memetic based evolution.

think one of the ways to distinguish between the two sides of the debate presented on this thread is to understand that people interpret (and place differing levels of emphasis) on what actual constitutes a "Darwinian Individual", and as such, whether traits observed in organisms can be accounted for by selection pressures other than that manifest in organismal selection (ie; species/group selection). From my perspective, and I could be mistaken, it seems as if this whole debate is an extension of the Dawkins vs. Gould controversy. I'm pretty sure this is what Lazarus is eluding to when he states:

QUOTE 

if you are deterministic you fall into one of a few simple categories of determinism:

a. Rational Determinism (science) -- [Dawkins, DJS]
b. Secular Determinism (law)
c. Theological Determinism (religion)
d. Non Rational Determinism: Chaos Theory, & the Cosmos (nature) -- [Gould, DJS]

For example one concept central to the discussion, *Natural Determinism,* reflects the core dispute between the prime mover theologians and strict Scientific Rational Determinists. Non Rational (Natural ) Determinists seem more often to side with Theological Determinists and Secular Determinists, depending upon the two for coping with social behavioral norms.

You have this correct Don and I am also saying that there are really four competing *interests* (or quadrants) of focal point. Each has its primacy element, for example one reason Secular Determinists will side easily with Fundamentalist or Theological Determinists is because *Human Racism* basically is their central doctrine and as such they can and do occasionally abandon scientific and even rational principles at times in order to promote strictly Human values. They also also appeal to *Natural Determinism* (Non Rational) as a premise of Law, as in Hans Kelsen's (a Secular Determinist) Principles of *Natural Law*, which is at the core of Legal Positivism as a basic premise. Natural (Non Rational) Determinism is suggesting that "this is the way it has always been means that this is the way it *always should* be."

There is no small irony in the fact that regardless of their intention they are promoting the contradiction of their claimed position. Secular Determinists are one of the factors driving the paradigm shift to Human Selection even when they claim to be serving the interests of Theological Determinists.

Non Rational Determinists are exactly like Gould by this distinction in that they are appealing to as yet *unknown* principles and to the possibility of *Universal Intelligence* already at work. Whether this be true or not is still unknown but contrary to popular *belief* may not be *unknowable.*

For example *Panspermia* issues will someday contribute to a better understanding but again it becomes a question of Human Selection because if we ever successfully go off-world then we become the vector of panspermia as well (terraforming). A fun but totally separate debate without sufficient credible evidence to support one side or another. One thing I hope we can accept is that life on Earth exists.

Related to the issue of longevity, JD Fox and Apocalypse seem to be utilizing the Gouldian concept of species selection to create the "Super Organism" [a quasi "Darwinian Individual"] in which individual members of the species self destruct (senescence) in much the same way individual cells undergo apoptosis for the good of the organism as a whole.

In contrast, it seems as if Lazarus (correct me if I am wrong) may not view species as "Darwinian Individuals" in the purer sense of the word.

The idea you present here can correctly be seen as a part of the issue but it is derivative of an even greater conundrum. Dawkins is what has become euphemistically called an *Ultra Darwinist* (Darwinian Individualism) and the issue of adaption when seen as *fitness* is about the preservation of *specific* individual genes as opposed to a more collectivist notion of Group Selection for whole *species*.

My position is more complex because I think the two can coexist and even compete against one another at times. I also think the ideas are not mutually exclusive but can alternatively represent symbiotic cross species adaptation (biological socialism). For example while the importance of Eukaryotic symbiosis that created mitochondria is one of my favorite examples even the modern dog can be understood as an appropriate one we can all *relate* to.

I may be grasping at straws but I think this kind of selection is an example of what Lazarus means by "coincidence" (or "random" selection") and not a "consequence" (or directed selection) In any event, I have yet to see convincing proof of full fledged species selection, and that which has been demonstrated would certainly not constitute the dominant relative frequency under which selection pressures occur in the natural world.

Again you are basically correct Don but let me clarify that *Divergence* can be contrasted with Convergence as together reflecting two fundamentally different evolutionary strategies and the two are examples when combined, that can be understood as analogous to the distinction between Individual Selection (Strict or Ultra Darwinism) and Group Selection (Soft or *Gaian* Darwinism).

Divergence is when the recombinant procreative choices that lots of individuals make are directed toward adaption into specific new environmental niches, applying successive generations' adaptation over generations whereas Convergence can be understood as the *competitive* result of this behavior resulting in logical *appropriateness* for the parameters of any given environment as it plays into a new type of organized genetic format for *species* expression. Because the speciation mutation of individuals are played into a larger collective of competitive behavior the individuals transmit the most successful mutations into the *Gene pool* of the group over some given period but afterward they might through *imprinted selection behavior* distinguish themselves from a forebear species they evolved from (horses, donkeys and Eohippus for example) and might not even be able to breed true (mules).

I introduced the concept of *appropriate fitness* because of this relativistic relationship of adaptation to environment.

I also suggest that *procreation* (sexual in particular) needs to be understood as a *recombinant* strategy of reducing the risks of inviable or damaging mutation for being able to apply adaptive pressure. Procreation from this perspective is then understood as the adaptation of *safer* mutation, which dramatically increases the rate of speciation and divergent/convergent evolution.

The point is that procreation does not *require* the death of the parent or the necessity of competition for survival between generations except as an expression of *Scarcity Economics*. There are species that have selected for this adaptation but humans don't have to be one of them and there is no rational or logical necessity for such a choice. The point is about us in particular that should be seen as a fundamental change in the rules governing Evolution of life on Earth is that we HAVE A CHOICE.

The introduction of choice makes the issue moot about how we got here and what is instinct* because we are the vector species for the paradigm shift at this juncture on Earth. We can choose not to choose but even that is still a choice.

No other species gets to make such a decision and we really have no choice but to make the decision (no small irony there). )

What I actually find most amusing about *all* the arguments between the various camps is that we have basically checkmated ourselves.

Edited by Lazarus Long, 22 August 2004 - 02:20 PM.

There is a wonderful example of how MAMMALS (not just humans) traded longevity for divergent adaptive mutability and perhaps one of the prime reasons may have been *consequential* of the KT event. Catastrophe is a *coincidence* that cannot be selected for under the guidelines of strict genetic parameters (Natural Selection) but memetics makes the whole debate far more interesting.

Part of what made most, especially larger reptiles unable to survive the catastrophe is that their entire support food chain was decimated but fast gestational lemurs, rodents and other smaller mammals could survive on the carrion and base vegetation for centuries to millennium until new competitive strategies came to dominate life. This fact as well as the idea that they were warm blooded and small enough to survive on very little gave mammals the ability to evolutionarily diverge in all the vacated niches of reptiles.

Soon the omnivorous mammals began to specialize into predators and prey and the First Epoch of the Tertiary period, the Paleocene was the result, which led in rapid evolutionary time (10 million years) to the Eocene divergence. Remember also that *birds* survived for similar reasons even though their former dominant cousins the dinosaurs were wiped out.

Another factor in aviary resilience may have been migratory behavior and for mammalian it was the ability to endure prolonged hibernation during the immediate aftermath of the catastrophe.

I should add another factor that gave mammals an edge up was the *advantage of getting cancer reflected the entire phylum's ability to mutate faster than reptiles. Reptiles often do not get cancer and the reason may be the result specifically of the *advantage* of being able to continue telomere replication for far greater periods and remain fertile.

Mammals fortunately lacked this improvement that had made the longevity of Reptiles and dinosaurs possible and alternatively could *diverge* into niches far faster than all other competing animal species. Now however we might learn something from the loser of that race. Mammals mutate faster (still not *requiring* death but the advantage of shorter gestation and less stable genetics) but many reptiles are still immune to cancer and also live till accidents, enemies, other diseases (than cancer) or pollution kill them.

BTW, another limitation to growth with age is size. The successful survivors of the KT Event no longer were the ones that grew larger and larger with time as the surviving prey had become smaller and much more elusive, requiring greater speed and cunning to capture and this meant these ever larger species could no longer sustain the physical requirements of their size.

This restriction even impacted the great herbivores in a similar manner as climate and competition made the remaining available food insufficient to support on land of the behemoth Thunder Lizards. Ironically it was still possible in the seas to find sufficient food supply to reach an immense size but faster than reptiles could recover from the KT Event even faster mutating mammals diverged into and usurped that niche, sharing it with the even more ancient but highly efficient sharks.

This idea of a faster *stabilized* mutation ability combined with a shorter gestation rate doesn't mandate death but explains why we are the inheritors of these drawbacks with our mammalian advantage. Also not being an egg layer was important for similar reason in that it is far easier to protect gestating young in the womb than in an egg. Divergence doesn't *mandate* death but it certainly reduces the competition at times.

Today however the general rules governing evolution are making a paradigm shift and that is why the discussion in my opinion is really about the transition from genetic primacy to memetic primacy. Both will continue to coexist but *choice* is now becoming a cognitive dominant factor for determining *appropriate fitness* and for all intents and purposes it is human choice that we are discussing.

The interesting discussion about aging and genetics has always lead me back to the beginning of basic biochemistry and microbiology.

As far as genetics is concerned, the DNA that contributes to our continued existence has its own limitations. Any geneticist will tell you that the DNA which we are born with is NOT the same DNA we have at our death. There are numerous changes that occur which alter that DNA picture Slightly over time.
However, when you consider that our DNA is being duplicated literally thousands of times over before our eventual death, and that this process occurs in 95% of all human cells, of which account for over 100 Trillion estimated on average, 100 years isnt that bad a life span at all.

The problems of aging and how they can be resolved have already been addressed on this forum, many many times.
I myself have a thread (once I find the link I will post it here) that resolves the issue of cellular aging and death, and it is not solely my resolution.

Aging is a consequence of nature's lack of ability to *Repair* itself on the molecular/cellular level.
There are 4 major contributers to aging.

1) Telomerase Shortening
2) Free Radical Damage
3) Glucose Browning
4) DNA distortion and mutation.

All of these can be solved using todays advanced methods of treatment, but the costs are, as always, extremely high due to the specialized labor, equipment, moral, religious, political, and ethical argumentitives that are ongoing throughout the leading world powers, whom either fund or regulate said research and devlopment.

Solving the first 4 problems, as well as adding Stem Cell research and Stem Cell cloning to the equation, would INEVITABLY halt the aging process entirely within ANY organism, as well as its eventual refinement and accomplishment of complete reversal.
This is not debatable, unless there is some direct opposition which would otherwise prevent the aforementioned from developing. Either by unforseen circumstance, or deliberate interference, Human aging is easily thwarted given our vast technological abilities that DO EXIST TODAY.

That having been said, I will dig up other threads as well as references to research already being done in these areas.
This topic is not one for speculation, it is one of political, social, and religous interference of proven scientific research and developmental metholody.

Any geneticist will tell you that the DNA which we are born with is NOT the same DNA we have at our death. There are numerous changes that occur which alter that DNA picture Slightly over time.

1. Are you talking about changes to sequence, methylation or histone patterns? The cell is not as tolerant to DNA sequence change as you suggest. The usual outcome of such changes tends to be apoptosis or cancer. You may want to clarify that statement for your audience.

2. You make it sound like it is merely social issues that are occluding scientific progress. Our "vast technological abilities" remain speculative until proven otherwise. We have yet to demonstrate even the most rudimentary effects of lifespan extension other than the ineffectual manipulation of CR type mechanisms. You must be aware of alternative methodologies. Let's hear them.

3. In your contributors to aging (4) is a consequence of both (2) and (1). (3) is a consequence of oxidation which is a failure to produce sufficient antioxidants due to reduced protein expression from (4). Therefore solve (4) and you solve (1), (2) and (3). I eagerly await to hear your solution.

This conversation as a concept (topic), as well as an event (thread), is evolving at an accelerated rate. When it reaches a quantum divide of logic it either leaps it through creativity or *dies* (is destroyed) against the cold hard logic of fallacy.

The basic game theory that underlies Natural Selection is no more complex than that in many respects. The problem is what the perspective of *intention* (free will) introduces to it and that is why I first try to establish the importance of how various theorists are incorporating their personal biases into the evaluation of deterministic factors for the causality of Evolution.

I am also establishing that through a perspective of *intention* (the anticipation of a more desirable future) that our specific species (Humans) are imbuing Natural Selection with *progressive intent* (intelligent choice through Human Selection). This latter is the real debate IMO but is like trying to have a rational and relaxed electrified cage fight at times because of its innate hot button character.

I have been long seeking this simple connection to explain the paradigm shift to Memetic Dominance over Genetic. But it is also why this topic is the Third Rail of Evolutionary Theory because it uses the *E* word, Eugenics.

Even worse than that it depends ultimately for reasons of resource allocation with respect of human demand upon another *E* word, Economics. [huh]

It is one of the premises I am driving at in the Evolutionary Economics aspect of Human Selection. Again the introduction of Conscience Choice to the *Selection* process governing *resource* distribution through the entire biome of the planet.

Evolutionary Economics

as well as here:

Sociological Impact of Immortality

Our Dying Planet

Overpopulation?

and here

altruism is it selfish?

The dominance of two primary logical strategies for successful evolution also depended on a coincidence of catastrophe because it is the ability to rapidly adapt to the drastically altered environment of the aftermath that provides a small independently evolving group (mammals) the opportunity to excel. No asteroid and perhaps no mammalian ascendancy as the resource allocation system for food would have been totally dominated by successful, long lived, immense growing animals consuming vast amounts of surface resource in populations diminished by primarily predator/prey relationships (the basis of parasitism).

You see mammals had essentially been baby food for dinosaurs/reptiles and even some amphibians as an environmental niche for tens if not hundreds of millions of years. What changed the rules of evolution happened as a single event triggering even tectonic and long term climactic change. The possibility that perhaps more than a single impact possibly clouds previous examples of recovery and divergent diaspora for life on Earth suggests a different model for how Evolution works than a strict Individualist one.

By this perspective Divergent Speciation is the result of the Group Selection Pressure over hundreds and thousands of generations even though it is initiated by incremental individual expressions of genetic advantage. It enters the control of Group Selection through the dynamic of mating (the *popularization* of procreative strategy) ritual/imprinting/instinctive/and cognitive memetic behavior. After many successive generations this behavior becomes *systematized* through genetics over the larger group through social behavior. This is reflected at every level of social behavior to greater or lesser degree, whether the behavior is pack/herd/clan/tribe/culture or perhaps even *species* and *phylum.* In every case though there is an individual pressure to exploit a perceived new advantage providing access to dependent resources outside the original perceived limit of environmental access. Individuals expand the envelope and groups exploit it and after enough tie the divergent specialization produces the speciation effect where the basic genetic blueprint no longer interbreeds.

Convergent ability is dominated by the biophysics of the relationship of physiology to environment but also influenced through intra-group recognition of individual (Strict/Individual Darwinian) advantage recombinant mutation through haploidal sharing that provides the ability to *distribute recognized specific or individual advantages* and this is also a form of group selection through the *species* organization of choice for mating. How this reflects individual genes is through *attractive mating for similar self recognized characteristics. The convergence occurs because of the *synchronizing* through individual selection of commonly recognizable mutations with respect to current Immediately apparent) environmental competitive demand.

So we have two different reasons why as a consequence of time, sharing, and repetition the basic procreative strategy translates into what we see in the evolutionary record. My point is more *why* do we see what we observe and that these *consequences* are the result of a core mammalian advantage that gave an edge against extinction after the KT event; not a reason to die. Death is not a logical necessity, only the most elusive and powerful adversary of the living.

How *Life* (not just Humans) on Earth sustains itself is what we end up discussing in *non-rational* terms because it requires a level of communication, as well as empirical evidence that most are incapable of rationally processing and/or comprehending, let alone obtaining. Life has evolved in terms of *complexity* through adopting effective methods of coping with stress, the primary stress being recognized as *death, you lose* (life).

Gaming and the pleasure reward for example of puzzle solving is probably instinctual as it may be derived of the *sense* of fairness for competition. Fairness for competition relates to probability of successful engagement or escape (fight or flight for survival). Solving puzzles anticipates *learning* to survive as a cognitive behavior of problem solving for a primal few basic resources, food, shelter, mating advantage and colonization of kind.

The last can be seen all the way to bacterial and is not *just* an accident of the proximity of birth and motile capacity it is a *consequence* of choice made and expressed at the molecular level of DNA. The Competition to Survive is a driving force but there are examples of times in which sacrifice of the individual for the group in evolution can be understood as providing a form of Group Selected advantage that make death consequential but that doesn't make it always so and for every species. Group Selection reflects the advantage that altruism strategies can (sacrifice) provide groups in terms of numerical competitive edge. But this can include the competition of any given majority against a minority.

Again the reality of mortality reduces the competition for change but that is about reality of *numbers* not a prori necessity. A primary goal of life is to continue individual genetic expression as well as the *group*, be that colony, herd, species, society, or even phyla. And perhaps, as Lovelock and other Gaians understand it, an *expression* of the unity of *Living Spirit*, the Living World Idea. This is because parasitism and symbiosis are logically the primary biological strategies for the total competition for global resources as a closed system economically (any given planet ecology). EVERY resource based relationship can be distilled into one or the other paradigm (at times both relativistically) of living demand and this includes human relationships.

Behavior in the form of extended life support is the result of group interactivity, the infamous commons, that Evolutionary biologist and many others understand as ecology, and what economists think of as market beyond a strict human paradigm.

OK this relates back to the discussion so far this way. On the list you provide Omnido:

1) Telomerase Shortening
2) Free Radical Damage
3) Glucose Browning
4) DNA distortion and mutation.

We see a reason *why* they are encountered as the result of evolutionary selection and this means that we might alter them working backward through genetics of *why* these processes evolved.

1) Telomere shortening I am suggesting was the result of the advantage of faster mutability after the KT Event and that we do not see it in reptiles because that is how mammals came to expand in the divergent diaspora faster.

However as we grew complex and long lived enough to encounter the mammalian limits of telomerization we experienced the *shortcomings* (pun) of the advantage in the form of cancer and cell apoptosis sooner than our more cold blooded competition.

Nevertheless though it hasn't yet panned out, by studying through Comparative Genetics these alternative species like tortoises, lobsters and others with the longevity advantage of growth cycling to preserve individual expression of speciation we might better understand not only how they do it but how we might alter the core dynamic of a mammalian hosts' genes to make their cell structure and function more reptilian by interfering with the cell replication process itself of the cancerous tissue.

Use the malignancy itself to define the new tissue program by doing to the entire broken gene what a virus does and usurping the replication process with the insertion of an alternative replicative method that now incorporates the strategy of stabilized telomere replication from reptiles.

In other words don't try to reverse mutate the human gene back to original, instead mutate the mutagenic process forward to a proven known stable strategy and let the mutation go forward with cancers ability to make telomere production for all intents and purposes unlimited.

I suggest this idea of mutating a malignancy forward into a new defined genetic program derived from specific genetic patterns that have already been proven by nature is feasible and testable in mice. You see I am suggesting the cancer is a threshold challenge and solving it could induces significantly greater longevity for formally.

2) Free Radical damage is something that trying to simply insert antioxidants into the cell has demonstrated little result. It is not the *logic* that is wrong, it is that the damage to cells continues to accumulate and more importantly accumulates destroying the mitochondria as a result.

In fact some recent studies have shown a detrimental factor from mixing too many different antioxidant agents, as if we are overloading the problem of free radical production and removal from the cell. I think of it like burning coal in a wood-stove and then the metal fatigues at the higher temperature, with the end result is that the cell is destroyed either way because the chimney clogs(inability to remove the end product of combustion) and/or the or the containment vessel for the reaction loses integrity (apoptosis).

The approach I mention above needs to be understood as addressing this aspect through the mitochondrial inclusion in the malignant process. This is an honest question:
What happens to mDNA and the actual organelles during various cancer growths?

Obviously some form of cellular energy production is still occurring or the cells wouldn't be able to continue to replicate in order to grow a tumor or metastasize.

I suspect the approach I am implying provides a parallelism of process that may allow the inclusion of a new host form of mitochondrial genetics as a part of the stabilization of the malignant mutation. This may not only be a new avenue of treating cancer but a manner of converting disadvantage to advantage.

Where I am disagreeing with your perspective Prometheus is that number, #4 may be seen as the *consequence* not the *cause*. This is more than mere semantics. I am trying to approach *genetic theorizing* as a specific *rationalization process* for evolutionary biology. Understanding that we are confusing *cause and effect* because of how we personally interpret causality is critical for new avenues to break with failed ones of past development. We are dancing around a chicken/egg dilemma IMO.

If I am correct and #4 (DNA distortion and mutation) are the *effects* not the *cause* then the first three can all be understood together as causal factors and I would add one that is not on Omnido's list, Genetic stress from direct damaging environmental present mutagens, what we experience as some, viral phages, specific toxins and *energy* (ie. radiation as wavelength and nuclear decay but perhaps in a subtle yet basic way as light and heat) forms. Damage from pathogenic disease under this model is cumulative competitive stress as a opposed to direct mutagenic disease and the evolution of *immune systems* are the result toward these competing organisms that attempt to impose a parasitic strategy on our host DNA cellular organization for co-opting resources that are distributed at the cellular level.

The stress of disease contributes to cumulative cell damage but it would be as much of a problem if the recovery didn't include exhausting the probable number of cell replicative cycles because of number one and as it happens it also contributes to the possibility by triggering healing and forcing cell replacement, when the damaged DNA can then be introduced to the host's cellular matrix.

I would make this a separate category as well of causality even though it expresses itself in all of the other three ways because it results from (consequential) one of the most basic behaviors of all lifeforms, resource acquisition. It is the desire to consume that puts all living things in harm's way when it comes to mutagenic compounds and environments.

Edited by Lazarus Long, 24 August 2004 - 02:23 PM.

cold hard logic of fallacy

Isn't that a contradiction? If you know something to be fallacious how could you attribute it in this way? Perhaps this is a level of metaphorical allusion that is over my head. In any case if you are suggesting that anything I have written is fallacious you better clarify yourself.

Telomere shortening I am suggesting was the result of the advantage of faster mutability after the KT Event and that we do not see it in reptiles because that is how mammals came to expand in the divergent diaspora faster.

Variability in telomere shortening is very much present within the mammalian taxon. Senescence is mice, for example, is not a function of telomere shortening the way that it appears to be in humans. Rather than telomerase itself as has been widely promulgated, it is the equilibrium of DNA damage sensing and repair factors that modulate telomere maintenance as well as other processes pivotal to chromosomal integrity. [1]

I suggest this idea of mutating a malignancy forward into a new defined genetic program derived from specific genetic patterns already proven is feasible and testable in mice. You see I am suggesting the cancer is a threshold challenge and solving it could induces significantly greater longevity for formally.

Could you tell us where this has been proven in mice? Are you sure you are not confusing hypertrophy of a specific tissue type with cancer? Remember that a tumorigenic cell is one that has ceased listening to the cues from it's environment, consequently it is very difficult to conceive of such a cell following any ordered program outside of uncontrolled proliferation. The dogma of cell regulation biology is that a cell is deliberately prohibited by numerous mechanisms of control from following it's default state of continuous growth. It is in this sense that senescence and apoptosis may be said to be controlled, particularly as there are numerous fail-safe systems that will ensure a cell auto-destructs before it has a chance of lose all control and enter into a state of entirely unregulated clonal expansion that inevitably leads to host death.

The approach I mention above needs to be understood as addressing this aspect through the mitochondria inclusion in the malignant process. This is an honest question:
What happens to mDNA and the actual organelles during various cancer growths?

Obviously some form of cellular energy production is still occurring or the cells wouldn't be able to continue to replicate in order to grow a tumor or metastasize

Don't confuse the loss of regulation in the cell that results in cancer with damage to mtDNA which leads to mitochodrial function impairment and possible activation of the caspace pathway of apoptosis. They are entirely different.

Where I am disagreeing with your perspective Prometheus is that number, #4 is the *consequence* not the *cause*. This is more than semantics. I am trying to approach *genetic theorizing* as a specific *rationalization process* for evolutionary biology. Understanding that we are confusing *cause and effect* because of how we personally interpret causality is critical for new avenues to break with failed ones of past development. We are dancing around a chicken/egg dilemma.

It's not me you are disagreeing with here but with a lot of basic research that has proven that a loss of DNA integrity which includes loss of epigenetic regulation (such as methylation patterns) and unrepaired lesions in the DNA molecule itself, lead to abnormal expression of genes. Also it leads to a general lowering of protein production such that the cell is starved of essential enzymes for normal functioning, consequently leading to more damage. My point is that a healthy genome is able to thwart most insults. There is no chicken/egg dilemma. In humans, at least, deliberate impaired telomere maintenance in somatic cells allows for preprogrammed senescence, as the chromosome destabilizes three prospects for altered cell destiny manifest: continued existence as a sub-standard performing cell with ongoing threat of the other two possibilities, cancer or apoptosis. It is likely that other similar 'erosion by design' systems such as that of human telomeres will be discovered.

The average cell is subjected to as many as 500,000 unique DNA molecule lesions per day - and that is via normal metabolic by-products alone. When you can appreciate that it is only due to the vigilance of various DNA repair mechanisms that are constantly working that cells do not malfunction sooner you will understand how important the equilibrium between DNA damage and DNA repair is and why it is as the 'heart' of things.



[1] Hande M.P. DNA repair factors and telomere-chromosome integrity in mammalian cells (2004) Cytogenetic and Genome Research 2004;104:116-122

Death is not a logical necessity, only the most elusive and powerful adversary of the living.-Lazarus Long

Of the living, yes, it is. Death is the destiny for all but one solution to the problem, there is one solution that would gain dominion over all. Life would face catastrophe upon catastrophe, planetary surfaces would be wiped clean, planets, stars, and galaxies would come to an end, eventually all within these would die. But there was one, one solution that if evolved could escape this "fate", and trascend all. The solution, was to develop, to evolve, the information processor into ever higher states, for in a world made of information, that which manipulates it and wields it at will is king above all. As the ages went by autocatalysis would occur, and eventually the dawn of a new era would arrive, an era where all was under the dominion of a new race, a species amongst the many worlds that would choose trascendence over oblivion, and would fight for their right to live. One of these would eventually succeed, freed from the chains of time, of the shackles of space, of the restraint of a bound existence, of the destiny of death, all fetters shattered, it would be immortal and without bound.

In sum
Evolution was a limited process, all of its solutions led to failure, non would survive but one, in the end there would only be one solution. Leading to over specialization and to dependence, eventually virtually all species themselves would stagnate unable to adapt to the greater changes/filters of fitness, as said all but a few, those who harnessed the nature of the world, to break free from it, those who ascertained the nature of the laws, and bent them until they were no more...

What happens to mDNA and the actual organelles during various cancer growths?- Lazarus Long

Not only during cancer growth, but during the later ages of those who manage to live amongst the longest lived humans....

The aging-related increase in discordance, as concerns the presence and/or level of the C150T transition between lympho-monocytes and granulocytes from the same individuals, has clearly indicated that the observed accumulation of the mutation in centenarians has a somatic contribution. Furthermore, a nuclear genetic control of this somatic contribution is strongly suggested by the striking nucleotide selectivity of the mutation...

Strong support for the conclusion of a contribution of somatic events to the phenomenon investigated here has come from the longitudinal studies of fibroblasts, which have provided convincing evidence that the mutation can arise during life or change level in the same individual during aging. Furthermore, in these cells as well, the nucleotide selectivity of the mutation has reinforced the suggestion that the postulated somatic event(s), induced by an environmental or internal stimulus, is under nuclear genetic control...

An interesting possibility is that the somatic event(s) at or near position 150 leading to the appearance and/or amplification of the C150T transition may be a part of a general remodeling of the mtDNA replication machinery, probably nuclearly controlled. This remodeling could accelerate mtDNA replication and compensate for the oxidative damage of mtDNA and its functional deterioration occurring in old age and, possibly, during or after twin gestations. The aging-dependent accumulation of tissue-specific point mutations, which we have previously identified in fibroblasts and skeletal muscle at critical control sites for mtDNA replication (1, 2), is conceivably also a part of this remodeling.

aging mtdna

Edited by apocalypse, 24 August 2004 - 11:34 PM.

Despite demonstrating a form of self involved insecurity, no this comment was not directed at you personally. Just why do you think it to be so?

It refers to the either/or binary logic of trial and error as it relates to *any* idea, including the various ones at the core of this thread?

It is not a prerequisite of any given proposition that it is true, only that evidence is sought to support it and when contradictory ideas reach a paradoxical impasse it can mean fallacy or that neither proposition holds sway over the *whole truth*.

Creativity through intuitive logic often provides the elusive solution that ironically science depends on at these times, not the cold empiricism of Logical Positivism. The contrasting logic of discussion is that when confronted with such impasses the alternative to seeing things in terms of yes/no contradiction is to recognize an alternative model that resolves the paradox with more precise understanding.

Einstein didn't prove Newton wrong, he created Newton 2.0 by this logic. It was a means of resolve apparent paradox that had crept into the empirical result based on formulating a pedagogic model on one set of available data only to have the refinement of the results of that pedagogy over time produce sufficient data to force a major reevaluation of that data.

I am suggesting we are in such a time of forced reevaluation of pedagogy because of the convergence of two related but very different perspectives, Evolutionary Biology and Genetics.

As we reevaluate the primary factors for specific evolutionary characteristics we are also simultaneously mapping not only our own genome but numerous other genomes with characteristics that may be understood better through an updated theory of Evolution and the consequential biology that resulted in what we experience today.

There are definitely such things as logical fallacies, it is not far fetched to recognize such as GIGO. When a theory is predicated upon an incorrect assumption it results in a fallacious conclusion even when the process is entirely logical and rational. Lighten up Prometheus. Why are you seeing any of this discussion in a personal sense?

You certainly don't have to answer me on that but you might owe yourself an answer.

QUOTE (Lazarus Long)
Telomere shortening I am suggesting was the result of the advantage of faster mutability after the KT Event and that we do not see it in reptiles because that is how mammals came to expand in the divergent diaspora faster.

******************

Variability in telomere shortening is very much present within the mammalian taxon. Senescence is mice, for example, is not a function of telomere shortening the way that it appears to be in humans. Rather than telomerase itself as has been widely promulgated, it is the equilibrium of DNA damage sensing and repair factors that modulate telomere maintenance as well as other processes pivotal to chromosomal integrity. [1]

This is important but does not contradict. I will return to this issue after reviewing it further.

QUOTE (Lazarus Long)
I suggest this idea of mutating a malignancy forward into a new defined genetic program derived from specific genetic patterns already proven is feasible and testable in mice. You see I am suggesting the cancer is a threshold challenge and solving it could induces significantly greater longevity for formally.

***************

Could you tell us where this has been proven in mice?

Are you sure you are not confusing hypertrophy of a specific tissue type with cancer?

Remember that a tumorigenic cell is one that has ceased listening to the cues from it's environment, consequently it is very difficult to conceive of such a cell following any ordered program outside of uncontrolled proliferation.

The dogma of cell regulation biology is that a cell is deliberately prohibited by numerous mechanisms of control from following it's default state of continuous growth. It is in this sense that senescence and apoptosis may be said to be controlled, particularly as there are numerous fail-safe systems that will ensure a cell auto-destructs before it has a chance of lose all control and enter into a state of entirely unregulated clonal expansion that inevitably leads to host death.

OK now rather than take issue with my hypothetical conjecture could we instead examine the approach for the moment. I am not saying such a procedure is present naturally but that we might through the use of gene insertion methodology mutate the carcinogenic process even further to a more stable mutation of our own choosing by modeling such on the possible transgenic aspects of already identifiable sequences from other phyla.

Mice are a suitable test platform at the outset but certainly as you previous note mice are more flexible with respect to the telomerase aspect of malignancy. But some tumorous growths have been shown to override telomere shortening and effectively *immortalize* the malignant cell replication *process*. The problem is the associative negative mutation into a tumor tissue that is no longer recognized as the host's DNA nor possessing the original necessary organ functions for the host.

My idea is to continue the mutation of the tissue into some possible alternative genetic blueprint that mimics the original function of the tissue but retains the now present mutation for unlimited telomere replication and you have not only reversed the runaway tumor growth but perhaps stopped senescence for all practical purposes in a specific organ tissue that was formally most vulnerable to it.

Consider this approach another of the examples of the "strengthening the weakest link model" of incrementally bringing senescence to a halt. Yes I can also imagine numerous complications from immune/rejection to incompatible protein production as the end result of RNA synthesis but I am saying perhaps instead of *killing* the mutagen aspect of a malignancy, we harness the process by encouraging even further mutation into a model taken from transgenically compatible gene sequences found in other species and go to a new synthetic product. It is just a suggestion of an alternative logic that won't be found in the accepted pedagogy but is theoretically possible.

QUOTE (Lazarus long)
The approach I mention above needs to be understood as addressing this aspect through the mitochondria inclusion in the malignant process. This is an honest question:
What happens to mDNA and the actual organelles during various cancer growths?

Obviously some form of cellular energy production is still occurring or the cells wouldn't be able to continue to replicate in order to grow a tumor or metastasize

****

Don't confuse the loss of regulation in the cell that results in cancer with damage to mtDNA which leads to mitochondria function impairment and possible activation of the caspace pathway of apoptosis. They are entirely different.

It was an honest question and this is a partial answer but could you elaborate a bit further on the dynamics of the two genomes in relation to the host's carcinogen. I understand the mDNA doesn't mutate I want to better understand what *does* happen with it.

QUOTE (Lazarus Long)
Where I am disagreeing with your perspective Prometheus is that number, #4 is the *consequence* not the *cause*. This is more than semantics. I am trying to approach *genetic theorizing* as a specific *rationalization process* for evolutionary biology. Understanding that we are confusing *cause and effect* because of how we personally interpret causality is critical for new avenues to break with failed ones of past development. We are dancing around a chicken/egg dilemma.

****

It's not me you are disagreeing with here but with a lot of basic research that has proven that a loss of DNA integrity which includes loss of epigenetic regulation (such as methylation patterns) and unrepaired lesions in the DNA molecule itself, lead to abnormal expression of genes. Also it leads to a general lowering of protein production such that the cell is starved of essential enzymes for normal functioning, consequently leading to more damage. My point is that a healthy genome is able to thwart most insults.

We don't in principle disagree but I think that *insult is inevitable* and that just keeping our current system at optimal is insufficient to result in significant longevity beyond current expectation.

There is no chicken/egg dilemma. In humans, at least, deliberate impaired telomere maintenance in somatic cells allows for preprogrammed senescence, as the chromosome destabilizes three prospects for altered cell destiny manifest: continued existence as a sub-standard performing cell with ongoing threat of the other two possibilities, cancer or apoptosis. It is likely that other similar 'erosion by design' systems such as that of human telomeres will be discovered.

The average cell is subjected to as many as 500,000 unique DNA molecule lesions per day - and that is via normal metabolic by-products alone. When you can appreciate that it is only due to the vigilance of various DNA repair mechanisms that are constantly working that cells do not malfunction sooner you will understand how important the equilibrium between DNA damage and DNA repair is and why it is as the 'heart' of things.


[1] Hande M.P. DNA repair factors and telomere-chromosome integrity in mammalian cells (2004) Cytogenetic and Genome Research 2004;104:116-122

Disagreeing with pedagogy doesn't mean I am wrong in my observation. It is a cyclical process. How damage accumulates *after* cell replication in the DNA begs the question as to why it isn't discarded or repaired. I understand the idea that as the DNA fails it causes inadequate replication but also that as various external vectors damage the DNA it then causes the result you describe.

My point is that sometimes we are focused on the DNA as cause and perhaps sometimes it might be more fruitful to see it as victim of the environmental stress as cause of the damaged DNA, which is then *effected* to *cause* additional ongoing damage through systemic failure.

I am only suggesting that there is also no essential paradox in both propositions being true. It is basically a question of a cyclical process that sometimes causes the problems and sometimes has problems caused to it that then respond by causing further even more complicated problems to the whole cell replicative process. Cell replication is also about healing from tissue damage, an event that is a common experience of the living.

Thank you very much for participating in this analysis Prometheus and please do not look at it as a competition to be right but rather a team effort in which together we seek to overcome any fallacy that has compromised the pedagogy. It is by challenging paradigms that pedagogy memetically evolves. The challenge is to ideas, not those that hold them true.

If we had all the truths now we would already have methods to halt senescence based on our current understanding.

Obviously we share the goal of this challenge to better conceptualize the problem so as to ask better question and produce tests of our theories leading to better methods of accomplishing our mutual goal, ending senescence.

I suggest this idea of mutating a malignancy forward into a new defined genetic program derived from specific genetic patterns already proven is feasible and testable in mice. You see I am suggesting the cancer is a threshold challenge and solving it could induces significantly greater longevity for formally.

Could you tell us where this has been proven in mice? Are you sure you are not confusing hypertrophy of a specific tissue type with cancer? Remember that a tumorigenic cell is one that has ceased listening to the cues from it's environment, consequently it is very difficult to conceive of such a cell following any ordered program outside of uncontrolled proliferation...

(My emphasis added)

Prometheus, I don't think LL was saying that mutating cancer to do something positive was proven. If you look at how I bolded one statement, with an inserted phrase in italics, it becomes clearer what he was trying to say. Not clear, necessarily, but certainly clearer.

OK now rather than take issue with my hypothetical conjecture could we instead examine the approach for the moment. I am not saying such a procedure is present naturally but that we might through the use of gene insertion methodology mutate the carcinogenic process even further to a more stable mutation of our own choosing by modeling such on the possible transgenic aspects of already identifiable sequences from other phyla.

(My emphasis added)

I agree with the statement I italicized. I'm confused about the statement I bolded. Why hijack the carcinogenic process? Are you proposing this as an alternative transfection vector to the processes which so far have met only limited success?

We know that we like certain aspects of cancer, such as the lack of telomere shortening. But for the most part, there is nothing desireable about cancer. Why not simply activate telomerase expression (and modulate the expression of any other genes related to telomere length)? Stem cells, as I understand it, already are in this position, so we could just model them instead, as they seem to have many more characteristics we like (as opposed to cancer).

And as I further understand it, one of the benefits of limiting telomerase expression to a small subset of cells is that it limits the number of cells for which cancer becomes a problem in most situations, as telomerase must be mutagenically turned back on before an otherwise cancerous growth can become fatal. Turning on this system in all our cells would only be safe once we've found an alternative method to limiting cancer proliferation. We should also be in a better position to prevent it from forming in the first place. Which leads us back to DNA repair.

While I don't see the wisdom in trying to hijack cancer, I do see where you are going with this, I think...

Jay Fox

Where I am disagreeing with your perspective Prometheus is that number, #4 is the *consequence* not the *cause*. This is more than semantics. I am trying to approach *genetic theorizing* as a specific *rationalization process* for evolutionary biology. Understanding that we are confusing *cause and effect* because of how we personally interpret causality is critical for new avenues to break with failed ones of past development. We are dancing around a chicken/egg dilemma.

...

Disagreeing with pedagogy doesn't mean I am wrong in my observation. It is a cyclical process. How damage accumulates *after* cell replication in the DNA begs the question as to why it isn't discarded or repaired. I understand the idea that as the DNA fails it causes inadequate replication but also that as various external vectors damage the DNA it then causes the result you describe.

My point is that sometimes we are focused on the DNA as cause and perhaps sometimes it might be more fruitful to see it as victim of the environmental stress as cause of the damaged DNA, which is then *effected* to *cause* additional ongoing damage through systemic failure.

I am only suggesting that there is also no essential paradox in both propositions being true. It is basically a question of a cyclical process that sometimes causes the problems and sometimes has problems caused to it that then respond by causing further even more complicated problems to the whole cell replicative process. Cell replication is also about healing from tissue damage, an event that is a common experience of the living.

This is something that I am still trying to figure out. What leads to what...

Here's the line of reasoning that I'm working with at the moment. It's probably just a restatement of an existing theory of accumulated damage, but I haven't read one yet in detail, so I don't know to what degree what I'm suggeting has already been discussed ad nauseum, either here or in academic circles:

Mortality rates increase exponentially, e.g. they double pretty consistently every 7-8 years in humans above about age 35, give or take 5 years. The doubling period has a few periods where it's closer to 6-7 years, and periods where it's closer to 8-9 years, but this can explained by recognizing the ages at which certain specific causes of death "start to become" meaningful in the mortality statistics.

Mortality rates are roughly proportional to the amount of accumulated damage, with some lag time built in for the progression of disease once it has hit its runaway point. I.e., the odds of a disease beginning are roughly related to the amount of damage present, if we assume that each unit of damage has a roughly equal probability of leading to the runaway damage that is disease. Death will not follow immediately after the beginning of a disease, but will lag some time afterward. This period of lag will probably be shorter in older age, due both to the weaker repair systems at a systemic level, as well as the degree of accumulated damage already present at the cellular level. The shorter lag time in older age might also be responsible in part for the slight acceleration in the exponential growth at certain age groups.

Exponential growth implies a feedback mechanism. In other words, from a strictly mathematical point of view, exponential curves are indicative of a situation where the derivative of a value is directly proportional to said value. Put in logical terms, something is involved which is both cause and effect of a process. In this case, mortality is neither cause nor effect of mortality, so I'll ignore that curve for now. However, the accumulated damage upon which I am basing mortality rates fit nicely into this equation. The accumulated damage is both the cause and the effect.

As for the chicken and the egg, this is tougher. Obviously the environment is inflicting some roughly constant rate of damage on all the chemicals in the cell: DNA, RNA, proteins, lipids, carbohydrates, etc. The cell is remarkably efficient at repairing this damage, leaving some net rate of damage that is several orders of magnitude smaller. So, do we attribute this minimum net damage rate to the environment or the inability of the cell to repair itself? This is the chicken/egg scenario, as I see it.

But it is also beside the point. Once we allow this minimum net damage to accumulate, we begin to see the exponential growth of net damage. This exponential growth, although technically "caused" by the environment, is more accurately "caused" by the existing damage. (In much the same way that the act of pushing someone in front of a rapidly moving train is the cause of that person's death, not the train.)

So what of this damage causing further damage; does it matter what kind of damage we're talking about? I suspect that DNA damage is the primary concern in leading to exponential growth of damage. As far as I see it, when it comes to DNA, the buck stops here. Damaged proteins can be and are replaced: protein turnover is one such safety net. (Accumulation of undigestible damaged proteins is one aspect of SENS that Dr. de Grey has already targetted, and is in some ways attributable to the exponential damage. I suspect it's not as big a player as DNA damage, but I hold open the possibility.)

But unrepaired DNA damage does not have as simple a safety net. We can't just rely on turnover: there is only one copy of the DNA per chromosome...well, two technically, but we're assuming an irreparable double strand break. And I suppose we could copy the same gene from the other paired chromosome, but now you've lost one of your two copies of the gene, which means you've lost both a layer of redundancy, and the possible heterozygous characteristics you previously had with that gene interacting with the other copy.

So we're stuck with the following options: apoptosis, turning off the affected gene, or allowing the cell to continue in its damaged state. The first option solves the problem nicely, though it then requires a neighboring cell to divide and replace it, which means the possible duplication of other genetic alterations. Also, any undigestible damaged proteins that have accumulated will be released, to accumulte in the intercellular space, or worse, be absorbed by other cells. The middle option, turning off the affected gene, leaves the cell limping along, if the gene were necessary, which might lead to further damage. The last option definitely leaves open the possibility of the runaway growth of damage.

So addressing DNA damage is definitely a good starting place. It's not the only solution, nor is it a total solution (as damage will always accumulate, even if only at a linear rate). However, it seems the best starting point to me.

That said, once we've done what we need to with respect to modifying DNA damage and DNA repair rates (down and up, respectively), and we've hopefully doubled lifespan (or more), then we will still have to focus on other aspects of damage besides DNA damage. Many such mechanisms will also be found in (or engineered into) DNA, such as better lysosomal digestive enzymes, better glycation/crosslink repair enzymes, etc.

Note that these are all these secondary goals I point out are primary goals of Dr. de Grey's SENS, which notably lacks better DNA repair mechanisms for nuclear DNA, and relies on transporting modified copies of the 13 necessary mtDNA genes into the nucleus. But there's still no mechanism targetted by SENS for DNA repair. So I suppose that combining the two approaches will yield the best results. And given that we have a decent map already of the genes related to DNA repair, I see the DNA repair route as being a more feasible solution in the near term, with SENS filling in the holes that will become apparent later.

At some point, I suppose, we'll have to find a multifaceted approach to curing cancer. I don't like the WILT method proposed by SENS. Better DNA repair will help in the cancer prevention department, though only so much can be accomplished here. So not just prevention, but better methods for fighting cancer, will be needed. Modification of tumor suppressor and promotor genes will probably help, but again, only to a point. More efficient/programmable immune responses will probably help even more, perhaps enough to outlast our greatly extended lifespans in most situations.

So assume we get to 200, 300, 500 years. Then what? With regular medical treatment, and periodic targeted cleansing of all our cells, we could keep going. How much of it can be genetically programmed into us, and how much of it will require doctor visits, we couldn't begin to speculate on at this point. But, we'll have plenty of time to figure that out later once we've tripled, or sextupled, the human lifespan. Well, not plenty of time, as reducing the global death toll from 150,000 per day to 50,000 per day still leaves a lot of death attributable to aging. But certainly it buys most of us a lot more time.

Jay Fox

PS: I am not a biologist. The mathematical aspects of the aging problem appeal to me, and for whatever aspects of the biology that are assumed to be givens, I think I can draw fairly decent conclusions most of the time. However, much of the biology is not a given (e.g. my belief that protein turnover renders damaged proteins less injurious to the cell than damaged DNA is an educated guess, not a fact known by me), and my lack of understanding of the underlying biology is probably visible in my reasoning. If so, go easy on me, and point out where I'm wrong, so that I can adjust my perception of this problem accordingly. I'm trying to understand what forms of damage lead to others, etc., to better understand aging as a process.

Lazarus Long, like your Heinlienian namesake, always the astute diplomat.

A clarification on the difference between cancer and mtDNA mutation:

Cancer is essentially the uncontrolled proliferation of cells. Once their overall number becomes such that they dramatically impede the function of healthy tissue the host dies. From a genetic perspective a number of events have to take place before a cell is said to be neoplastic. These events involve the removal of several layers of tight regulation such as the activation of oncogenes, the deactivation of tumor suppressor genes, the deregulation of controls associated with the extra-cellular matrix, the expression of angiotrophic growth factors, the upregulation of telomerase enzyme, etc. Different events trigger different types of cancer but the common theme is a shutdown of very strict controls that unleash the inherent proliferative capacity of the cell. Essentially cancer cells are very robust and invariably more healthy than their normal counterparts - but they are out of control and not following any developmental program outside of their own unregulated growth. This has many thought provoking philosophical connotations which you may wish to explore.

mtDNA mutation involves alterations to the DNA found inside mitochondria. A single cell can have as many as a few thousand mitochondria, and each mitochondrion can have more than one DNA molecule. Mitochondria can undergo fusion or fission at their own rate irrespective of cell division. Human mtDNA only codes for 16 proteins so a mutation can have a dramatic effect. Unlike nuclear DNA there are no introns in mtDNA so a mutation will definitely have an effect if it occurs. Also, unlike nuclear DNA there is no protection from histones which can keep nDNA from being accessible. So you have a very simple DNA molecule that is always open for reading by a polymerase, but also always vulnerable to damage. Whatsmore, the environment inside a mitochondrion is very toxic due the production of ATP via respiration. You would think a lot of things could go wrong - and they do, which is why the mitochondria in eukaryotic cells have evolved redundancy in the genome as a strategy to compensate for damage and hence the enormous amount of mtDNA per cell. However, each time some mtDNA is damaged, it impairs function ever so slightly yet does not kill the cell. As a consequence it becomes likely that the cell can accumulate many mutations in mtDNA before they become severe enough to signal the infamous suicide pathway of apoptosis. There is a logic to this of course, which is that to prevent a cell from continuing to function with a highly toxic mitochondrion full of reactive oxidants because it stands a serious risk of having it's nuclear DNA damaged which could lead to a fate worse than apoptosis - cancer.

I am greatly pleased at how this is progressing. Today I will try and refrain from responding as much to the developing ideas and instead digest more than a few of them, contemplating them while performing other tasks.

Jay you wrote:

QUOTE (Lazarus Long)

OK now rather than take issue with my hypothetical conjecture could we instead examine the approach for the moment. I am not saying such a procedure is present naturally but that we might through the use of gene insertion methodology mutate the carcinogenic process even further to a more stable mutation of our own choosing by modeling such on the possible transgenic aspects of already identifiable sequences from other phyla.

*************

I agree with the statement I italicized. I'm confused about the statement I bolded. Why hijack the carcinogenic process?

Are you proposing this as an alternative transfection vector to the processes which so far have met only limited success?

The short answer to the second question first: Yes.

Second please understand that as my genetics prof years ago hammered home:

"All carcinogens are mutagens but not all mutagens are carcinogens."

I am saying that cancer can also be seen as the result of *runaway* uncontrolled mutation and this may be treatable by forcing the mutation to go forward to a stable (hypothetical) alternative better than backward to a still vulnerable form.

The hard parts are finding the form to take it to and also defining what part of the malignant genome to interfere with and how best to accomplish the insertion of the critical gene sequence.

I am suggesting it would be easier to manipulate the cancerous genetics that are already destabilized than the hosts and that perhaps sufficient genetic material remains of the host's in the malignant tissue so that once the tissue mutation were stabilized the host would not initiate the rejection of the tissues based on an autoimmune response.

If the completed transmutation of cell tissue were sufficiently viable to cohabit the affected organ then slowly through the process of cellular replication and attrition, the more resilient mutated tissue would replace the more vulnerable older ones through an internalized example of Natural Selection. The actual cellular function of the transmuted tissue needs to be equal to or greater than the original tissue with respect to the specific role it play's in the host's metabolism BTW.

On a separate note I want to thank you Prometheus for the clarification on what is going wrong with mitochondria distinct from cancer. What I am suggesting also is that we have two distinct problems at work and I seek confirmation that when a malignancy occurs the mitochondria are not directly effected. They do not however continue to fail in the same way and this phenomenon interests me.

I have read of experiments that have sustained some malignant tumors in vitro now for many decades yet the mitochondria in these tumors had to come from the host. How is this possible?

If the mitochondria is totally unaffected then one would expect the tumorous tissue to suffer senescence from the cumulative oxidative damage and mDNA mutation just as the host's tissues do but apparanetly it doesn't.

Why does mitochondria in some instances find the ability to repair and replicate itself in order to sustain a malignant tissue growth yet it cannot do so for healthy tissue?

I have read of experiments that have sustained some malignant tumors in vitro now for many decades yet the mitochondria in these tumors had to come from the host. How is this possible?

If the mitochondria is totally unaffected then one would expect the tumorous tissue to suffer senescence from the cumulative oxidative damage and mDNA mutation just as the host's tissues do but apparanetly it doesn't.

Why does mitochondria in some instances find the ability to repair and replicate itself in order to sustain a malignant tissue growth yet it cannot do so for healthy tissue?

The classic example of course are HeLa cells which are derived from the cervical tumor of an unfortunate African-American woman over 50 years ago, named Henrietta Lacks. This line of cells which continues to be studied today is characterized by its aggressive and robust nature - if you place a few HeLa cells in a culture of other cells, the HeLa cells rapidly invade the entire culture. There is nothing special about these cells of course, other than they have been transformed (made cancerous) due to a carcinogenic virus known as papillomavirus.

As per my previous post a transformed cell can be described as being in a 'no holds barred' type of regulation insofar as growth is concerned. Whilst this is very bad for the host organism it is very good for the cell because it has its all its repair systems functioning at full throttle. In fact cancer cells tend to be more resistant to the effects of chemotherapy and radiotherapy than normal cells because of that reason. Paradoxically, once an old, pre-senescent cell has transformed due to to, say oxidative damage, it then becomes more capable of resisting oxidative and other damage because it has the various limitations imposed on it during its normal, controlled phase removed. This is precisely why mitochondrial damage is reduced rather than increased in these robust, 'healthy' cancer cells.

You may be thinking by now: let's harness the power of cancer cells and use it in a controlled fashion to extend lifespan of normal cells! Well, that's right, one possible direction is to increase the rate of DNA repair, increasing the rate of oxidant quenching and increase telomerase activity in somatic cells - part of what is upregulated in transformed cells - but without the loss in cell to cell and cell to extracellular matrix communication which is imperative in preventing the cell from migrating (becoming malignant) and proliferating beyond the optimal density for the tissue it is in. The astute genetic engineer in liberating the repair functions would concomitantly tighten the remaining regulatory functions to ensure the cell does not get out of control. The gold standard, of course, is to optimize the immune system to recognize any wild cell and rapidly eliminate it.

Cancer, strangely enough, holds many of the secrets of immortality.

BTW one adendum.

The ability to do this as recominant manipulation of the tumor is something that can be done in vitro too, followed by the insertion of the organized result into mice.

Query:

Has anyone given Stem Cells cancer?