19 replies to this topic

[chubtoad]

http://www.nature.co...l/050131-6.html

Bacteria may not have to deal with grey hair and wrinkles, but they do appear to grow old. By following microbes with a camera, researchers have revealed aspects of their life cycle. Their innovation could help people investigate the molecular mechanisms involved in ageing.

[manofsan]

So this is a question I've wondered about for some time--

If you guys say that all active cells in the body are subject to aging deterioration, and that germ-line integrity of an organism is mainly preserved by specific protection and inactivity of gamete cells...

Then what about ordinary bacteria and protozoa which are unicellular and don't have the benefit of gamete specialization? How are they able to preserve their germ-line? Why don't such organisms fall apart after enough reproductive divisions and associated defect accumulation?

Or are they in some constant battle of natural selection, with their germ-line constantly being weeded of defects pruned back to "normal" by routine forces of natural selection?
That would be weird, since I would expect entropy from mutation to rapidly degrade genomic quality vis-a-vis life-sustaining functions. Comments?

[John Schloendorn]

Here is the original story.

Chip,
Nice finding! I think the authors are venturesome to call this "aging", which is normally reserved for multicellular phenomena that involve genetic and epigenetic degradation. It is functionally similar to our type of aging, but mechanistically quite different.

I disagree with the authors that their finding could suggest that

...it is impossible to achieve perfect molecular maintenance through natural selection.

It is easy to imagine that the bacterium could escape the adverse effects of its "aging" phenotype by synthesizing fresh pole proteins and lipids from the pristine genetic information that it still has. (After all it does it once on every division. It would simply have to do it twice.) The fact that it "chooses" not to do so could be seen, as the authors also suggest, to argue for an evolutionary advantage of "programmed" aging, or antagonistic pleiotropy similar to the postulates for multicellulars.

Manofsan,

Or are they in some constant battle of natural selection, with their germ-line constantly being weeded of defects pruned back to "normal" by routine forces of natural selection?

Basically yes. I would say the same holds for multicellulars' germ line mutations.

That would be weird, since I would expect entropy from mutation to rapidly degrade genomic quality vis-a-vis life-sustaining functions. Comments?

Why weird? This is just how evolution works. Most mutations lead to loss of replicator power, while only a few maintain, or extend replicator power and allow the few creatures that underwent them to become many. (I've written about this mechanism in more detail)

[manofsan]

Okay John, I guess I sidetracked -- what I wanted to point out was that protozoa can't remain inactive/non-senescent like gametes. If they're metabolically active then they're senescent, although they won't have telomeres and would freely replicate rampantly.

But if as you've said that natural selection keeps a colony of protozoa qualitatively pure, then how come natural selection can't keep a group of cells in a multicellular organism similar pure across their many replications during the organism's lifespan?

In other words, why are protozoa/bacteria more immortal than human cells?
Wouldn't protozoa/bacteria have the same rate of senescence as human cells?

Human cells would mainly die from apoptosis rather than the natural selection that applies to protozoa/bacteria. But mainly, from what you're saying, it's that rampant growth rate of protozoa/bacteria that gives them the edge over human cells in preserving quality -- they simply out-multiply the inferiors in a way that human cells cannot do without being cancerous.

Would it be possible to use cancer cells as experimental models towards finding immortality for human cells? Just try out various varieties of cancer cells competitively, and see which breed can keep multiplying the longest without wearing down. Then if you can fix/remove the unregulated growth, you have the superior immortal breed of human cell that you want -- one which is prone to producing fewer defects associated with senescence.

Comments?

[John Schloendorn]

Manofsan,
Good thoughts there.

But if as you've said that natural selection keeps a colony of protozoa qualitatively pure, then how come natural selection can't keep a group of cells in a multicellular organism similar pure across their many replications during the organism's lifespan?

I would argue that natural selection could, if the selective pressure were right. Apparently, there just is no such pressure, or it is compensated. I discuss this group of questions step by step in the article cited. (Don't be afraid, it's written for non-biologists)

In other words, why are protozoa/bacteria more immortal than human cells?
Wouldn't protozoa/bacteria have the same rate of senescence as human cells?

That would be puzzling to someone who believes that aging is uncontrolled wear and tear damage, unless he can demonstrate superior DNA maintenance mechanisms in humans, and reasons why they would not evolve in bacteria. This observation is a favourite of those who argue for programmed aging theories. (Note that "senescence" is actually a technical term to designate a defined developmental pathway in human cells that arrests their growth and division.) See where we're going?

If evolution were an engineer, this would be less like she were unable to find a solution to multicellular aging, but more like she were unwilling to.

from what you're saying, it's that rampant growth rate of protozoa/bacteria that gives them the edge over human cells in preserving quality -- they simply out-multiply the inferiors in a way that human cells cannot do without being cancerous.

Hm, yeah, I think that's a cool way to put it. This may be related to the gradual loss of adult stem cells with age, which is proposed to be a cancer defense.

Would it be possible to use cancer cells as experimental models towards finding immortality for human cells? Just try out various varieties of cancer cells competitively, and see which breed can keep multiplying the longest without wearing down. Then if you can fix/remove the unregulated growth, you have the superior immortal breed of human cell that you want -- one which is prone to producing fewer defects associated with senescence.

A cancer cell with the unregulated growth fixed is basically a stem cell. So you see this type of strategy is being heavily pursued. But let's be clear about one thing - I don't see the need for "a superior immortal breed of human cells". All we really need is the technology to replace old cells with young ones. The young ones might then be given time to age, and we simply do it again. This may be even safer than using immortal cells for good, because the "unregulated growth fix" tends to degenerate over time, and cells tend to become cancers. Some even argue to shorten the life span of these replacement cells deliberately and perform the replacement more often, in order to minimize cancer risk.

[manofsan]

I like the way you think John - which then gets us back to previous discussion board threads on high culling rate combined with high replication rate -- Let's call it Very Dynamic Equilibrium, because the strategy hinges on speedily throwing out the bad and increasing the good. That's more metabolic activity and not less, if all other things are equal.

But then we can't rely upon gamete-style metabolic inactivity as our means of preserving DNA quality. So you need the active DNA repair systems with good response time to remove single-nucleotide mutations before they get entrenched into double-strandedness.

What I'm surpised at is why the mitochondria of cancer cells don't degrade with all the replication, to cause them to wear out. If as Aubrey says the mitochondrial deterioration causes many symptoms of old age, then how come cancer cells don't suffer from reduced mitochondrial efficiency as they continue to multiply along?

A mitochondrial cure alone would be worth a lot, in terms of fighting the aging battle, leave aside the nuclear DNA repair mechanisms.

I suspect it will be the advent of lab-on-chip automation devices that will bring us more progress in evaluating and selecting various cellular varieties for anti-aging advantages.

Comments?

[John Schloendorn]

Very Dynamic Equilibrium, because the strategy hinges on speedily throwing out the bad and increasing the good. That's more metabolic activity and not less, if all other things are equal. But then we can't rely upon gamete-style metabolic inactivity as our means of preserving DNA quality

Hmm, germ cells are not only functionally inactive, but also have higher levels of DNA repair activity. I would say metabolic activity is by definition the only means to do the processing and preservation of genetic information that life is all about. Therefore I'd be surprised if it were in all cases bad for our genetic information.

If as Aubrey says the mitochondrial deterioration causes many symptoms of old age, then how come cancer cells don't suffer from reduced mitochondrial efficiency as they continue to multiply along?

(Not just Aubrey says so.) I don't know if your question has been investigated. Perhaps selection again. The few that stay good by chance might out-replicate the damaged ones.

A mitochondrial cure alone would be worth a lot

I could not agree more. But it would probably be more difficult to implement than a cure for both mitochondrial and nuclear mutations at once by cellular replacement. (I know I'm repeating myself. It's just that a number of people here don't act as if this were a valid idea, but also don't provide counterarguments. So I issue this wake-up call at every opportunity.)

I suspect it will be the advent of lab-on-chip automation devices that will bring us more progress in evaluating and selecting various cellular varieties for anti-aging advantages.

Evaluating - yes. Implementing - no.

[manofsan]

John wrote:
"a cure for both mitochondrial and nuclear mutations at once by cellular replacement."

You're right, cellular replacement means high rate of apoptosis and regeneration. Killing might sound like the easier part, but you'd have to be able to select for every possible DNA deviation to kill off, which is ridiculous. Unless you could somehow select based on phenotype. Likewise, regeneration means replication which is also error-prone.

I hear what all you guys are saying about DNA repair, but repair can never be 100%. There needs to be some sort of ideal data template to compare against, in order to truly remedy genomic data loss.

I know it sounds stupid, but somehow I find the idea of DNA molecular synthesis from hard-drive based genomic data to be alluring. Because the data on your hard drive can always be kept pure, without degrading over time. But biomolecules are very vulnerable to degradation by contrast. (I can't for example ever imagine large corporations or govts storing their information in the form of nucleic acids!)
The problem with a hard drive based genome is that you can't get it into the billions of cells distributed across your body. Only nucleic acids can do that -- but the catch is that they have that inherent danger of degrading along the way, as they replicate. The only way to economize on those errors is to have cells dedicated to somatic replication and avoiding the usual senescent contribution to bodily function/sustenance. But again, economization/minimization of errors is not truly the same as elimination of errors.

What if there were some way of storing data in non-degradable form, and getting it into a cell, and then translating it into the nucleic acid information that the cell is accustomed to using? Could quantum entanglement or nano-sized EM transcievers be a possibility? You would dsitribute into each of your cells a tiny molecular-sized device that could recieve electromagnetic wave transmissions from outside the body. It would then "write" that incoming information into nucleic acid form, directly on the spot.

That might sound crazy, but it could be possible one day, with advances in molecular-scale electronic components. This transceiver would have to be some sort of electromagnetically-interactive equivalent of the ribosome perhaps.

I know it all sounds like silly fantasy. Sigh.

It's just that biomolecules are so frustratingly fragile, short-lived and unreliable as information storage devices. Biology always needs Darwinism to correct it and keep it in line, otherwise it easily falls prey to entropy and deterioration. This dependency on Darwinism seems unremovable, perhaps because all our biological infrastructure has been built by Darwinism in the first place.

[manofsan]

Picking up where I left off -- it's not possible to have biological tools seem ill-suited to act on genomic data quality directly, correcting deviations in each and every nucleotide. Darwinism acts at the higher level of outcome, with phenotypes as the mediating competitors. Our Darwin-designed biological infrastructure doesn't seem to particularly care about the any one lowly nucleotide or information bit, and therefore isn't really designed around meeting such a need. But for true data quality control, that's exactly what you have to be concerned with. One bit here, another bit there, etc, and it can really trip everything up, when it adds together. Hence, aging.

I wonder how one might set up Darwinistic selection to develop anti-aging solutions for us. Hypothetically, if you had a species or ethnic group that was oriented towards reproducing at a later age in life compared to everyone else, then this might help to select for longevity, with the implied innovations in DNA repair mechanisms, mitochondrial improvements, etc. Could we set up Darwinism to reverse-engineer these things for us?

Darwinism seems to be the only thing we can count on in the world of biology -- perhaps our only hope against aging is to make it work for us there too.

[John Schloendorn]

I wonder how one might set up Darwinistic selection to develop anti-aging solutions for us.

With a biologist who plays god and selects the right kind of stem cell? Sorry, orders his lab on a chip to do so )

[manofsan]

Oh, but Prometheus, in our artificial experimental environment we could only allow the lab rats or sexual protozoa past a certain age to compete reproductively. We could also arrange to have our own man-made mutation, rather than depending on random acts of nature to cause mutation. Our man-made mutations could exclusively be applied at the gamete level, which wouldn't interfere with the normal routine activity of the rest of the cells in an organism. Therefore, gamete-specific mutation can be the basis for germ-line variation, leaving the rest of cells free to concentrate on "keeping what they're born with" (ie. resisting mutation)

In computer programs based on the genetic algorithm paradigm, it's easy to setup the method of variation, as well as to measure any parameter and use it as the basis for selection. It may be slightly harder with real life biological subjects, but it should still be doable.

[John Schloendorn]

Sorry, somehow missed that previous post, here we go!

Killing might sound like the easier part, but you'd have to be able to select for every possible DNA deviation to kill off, which is ridiculous.

My ideal criterion for killing would be like "has been hanging around in my body for too long", i.e. does not carry the right suicide gene / chemoresistance combination that I change every three score and ten years. But I agree, this is science fiction.

I hear what all you guys are saying about DNA repair, but repair can never be 100%. There needs to be some sort of ideal data template to compare against, in order to truly remedy genomic data loss.

For your very reason, I'm not saying anything about DNA repair [wis] (yet) The ideal template is the germ line, from which embryonic stem cells are derived. It carries no deleterious mutations in most cases, or otherwise we could not have young, healthy offspring.

somehow I find the idea of DNA molecular synthesis from hard-drive based genomic data to be alluring.

Jesus, have you ever thought about putting a stick through a stone disc? One could do all sorts of useful things with that device, drive carts and ultimately make even hard disks work. Sorry about the pun, but why would you even move a finger, when nature already does it for you?

But biomolecules are very vulnerable to degradation by contrast

Nature managed not only to store, but, arguably, also to improve her huge amount of genetic information in biomolecules, for 3.5 billions of years. That is, well, 3.5 billions of years longer than any computer did. (Not saying they couldn't. See above.)

If I may turn your own weapons against you, maybe this would interest you ) (free full text available)

Could quantum entanglement or nano-sized EM transcievers be a possibility?

Definitely quantum entanglement! That's why I'm working on this stuff, to see times when we do such things [tung]

Biology always needs Darwinism to correct it and keep it in line, otherwise it easily falls prey to entropy and deterioration

Manofsan, no static device can last forever, however sophisticated you build it. Evolution is the only entropy-dissipating mechanism we know, or can think of. If we want to last forever with it, we don't have to change much at all. We have to move our personalities away from the things that replicate, mutate and perish (presently genes) and closer to the things that benefit from the dissipation of entropy (presently species).

I know it all sounds like silly fantasy. Sigh.

Fantasy is not silly. It's the absolute prerequisite for ever doing anything intelligent. Even though I had quite a go at it, thanks so much for sharing yours!

Edited by John Schloendorn, 04 February 2005 - 09:56 AM.

[manofsan]

John, if say we talk about attaining a lifespan of 500 yrs, a man-made machine can easily preserve its structural and informational integrity for that long. But biological biomolecules would be very seriously challenged to preserve informational and structural integrity for that amount of time. Even using the usual self-replication approach, the biological systems will incur the mutation errors along the way, with only the force of natural selection darwinism to weed off those errors/deterioration. And of course darwinism is blind to explicit gene-preservation and is really only sensitive to outcome, which is more related to phenotype. Nucleotides are then on the bottom of Darwin's contact list, behind outcome and phenotype.

Natural selection seems wasted or under-utilized when it is restricted to only weeding off the routine negative deviations from already healthy genomes.

Perhaps we need to think more about how to make natural selection do more work for us, and how to exploit it properly. After all, biological systems are built around natural selection, and so perhaps that's the natural time-honored route to go.

So then, if you had to structure situations that could then harness natural selection to extend lifespans, then how would you do it?

As said before, you could have a population of mice/protozoa/humans/monkeys/whatever who would be discouraged/prevented from breeding until later in life. Suppose you take the oldest chimps in a tribe and then let them breed a whole lot. Then take the very oldest from that resulting group and let them breed a lot. And so on, and so on, etc.

Wouldn't you eventually wind up with a bunch of chimps that are naturally much longer-lived than the average chimp?

Why isn't this simple approach the best one for a Methuselah Mouse Prize? Sure, you'd have to go through a lot of chimps, but at least your process would be reliable and simple. As a matter of fact, this kind of thing could have been initiated centuries ago, and by now we'd have much longer-lived chimps.

[manofsan]

John wrote:
" Evolution is the only entropy-dissipating mechanism we know, or can think of. If we want to last forever with it, we don't have to change much at all. "

Evolution only follows the dictates of the environment. So if we want to use evolutionary methods to devise anti-aging solutions for us, we have to focus on engineering environments in such a way they will make evolution do what we want.

If evolution results from the iterative combination of variation and natural selection, then this means we have to engineer variation and also selection processes, to improve upon nature and to re-orient evolution in directions we want to go.

I was reading Aubrey's comments about marginal advances in life-extension versus radical advances. Well, whether or not evolution achieves tiny incremental or large incremental advances depends on the kinds of variation we supply it with, and how robust our selection process is.

It's hard to imagine us totally re-inventing alternatives to the wheel, re-engineering our life-sustaining processes from the ground up to improve life-extension, but I mentioned hard drives, quantum entanglement and molecular transceivers as possibilities.

Meantime, perhaps we should come up with ways to make evolution more efficient, as well as ways to harness it for life-extension. An obvious advantage of this approach is that it would be extending off of what we already have. We are already made of these biomolecules, so they have to be our starting point, and evolution already knows how to work with these. "You don't go into the anti-aging war with the army you want, you go into it with the army you have"

[olaf.larsson]

"biological biomolecules would be very seriously challenged to preserve informational and structural integrity for that amount of time. " Not far from here there is a 1000 year old oak, appearently it has no problems with structural intergrity.

[apocalypse]

"biological biomolecules would be very seriously challenged to preserve informational and structural integrity for that amount of time. " Not far from here there is a 1000 year old oak, appearently it has no problems with structural intergrity.-wolfram

Indeed.

I hear what all you guys are saying about DNA repair, but repair can never be 100%. There needs to be some sort of ideal data template to compare against, in order to truly remedy genomic data loss.-manofsan

Not necessarily, there are organism that've lasted for thousands of years(i.e. wolfram's example). And there are animals that appear to be ageless, though similar closely related species of some are said to age, quite fast actually. While one could say there are substantial difference between them and us... the fact that closely related species would show one exhibiting aging and another apparently not, is quite telling. Even breakdowns can be built-in. Cancer can be more effectively controlled(than is usually the case in most organisms it'd seem) with minor modifications, and error tolerance effectively dealt with or else giant sized organism would be extremely difficult to evolve due to the need for fundamental changes(besides the energy requirements), something that seems not to be the case.

As said look at cancer it is said to be an unsurmountable problem, yet you can scale the size of an organism, and thus the number of cells while allowing for substantially long lifespan. All with what's most likely a few modifications, and the added components which add more errors can be tolerated and all, allowing for things to scale way up. Aging too, appears to have been eluded by some organisms.

ed

[manofsan]

wolfram:
"Not far from here there is a 1000 year old oak, appearently it has no problems with structural intergrity. "

Ok, point taken. However the average human being cannot adopt the slow metabolism of the 1000 year oak, or the 100-yr turtle. It's not compatible with our lifestyle. By contrast, a short-lived hummingbird or many of these short-lived bugs are constantly active. So aging is just as much a core part of our biology as are carbon and water.

If caloric intake restriction is broadly considered to be a means of conserving/prolonging lifespan, then shouldn't we look at species having both higher caloric expenditure and lifespans as pointers to naturally-evolved mechanisms that extend lifespans relative to caloric intake/expenditure?

I read comments in the wake of the Human Genome Project success, made by either Crick or Watson, that society needs to then go after biometric cataloguing in order to make the most use of genomic knowledge. So what I mentioned in the immediately preceding paragraph would be an example of this, as applied towards life-extension.


Anyhow, I still think that our biological infrastructure is entirely designed by entropy and variation and mutation, of which aging is necessarily a part, and therefore aging and its root causal fragilities are inherently a result of this mutation-based evolution paradigm.

[John Schloendorn]

However the average human being cannot adopt the slow metabolism of the 1000 year oak

Seen what a 1000 year oak's metabolism does in spring?
Apart from that, the oak information is being preserved and improved for much longer than 1000 years in other oaks, which all happens exclusively via biomolecules.

[apocalypse]

Ok, point taken. However the average human being cannot adopt the slow metabolism of the 1000 year oak, or the 100-yr turtle.-manofsan

The thing is, after centuries in the case of some turtles(IIRC), or many millenia in the case of some trees one should expect to see at least some sort of measurable decay, not increases in reproductive ability(some of the turtle or turtle-like species), or negligible change. IIRC as I've said, I think there was at least one of the animals regarded as possibly negligibly senescent, that had a close relative(species) with a lifespan of around 12years.

If caloric intake restriction is broadly considered to be a means of conserving/prolonging lifespan, then shouldn't we look at species having both higher caloric expenditure and lifespans as pointers to naturally-evolved mechanisms that extend lifespans relative to caloric intake/expenditure?-manofsan

I agree, but I believe that species that seem to exhibit negligible senescence are promising too, especially comparisons when available with closely related aging ones.