149 replies to this topic

[OP2040]

So my view is yes to group selection and evolution of life-span as being niche specific. But no to selection of a specific aging pathways for their own sake.

 

I view the body as a system for resisting entropy as best it can, and given the chance, I.e. low death rate from external causes, it will get better at it through succeeding generations. Sometimes a species does have to select for faster growth and faster breeding, and this may also drive faster aging.

 

Michael Rose has does some great work with flies. And he has proven that fertility and aging can be de-coupled, as his flies are much longer lived AND produce more young. But they still lose out in competition will wild type flies. The conclusion? Life can select longer lives. But doing it without compromise takes time and (evolutionary) effort.

 

Fair enough.  While this may or may not be described as "programmed aging", it is certainly very far away from any damage theory of aging. 

 

The main conclusion should be that the way to intervene in aging should be largely genetic.  In my view it should be enhancing gene expression patterns related to youth.  Almost all of the aging-related studies I've read make the claim that the gene they are talking about is highly conserved or exists as a close homolog in humans as well.  This means that those genes simply need to be turned on, probably transiently.  First, they need to be unlocked (epigenetic reversal) and then turned on. 

 

There are just too many examples, even outside of the usual animals we talk about, where regenerating various tissues over and over again is no problem at all.  Deer antlers regrow in the exact same shape every year.  I think it's elephants that have close to a dozen sets of new teeth over their lifetime.  You can go on and on with examples like this. Some of these tissues become very, very damaged in between bouts of complete regeneration.  I think some day we will consider these things very easy to do and wonder why it took so long.  We don't usually think of regenerating specific organs as anti-aging.  But if we can regenerate any organ easily, I don't see what would cause us to age.

[QuestforLife]

Fair enough.  While this may or may not be described as "programmed aging", it is certainly very far away from any damage theory of aging.

Not really. Damage is just the consequence of entropy (beyond that repaired or prevented by the body). 
 

The main conclusion should be that the way to intervene in aging should be largely genetic.  In my view it should be enhancing gene expression patterns related to youth.

I agree and that is why I advocate telomerase therapy, which has shown that lengthening telomeres restores youthful gene expression in those cells.
 

There are just too many examples, even outside of the usual animals we talk about, where regenerating various tissues over and over again is no problem at all.  Deer antlers regrow in the exact same shape every year.  I think it's elephants that have close to a dozen sets of new teeth over their lifetime.  You can go on and on with examples like this. Some of these tissues become very, very damaged in between bouts of complete regeneration.  I think some day we will consider these things very easy to do and wonder why it took so long.  We don't usually think of regenerating specific organs as anti-aging.  But if we can regenerate any organ easily, I don't see what would cause us to age.

Yes, I agree. We will master regeneration. But it would be useful to understand why nature for the most part does not use it, or why and how it does in those special cases where it does.

[OP2040]

I agree and that is why I advocate telomerase therapy, which has shown that lengthening telomeres restores youthful gene expression in those cells.

 

It's interesting that most of our interventions have been for the non-primary hallmarks, whether it be NAD+, mitochondrial, senolytics....

These have been very interesting and much progress has been made.  But we have no reason to expect that they will do anything but slow down the rate of aging or improve healthspan somewhat.

 

What we need are robust interventions for the primary hallmarks.  Telomeres are one of them, and we can't really do much there yet.  The others being proteostasis, epigenetics and dna damage.  This looks like a list if the various pathways by which most regenerative and n.s, animals do what they do.

 

If you look at these categories, our current tools are very rudimentary, but there has been some amazing progress in epigenetics in the last few years. I am a firm believer that if we can engineer solutions to these, or mimic the aforementioned animals, it is game over.  I really don't think damage plays a role until there is extensive tissue damage, which is of course relevant.  But even there, I think it could be walked back step-wise.

 

I haven't thought about telomeres in a while because the interventions are so distasteful.  You have take out a second mortgage to use a susbstance (TA-65) that might lengthen some subset of telomeres.  That's not even close to good enough. 

 

The encouraging thing is that even within the primary hallmarks, there seems to be a hierarchy.  Epigenetic reversal may be all that's needed, as it is proving to pretty much restore the other three as well.

 

[Mind]

The main conclusion should be that the way to intervene in aging should be largely genetic.  In my view it should be enhancing gene expression patterns related to youth.  Almost all of the aging-related studies I've read make the claim that the gene they are talking about is highly conserved or exists as a close homolog in humans as well.  This means that those genes simply need to be turned on, probably transiently.  First, they need to be unlocked (epigenetic reversal) and then turned on. 

 

 

This is definitely worth pursuing, it could produce significant age reversal in many systems, however, after reading through the bioelectricy thread, and watching the latest video (in the last post), it makes me wonder if genetic engineering approaches to aging will have some endogenous limits.

[xEva]

This makes sense to me.  Negligibly senescent animals often don't have much in common.  But one thing they might have in common is that they live in relatively safe environments as far as predation goes.  This evidence doesn't necessarily jive with the population boom and bust idea, but it would still be based on group selection.  The good news is that apparently various longevity genes are a thing that can and have been selected for many times in evolutionary history.  Or conversely, there could be death genes that are selected against.

 
AFAIK most animals with negligible senescence live in/off oceans, which are so vast that population boom and bust do not apply.  They share this environment with related species that have steadier rates of aging similar to ours.
 

which brings another point, which is addressed to QuestforLife and Co:

 

I know descriptions of natural death in only 2 species w.n.s., albatross and naked mole rat. Reportedly, n.m.rats become sorta sluggish in the last few days (a week -?) and then just drop dead for no immediately apparent reason. And I could not find out what exactly kills them in the end.

 

And then I remember a description of death of an albatross (though only one individual observed through the years at its nesting site -- you can't keep them in captivity). Albatross are thought to live at least 60y and show no signs of aging. The individual observed succumbed to what seemed aging in the last 2 years of its life. Its exact age was unknown.

 

These life histories do not fit with the stochastic damage theory, which presupposes a more or less steady rate of deterioration. And again, in semelparous speices death is said to be "programmed". IMO it's logical to assume that natural death is always programmed, and the form it takes is what suites best the survival of the group in question.

 

 

 

I refer back to Michael Rose's work on fruit flies.  Fruit flies that live more than twice as long with not one deleterious consequence.  To me that says a lot about aging and death being a "functional" aspect of evolution.  I don't think we have all the answers, but we really need to toss out any theory that implies that aging is based on entropy or damage-alone.  It is very clear that, given the right evolutionary circumstances, living indefinitely is easy-peasy.

 
ah QuestforLife beat me to it! Michael Rose long-lived flies evolved for the conditions in the lab where they were bred. They did not do well in a more natural environment where they were outcompeted by the wild type flies.
 
So when you speak of improving on human genome, what environment you have in mind? The one we have now, which of the many climes? or the ones that are coming?  How about spaceflight?
 
(though I imagine it will be done in the future. Say you sign up for a gig on Mars, and so you edit your genome, oh just a bit, to better cope with space flight + the conditions on the Mars station. And then you edit it back when you return. Would be cool, no?)

Edited by xEva, 13 December 2018 - 04:57 PM.

[OP2040]

I think you're right and bioelectricity is upstream of even gene expression, therefore should be even more powerful if we ever perfect it.  One bioelectrical intervention contributes to a whole cascade of gene expression changes, and even more when you get down to even lower levels. 

 

One of the Levin findings that is most intriguing is that for something like a planaria, genetic makeup doesn't even matter that much.  They have completely scrambled genomes, but as long as the right genes are "around" the signal can orchestrate tissue renewal through them. 

 

Having said that, I think we're closer to intervening for individual organs by turning genes on and off in vivo.  At this point it's all about delivery, delivery and delivery.

[xEva]

guys, in your talk about the longevity genes, an assumptions shines through that life is evolving from short lifespans to indefinite (in individuals of a group). But there is also the opposite view, namely that indefinite lifespan is a given and the pro-death (or aging) program sits on top of the developmental program.  It could be a later evolutionary development, when the need for individuals' death arose as different groups began to compete in limited space. Apparently, this turned out such a successful strategy that it became the dominant one (at least on land, but there are many immortal species in the oceans).

 

If the above view is correct then there is no pro-longevity genes -- or they all are pro-longevity, in a sense. Is there pro-death genes? Considering how everything is intertwined and how different products of each gene have multiple functions, I doubt it. Which leaves us with the program itself -- or rather how it is implemented in this last step of the development.

 

In this regard it's interesting to read the two studies that are referenced in the C. elegans paper above:

 

Germline stem cell arrest inhibits the collapse of somatic proteostasis early in Caenorhabditis elegans adulthood, 2013

from Abstract

... the effect of GSCs [germ line stem cells] on the collapse of proteostasis at the transition to adulthood is due to a switch mechanism that links GSC status with maintenance of somatic proteostasis via regulation of the expression and function of different quality control machineries and cellular stress responses that progressively lead to a decline in the maintenance of proteostasis in adulthood...

 

Regulation of Life-Span by Germ-Line Stem Cells in Caenorhabditis elegans, 2002

Abstract
The germ line of the nematode Caenorhabditis elegans influences life-span; when the germ-line precursor cells are removed, life-span is increased dramatically. We find that neither sperm, nor oocytes, nor meiotic precursor cells are responsible for this effect. Rather life-span is influenced by the proliferating germ-line stem cells. These cells, as well as a downstream transcriptional regulator, act in the adult to influence aging, indicating that the aging process remains plastic during adulthood. We propose that the germ-line stem cells affect life-span by influencing the production of, or the response to, a steroid hormone that promotes longevity.

 

"progressively lead to a decline in the maintenance of proteostasis in adulthood" -- sounds familiar, doesn't it?

Edited by xEva, 13 December 2018 - 07:54 PM.

[OP2040]

Eva,

There is no reason to rule out the fact that there may be pro-death genes, either on their own or in addition to pro-longevity genes.  I tend to speak in terms of gene expression though.  I don't believe for a moment that there genes we either have or don't have that may represent either of these scenarios.  Rather we have all the genes we need and whether they are oriented toward a pro-death state or a pro-longevity state is based on their epigenetic state and activity.  Almost every study shows that the genes themselves are highly conserved among almost all species.  So we almost always have the same gene or a close homolog to both very short lived or negligibly senescent animals. 

 

In fact, this makes it more likely that there are "pro-death" gene expressions.  The main argument against such a thing existing is that death genes have never been found.  I don't buy that reasoning at all.  All the repair-related genes are pro-longevity when they are upregulated, and pro-death when they are downregulated. 

 

I never really thought much about the germline's role in activating death genes.  It's a truly fascinating piece of evidence so thanks for bringing it to everyone's attention.  All of these lines of evidence are good news.  If indeed many of the components of aging are "switch-like", we now have the tools to easily flip the switch.  It's just a matter of finding all the relevant switches, finding the most upstream switches and developing a targeted delivery.  We have talked a lot about repair mechanisms and it seems there is a general consensus that these represent a main class of downstream targets that may in fact be controlled by one or a handful of said switches.  Obviously "repair mechanisms" is quite a generalization that might include a number of pathways.  But some of the evidence seems to suggest that these pathways work in concert, hopefully mitigating the need to micromanage.

 

Anybody want to wager a guess on what may constitute one or more of the master switches, or triggers, that get the aging ball rolling?

1. We have already discussed the idea that reproductive maturity makes a lot of sense as a trigger, but it's not yet clear exactly what is happening after that.  The germline signal idea is a great candidate though.

2. Acute or system injury plays an epigenetic role in triggering faster aging by adding epigenetic marks and shutting down gene expression, or in the case of regenerative animals it triggers regeneration.

3. Thymic involution happens at a very young age,  It's definitely very trigger-like.  If it is a trigger for aging though, it would be one that gets flipped, and then unfolds very slowly over the course of a lifetime.

4. Brain stuff - a master switch in the brain, like the hypothalamus is always fun to think about.  There exists some evidence, but it's quite thin on the ground at this point.

 

 

 

 

[Rocket]

 

Anybody want to wager a guess on what may constitute one or more of the master switches, or triggers, that get the aging ball rolling?

 

Ageing begins almost immediately following fertilization of the egg.

 

There is no trigger to get the ball rolling with atherosclerosis, mitochondrial decline, or glycation accumulation. The trigger that begins the ageing process is simply coming into existence and being biological. Then of course is the wear and tear on the parts of the body that cannot heal themselves, such as teeth, discs, connective tissues. . . No trigger required other than simply being alive. 

 

While I am sure that some of the detriments of ageing are genetically controlled, the bulk of the ageing process does not require our bodies trying to kill themselves; it's simple materials science and chemistry.

 

Consider how elastic and flexible the body is of a 2 year old compared to a typical 25 year old. There is no comparison. Is there a trigger for that? I doubt it.

Edited by Rocket, 14 December 2018 - 05:39 PM.

[OP2040]

Ageing begins almost immediately following fertilization of the egg.

 

Sure, if you want to define aging as "any damage" but you would be alone in the entire world in defining it that way.  It is very clear that since life is a process, not a thing, aging should be defined as to when the process beaks down.  Therefore, the best definition for practical purposes would be the age at which the mortality rate begins to increase with every added year, and that doesn't happen in any statistically significant way until late 30s or so. We could be even more strict with our definition, but there's no need to be.  If you could theoretically intervene and stop the aging process at 20, then it is stopped and the person is simply not going to die of aging-related disease.  They would have no greater chance of dying next year than they do this year.

 

if you choose to define aging as "damage" or "entropy" then everything in the known universe "ages" and we might as well shut down this board right now.  Living things repair damage, that's what they do.  If they didn't, there would be no living things.  You can't just stop at some arbitrary place and say that this is where "damage begins".  The germline is quite old, and it is just as subject to the damage/entropy principle as anything else.  So all you're really saying is that the germline is able to renew itself, but the soma is not.  At least that would be a tenable argument.  Life overcomes entropic damage quite easily.   The only question is whether that overcoming is switch-like, or stochastic.

 

Saying that a fetus is aging because it has some dna breaks or whatever is really saying absolutely nothing of any relevance.

Edited by OP2040, 14 December 2018 - 06:26 PM.

[OP2040]

Consider how elastic and flexible the body is of a 2 year old compared to a typical 25 year old. There is no comparison. Is there a trigger for that? I doubt it.

 

I don't consider a 2 year old, 15 year old or 25 year old as undergoing senescence which you seem to be implying here.  All of these are in different phases of life history but all are characterized by youth and non-senescence.  We've been discussing this in the thread as well.  There are clearly triggers for different life history stages as well.   There are probably quite a lot of developmental triggers depending on how far you want to break them down.  At various ages, something triggers the next round of the developmental cycle.  The debate has been whether the beginning of senescence happens in this same way, or if perhaps due to a selection shadow, senescence is simply the end of of all development.

Edited by OP2040, 14 December 2018 - 06:24 PM.

[xEva]

Ageing begins almost immediately following fertilization of the egg.

 

There is no trigger to get the ball rolling with atherosclerosis, mitochondrial decline, or glycation accumulation. The trigger that begins the ageing process is simply coming into existence and being biological. Then of course is the wear and tear on the parts of the body that cannot heal themselves, such as teeth, discs, connective tissues. . . No trigger required other than simply being alive. 

 

While I am sure that some of the detriments of ageing are genetically controlled, the bulk of the ageing process does not require our bodies trying to kill themselves; it's simple materials science and chemistry.

 

Consider how elastic and flexible the body is of a 2 year old compared to a typical 25 year old. There is no comparison. Is there a trigger for that? I doubt it.

 

re "Ageing begins almost immediately following fertilization of the egg."  -- this is just variation on a catchy slogan that has nothing to do with reality.

 

atherosclerosis, mitochondrial decline, glycation accumulation, lack of elasticity and flexibility -- are all consequences of accumulation of damage to proteins which are not repaired in a timely manner.  How timely the proteins are repaired is the reflection of "expression and function of different quality control machineries and cellular stress responses" which appear to be regulated. The existing evidence suggests that there is indeed a trigger that leads to the progressive "collapse of proteostasis" in adulthood [see quotes from the abstracts posted above], which in turn eventually leads to atherosclerosis etc.

 

Worn out tooth enamel can be remineralized.

Edited by xEva, 14 December 2018 - 07:00 PM.

[Rocket]

I don't consider a 2 year old, 15 year old or 25 year old as undergoing senescence which you seem to be implying here.  All of these are in different phases of life history but all are characterized by youth and non-senescence.  We've been discussing this in the thread as well.  There are clearly triggers for different life history stages as well.   There are probably quite a lot of developmental triggers depending on how far you want to break them down.  At various ages, something triggers the next round of the developmental cycle.  The debate has been whether the beginning of senescence happens in this same way, or if perhaps due to a selection shadow, senescence is simply the end of of all development.

 

I am not implying senescense at all. I am implying precisely what I pointed out. The body of a 2 year old is FAR more flexible than a average 25 year old playing games 10 hours a day. The connective tissues and cartilege and intervertebral discs change over time... No senescence implied. No triggering event.

 

No trigger.

 

No programming.

 

Materials change over time. Materials such as discs that don't have blood flow to regrow and heal. 25 year old individuals hardly have any senescence to matter. Is there a trigger that causes discs to lose their pliability and plasticity? No. Its a natural consequence of discs to dry out and harden.

 

I say precisely what I mean. If ever mean to imply senescence I will say senescence. 

 

If there is a gene that can be turned on to restore disc plasticity and connective tissue elasticty, I would like to know what it is.

 

Is there a gene that can be turned on to prevent the accumulation of "junk" in the vascular system? The junk starts accumulation as soon as the vascular system exists. Young children have fat streaks visible. 

 

The programmed hypothesis of ageing is that the human body would live in essentially great youthful like health indefinitely if only the boogy man under the front porch... the death program... would just be turned off.

 

The body doesn't require a program to fail and fall apart. As I said, I am sure there are genes that can be turned on to improve health, but there is no boogy man program killing us. Some races and populations of people live longer and in better health than other races and populations... Hence evidence that there are some genes that can extend healthspan.

 

My house doesn't require gremlins to break things in the night while I am sleeping. My house simply does not have repair mechanisms built into it to repair things as they begin to fail. 

 

If the programmed theory of ageing is that our cells would remain in homeostasis and youthful, except there is a chemical program of some kind in the brain someplace that comes along and messes things up. That is crazy. 

Edited by Rocket, 14 December 2018 - 07:45 PM.

[xEva]

  They would have no greater chance of dying next year than they do this year.

 

the lowest mortality rate in humans happens to be at ~11y, or just before puberty -- which is in line with the "germline trigger" hypothesis. But humans keep on developing until ~25 (brain), and most 25 yo appear "undamaged". There is an old thread about this https://www.longecit...air-mechanisms/

[xEva]

OP2040@ here is a paper just up your alley: Mechanisms underlying longevity: A genetic switch model of aging. 2017 All about longevity genes and epigenetics.

Edited by xEva, 15 December 2018 - 03:41 AM.

[OP2040]

The first article is pretty old but I can't believe it slipped by me.  Isn't it amazing, btw, that we think of 2015 as "old" when it comes to these things.  I think we're living through a revolution that we may not even see because we're in it.  The second one, in the same vein, is a study proposing a "genetic switch" theory of aging.  I rather like that term and pretty much sums up how I think it works. 

 

https://www.eurekale...u-sfo072015.php

 

https://www.ncbi.nlm...pubmed/28797825

 

Right Eva, it is right up my alley, that's why I posted it on page 2 of this thread.... Not easy to see unless you click the link so I can see how it wasn't noticed..

 

Anyway, I think we all have our own theories and biases, but we all want to get to the same place.  It would be great if we could get things down to a more practical level.  What are the implications of some of these theories?  What experiments should be done?  How can some of the great studies from mice be translated properly?  And how can we incorporate better delivery mechanisms and testing regimes so that we know these things may work in people?

 

If I had to guess where this stuff will take off, where the rubber meets the road, it will be when we can regenerate just one organ in vivo in a sufficiently older person.  At that point, everything changes, literally everything! 

[xEva]

Right Eva, it is right up my alley, that's why I posted it on page 2 of this thread.... Not easy to see unless you click the link so I can see how it wasn't noticed..

 

Anyway, I think we all have our own theories and biases, but we all want to get to the same place.  It would be great if we could get things down to a more practical level.  What are the implications of some of these theories?  What experiments should be done?  How can some of the great studies from mice be translated properly?  And how can we incorporate better delivery mechanisms and testing regimes so that we know these things may work in people?

 

If I had to guess where this stuff will take off, where the rubber meets the road, it will be when we can regenerate just one organ in vivo in a sufficiently older person.  At that point, everything changes, literally everything! 

 

oh that's right!  That's why I also post the title, not just the link. Though I'm not particularly fond of this paper. It said nothing new, but it had  good collection of refs. I bumped into it following papers that referenced that C.elegans paper above.
 

re "regenerate just one organ in vivo in a sufficiently older person", I don't think it's possible without addressing first "the milieu" -- and this has to be addressed regardless. Without knowing how to make it "younger", even small repairs won't last. As heterochronic parabiosis experiments showed, young cells quickly become old in the old environment and vice versa. On the other hand, it may turn out that when the milieu is made "young", everything will fix itself on its own accord -?

Edited by xEva, 15 December 2018 - 08:33 PM.

[xEva]

Oh! look at all these lovely red buttons! Seems a grumpy old fart ran through the page.

He must be on sustained 30% CR -- no! make it 40%. There is no angrier and meaner people than those who are perpetually hungry. I noticed that they also often have difficulty comprehending reading material.

Everyone knows that human mortality rate is lowest at about 11. And those who don't can easily look it up.

So, who's ill informed here?  

Maybe you should have an ice cream

[Rocket]

If ageing were able to be turned on and off via genes (the programmed theory), then surely over the milenia some individuals would have had genetic mutations that turned off the ageing process. At least one individual would had their genes turned on that maintained their body in a youthful state of health.

None have ever occurred. Not one, ever. Throughout all history.

The only genetic mutations that have occurred and DO occur are ones which shorten life... e. g. progeria as one example.

[QuestforLife]

If ageing were able to be turned on and off via genes (the programmed theory), then surely over the milenia some individuals would have had genetic mutations that turned off the ageing process. At least one individual would had their genes turned on that maintained their body in a youthful state of health.

None have ever occurred. Not one, ever. Throughout all history.

The only genetic mutations that have occurred and DO occur are ones which shorten life... e. g. progeria as one example.

Yes to get slow or indeed no aging, you need a long period in a protected environment or having first evolved a very secure adaptation or strategy. But change things again and fast aging probably re emerges quickly. That is why aging is the default state.

All this leads me to the conclusion it is hard and costly in evolutionary terms to slow aging and that repair mechanisms need an evolutionary reason to exist or if they do exist, to remain active past the growth phase.

[OP2040]

Fair point Rocket, to an extent.  If we are saying that aging is the default state due to entropy or whatever, that sounds reasonable.  But that means that for some period of time, non-senescence is imposed somehow, aka programmed.  We can argue all day about when and how long that period of time is, but I can't accept that it doesn't exist at all as it seemed you were previously attempting to say.  If entropy and damage are such juggernauts, then there has to be a countervailing force, I don't see how you can get around that.

 

The thing is damage theories are extremely dangerous and impractical. Medicine has been working with the damage theory since the beginning of time with no progress whatsoever.  The salient point here is the programming.  Even if it is only the youthful phases of life history that are programmed, then the answer is still to impose that youthful programming, not try to clear damages. 

 

This is my big problem with the damage theories.  It's like saying that your houseplant died early because of entropy and damages.  Well, no it died because you didn't water it, the entropy and damages are just background noise of the universe.  Not a great analogy but I think it gets the point across.

 

Damages are a natural fact of the world.  Life somehow overcomes that natural fact.  Therefore, damages cannot be the specific cause of aging.  If it is not the specific cause, then targeting it is a huge waste of time and resources.  And that is precisely what we've seen happen.

 

 

 

 

[OP2040]

All this leads me to the conclusion it is hard and costly in evolutionary terms to slow aging and that repair mechanisms need an evolutionary reason to exist or if they do exist, to remain active past the growth phase.

 

It is costly in terms of opportunity cost.  In other words, if an species focuses too much on maintenance and repair, they lose out on reproductive success, evolvability, and ecological stability.   These alone are plenty enough reason for aging to to be a thing.

 

Costly, yes. Hard, no.  It should be very easy to regenerate or rejuvenate.  It is done with ease in enough circumstances that we can reasonably assume that it's not a hard trick at all.  This is at the heart of this debate.  One of the claims of the programmed aging folks is that the body knows how to stay young, so to speak.  It does not do so past a certain age, due to the specific circumstances of evolution.  Flip a number of switches and it will stay youthful.  On this specific point, I'm completely convinced.

 

[Rocket]

I'm saying there are no longevity anti-ageing genes. For if there were, probability dictates that a certain population would have had genetic mutations to turn those genes "on" and the individuals would remains in a never before seen state of youthful health.

 

Genetic mustations occur all the time, and they always shorten life, and never extend life. So where is the evidence of longevity anti-aging-genes? 

 

They don't exist, else they would have been observed in individuals much like progeria and other life shortening mutations are seen randomly.

 

Maybe a bad analogy............. The movie Unbreakable (truly a great movie), on the one extreme the character with osteogenesis imperfecta, and on the other hand, the Bruce Willis character. In realt life osteogenesis imperfecta exists. There are no and have been no opposite Bruce Willis characters to ever live.

 

If this is a bell curve and most people fall in the median, and some people (progeria and others) fall at the low life expectancy, why...... why is there no one at the other end of curve who remains youtfully healthy throughtout a long lifespan? 

 

They do no exist. They never existed. 

 

Programmed ageing does not exist, else there would be people whose genetic mutations turn off ageing.......... It's never, ever, been seen throughout all of history. Where has there been a 150 year old human? A 10 year old field mouse? A 75 year old dog?

 

Those genese do not exist, else through probability we would have seen examples. There has never been ONE example.

 

 

Edited by Rocket, 16 December 2018 - 01:23 PM.

[Turnbuckle]

It is costly in terms of opportunity cost.  In other words, if an species focuses too much on maintenance and repair, they lose out on reproductive success, evolvability, and ecological stability.   These alone are plenty enough reason for aging to to be a thing.

 

Costly, yes. Hard, no.  It should be very easy to regenerate or rejuvenate.  It is done with ease in enough circumstances that we can reasonably assume that it's not a hard trick at all.  This is at the heart of this debate.  One of the claims of the programmed aging folks is that the body knows how to stay young, so to speak.  It does not do so past a certain age, due to the specific circumstances of evolution.  Flip a number of switches and it will stay youthful.  On this specific point, I'm completely convinced.

 

 

I agree with this for the most part, and with Rocket's comment as well. While there is programed death in many species, evolution has favored longevity in humans for as long as we've had culture, as for most of that time culture was maintained by the older members of society via oral tradition, and culture has enormous survival value. So there is no programmed death for us, rather, aging proceeds at a cellular level in an exponential fashion, and it's the exponential nature that makes it look programed, with most of the population dying off at certain age and very few living much longer. This is primarily the result of the buildup of senescent cells and senescent cells driving nearby cells into senescence in chain reaction fashion. Eliminate senescent cells with senolytics and replace them with endogenous stem cells, and lifespan could be drastically increased. The following data from baboons [source] clearly shows the exponential growth of senescent markers in skin cells --

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Edited by Turnbuckle, 16 December 2018 - 01:49 PM.

[OP2040]

@ Rocket, as far as I understand the current science, mutations have a very small role to play for a species.  It is much less common for a mutation to amount to anything than previously thought.  This may not be the case for extremely long evolutionary history, where mutations can account for some things.  But for the most part, adapatation plays the predominant role.  So lets  say a mutation arose that provided for much longer lifespan.  The individual or lineage in which it arises would quickly die out due to adaptation issues as previously stated to do with evolvability, ecosystem or reproduction, to name a few of the most prominent adaptive mechanisms.

 

There is already a kind of consensus for theorists of aging that aging is based completely in evolution, and is completely a product of evolutionary history.  Thus it has to be explained using that framework since there is nothing in evolution that precludes indefinite lifespan. This idea goes all the way back to Weismann, and as far as I know there is no mainstream theory that denies it. 

 

Again, the question here would be what role mutations play, and they play very little role in the evolution of aging.  You provide a good example of progeria, but let me use it to re-emphasize the point.  A mutation that does not go against the grain of evolution can stick around.  Nothing about progeria interferes with the highly selected for things like evolvability, ecosystem stability or reproduction, and so it has not been actively selected against.  Whereas a mutation against aging is very maladaptive in terms of these things.  It decreases evolvability (or genetic diversity) dramatically, it destabilizes the population extremely, and it destabilizes the reproductive regime.  These are just a few examples of the most prominent adaptive traits that most species have followed.  There may be others,or one of these may be far more important than the others.

 

 

[OP2040]

I promise I did not deliberately search for this.  I periodically search the ScienceDirect database for papers on senescence.

 

 

"Why does women's fertility end in mid-life? Grandmothering and age at last birth"

 

Highlights

•

A probabilistic agent-based model of the evolution of human post-menopausal longevity.

•

Both longevity and age of last birth can mutate.

•

Grandmothering drives the shift from great ape-like to human-like life history without extending the end of fertility.

•

Simulations reveal two stable life-histories with no intermediates.

 

 

 

I haven't dug into what they mean by line #2 just yet, but you can see how the entire article may have relevance for the discussion.

[Rocket]

@ Rocket, as far as I understand the current science, mutations have a very small role to play for a species.  It is much less common for a mutation to amount to anything than previously thought.  This may not be the case for extremely long evolutionary history, where mutations can account for some things.  But for the most part, adapatation plays the predominant role.  So lets  say a mutation arose that provided for much longer lifespan.  The individual or lineage in which it arises would quickly die out due to adaptation issues as previously stated to do with evolvability, ecosystem or reproduction, to name a few of the most prominent adaptive mechanisms.

 

There is already a kind of consensus for theorists of aging that aging is based completely in evolution, and is completely a product of evolutionary history.  Thus it has to be explained using that framework since there is nothing in evolution that precludes indefinite lifespan. This idea goes all the way back to Weismann, and as far as I know there is no mainstream theory that denies it. 

 

Again, the question here would be what role mutations play, and they play very little role in the evolution of aging.  You provide a good example of progeria, but let me use it to re-emphasize the point.  A mutation that does not go against the grain of evolution can stick around.  Nothing about progeria interferes with the highly selected for things like evolvability, ecosystem stability or reproduction, and so it has not been actively selected against.  Whereas a mutation against aging is very maladaptive in terms of these things.  It decreases evolvability (or genetic diversity) dramatically, it destabilizes the population extremely, and it destabilizes the reproductive regime.  These are just a few examples of the most prominent adaptive traits that most species have followed.  There may be others,or one of these may be far more important than the others.

 

Listen, I am a physicist and an engineer and not a bioscientist. If I misued the work mutation then forgive me my ignorance.

 

If ageing were programmed then over the thousands of years and billions of lives then there should be cases of the normal programming going awry and leading to increased healthspan and increased lifespan. There should be at least 1 case... a handful of cases... There are exactly ZERO cases of programming going awry and giving rise to a 175 year old human being who lived in relatively good health.

 

Whenever "programming" goes awry it leads to shortend lifespan and decreased healthspan. Progeria is the one that comes to mind because its the easiest to make a point of it.

 

Probability dictates that if there are genes and combinations of genes that can be activated that will lead to slowed ageing, increased healthspan, increased lifespan, that there should be cases thoughout the history of billions of lives.

 

There are EXACTLY zero cases throughout all of history. Not one case. Not even among non-humans. Ever seen a 150 year old person? A 75 year old german shepard? No. And you never will. These genes do not exist.

 

Whenever "programming" goes awry you get less life and less health. Never the opposite.

 

That should speak volumes about the programmed theory of ageing.

 

Apparently according to the believers, faulty programming can only shorten life and we have simply yet to see a case where it does the opposite. Really? with billions of data points, and not one case? Hmmm. Sounds like the hypothesis is incorrect.

Edited by Rocket, 16 December 2018 - 05:48 PM.

[OP2040]

There are many reasons why we wouldn't see this in humans.  First, the probability of it happening goes up quite a bit even if it's just a handful of mutations needed.  Second, for the vast, vast amount of human history, mortality was almost all extrinsic, due to microbes, war or famine,  In a state of nature, even a broken leg can kill you fairly easily.  Third, is there some expectation that this would be recorded since the vast, vast majority of human history we have no re recorded evidence of anything, just oral myths and legends. 

 

My current stance is that all developmental life stages are programmed, except senescence.  So I'm not sure that we are even disagreeing all that much.  This is what I'm hearing from you, so please correct me if I'm wrong:

1. Entropy and damage are the default state within which living things have to operate.

2. There is no point at which this damage and entropy are not acting on a living body, including very early life

3. Therefore, there is no evidence of programming, just a stochastic balance between damage and maintenance, which will inevitably tilt toward damage accumulation over time.

 

I completely concede the self-evident truth of #1 and #2 but take issue with deriving #3 from that.  "Something" has to happen during fertilization or embryogenesis that represents a programmed resetting of the aging clock to 0.  We know that embryos and sperm are damaged all the time, they are not kept in a pristine state.  We actually already know of a few things that reset, like lysosomal function.  How do the damage and repair mechanisms upregulate in order to reset to age = 0 if not programmatically?

 

If you allow for reprogramming at that level, then it's not too hard to imagine it for all manner of developmental stages.  I'm still on the fence when it comes to senescence itself being positively programmed rather than merely program cessation.  But the larger point is that life can and does use genetic programming of one sort or another to rejuvenate, repair, maintain and do all kinds of dramatic things with the phenotype. 

 

Anyway, I don't really care what your profession is, the evidence and the logic are all that matters here.  Biologists are currently failing miserably at understanding aging, so it's a free-or-all as far as I'm concerned.  I really respect your opinion or else I wouldn't bother taking the time to respond. 

 

 

Edited by OP2040, 16 December 2018 - 06:53 PM.

[xEva]

Listen, I am a physicist and an engineer and not a bioscientist. If I misued the work mutation then forgive me my ignorance.

 

If ageing were programmed then over the thousands of years and billions of lives then there should be cases of the normal programming going awry and leading to increased healthspan and increased lifespan. There should be at least 1 case... a handful of cases... There are exactly ZERO cases of programming going awry and giving rise to a 175 year old human being who lived in relatively good health.

 

Whenever "programming" goes awry it leads to shortend lifespan and decreased healthspan. Progeria is the one that comes to mind because its the easiest to make a point of it.

 

Probability dictates that if there are genes and combinations of genes that can be activated that will lead to slowed ageing, increased healthspan, increased lifespan, that there should be cases thoughout the history of billions of lives.

 

There are EXACTLY zero cases throughout all of history. Not one case. Not even among non-humans. Ever seen a 150 year old person? A 75 year old german shepard? No. And you never will. These genes do not exist.

 

Whenever "programming" goes awry you get less life and less health. Never the opposite.

 

That should speak volumes about the programmed theory of ageing.

 

Apparently according to the believers, faulty programming can only shorten life and we have simply yet to see a case where it does the opposite. Really? with billions of data points, and not one case? Hmmm. Sounds like the hypothesis is incorrect.

 

There are few misconceptions in your view.

 

first. re "There are EXACTLY zero cases throughout all of history. Not one case. Not even among non-humans."

 

This is not true . There are animals that do not age -- as in don't age at all, not even 'negligibly'. This is a good read: Diversity of ageing across the tree of life, 2014

 

 

second, re genes and programming

 

Don't know if you're familiar with programming, but most programs consists of instructions (code) and data array. The code part is what commonly is called the 'program'. That's the most important part. The data array is something the code uses when the program is executed.

 

Genes are the data array. In human DNA, they make up 1% to 2%, and the rest is... something else. Presumably, somewhere in that 98%-99% portion of the DNA, lies the instructions code, or the 'program' itself. What exactly the code consists of and how it is executed, to my knowledge, no one knows (and if anyone knows of a hypothesis posted somewhere, I'd love to read it). 

 

When we say that the development is programmed (and no one denies this) we just state what is apparent, but we do not know how it works. We can only describe what's going on, i.e. we trace the 'pathways' and list the participating molecules and try to discern their role by impeding or augmenting their action.

 

On the example of the C. elegans paper above, they traced the 'trigger', a molecular signal that originated in the germline stem cells, which, via a specific pathway, caused the gene that encodes for a protein essential for stress response to be available only 30-40% of the time (compared to the baseline that they recorded before the animal reached reproductive maturity).

 

It is a developmental program, because it happens not randomly or in response to some external stimuli, but 'within a 4h window' after the animal  reached the most important stage in its development. In this study, they specifically focused on the heat shock response, but they also noted that all other stress response pathways became suppressed. Of course, this affected the animal as a whole -- i.e. it began to 'accumulate damage' or age.

 

According to a study they cite, removal of the germline stem cells "increased the lifespan dramatically" -- i.e. removal of germline stem cells interrupted this pro-aging program. It is pro-aging, because it leads to 'accumulation of damage', which had been repaired while the animal was still developing.

 

 

re loss of function gene mutation in progeria

 

In programming, changes in the data array does not affect the code itself, but naturally it does affect the output, or the result of the program. When a gene is mutated, this usually results in the loss of function of the resulting protein and the pathway(s) in which it participates. Even though it's incorrect to draw direct parallels, still, one can liken a 'molecular pathway' to a little sub-program or a subroutine, as it's called in programming. 

 

In your example of progeria, the developmental program is unchanged. Instead, one of the proteins that makes up the nuclear envelope is defective, and this leads to 'loss of function' problems that result in the disease that kills the person in the second decade of life. Here an important 'subroutine' is affected, but not the 'main' program itself.

 

 

re 'good' mutation that could increase lifespan

 

There are cases of people having multiple copies of 'good housekeeping' genes and they tend to live longer. This does not affect developmental program, but only mediates the effects of the pro-aging routine which suppresses the housekeeping genes.  

 

 

So you see? It's not so much genes, though of course they are important, it's how the genes are directed to function by the program.

Edited by xEva, 17 December 2018 - 05:32 AM.

[xEva]

Here is an interesting paper: A genomic lifespan program that reorganises the young adult brain is targeted in schizophrenia, 2017

 

From the abstract:

The genetic mechanisms regulating the brain and behaviour across the lifespan are poorly understood. We found that lifespan transcriptome trajectories describe a calendar of gene regulatory events in the brain of humans and mice. ... A major lifespan landmark was the peak change in trajectories occurring in humans at 26 years and in mice at 5 months of age. ...

 

From the digest:

Skene et al. examined how the genes are turned on and off across the lifespan of healthy mice and humans. The results showed that in both mice and humans, a ‘genetic lifespan calendar’ controlled every cell type in the brain and directed the way they worked at different ages. The timing was so precise that it was possible tell the age of a mouse or a person simply by looking at the way the genes were expressed in a tissue sample.

 

Interesting that they could predict age with an accuracy of 5.5y in humans and 28d in mice. "Remarkably, they showed accurate age predictions across the entire range of ages in both species (human, R2 = 0.88, mice, R2 = 0.94) using only 40 probes in humans and 100 in mice."

 

Again, they found a ‘genetic lifespan calendar’ and, using it, can accurately tell age, but what drives this calendar? It's gotta be a program. It's not a series of stochastic events.