50 replies to this topic

[Karomesis]

I haven't seen any threads here on what Michael Rose discussed at his SENS III lecture, I was intrigued by what he said about Gompertzian logic breaking down once the late life plateu was reached. Causing me to completely rethink the "accumulating damage" theory in the process.

He was not very specific describing any of the mechanisms/genes he would alter once reverse engineering of the process was complete. And to those of you here who are aware of his lecture, what are your thoughts/critiques of it?

here is the lecture.( thanks alot for posting the vids Richard )

http://richardjschue...g2_itemId=56908

[resveratrol]

Thanks for posting this, Karo. I was going to open a topic on this as well.

He made some rather provocative statements but gave few leads as to what specific mechanisms he proposed to explain his statements (and Google hasn't been much help so far).

Specifically, the slide at around 16:10:

Why does this matter for SENS?

* This is huge for non-evolutionary SENS, because the SENS proposal is based on a simple model of fixing damage
* This model is in turn based on the erroneous assumption that aging is a process of accumulating damage, the ubiquitous non-evolutionary gerontological model, that leads to unrelenting Gompertzian aging
* But this Gompertzian aging DOESN'T HAPPEN
* Instead, aging is a loss of adaptation, NOT an accumulation of damage

I must admit I don't fully understand, even after watching the lecture twice,

* Do the experiments to which Rose refers really prove that the damage-based model is completely invalid? If so, I don't see how. He claims that "that's not fundamental or intrinsic to the process," but doesn't seem to even so much as hint at what factors could possibly replace them.

* What does Rose mean by a "loss of adaptation"? He later states that "In fact, a lot of work that I'm not discussing today indicates that allocation is a much more important process than damage as a mechanism of aging." Allocation of what, exactly ...?

Edited by resveratrol, 08 October 2007 - 10:13 PM.

[Karomesis]

* Do the experiments to which Rose refers really prove that the damage-based model is completely invalid? If so, I don't see how.

I guess his argument was, if accumulating damage is the "reason" we age, then why does it seem to stop?

and the "loss of adaptation" I think was his ace in the hole. Various organisms, Kenyons astonishing C.elegans included, have lived double even quadruple their normal maximum LS. But there's a catch, loss of evolutionary fitness, in which case the organism is basically worthless.

His D.melanogaster experiments are a testament to this fact, the longer lived fruit flies were "fitter" from an evolutionary standpoint. Just because we all want to stop aging, doesn't mean evolution is sidestepped, and he essentially reinforces this.

[resveratrol]

and the "loss of adaptation" I think was his ace in the hole. Various organisms, Kenyons astonishing C.elegans included, have lived double even quadruple their normal maximum LS. But there's a catch, loss of evolutionary fitness, in which case the organism is basically worthless.

His D.melanogaster experiments are a testament to this fact, the longer lived fruit flies were "fitter" from an evolutionary standpoint. Just because we all want to stop aging, doesn't mean evolution is sidestepped, and he essentially reinforces this.

Perhaps I'm a bit dense, but I'm still not getting what specifically is meant by a "loss of adaptation" -- i.e. what actual mechanisms at the cellular level could explain aging in a way that (he believes) SENS cannot.

[resveratrol]

I mean, in a certain sense, it almost feels like he's getting up there and saying, "Oh, by the way, all these other things they're talking about here at the conference aren't really important. The actual mechanism is something else entirely. But I'm not going to tell you what that something else is, or even tell you whether I know what it is or not, or even so much as hypothesize or generally try to describe the bounds of what it could be. Good night."

Which is a bit frustrating, because it really gives us nothing to go on.

Edited by resveratrol, 08 October 2007 - 10:14 PM.

[Mind]

Did you watch the Q&A part at the end? I think some of the questions helped in understanding some of the concepts. He explained how he would analyze his long-lived populations of mice and find out how they "do it". What genes can be tweaked? What metabolic pathways are most important? Kind-of like what Kenyon stumbled upon (one pathway) but on a grander scale.

Which brings me to side bar....if Rose has already analyzed his immortal fruit fly populations, why has nothing come from it? (no big anti-aging breakthroughs). Is it because fruit flies are too different from mammals? Are there almost no analogous mechanisms of aging? Are fruit flies useless for studying human aging?

Also, it seems like there might be a chicken and egg scenario going on here (I think one of the questioners in the video was asking about it....the "cart and horse" comment). Rose says the loss of adaptation leads to accumulating damage, not the other way around and he bases this statement on the fact that aging stops in his long-lived fruit flies. However, I wonder if his fruit flies ARE aging, but at such a slow rate as to make it imperceptible. Think about a long lived human (over 100 years). They usually do not do much, their heart is weak, they don't eat much, and their bodies do not change much. They are at a point in life where a large percentage of the cells in their body are dead or not working and a lot of junk has built up. In short, it does not take as much "work" to keep alive what few viable parts of the body are left. Less/slower metabolism=much slower rate of aging (making it look like aging has stopped), and thus damage could still be the key or one of the keys to aging.

[Athanasios]

OK, I haven't had the time to listen... i know i know, why am i posting then....

Like member resveratrol says, what causes this loss of adaption. Wouldnt that cause be classified as damage? If not, is he suggesting the infamous aging clock?

I also would like to see what maestro may say in this topic as he has had some interesting opinions in regard to aging and changes in metabolism and gene networks. Come on maestro.

[Karomesis]

They usually do not do much, their heart is weak, they don't eat much, and their bodies do not change much. They are at a point in life where a large percentage of the cells in their body are dead or not working and a lot of junk has built up. In short, it does not take as much "work" to keep alive what few viable parts of the body are left.

agreed.

But the same argument could be used to describe why it takes just a tiny bit of damage to terminate the organism. It's like asking why those same centenarians die, they just.....fail.

[John Schloendorn]

A Gompertz curve would be predicted by models involving static systems receiving random damage to their components. However, living systems are rather dynamic, continue to self-repair and only a small fraction of their workings is even understood. In theory, the complexity of living organisms can certainly provide the mechanics to make an accumulation of damage non-random in any thinkable way. As another example, the existence of a long-lived subpopulation can cause an apparent decline in late life mortality. In the end, it is neither known how a Gompertz curve is caused in the typical population of aging organisms, nor why Rose's long-lived flies deviate from it. All one can conclude from a non-Gompertz mortality curve is that we are not looking at static systems receiving random damage to their components.

That said, I also don't see how damage and adaptation can compete with each other for a role in causing aging, because they are such different concepts. It's like asking, is the breakdown of cars caused by the accumulation of rust, or by the lack of maintenance? Both are obviously true in their own sense, and this seems to have no bearing at all on the idea that continuous repair can keep the car on the road. In evolutionary terms, a lack of evolutionary pressure to adapt the organism to adverse conditions in old age is precisely what permits damage to accumulate.

Repairing damage in a system will cause it to function well. There is not even any information in this statement. It's a tautology, a way of defining what one means by "damage"...

[Karomesis]

Great post John.

this is the kind of posting I enjoy at imminst and I think more than a few people here are capable of.

[resveratrol]

A Gompertz curve would be predicted by models involving static systems receiving random damage to their components. However, living systems are rather dynamic, continue to self-repair and only a small fraction of their workings is even understood. In theory, the complexity of living organisms can certainly provide the mechanics to make an accumulation of damage non-random in any thinkable way. As another example, the existence of a long-lived subpopulation can cause an apparent decline in late life mortality. In the end, it is neither known how a Gompertz curve is caused in the typical population of aging organisms, nor why Rose's long-lived flies deviate from it. All one can conclude from a non-Gompertz mortality curve is that we are not looking at static systems receiving random damage to their components.

Fascinating. So if the damage is not entirely random, and the systems are non-static, both of which really certainly apply in this case, that could cause the kinds of artifacts in the mortality curve that he's talking about.

That said, I also don't see how damage and adaptation can compete with each other for a role in causing aging, because they are such different concepts. It's like asking, is the breakdown of cars caused by the accumulation of rust, or by the lack of maintenance? Both are obviously true in their own sense, and this seems to have no bearing at all on the idea that continuous repair can keep the car on the road. In evolutionary terms, a lack of evolutionary pressure to adapt the organism to adverse conditions in old age is precisely what permits damage to accumulate.

Repairing damage in a system will cause it to function well. There is not even any information in this statement. It's a tautology, a way of defining what one means by "damage"...

Thanks, John; I really appreciate your helping me make sense of this. I'm glad to see I wasn't the only one thrown for a loop by Rose's lecture.

I really got the sneaking suspicion that some of his statements were intentionally provocative in terms of undermining SENS far more than was justified by the research he presented (perhaps, if I may be cynical, in an attempt to secure funding?), and this post really helps put things in perspective.

Edited by resveratrol, 09 October 2007 - 04:29 AM.

[modelcadet]

  I'm glad to see I wasn't the only one thrown for a loop by Rose's lecture.

I too thought his premise odd. First off, I hate when people anthropomorphize or valuate aspects of the evolutionary process (a side effect, I believe, of the unjustified juxtaposition of the flying spaghetti monster against empiricism, reason, etc.) Unless I'm mistaken, the gist of his argument is as follows: Adaptation happens via reproduction (a gross oversimplification, by most accounts). Once we finish reproducing, we're evolutionarily worthless, ergo age-related characteristics do not enter into the natural selection process (first, what's to say aging isn't indeed a factor in selection). He suggests artificially lengthening the reproduction cycles of species to *hopefully* shape the adaption of a species to live longer, then compare this species with its ancestors to determine strategies for addressing aging. The thing is... why do you have to observe the evolution of a species at all? Why can't you just compare across species or use different members of the same species? With the latter case, after all, you have equivalent gene pools.

Anyway, I'm interested in this guy he referenced in his talk, towards whom he harbored some resentment. That guy might actually be a pretty good scientist. Or at least one graceful enough to avoid such drivel in a limited presentation.

[resveratrol]

Anyway, I'm interested in this guy he referenced in his talk, towards whom he harbored some resentment.  That guy might actually be a pretty good scientist.  Or at least one graceful enough to avoid such drivel in a limited presentation.

Are you referring to Aubrey? If you're interested in his work, his book just came out; I recommend it highly.

[Mind]

But the same argument could be used to describe why it takes just a tiny bit of damage to terminate the organism. It's like asking why those same centenarians die, they just.....fail.

The only response I can come up with is that the remaining viable cells within a centenarian are the most robust, as they have withstood and/or repaired most of the damage that has accumulated through the first 100 years. If they continue to encounter the same stress/damage through the later years of life, it doesn't have much effect on them (although they might still age very slowly), thus making it seem like aging has stopped.

Anyway, to get back to the car maintenance vs. accumulation of rust analogy that John brought up. Rust is one type of damage that occurs and the "maintenance" on a car is performed by humans. In the body, the maintenance is performed/directed by an evolved system of genes. Rose is proposing to tweak this evolutionary process with the goal of maximally extending lifespan. It seems like a valid approach and he could obviously win the mouse prize if he was successful. However, I don't think his approach has garnered as much attention or funding because it isn't apparent how this approach will translate into immediate applications to ameliorate aging in humans. He is speaking at a very abstract level. In contrast, Aubrey's SENS is much more concrete. Damage causes pathology. Pathology causes death. Fix the damage. Reduce the odds of death. Even the layman can understand that fixing/removing the plaques responsible for Alzheimers or heart disease are worthwhile and possible.

[maestro949]

However, I don't think his approach has garnered as much attention or funding because it isn't apparent how this approach will translate into immediate applications to ameliorate aging in humans.

This is true but could be changing soon if I understand what he is proposing. We are rapidly gaining quite a bit of insight into what gene expressions are changing in aging organisms. Modulating expression levels via RNAi is now feasible and will likely be a routine therapy vehicle in decades to come. RNAi and related therapies will likely displace many small molecule interventions and could be significant means for treating aging related diseases and even slowing the aging process itself.

The task of sorting out which expression levels are relevant and can be safely tweaked is going to be one heck of a challenge and take quite of bit of time but once
progress starts down this path we could unravel this ball of yarn quickly as we did with the human genome.

[resveratrol]

The task of sorting out which expression levels are relevant and can be safely tweaked is going to be one heck of a challenge and take quite of bit of time but once
progress starts down this path we could unravel this ball of yarn quickly as we did with the human genome.

FYI, here's a somewhat relevant link discussing some of this sort of thing in roundworms. Hopefully we'll be able to find a lot of these sorts of genes in humans before long.

[maestro949]

...That said, I also don't see how damage and adaptation can compete with each other for a role in causing aging...

It might be a bit of a stretch but I assumed he was referring to adaptation as a loss of elasticity in the cells ability to iteratively self tune itself over time. i.e. cell strains continue to evolve/adapt/change to a degree (albeit very slowly) even after they have specialized into their particular functional cell types. In this scenario each cell is effectively going down it's own evolutionary branch so to speak such that no two are expressing an identical protein mix. The studies of twins having drift in gene expression patterns as they age comes to mind here.

The only way I could see this competing with damage is if the cell is actually damaging itself in it's quest to adapt to it's own deleterious changes! Repair mechanisms gone wild perhaps? That would be weird but with so much complexity nothing would surprise me. This is evolution and clearly not something engineered with any forethought.

FYI, here's a somewhat relevant link discussing some of this sort of thing in roundworms. Hopefully we'll be able to find a lot of these sorts of genes in humans before long.

I'd settle for an immortal C. elegans at this point. Can you imagine the interest that would garner?

Edited by maestro949, 15 October 2007 - 09:37 PM.

[kevin]

The set of parameters which describe the life-story of a particular organism are geared towards reproduction... ie. the continuance of the pattern of the organism as indicated by the information in its germ line. Like a shot from a cannon, organisms employ various strategies to enable the continuance of the information in our DNA, and then entropy ensues and the blush is off the rose.

Aging is not a 'loss of adaptation'. Although one might say it is so in a similar fashion to the 'cup is half empty' rather than 'half full', it isn't a matter of semantics as a loss of adaptation is preceded by damage, not the other way around. There is no programmed loss of adaptation, merely a tuning of parameters by natural selection during the reproductive period.

As evidence that the loss of adaptation is not the right direction to take, witness the ingenious ways the body is capable of hyperevolution.

When it suits (ie. survival depends on it), it is possible to create systems which are hypermutational and variant within the confines of normal biology (ie. immune system VDJ recombination for antibody diversity). So it is not as if evolution can't be sped up. We tend to think of evolution as a slow process, but I'm beginning to think that when pressed, mechanisms may be employed to accelerate diversity from necessity. The constant pressure of pathogens resulted in a very neat recombination mechanism and the germ line is constantly recombining and shuffling things around.

Loss of adaptation is not the issue, lack of maintenance is and that lack of maintenance is a result of two components, genetic and environmental. That is not to say there aren't isn't some genetic tuning that couldn't be done given our current system. Bowhead whales live 200 years or so.. but I tend to think that as long as reproduction is the focus of evolution, (and it is the focus of biological evolution but perhaps not informational evolution), it will be difficult to optimize a system for self-sustaining longevity. The raw materials and algorithms which create organisms from competitive natural selection also seem to put a cap on what is possible. With intelligence however we can perhaps step out of the 'solution space' for a normal evolved organism and explore some of the more novel combinations which could not be reached by the slow methodical course evolution normally takes.
KP

[Karomesis]

With intelligence however we can perhaps step out of the 'solution space' for a normal evolved organism and explore some of the more novel combinations which could not be reached by the slow methodical course evolution normally takes.
KP

I agree.

Kevin, Have you had a chance to talk to Michael Rose? I'm still under the distinct impression that alot of us are taking his lecture the wrong way.

the process of our intellect based bypassing of the process of aging does not sidestep evolution, it is still the fittest organisms that maintains the slowest rate of aging, and I'm guessing his MO is to speed it up dramatically via some as yet unmentioned pathway/gene using his research of d.melanogaster as the cornerstone.

To say during his lecture that he could do it quicker than the basic SENS approach takes some serious cajones. I highly doubt he's the type of guy to not back it up with something of substance.

It's also unfortunate he doesn't post here, maybe someone like Aubrey can get him to give us his 2 cents on the matter, I know I'm still very interested in what he has to say.

[kevin]

I actually had a really good chat with him over supper one evening and our conversation was actually around this subject. To me it seemed pretty clear after talking to him.. and he certainly isn't one to say things half-heartedly. I should say that I don't think humans or biology is optimized for longevity so there is a lot of room for improvement, I don't think it is the fastest way forward though.

It's unlikely that someone like him would be unclear in his presentation although what he's saying seems a bit at odds with accepted wisdom.. I like the fact that someone is willing to turn something around and look at it from other perspectives even if I don't appreciate the entire package.

I bet Aubrey has some ideas and perhaps he and Michael have already talked about this as they discussed his ideas at SENS3. Perhaps a quick email to Michael about the conversation might be interesting enough to encourage him to look at some of the comments here and help clarify things for people.

[eternaltraveler]

If anyone has ever read any of Heinlein's books, that is essentially what Rose is proposing. Direct evolution of longevity.

-Step 1 create long lived mice through directed evolution
-step 2 figure out difference between Methuselah mice and normal mice
-step three hope difference isn't something we are already doing to a large extent (we already live 15 times longer than even these artificial long-lived mice would)
-apply to humans.

First I'll say it is very very likely long lived mice can be evolved. However we have no idea how applicable the longevity genes we find in these mice will be to human beings, and it is going to take a really long time to evolve these mice.

And even assuming 100% success in breeding these mice and 100% applicability to humans it isn't going to be worth a damn in repairing existing damage.

And talking about aging as not being an accumulation of damage but a loss of adaptability or whatever is just a bunch of goobly gook along the lines John mentions (ie repairing damage makes a system function better). Rose just completely dismisses that aging is an accumulation of damage based on his non-Gompertz curve of flies. Despite the fact that we can see the damage and a non-Gompertz curve is completely understandable for all the reasons John mentions.

All that said the work does have some value, and if you have 10,000 years you could even use it to evolve humans to live a long time. It sure isn't an alternative to SENS, but it would be nice to know more specifically what genes are involved in aging. I suspect you could get more useful data out of comparison of supercentenarian genomes to average human genomes though (ie, more useful for humans, not mice).

[caston]

Invite him here.

[maestro949]

Thanks for the clarifications kevin/elrond. It'd be great if we could get him to elaborate as to how he thinks this approach is elaborate to SENS.

First I'll say it is very very likely long lived mice can be evolved. However we have no idea how applicable the longevity genes we find in these mice will be to human beings, and it is going to take a really long time to evolve these mice.

Agreed. Perhaps in a shorter lived species but even if we did end up with perfect data sets between standard mouse and mighty mouse it would be a bitch to transform a live mouse into his caped counterpart. Cars seem to be a popular analogy so the comparison would be like trying to swap out an engine, tranny and electrical system while the car is going around a racetrack.

(ie repairing damage makes a system function better)

It depends on what damage you fix obviously. Sanding off some rust, slapping some bondo on and repainting the car might reduce your wind drag getting you 0.001 mpg but who cares. If your automatic transmission (the most complex component in an automobile) fails, slightly more difficult damage to fix but still nothing compared to cancer, declining immune systems, dozens of amyloids and epigenetic alterations that accumulate with age.

[eternaltraveler]

It depends on what damage you fix obviously. Sanding off some rust, slapping some bondo on and repainting the car might reduce your wind drag getting you 0.001 mpg but who cares. If your automatic transmission (the most complex component in an automobile) fails, slightly more difficult damage to fix but still nothing compared to cancer, declining immune systems, dozens of amyloids and epigenetic alterations that accumulate with age.

of course. You're basically comparing SENS type interventions with a face-lift here )

[maestro949]

of course.  You're basically comparing SENS type interventions with a face-lift here )

Ha, well, we already know how well those work don't we. Whereas have little data as to how well any SENS intervention will work. Attempting to implement SENS interventions could just as easily lead to the same whack-a-mole approach we already have with the big "C". Even after reading Aubrey's book I don't see how it's especially distinguished from any other particular approach. His message that aging research should be a priority, the MMP, drumming up support and what the issues are (the 7 deadlies) are all right on track. Aging needs to be fixed and we're at a point we should be able to do but we need to keep the list of options wide open as to what we slot in as solutions for each problem.

[eternaltraveler]

of course.  You're basically comparing SENS type interventions with a face-lift here )

Ha, well, we already know how well those work don't we. Whereas have little data as to how well any SENS intervention will work. Attempting to implement SENS interventions could just as easily lead to the same whack-a-mole approach we already have with the big "C". Even after reading Aubrey's book I don't see how it's especially distinguished from any other particular approach. His message that aging research should be a priority, the MMP, drumming up support and what the issues are (the 7 deadlies) are all right on track. Aging needs to be fixed and we're at a point we should be able to do but we need to keep the list of options wide open as to what we slot in as solutions for each problem.

what other particular approach?

The idea is fixing those 7 will let you stick around long enough to benefit from more robust rejuvenation further technology is likely to bring.

[maestro949]

what other particular approach?

No one approach in particular but rather the various array of interventions being used all along: pharmaceuticals (chemo), radio-based therapies, viral vectors, phages, artificial organs, surgery, avoiding harmful substances and lifestyles. Of course we'll add stem cells, RNAi, gene therapy, nanotech and other sophisticated approaches that technology and research open up for us once they're tested and proven as safe alternatives. The point I was trying to make is that we may fix things only to find out that those fixes don't actually yield the gains we had hoped for. Not unlike the mechanic who keeps replacing engine parts when he's not quite sure what the problem is.

The idea is fixing those 7 will let you stick around long enough to benefit from more robust rejuvenation further technology is likely to bring.

No argument here. I am fully on board with the concept of escape velocity. What specific interventions gets us onto that trajectory still seems fairly wide open to me though.

[eternaltraveler]

i think we're confusing aubrey's particular preferred fixes for the 7, vs the recognition that it is these 7 that need to be treated (somehow).

If Dr. Zheng Cui's idea on neutrophils panned out for cancer I think we'd all be jumping for joy, and then we'd be talking about the 6 deadly things.

The particular approach I was talking about was simply recognizing that these are 7 things we need to attack. If that was done it would be great if there was a ton of money flowing into diverse approaches to tackle the problems.

[eternaltraveler]

its basically packaging the concept that aging has more than a snowball's chance in hell of being treated because it isn't 10 billion fixes of metabolism we need to fix for step one, it's just 7 basic types of damage.

We can work on fixing the ten billion bits of metabolism once we add a chunk to our lives by taking care of the 7. In that extra time the tools needed for more complicated fixes will be much more available than they are now.

[maestro949]

i think we're confusing aubrey's particular preferred fixes for the 7, vs the recognition that it is these 7 that need to be treated (somehow).

Perhaps. I think even Aubrey would even agree that the door needs to be kept open. Why else would he invite people who have alternate theories?

If Dr. Zheng Cui's idea on neutrophils panned out for cancer I think we'd all be jumping for joy, and then we'd be talking about the 6 deadly things.

It sounded interesting but claims of cancer cures need to go into the perpetual motion category until they make it past stage 3 trials.