50 replies to this topic

[eternaltraveler]

naturally. Only speaking hypothetically.

[Karomesis]

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).

That's exactly why I was so intrigued by Roses lecture, he said he "could" in fact do it "sooner" than Aubrey's approach.

I'm very interested, even in a highly speculative sense, of how in the hell he would go about doing it so rapidly. I'm guessing here, but I'd say it has something to do with his "reverse engineering" of the fruit flies somehow correlating to our pathways as well.

[ag24]

Hi all - someone said something in the chat last night that directed me to this thread. I have indeed been in quite extensive dialogue with Michael Rose since SENS3. The summary of where we stand is as follows:

1) Michael indeed has no specific, mechanistic, biological hypothesis for how an organism can acquire, late in life, the ability to continue to function without laying down side-effects of metabolism that increase its frailty (i.e. its likelihood to die in the next time period).

2) However, he likens this to the situation with any data-driven paradigm shift: you get the data, it's telling you something bizarre, but it's telling you unambiguously, so you accept it and plough on with research until you understand where your pre-existing theory is wrong. Moreover, he claims that late-life non-aging is in fact a corollary of classical evolutionary theory (particularly the synthesis articulated by Hamilton): in other words, that the only pre-existing theory that's wrong is the theory that metabolism is always bad for you.

3) I accept that data are data, but I point out that we must examine one alternative, namely that Michael's flies are not telling us what he thinks they are. I claim (a) that Michael's claim that Hamiltonian theory predicts late-life non-aging is erroneous (and that other evolutionary biologists agree with me) and (b) that the experiments he's done do not (as he claims) falsify the alternative (lifelong heterogeneity, LH) theory for the deviation from Gompertzian mortality seen in late life. LH says that damage accumulates throughout life and frailty increases exponentially, i.e. each individual is Gompertzian, but that differences between individuals in the two Gompertz parameters, especially in the "mortality risk doubling time", lead to a plateau when a population is considered as a whole.

4) Michael has basically stopped denying the validity of my refutation of his most direct alleged falsification of LH (see Mueller et al, Exp Gerontol 38:373; de Grey, Exp Gerontol 38:921; Mueller and Rose, Exp Gerontol 39:451; de Grey, Exp Gerontol 39:453). He remains adamant that other, less direct evidence (such as with regard to fecundity patterns) falsifies LH, but I maintain that these other classes of evidence at best falsify only certain versions of LH.

5) Michael's position is that LH consists of a family of hypotheses so broad that it can indeed never be falsified entirely, but he likens LH to Ptolemaic cosmology, which could always be rescued by one more epicycle, and that the late-life non-aging theory is now the most parsimonious one available. I claim (a) that the versions of LH that have not been falsified are actually the siomplest (most parsimonious) ones and (b) that the late-life non-aging theory is not as parsimonious as he claims because it is incomplete (lacking in any mechanistic component).

6) Regarding whether Hamilton theory predicts plateaus, Michael and Larry Mueller have done some intriguing simulations of what would happen that appear to support his position. The first one (which is published: Proc. Natl. Acad. Sci. USA 93: 15249-15253) was vulnerable to a major objection, but Michael has shared the results of unpublished refinements that fix the problem. Only the results though, so far, so I can't say whether the new simulation has other problems.

[Athanasios]

Thanks for elaborating Aubrey. It helps a lot when you reference published discussions and research, such as in #4 and 6.

I need to read his explanations as I am surprised that he wouldn't take this more into account:

... the versions of LH that have not been falsified are actually the siomplest (most parsimonious) ones and (b) that the late-life non-aging theory is not as parsimonious as he claims because it is incomplete (lacking in any mechanistic component).

[Mind]

Another discussion of SENSE has developed.

One of the comments at the Ouroboros site:

That isn’t his point, exactly. Rose’s point is that in a model where accumulation of damage is constant or accelerating, and that this is the primary cause of aging (where “aging” is a time-dependent loss of fitness), then there shouldn’t be mortality plateaus.

I can't help but come back to a point I raised earlier, even at the risk of displaying my ignorance in the fields of biogerontology and evolutionary biology. Perhaps the accumulation of damage is not constant or accelerating in older individuals - maybe the damage accumulation plateaus and that is why mortality plateaus. Isn't metabolism (the main cause of damage accumulation) slower in older individuals or in the very least there are fewer mitochondria in operation? There are certainly less functional cells in an older individual. The small number of cells that have survived within an exceptionally long-lived individual must have the best repair mechanisms. This would seem to point toward a plateau in damage accumulation.

Now this doesn't invalidate SENSE as an approach to help with the aging problem as tweaking the repair mechanisms through gene therapy would help, but it still seems like SENS is the more direct approach that could be implemented on shorter time scales.

Someone suggested that Michael Rose should be invited here to comment. He was invited to the Sunday text chat back in December of 2007 (but was thwarted due to technical problems) and he has a standing invitation to the Sunday Evening Update. He said he wanted to wait until he was published in Rejuvenation Research before appearing on the program.

[maestro949]

I can't help but come back to a point I raised earlier, even at the risk of displaying my ignorance in the fields of biogerontology and evolutionary biology. Perhaps the accumulation of damage is not constant or accelerating in older individuals - maybe the damage accumulation plateaus and that is why mortality plateaus. Isn't metabolism (the main cause of damage accumulation) slower in older individuals or in the very least there are fewer mitochondria in operation? There are certainly less functional cells in an older individual. The small number of cells that have survived within an exceptionally long-lived individual must have the best repair mechanisms. This would seem to point toward a plateau in damage accumulation.

An alternate theory to explain the plateau that I've been tinkering with using a small C# gene expression simulator app is testing the idea that the environmentally variable impacts on epigenetic mutations can lead to patterns of gene expression that get stuck in either deleterious global states, neutral states or beneficial states. Purely random mutations would simply cancel themselves out and lead to a perfect Gompertz curve but even a slightly favorable weighting towards globally beneficial states would generate a plateau like effect. It's perfectly plausible that an anciently conserved regulatory mechanism within the RNA machinery is weighted in this direction. Otherwise life might not exist at all

[Mixter]

Hmm, but what would the dysregulation of adaptation reduce to?

Can't essentially most dysregulation of metabolites be traced back
to a lack of efficient metabolism, i.e., energy, and if we restore
mitochondrial and cellular function, including clearing the garbage,
then we'd restore the capacity for efficient metabolism, and thus
efficient adaptation?

Maybe adaptation is about more than that, but if so, exactly what points which cannot be traced back to inefficient metabolism as a result of damage?

[maestro949]

Hmm, but what would the dysregulation of adaptation reduce to?

A hierarchical system can be reduced to something however biology is just a big cyclical system run by chemical gradients. Not all of the subcycles within metabolism have a means to reverse their direction. Several metabolic processes and genes can be switched off and left in a switched off state as evolution only invests energy in designing the switching fabric it needs to generate another successful round of offspring.

Can't essentially most dysregulation of metabolites be traced back to a lack of efficient metabolism, i.e., energy, and if we restore mitochondrial and cellular function, including clearing the garbage, then we'd restore the capacity for efficient metabolism, and thus efficient adaptation?

Theoretically but "restoring cellular" function to an aged cell which has many of the hallmarks of precancer is quite tricky. Nature rarely, if ever, does this on it's own. It either provides robustness, redundancy and protein turnover to slow it's progression towards this state in the first place, divides to diffuse the damage, fixes the damage as far upstream as it can, e.g. during the replication process, or signals (internal or triggered via cell surface death receptors) to tell the cell to destroy itself via apoptosis. If all those fail and the cell goes onco, last ditch effort is the immune system mops them up. We should be able to nudge some of these existing processes back towards optimal states (the earlier in the cell's life the better) by leveraging it's own regulatory machinery but wholesale engineering efforts to treat cellular dysfunction and damage will be met with the harsh reality that every other drug or therapy we introduce faces... side effects of unintended consequences due to our ignorance.

Edited by maestro949, 07 July 2008 - 06:42 AM.

[AgeVivo]

The plateau has long been explained by the reliability theory og aging and longevity , which I believe is the best explanation so far of mortality shapes (in short we die as soon as one vital organs such as kidneys or brain dies, and each organ has a high level of internal redondancy such as more cells than needed; this is sufficient to have the plateau; you can add dynamic reparing etc you still get the plateau). The (Makeham-)Gompertz model just approximate the instantaneous risk of dying by an exponential of age, this can't hold at extreme lifespans because by definition the risk must remain below one. In brief, no need to imagine misadaptation or whatever to get a plateau.

However I personally believe that there indeed are set up of cells that make us old. Not just the damage. In particular (although this might be quite different), to make a clone there is apparently a need to 'reset' the cytoplasm (eg nuclear transfert into an ovocyte). A reset or re-expression of genes also to make stem cells out of skin. Also some work from Irina Conboy described that blood samples and grafts (can't remember what exactly, but many of you probably know what I'm talking about) from old donor would impair young mice, and that only massive blood transferts from young mice would improve aging-indicators of old mice.

I do share the opinion that removing the damage is very usefull and that SENS are truly great ideas with this respect. I think that we should keep our minds open because obviously nothing is garantied to work (especially on time;-). I like Michael Rose's work because I think that lifespan data and experiments are one of our best guides. With such a guide, Kenyon's lab was able to extend the lifespan of C elegans by 10 times! We can probably do the same with mamals (although "If birds can fly, why can't we?" ;-) I think that caloric restriction (or rather methionine restriction: not that well known but no need to fast and rodent and human data are very positive) or even grafting an extra heart (to give a more extraordinary exemple) have good chances to make us live quite long too.

[maestro949]

I do share the opinion that removing the damage is very usefull and that SENS are truly great ideas with this respect.

What if the damage is the result of cellular dysfunction though rather than the cause? What if the important damage that restores optimal function and homeostatic balance is the yet-to-be-elucidated upstream control mechanisms buried in the epigenetic programming logic? Jan Vijg raises this point time and again in his book Aging of the Genome.

Simply targeting end products (e.g. damage protein complexes) may leave the aging machinery in place that generated them in the first place and the damage simply returns shortly after cleaning it up. If the nuclear machinery (the factory) is turning out bad or the wrong quantity of proteins, fixing the end products could become a futile firefight if the factory is slowly declining in fidelity and increasingly turning out a bad product with age.

This doesn't mean that targeting the genomic regulatory mechanisms is a silver bullet. Far from it and Aubrey's criticism in the complexity in attempting to doing so presently has much merit. Vijg feels pretty strongly about this too...

Irrespective of our progress in developing new measures for prevention or therapy, genome instability will be the final curtain and the ultimate limit to life. Genomes cannot be cleansed of all genetic damage, because it is their nature to change and undergo mutation. Indeed, to keep genomes free of change would be to tamper with the logic of life itself.

I believe tampering with the logic of life itself is ultimately going to be one of our best options for intervention. Despite the present challenges, the genomics revolution is likely going to provide us with some very economical targets for slowing the rate of accumulating damage. CR is the best evidence that rate of damage can be slowed. It is thought to upregulate damage repair mechanisms which means there are pathways here that we can also target. The ability to tamper with the epigenetic code will allow us to activate stem cells, target cancer, kill aberrant or senescent cells and treat just about every disease.

[lunarsolarpower]

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?

I haven't seen further exposition on the sort of interventions Michael proposes to do based on his research. When I saw him talk he gave the example that his long-lived flies had a much different lipid composition in their bodies than wild-type. When they fed a diet to wild-type flies that induced them to have much the same altered lipid ratio their lives were also extended although not as greatly as those that were of the long-lived variety. I seem to remember him saying he had quite a number of different properties of the long-lived flies that could be emulated in similar ways and many could be applied to humans. In fact, at the time he was soliciting healthy male test subjects for his latest venture along these lines.

Edited by lunarsolarpower, 08 July 2008 - 04:36 AM.

[AgeVivo]

What if the damage is the result of cellular dysfunction though rather than the cause?

Maestro, you take my point and I perfectly second your reasonings.

Here are my current thoughts concerning what you call "cellular dysfunction":

- it seems to be at least partly linked to membrane scars that happens with cell divisions (microscope observation last year in Paris that single cell organisms, when dividing, create a scar on the membrane, and that the 'grand children' inheriting the sides of membrane that have scars stop dividing and die; I would need to look for the paper) and I think there is a link with the link observed accross species AND within species between membrane fatty acid composition and longevity (I would need to look for the paper).

- it seems to be also at least partly due to accumulation of proteins. I in particular think of extended longevity when reducing the number of circular proteins that accumulate in budding yeast (paper from Gary Ruvkun I think). I also think of Podospora Anserina (a filamentous fungus whose age can be very simply measured) whose longevity was multiplied by many times after having deleted genes that produce similar proteins (one of these papers, I need to read to find which ones exactly). With respect to accumulation of proteins, LysoSENS would be actually extremely usefull (the unknown exact definitions of damage and cellular dysfunction overlap; the question of course is: in which measure?)

- probably things in the blood (again, blood transfusion from old mice to young mice, Irina Conboy; also G Butler Brown I think)

- concerning genes? I don't feel it is a real limitation (again, stem cells derived from adult skin cells) (perhaps slightly for specific immune cells, Rita Effros)

-concerning gene expression/mRNA/proteins: I guess it is due to the environment I just described (again, because changing that environment can make healthy stem cells and egg cells)

(Of course, all this might just be wishful thinkings. Experiments is then the key.)

[maestro949]

- it seems to be at least partly linked to membrane scars that happens with cell divisions (microscope observation last year in Paris that single cell organisms, when dividing, create a scar on the membrane, and that the 'grand children' inheriting the sides of membrane that have scars stop dividing and die; I would need to look for the paper) and I think there is a link with the link observed across species AND within species between membrane fatty acid composition and longevity (I would need to look for the paper).

I suspect you're talking about budding yeast scars? Do similar scars that exist in mammalian cell divisions mechanistically interfere with intracellular signaling and contribute to symptoms of aging? I don't think these are the crosslinks that SENS argues we need to deal with though I may be wrong.

- it seems to be also at least partly due to accumulation of proteins.

It's known that the ubiquitination mechanisms that are responsible for breaking down proteins decline with age. Young organisms do not accumulate proteins because they are efficiently turning them over. Aged cells are turning out the wrong levels of ubiquitins along with misfolded proteins. So a preferred solution might be to targeting upstream control factors controlling ubiquitin levels or to simply destroy and replace the aged cells altogether.

- probably things in the blood (again, blood transfusion from old mice to young mice, Irina Conboy; also G Butler Brown I think)

Agreed. Good work is being done here. The levels of circulating proteins in the blood that are inhibiting regenerative potential are products of cellular gene expression being regulated within one or more tissues. Tinkering with the regulation of these circulating proteins is a viable strategy for rejuvenation.

- concerning genes? I don't feel it is a real limitation (again, stem cells derived from adult skin cells) (perhaps slightly for specific immune cells, Rita Effros)

Stem cells are a nice catchall for dealing with the "quantity of cells" and replacing aged cells issues but the magic of stem cells lies in epigenetics regulation as well.

-concerning gene expression/mRNA/proteins: I guess it is due to the environment I just described (again, because changing that environment can make healthy stem cells and egg cells)

Gene expression is what produced that environment in the first place. To change the environment is to change the product of what proteins are being produced thus targeting the regulatory machinery that is turning them out.

[Mind]

I suspect you're talking about budding yeast scars? Do similar scars that exist in mammalian cell divisions mechanistically interfere with intracellular signaling and contribute to symptoms of aging? I don't think these are the crosslinks that SENS argues we need to deal with though I may be wrong.

This is an interesting idea that I haven't heard before. Any other research out there about membrane scars?

As far as the SENSE approach. Rather than spending years or decades breeding long-lived strains of animals, why not just throw more effort into researching animals that do not show signs of aging. Has anyone seen any results from Ageless Animals recently? Are these animals able to clean up junk within their cells? Or do they not generate the same type of undigestible metabolic byproducts because they are cold blooded (rock fish, tortoise)?

[maestro949]

I suspect you're talking about budding yeast scars? Do similar scars that exist in mammalian cell divisions mechanistically interfere with intracellular signaling and contribute to symptoms of aging? I don't think these are the crosslinks that SENS argues we need to deal with though I may be wrong.

This is an interesting idea that I haven't heard before. Any other research out there about membrane scars?

I've only seen reference to them as aging biomarkers for budding yeast in the gerontology literature.

As far as the SENSE approach. Rather than spending years or decades breeding long-lived strains of animals, why not just throw more effort into researching animals that do not show signs of aging.

The value here is that you can study your organism before and after the "evolutionary" changes. You can evaluate what genetic or epigenetic changes occurred and then see if causing mutations to homologous genes in higher level mammals yield a similar benefit.

Has anyone seen any results from Ageless Animals recently? Are these animals able to clean up junk within their cells? Or do they not generate the same type of undigestible metabolic byproducts because they are cold blooded (rock fish, tortoise)?

I don't think much research has been done on this front. It was interesting to see a correlation between depth and lifespan. Could predation or water temp be a factor here?

[AgeVivo]

membrane scars

I was referring to several concordant things: budding yest scars indeed (Ruvkun), aging of E.Coli daughters (great & free: http://www.pubmed.org/15685293; perhaps also this one but I am not sure: http://www.pubmed.org/18476823 free registration to get), a theory of aging that says that each cell division is a terrible assault (Robert Ladislas I think), and connexions between aging and membrane composition (eg http://www.pubmed.org/17928583)

throw more effort into Ageless Animals.

Humans invented planes based on bird observation. Researchers studied crocodile hemoglobin and found out how to modify our own hemoglobin to better resist to lack of oxygen. The real-life application doesn't sems quite far (http://mfoundation.o...hread.php?t=792). I wonder what exactly is blocking?

Are these animals able to clean up junk within their cells? Or do they not generate the same type of undigestible metabolic byproducts because they are cold blooded (rock fish, tortoise)?

wonder whether this could be easily measured with LysoSENS instruments, using samples from very old turtles..

Edited by AgeVivo, 12 July 2008 - 10:09 PM.

[maestro949]

membrane scars

I was referring to several concordant things: budding yest scars indeed (Ruvkun), aging of E.Coli daughters (great & free: http://www.pubmed.org/15685293; perhaps also this one but I am not sure: http://www.pubmed.org/18476823 free registration to get), a theory of aging that says that each cell division is a terrible assault (Robert Ladislas I think), and connexions between aging and membrane composition (eg http://www.pubmed.org/17928583)

Yet another interesting candidate for a source of damage. Should it be promoted to a theory of aging though or should this just fall under a more broad "theory of damage accumulation" as simply one example of damage. It would have to demonstrated that this is a key trigger of all downstream mutations, aggregates, regulatory dysfunction etc for it to be recognized as a theory of aging.

throw more effort into Ageless Animals.

Humans invented planes based on bird observation. Researchers studied crocodile hemoglobin and found out how to modify our own hemoglobin to better resist to lack of oxygen. The real-life application doesn't sems quite far (http://mfoundation.o...hread.php?t=792). I wonder what exactly is blocking?

Is this the thinking behind oxygen bars? It might be worth answering the question : Have there been any studies that show that an increases in oxygen intake has any type of health or rejuvenation benefits? Once we can test for aging biomarkers (gene expressions, etc) we should be able to answer questions like this.

Are these animals able to clean up junk within their cells? Or do they not generate the same type of undigestible metabolic byproducts because they are cold blooded (rock fish, tortoise)?

wonder whether this could be easily measured with LysoSENS instruments, using samples from very old turtles..

Good question. One idea might be to inject the indigestible targets of concern into healthy cells of various organisms (and perhaps even younger human cells) and see if they are capable of breaking them down. If they do then gene expression profiles could be run in conjunction with knockouts to narrow down the gene products responsible.


Regarding SENSE (we're getting off topic as usual)...

I read the paper and it makes more sense to me now (no pun intended). Essentially he's arguing that the cumulative damage theories of aging do not have sound data to back them up whereas it can be shown that lab models can have their lives extended significantly by selection and other means such as calorie restriction. For this reason there must be mechanistic processes that are governing longevity. A valid point IMO but there's not a lot of data as to what these mechanisms are at a gene regulatory and metabolic level. A key paragraph from the paper :

... [T]he point here is that we have clear evidence of a different category of aging mechanisms from those that are mere damage. There may be many types of aging mechanism other than these two. Nor is it being supposed that allocative mechanisms of aging never entail increased damage. They may involve damage in some cases. From a Wrightian view of the evolutionary process, we generally expect physiological genetic mechanisms to interdigitate, forming a network of causation that involves epistasis, pleiotropy, and other complexities.

In my opinion, this last sentence is the most relevant. There may be both a change in regulatory mechanism that originate from the evolutionary programming and damage accumulation (causual and resulting) that may in turn also affect these mechanisms that again, in turn, has a ripple effects that cascades throughout the network of cellular and organ systems eventually manifesting itself as diseased or frail organism that can't compete with the environment. Wow, that was a mouthful. In essence though, perhaps it isn't one or other but rather a much more nefarious and complex network of systematic degradation. In this model, targeting the damage might improve things a bit but it's not a guaranteed fix but nor is targeting the regulatory machinery as CR'ed animals and evolutionarily selected organisms still die, just slightly later than their wild types (relatively speaking).

Edited by maestro949, 15 July 2008 - 06:44 PM.

[AgeVivo]

Sorry for my very late response. I wasn't sure enough of my views about aging to answer.
I thought i'll talk about 'my current views' of aging


The body of an organism accumulates many troubles (that we can call 'cumulative damage', but it can be a too high proportion of senescent cells for instance, so the word isn't perfect) that are inherent to its organization: the parameters of the body (eg possibility for a cell to go scenescent and cancerous; eg main protein and gene interactions) have been roughly tuned by hazard and natural selection and aging is a byproduct.

- So this 'pseudoSENS' and 'pseudoEvolutionaryProgram' are perfectly compatible.
- Plateau of mortality rates: it doesn't rule out anything: the fact that the body requires several redondant and faulty organs to work (cumulative 'damage', increasing troubles) is sufficient to explain the plateau (one explanation beeing the one from Leonard Gavrilov that i mention earlier in this thread)
- membrane scars: it has been promoted to a theory of aging by some but doubt it is really a trouble, otherwise lobsters's aging would be as obvious as ours, children would have a tendency to live slightly less long (and trees's aging would be more obvious...but their membrane is very different)
- using crocodile oxygenation tricks: we/mice would probably live longer: worms live longer under hypoxia because that's closer to their environment but rodents do not. much effort (and natural selection) is required to oxygenate the body, so we are probably slightly underselected=underoxygenated so a *little* more oxygen in the air might be better, but oxygen bars probably slightly harm. However, having a blood that better handles oxygen (using tricks from crocodiles) would probably release the load on the whole body, without too much or too low oxygen: thanks to chemoreceptors we would naturally breathe slowlier, the heart could beat slowier, pressure might be slightly slowier
- using tortoise/rock fish degration tricks: would surely help, in the same way
- CR: releases the load (same idea as crocodile oxygenation)? program selected by evolution? no idea

PLEASE tell me if you think something contradicts my views of aging (which were usually not mine initially). Thanks

I'm now thinking about whether Michael Rose 's observations, or similar methods, has good chances to work for us (which is questionable, as pointed out by Elrond). I'll try to give my view of it when i have one.

[brokenportal]

All in favor of trying to set up a ustream debate between deGrey and Rose? Say I.

I.

[AgeVivo]

I.

[AgeVivo]

3 thinkings along Michael Rose's approach:

• MPrize @ home could serve to check that caracteristics that extend lifespan of flies also extend lifespan of mice.
• If it is still desired to create a long lived mouse strain, genome tagged mice might be used as the starting strain, so that it is much faster to find out the changes between the initial strain and the long-lived created strain
• Rather than delaying childhood as an evolutionary tool for selecteing longevity, one could select children of the flies that live the longest. It requires a big but not huge buffer of flies (the size is not exponential; it depends on the longevity of flies)

Edited by AgeVivo, 13 May 2009 - 07:35 AM.