96 replies to this topic

[elwalvador]

Aging may not be caused by the accumulation of cellular damage, as a prominent theory suggests. Instead, the process may result from the deterioration of crucial developmental pathways, according to a study published tomorrow in Cell.

"What we found is, I think, a different way to think about aging," Stuart Kim of Stanford University, main author of the study, told The Scientist.

Kim and his colleagues used microarray gene chips to compare the genes being expressed in old and young C. elegans worms. They found 1254 genes that had different expression levels between the two groups. Almost all of these genes were developmental genes, necessary for proper intestinal and skin development in young worms.

Kim's team also found a set of three transcription factors that had different expression levels in old worms. Two of the transcription factors -- called ELT-5 and ELT-6 -- were overexpressed in old worms. In turn, those two suppressed the expression of the third transcription factor -- called ELT-3. When ELT-3 was suppressed by the other two, the 1254 developmental genes were turned off.

When the researchers blocked ELT-5 and ELT-6 in RNA interference experiments, ELT-3 expression went up, expression of the 1254 genes went up, and the worms lived 50% longer. This suggests that ELT-3 controls the continued expression of the developmental genes and might be the crucial link between aging and development.

The researchers don't yet know what is pushing the transcription factors off balance, but their results suggest the culprit is not environmental factors of cellular damage such as oxidative stress. Exposing young worms to extreme oxidative stress didn't induce overexpression of ELT-5 and ELT-6. Kim's team is now looking into what unbalances the transcription factors in the first place.

"People have been looking for gene expression changes in aging for a while," Brian Kennedy, from the University of Washington, told The Scientist. "To have it linked to a specific set of transcription factors is definitely a step forward; now there's a potential mechanism by which those changes in gene expression occur."

According to Kim's theory, oxidative damage to cells still occurs over the course of an organism's lifetime, but it's not the only cause of aging. Oxidative damage is like rust accumulating on a car, said Kim. In this new model of aging, the rusting still happens, but internal mechanisms in the car -- like the gas or break pedals -- start breaking down. The proportion of aging attributed to environmental factors versus this internal mechanism is still a mystery, said Kim. "I think Dr. Kim is right to raise this hypothesis," Kennedy said. "A lot of previous studies were done at the organism level. Now people are trying to ask what specific tissues are these genes having their effect in that causes increased lifespan. So looking at tissue specificity [like intestine and skin development] is very informative."

Kim added that an internal aging mechanism might explain why some organisms live for two weeks (C. elegans), some 80 years (humans), and some 200 (sea turtles). Under Kim's theory, different organisms' developmental pathways degrade at different rates. Depending on natural selection, degradation might set in much earlier for some organisms than others, he said. "That could be contributing to why some animals live to 40, and others to 80." Article link: Rethinking Aging

It's not just free radicals causing us to age. We need to shut off certain genes too.

Edited by elwalvador, 24 July 2008 - 10:45 PM.

[Athanasios]

Chicken or the Egg?

We have proponents of both here.

Fixing damage that leads to pathology seems to work pretty well.

[Ethan]

This is a fantasticly interesting and important study! If there is even some truth to his theory, which sounds extremely plausible, than this will be something that needs to be addressed. I don't see how this is an either or or one before the other issue, i.e. cellular damage leading to aging or degradation of pathways leading to aging. Since everything decays this should have to be put in as a piece of the puzzle. Very good find. If there is any follow-up from Kim you find in the coming months please post them.

[VictorBjoerk]

so we have "evil genes" that causes us to age?

[Ethan]

so we have "evil genes" that causes us to age?

The study is more about "evil transcription factors." I don't extrapolate from this article that these proteins cause us to age, but they may help determine the lifespan of a species by acting as a biological clock of sorts, irrespective of damage occuring elsewhere and the degradation of certain "developmental pathways" may also be contributing to the aging process.

[Mind]

I agree with Cnorwood here in that it could be the chicken and egg scenario all over again. If there is an aging "gene" or program then it has proved notoriously hard to pin down. The only thing that comes close is telomeres.

Also, from what I can tell it is not an either or proposition. Cellular damage most certainly causes some pathology that can eventually result in death, even if it is not the primary cause of aging, so fixing it would be good for overall health. In this regard the SENS program (and damage theory of aging) is beneficial. Even in the extreme and unlikely case that cellular damage isn't even remotely related to the fundamental aging process, SENS has raised awareness, money, and new research to combat the problem, and thus has served humanity greatly.

[Ethan]

I agree with Cnorwood here in that it could be the chicken and egg scenario all over again. If there is an aging "gene" or program then it has proved notoriously hard to pin down. The only thing that comes close is telomeres.

Also, from what I can tell it is not an either or proposition. Cellular damage most certainly causes some pathology that can eventually result in death, even if it is not the primary cause of aging, so fixing it would be good for overall health. In this regard the SENS program (and damage theory of aging) is beneficial. Even in the extreme and unlikely case that cellular damage isn't even remotely related to the fundamental aging process, SENS has raised awareness, money, and new research to combat the problem, and thus has served humanity greatly.

If an "aging program" is not part of the overall picture then how did tampering with gene expression increase the lifespan of C. elegans by 50%? I am not sure, but I am certain genes are not simply turned on and off through life, but expressed differently over time. One of the things that is so interesting about this study is that it seems to support what I think is a well excepted idea that there are developmental periods of genetic expression. Therefore there must be periods of time that genes underexpress themselves later in life or express themselves in a different fashion that through these means amounts to the acceleration of the aging process. If true, by no means does this have to be the only or largest factor involved.

As far as your second paragraph is concerned, you seem to be indicating that I am anti-SENS, which raises an important issue. Just because I am extremely open to as many perspectives on aging as can be lucidly stated and substantiated with credible evidence, does not mean I am anti-SENS. I support SENS research fully, but even the Methuselah Foundation makes it very clear they do not have all the answers and they are constantly going to need to be reforming their assumptions as the aging picture is further illuminated. My concern is that by not highlighting credible studies such as these, that produce a 50% increase in this species of worms, SENS is being done a disservice. Competition between good ideas ultimately benefits those who are challenged by them. It does not pay to draw lines in the sands and choose a side when everyone is working on the same goal. There is a very eclectic group of topics on this site, so I am sure you agree.

[maestro949]

If an "aging program" is not part of the overall picture then how did tampering with gene expression increase the lifespan of C. elegans by 50%?

I agree. There are clearly more ideal sets of gene expressions that lead to a healthier/younger/more optimally functioning organism that can better survive environmental assaults. While the decay in this combinatorial set of expressions are somewhat time dependent, it's not a program but rather a form of evolutionary neglect to invest energy in building repair mechanisms and enough redundancy for sustaining specific types of pathways and system failures, particularly those that manifest themselves as the common diseases of aging, e.g. cancer. CR and other gene studies make it clear that by regulating specific genes it is very likely that we can significantly delay some forms of damage to the genetic regulatory network and thus delay the downstream pathologies.

As far as your second paragraph is concerned, you seem to be indicating that I am anti-SENS, which raises an important issue. Just because I am extremely open to as many perspectives on aging as can be lucidly stated and substantiated with credible evidence, does not mean I am anti-SENS. I support SENS research fully, but even the Methuselah Foundation makes it very clear they do not have all the answers and they are constantly going to need to be reforming their assumptions as the aging picture is further illuminated. My concern is that by not highlighting credible studies such as these, that produce a 50% increase in this species of worms, SENS is being done a disservice. Competition between good ideas ultimately benefits those who are challenged by them. It does not pay to draw lines in the sands and choose a side when everyone is working on the same goal. There is a very eclectic group of topics on this site, so I am sure you agree.

Well said. It's possible to support the efforts of SENS and continue looking for more optimal strategies.

[Mind]

There is a very eclectic group of topics on this site, so I am sure you agree.

I agree. Aging is complex and most likely has a multifaceted solution, and the SENS outline is not fixed.

Just want to be sure we don't throw away the damage theory of aging. It is unlikely that we will be able to tweak one gene and - poof - aging will be gone.

[ag24]

Hi everyone,

This paper has had a lot of attention, largely because of the authors' conclusion that their data shows a role for something over and above damage in driving aging. However, as far as I can see the conclusion is not robustly supported by the data (to say the least). What are the predictions if damage accumulation is all that matters in aging? Well, we can certainly expect that certain gene expression levels will change with age in response to the changing levels of damage. We can also expect that there will be a cascade of such changes, with some changes being caused by others rather than directly by the damage itself. We can also expect that stimuli which turn on protection against aging, such as calorie restriction or its genetic simulation (e.g. by mutating daf-2 or by inducing dauer), will at least sometimes work by "unnecessarily" activating the same gene expression pathways that are activated by damage, because many of those pathways will be attempts to combat that damage, and turning them on "prematurely" will thus be a way to slow down that damage's early-life accumulation. So in other words, the only part of the paper that even putatively challenges the idea that damage is all that matters is the section entitled "Environmental Stress Does Not Regulate the elt-3 Transcriptional Circuit". But hang on... first of all, bizarrely, there is no figure or table giving the actual data from the experiments described there. Secondly, the authors did see a change in their elt-3 expression when they imposed oxidative stress. They claimed that this was still inconsistent with damage being the whole problem, because the change was in the opposite of the expected direction. But that reasoning is based on confusing oxidative stress with oxidative damage (which is what oxidative stress accelerates the accumulation of). There's good evidence (as well as it being common sense) that organisms respond to oxidative damage by reducing oxidative stress to the extent they can - in particular, oxygen metabolism is lowered. It's perfectly reasonable to suppose that elt-3 and friends are not responding directly to the increase of oxidative damage with age but to the consequent reduction in oxidative stress, in which case raising oxidative stress will have the effect they saw. And the fact that one of their target genes, one that goes down in aging but up in response to paraquat, is SOD, obviously supports that interpretation.

So in conclusion, I'm all for careful exploration of the possibility that aging may partly be the accidental continuation of development, or whatever, but this paper sure doesn't seem to provide any evidence for that, despite the attention it's received.

[Mind]

It's possible to support the efforts of SENS and continue looking for more optimal strategies.

More optimal strategies might exist, however the engineering/fix-the-damage/SENS strategy seems to me to be the most optimal at this point and has the greatest chance of producing positive useful short-term results.

[forever freedom]

Hi everyone,

This paper has had a lot of attention, largely because of the authors' conclusion that their data shows a role for something over and above damage in driving aging. However, as far as I can see the conclusion is not robustly supported by the data (to say the least). ...

Good post. Makes things much clearer to me.

Edited by Michael, 02 April 2009 - 03:13 PM.
Snipped redundant quotation

[Ethan]

It's possible to support the efforts of SENS and continue looking for more optimal strategies.

More optimal strategies might exist, however the engineering/fix-the-damage/SENS strategy seems to me to be the most optimal at this point and has the greatest chance of producing positive useful short-term results.

I am certain that nobody was suggesting otherwise at anypoint, however, when a researcher of Dr. Kim's stature puts forth a study and a theory, it should be given consideration. This is a description of Kim's work at the Stanford School of Medicine.
Stuart K. Kim, Ph.D.
Aging, Diabetes, Cancer

Aging is among the most universal of biological processes and perhaps also among the most mysterious. Numerous age-related changes are apparent at the organismic level, but we are only now starting to understand age-related changes at the molecular level. Oxidative damage, replicative senescence, accumulated stress and metabolic rate have each been proposed to specify life span. Dr. Stuart Kim’s laboratory is using functional genomics approaches to uncover the underlying genetic networks that determine longevity in the nematode C. elegans, an excellent model organism in which to study aging. The normal life span for worms is 2 weeks but under poor growth conditions, worms enter the dauer state and have life spans that can be 10 times longer. Powerful genetic screens have been used to identify mutants with increased life span. In particular, loss-of-function mutations in genes in the C. elegans insulin signaling pathway (such as daf-2 insulin receptor and age-1 PI3 kinase) extend life span. These results indicate that insulin signaling plays an important role in specifying life span, probably by regulating rates of cellular metabolism. Although previous genetic experiments have identified upstream regulatory pathways that influence the rate of aging, metabolic processes and genetic pathways that lie downstream of the insulin signaling pathway and that directly influence cellular senescence and organismic longevity are poorly understood.

To identify terminal effector genes that may directly influence life span, Dr. Kim’s group is using DNA microarrays containing nearly every gene in C. elegans to profile gene expression changes during normal life span, during the dauer stage and in mutants with increased longevity. In analyzing these gene expression patterns, Dr. Kim seeks to identify common genetic mechanisms involved in specifying life span. A surprising result is that Dr. Kim’s preliminary studies found only 164 aging-regulated genes from an extensive microarray analysis of gene expression changes during the normal life span. This result indicates that gene expression in old worms is relatively stable. The 164 aging-regulated genes include two insulin-like genes and a sir-2 homolog that increase at the end of life. Previous studies have shown that insulin signaling and sir-2 regulation act to specify life span in C. elegans. Heat shock genes decrease in old age, possibly resulting in increased levels of protein denaturation, decreased cell function and organismal senescence.



Aubrey addressed the study (thank you for doing so Aubrey) and raised a lot of apparent flaws in it. This subsection is on aging theories and it is precisely these types of discussions that should be encouraged.

[maestro949]

It's possible to support the efforts of SENS and continue looking for more optimal strategies.

More optimal strategies might exist...

Thus investment is needed to find them as all currently proposed strategies are too expensive, requiring many billions of dollars of research and many billions more in bring-to-market R&D and investment costs not to mention the decades (or more) of time for this to occur. They also enjoy the same potential failure rate of every other therapeutic intervention we've thrown at aging in the past 50 years. IMO, if those more optimal strategies don't pan out, we're dead, right on schedule with the laws of mortality.

... however the engineering/fix-the-damage/SENS strategy seems to me to be the most optimal at this point...

Fixing damage is indeed the only solution and an engineering approach will ultimately be required is a no-brainer. Like everything else, biological systems break down over time and need to be fixed. A 12 year old could recognize this. However the identification of what the most important damage that needs to be fixed and when during the aging process it needs to be addressed for maximum longevity is still wide open and will be until somebody demonstrates otherwise.

The notion of researching all preventative fixes between gene product to pathology endpoint such that finding any damaged link in the chain early and fixing it before it cascades into more expensive damage types is very appealing and should not be dismissed because looking upstream at the regulatory machinery is too complex. An ounce of prevention is worth a pound of cure rings especially true when observing the numerous aging pathologies that exist, many of which may occur due to upstream factors, that is, other damage such as DNA, chromatin remodeling, methylation and other factors that affect gene expression. Dismissing the research of all aspects and originations of aging damage and arguing that it is futile is dangerous to the meme. I find this rhetoric disturbing and feel that it's way too early to take any approaches off the table and focus squarely on a handful of strategies.

... and has the greatest chance of producing positive useful short-term results.

Our understanding of the aging process is far too limited to adequately predict with any real accuracy as to what solutions are most optimal. If any were truly showing any usefulness as short-term strategies there would be considerable evidence demonstrating this in mammalian trials. We have nothing. Nothing even remotely close.

[Mind]

Like everything else, biological systems break down over time and need to be fixed. A 12 year old could recognize this.

Tell that to all the believers in the program theory of aging. There are plenty of them out there that think if we just tweak the genome a little, or insert the right mix of hormones, that - poof - aging will be solved. I even have people emailing me once in a while saying Aubrey and the damage theory of aging is seriously flawed/crazy/nuts.

Edited by Mind, 15 January 2009 - 09:58 PM.

[maestro949]

Like everything else, biological systems break down over time and need to be fixed. A 12 year old could recognize this.

Tell that to all the believers in the program theory of aging. There are plenty of them out there that think if we just tweak the genome a little, or insert the right mix or hormones, that - poof - aging will be solved.

I doubt anybody who has seriously studied aging believes the solution to be this simple. Anybody making these suggestions discredits themselves immediately to one who has done even basic research into aging. An analogy would be a creationist trying to argue their case to a scientist. It's a futile and hopeless effort.

Personally I think too much emphasis is placed on trying to prop up one theory vs. another. IMO the entire debate is flawed as the answer to the two questions: is aging programmed or is aging due to damage could be argued as yes and... yes (or just as easily no and no due to the ambiguity and the nature of the question). If you identify Evolution as the programmer then you could safely state that evolution programmed us to have just enough repair machinery to fix just enough damage to survive another generation in the wild. No more, no less. There are obviously some specific biological clocks wired in to generate what some could argue as damage as well though evolution makes no distinction. Good examples are the genetically regulated telomere shortening, a drive towards cellular senescence, downregulation of tissue renewal facilities but by far the best example is thymic involution where the thymic function is proactively dismantled. I think this would fall into Aubrey's "whatever" category above. Is the organism trying to kill itself at a specific age? Unlikely. It's more likely that evolution programs like the software engineers on my team. If they can get it past the QA cycle, good enough. Whether it survives in the wild (production in my case), as long as enough do to reproduce, who cares about the rest or how long the organisms live beyond producing offspring. If evolution has to hack in some time bombs to thwart cancer, modulate the development process to match what the environment can afford or prevent hyperimmune responses to get the organism to a reproductive age then so be it, it will.

But I'm preaching to the choir as most of us are already aware of this. The point is, the emphasis needn't be on propping up one theory or another, drawing circles around a series of interventions or drawing battle lines in the sand but rather should be on finding what interventions we can safely and economically make that lengthen our lifespans. Soon too. From our naive perspective, everything that inhibits the optimal functionality of our systems is effectively damage yet nearly all efforts to intervene tend to fail because of our lack of understanding of what damage really is. Based on this we should continue to assume that most if not all theoretical interventions will continue to fail. With this in mind, expanding our knowledge of the origination of damage and searching for more places to intervene should remain a key strategy of longevity rather than simply trying to focus on engineer solutions to the damaged endpoints we're aware of.

Edited by maestro949, 01 September 2008 - 04:35 PM.

[Nova]

The person dies for 3 reasons:

1) cage oxidation - because of the big concentration of oxygen. 2) cancer disease of a cage, - because of a cell fission considerable quantity. 3) loss of elasticity of a fabric - because of big numbers of slags in a cage. All it inevitably leads a death organism. There is only one way of rescue - carrying over of consciousness to other body. But, how consciousness to recover? Consciousness carrying over should be carried out on the computer, with the help nano robots. Others nano robots should write down memory of the person on DNA of a chromosome and introduce this DNA in gene an embryo. New genes of an embryo will give the chance to recover consciousness in a new body.

[VinceG]

Like everything else, biological systems break down over time and need to be fixed. A 12 year old could recognize this.

Tell that to all the believers in the program theory of aging. There are plenty of them out there that think if we just tweak the genome a little, or insert the right mix or hormones, that - poof - aging will be solved.

I doubt anybody who has seriously studied aging believes the solution to be this simple. ...

Personally I think too much emphasis is placed on trying to prop up one theory vs. another. IMO the entire debate is flawed as the answer to the two questions: is aging programmed or is aging due to damage could be argued as yes and... yes (or just as easily no and no due to the ambiguity and the nature of the question).

I basically concur with respect to not looking for or propping up any favorite theory of aging. Note that when it comes to aging of automobiles there are no pitched battles between the school that blames it on rust (oxidation), the mechanical wear-and-tear school and even the school that believes the automobile companies have built in obsolescence. We all accept that there are lots of reasons that can cause automobiles to age and essentially all of them can be countered by repair-shop engineering solutions. I strongly disagree with the last two points, however. We very much know what damage is: oxidative stress, inflammation, telomere shortening, cancers, cardiovascular disease, etc. - the things that cause old people to get sick and die.) What we don't know is exactly how these relate to each other and what is more basic to what else. There may be key variables hiden to us now - and there might not be. I believe there are a number of engineering solutions to aging that can be applied right now and more are becoming available almost monthly (see my position paper http://www.vincegiul...ngfirewalls.htm) While these solutions may be partial and early-stage crude, they are far better than ignoring them right now. And they are subject to continuing improvement. The solution to a rusted fender today is to be found in an autobody shop, not in a lab studying the quantum crystal structure of new nanomaterials. I also strongly support expanding our basic knowledge of course. In twenty five years, fenders based on metal nanomaterials might not rust at all. My car can't wait though, and at my age I can't wait for 2033 anti-aging solutions either. There should be no conflict between using and improving our engineering fixes today and expanding our knowledge for the future. We need to do both. Vince

Edited by Michael, 02 April 2009 - 05:24 PM.
Snipping redundant quotation

[maestro949]

Note that when it comes to aging of automobiles there are no pitched battles between the school that blames it on rust (oxidation), the mechanical wear-and-tear school and even the school that believes the automobile companies have built in obsolescence. We all accept that there are lots of reasons that can cause automobiles to age and essentially all of them can be countered by repair-shop engineering solutions.

The analogy isn't really fair though. An automobile, even a 2009 luxury vehicle packed with electronics, is a quite simple device compared to a complex organism that can make adaptations and heal itself. Furthermore we engineered the vehicle and have the Chiltons manuals. To make this a fair analogy you'd have to give an automobile to 3rd century BC Greeks and see how well they do with getting much mileage out of it.

We very much know what damage is: oxidative stress, inflammation, telomere shortening, cancers, cardiovascular disease, etc. - the things that cause old people to get sick and die.)

We understand the basics of what damage (at least that's how we see it, to the organism, it's just change that it may or may not adapt to) is accumulating at the cellular and organ level but when trying to understand metabolic and protein interactions that give rise to those changes, we lose clarity pretty quickly. We also don't know the ramifications or side effects of what reversing various damage types will actually have. Of course it seems straight forward, however in practice, it never is. Broken fender, replace fender. Broken immune system, er, different story. How do you fix something that is intricately wired into everything else without impacting all of those other components?

What we don't know is exactly how these relate to each other and what is more basic to what else. There may be key variables hidden to us now - and there might not be.

I'd argue that most of the key variables are still hidden to us. Telomeres are an interesting marker but it's wired into a sophisticated network of regulatory mechanisms and by simply tweaking telemorase levels, it's unlikely that organisms are going to live longer. And if they do, it's only a nominal gain. You'd need to successfully find a significant number of these nominal gains to really impact longevity.

I believe there are a number of engineering solutions to aging that can be applied right now and more are becoming available almost monthly (see my position paper http://www.vincegiul...ngfirewalls.htm) While these solutions may be partial and early-stage crude, they are far better than ignoring them right now. And they are subject to continuing improvement. The solution to a rusted fender today is to be found in an autobody shop, not in a lab studying the quantum crystal structure of new nanomaterials.

I disagree that there are many engineering solutions that can be applied to aging in the near term. Researched perhaps, but not applied. There's a significant distinction as researching a target interventions does not necessarily and automatically lead to an implementable solution due to the costs, complexities, counter-intuitive behavior of biological systems and numerous feedback mechanisms embedded within. Nearly all single-point fixes we try to implement triggers a cascade of counter-reactions that are unanticipated thus the only safe assumption is that the majority of fixes we research will continue to have a high probability of failure and simply lead back to a point of basic research, even if constrained to aging research. So the question I have is what magic lies in any anti-aging therapeutic proposal that makes it immune to the side affects we see with failed gene therapy, failed stem cell therapy, failed pharmaceuticals, cancer chemotherapies, etc? All of these are engineering efforts no? Granted that most research efforts into disease aren't as targeted at aging issues that we'd like to see, there are numerous like efforts to everything I've seen proposed going on at the molecular level that continue to fail. Our ability to intervene has a terrible success rate at just about every level. Is there a conspiracy? Are these oncologists, stem cell researchers and geneticists intentionally sabotaging their results or are they simply fools flailing around and researching the wrong stuff? I don't think either is the case. They are stuck battling one thing... Complexity. They try to put a new fender on the car in the auto body shop and a piston shoots through the engine block damaging the electronic fuel ignition. It seemed like the intuitive thing to do but who would have thunk that a fender was somehow tied to piston function. That's biology.

I also strongly support expanding our basic knowledge of course. In twenty five years, fenders based on metal nanomaterials might not rust at all. My car can't wait though, and at my age I can't wait for 2033 anti-aging solutions either. There should be no conflict between using and improving our engineering fixes today and expanding our knowledge for the future. We need to do both. Vince

I agree however if the interventions keep failing and leading us back to a common denominator of basic aging research, then we better keep the emphasis on building more tools that help us eliminate the ignorance and comprehend the complexity. Sure, lets keep testing theoretical interventions as we may get lucky from time to time (serendipity still contributes more to science than anything else) but lets not kid ourselves into thinking we have some magic beans that trump what researchers on the cutting edge are already working with.

[Mind]

I agree however if the interventions keep failing and leading us back to a common denominator of basic aging research, then we better keep the emphasis on building more tools that help us eliminate the ignorance and comprehend the complexity.

Bio-informatics and computer simulation should help speed things along in the near future. Help with the complexity.

[maestro949]

I agree however if the interventions keep failing and leading us back to a common denominator of basic aging research, then we better keep the emphasis on building more tools that help us eliminate the ignorance and comprehend the complexity.

Bio-informatics and computer simulation should help speed things along in the near future. Help with the complexity.

Indeed, comparative genomics, microarray and other types of computational analysis is showing quite a bit of early promise, but some new and novel approaches and technologies will still be needed for the more sophisticated integration efforts as those trying to merge the various datasets are struggling with the complexity, noise, combinatorial explosions, dynamics, etc. I'd agree that long-term this is going to have a very significant impact on aging due to the stochastical nature of the aging process. Hell, even twins don't age in a similar manner!

[VinceG]

Note that when it comes to aging of automobiles there are no pitched battles between the school that blames it on rust (oxidation), the mechanical wear-and-tear school and even the school that believes the automobile companies have built in obsolescence. We all accept that there are lots of reasons that can cause automobiles to age and essentially all of them can be countered by repair-shop engineering solutions.

The analogy isn't really fair though. An automobile, even a 2009 luxury vehicle packed with electronics, is a quite simple device compared to a complex organism that can make adaptations and heal itself. Furthermore we engineered the vehicle and have the Chiltons manuals. To make this a fair analogy you'd have to give an automobile to 3rd century BC Greeks and see how well they do with getting much mileage out of it.

We very much know what damage is: oxidative stress, inflammation, telomere shortening, cancers, cardiovascular disease, etc. - the things that cause old people to get sick and die.)

We understand the basics of what damage (at least that's how we see it, to the organism, it's just change that it may or may not adapt to) is accumulating at the cellular and organ level but when trying to understand metabolic and protein interactions that give rise to those changes, we lose clarity pretty quickly. We also don't know the ramifications or side effects of what reversing various damage types will actually have. Of course it seems straight forward, however in practice, it never is. Broken fender, replace fender. Broken immune system, er, different story. How do you fix something that is intricately wired into everything else without impacting all of those other components?

What we don't know is exactly how these relate to each other and what is more basic to what else. There may be key variables hidden to us now - and there might not be.

I'd argue that most of the key variables are still hidden to us. Telomeres are an interesting marker but it's wired into a sophisticated network of regulatory mechanisms and by simply tweaking telemorase levels, it's unlikely that organisms are going to live longer. And if they do, it's only a nominal gain. You'd need to successfully find a significant number of these nominal gains to really impact longevity.

I believe there are a number of engineering solutions to aging that can be applied right now and more are becoming available almost monthly (see my position paper http://www.vincegiul...ngfirewalls.htm) While these solutions may be partial and early-stage crude, they are far better than ignoring them right now. And they are subject to continuing improvement. The solution to a rusted fender today is to be found in an autobody shop, not in a lab studying the quantum crystal structure of new nanomaterials.

I disagree that there are many engineering solutions that can be applied to aging in the near term. Researched perhaps, but not applied. There's a significant distinction as researching a target interventions does not necessarily and automatically lead to an implementable solution due to the costs, complexities, counter-intuitive behavior of biological systems and numerous feedback mechanisms embedded within. Nearly all single-point fixes we try to implement triggers a cascade of counter-reactions that are unanticipated thus the only safe assumption is that the majority of fixes we research will continue to have a high probability of failure and simply lead back to a point of basic research, even if constrained to aging research. So the question I have is what magic lies in any anti-aging therapeutic proposal that makes it immune to the side affects we see with failed gene therapy, failed stem cell therapy, failed pharmaceuticals, cancer chemotherapies, etc? All of these are engineering efforts no? Granted that most research efforts into disease aren't as targeted at aging issues that we'd like to see, there are numerous like efforts to everything I've seen proposed going on at the molecular level that continue to fail. Our ability to intervene has a terrible success rate at just about every level. Is there a conspiracy? Are these oncologists, stem cell researchers and geneticists intentionally sabotaging their results or are they simply fools flailing around and researching the wrong stuff? I don't think either is the case. They are stuck battling one thing... Complexity. They try to put a new fender on the car in the auto body shop and a piston shoots through the engine block damaging the electronic fuel ignition. It seemed like the intuitive thing to do but who would have thunk that a fender was somehow tied to piston function. That's biology.

I also strongly support expanding our basic knowledge of course. In twenty five years, fenders based on metal nanomaterials might not rust at all. My car can't wait though, and at my age I can't wait for 2033 anti-aging solutions either. There should be no conflict between using and improving our engineering fixes today and expanding our knowledge for the future. We need to do both. Vince

I agree however if the interventions keep failing and leading us back to a common denominator of basic aging research, then we better keep the emphasis on building more tools that help us eliminate the ignorance and comprehend the complexity. Sure, lets keep testing theoretical interventions as we may get lucky from time to time (serendipity still contributes more to science than anything else) but lets not kid ourselves into thinking we have some magic beans that trump what researchers on the cutting edge are already working with.

I don't think we have a conflict about more and deeper aging research and expanding the boundaries of what we know. I also acknowledge the incredible complexity of biological systems, the importance of multiple feedback loops, and the need for us to develop increasingly better systems understanding of what is going on. However, I do think we may now have some powerful "beans" and these actually are known to be "magic" because of recent cutting edge research that leads to understanding of the biochemical mechanisms of operation of those beans - the kind of research you are calling for. When I talk about curcumin, ashwagandha, or astragalus, what might come to mind is that these are ancient Indian and Chinese herbal remedies - unscientific unproven folk cures. But look at the contemporary research literature on these substances. You will find hundreds if not thousands of studies that deal with their gene activation paths, biochemical actions and their clinical usefulness. Why, exactly, should we not use what we already know as well as strive to learn more? Looking at the history of any major stream of technology - the computer field being an example I know well - engineering and science always grew together starting in the late 40s- one feeding the other. The motivation for most of the needed research came from a practical drive to improve the original engineering solutions. This argument that "there is nothing out there now in antiaging interventions worth bothering about so we must concentrate only on science" reminds me of the late 1950s when I found myself at conferences with Artificial Intelligence researchers who seriously declared that computers were only secondary technical artifacts and that real progress was to be made through focusing on AI research. You know how that all turned out. True, our relative ignorance of the underlying mechanisms of aging at the moment runneth over, but if we are to get anywhere in antiaging research we need to generate a societal feedback loop where the general society gets more and more involved. And this will require putting the best practical knowledge we have to work at every point. Indeed, what we do now may look primitive in 2030, but in 1955, use of 1955 computers was far better than nothing and is what got the field going. Let's not fight about this, please. I believe the antiaging field will grow in importance over the coming decades just like the computer field did, and I want to be part of that movement all along.

[maestro949]

However, I do think we may now have some powerful "beans" and these actually are known to be "magic" because of recent cutting edge research that leads to understanding of the biochemical mechanisms of operation of those beans - the kind of research you are calling for. When I talk about curcumin, ashwagandha, or astragalus, what might come to mind is that these are ancient Indian and Chinese herbal remedies - unscientific unproven folk cures. But look at the contemporary research literature on these substances. You will find hundreds if not thousands of studies that deal with their gene activation paths, biochemical actions and their clinical usefulness.

These are all short-term studies, mostly in mice with little data as to what the long-term results would be, whether these have negating or synergystic effects when taken in combination with other substances or what the subtle side effects are to other biochemical pathways and how they will affect different people at various ages. May some of these help slow aging a bit, perhaps, but trying to stack numerous tiny changes based on limited trial data is wishful thinking. The current of the aging process is too strong to dam up with lots of lightweight solutions.

Why, exactly, should we not use what we already know as well as strive to learn more?

I'm not arguing that we shouldn't use what we have, we have no choice, but rather that the data we have now, it's still far too insignificant in its quantity, quality and organization for any nearterm attack on aging that will result in much significance. We have to continue looking for disruptive changes that are radical in their affect. Those that place the fulcrum at a more optimal leverage point for maximum gain. We still don't have a viable strategy for doing this.

Let's not fight about this, please.

No desire to fight here. Discussion and debate are healthy though.

I believe the antiaging field will grow in importance over the coming decades just like the computer field did, and I want to be part of that movement all along.

I'm with ya.

[VinceG]

However, I do think we may now have some powerful "beans" and these actually are known to be "magic" because of recent cutting edge research that leads to understanding of the biochemical mechanisms of operation of those beans - the kind of research you are calling for. When I talk about curcumin, ashwagandha, or astragalus, what might come to mind is that these are ancient Indian and Chinese herbal remedies - unscientific unproven folk cures. But look at the contemporary research literature on these substances. You will find hundreds if not thousands of studies that deal with their gene activation paths, biochemical actions and their clinical usefulness.

These are all short-term studies, mostly in mice with little data as to what the long-term results would be, whether these have negating or synergystic effects when taken in combination with other substances or what the subtle side effects are to other biochemical pathways and how they will affect different people at various ages. May some of these help slow aging a bit, perhaps, but trying to stack numerous tiny changes based on limited trial data is wishful thinking. The current of the aging process is too strong to dam up with lots of lightweight solutions.

Why, exactly, should we not use what we already know as well as strive to learn more?

I'm not arguing that we shouldn't use what we have, we have no choice, but rather that the data we have now, it's still far too insignificant in its quantity, quality and organization for any nearterm attack on aging that will result in much significance. We have to continue looking for disruptive changes that are radical in their affect. Those that place the fulcrum at a more optimal leverage point for maximum gain. We still don't have a viable strategy for doing this.

Let's not fight about this, please.

No desire to fight here. Discussion and debate are healthy though.

I believe the antiaging field will grow in importance over the coming decades just like the computer field did, and I want to be part of that movement all along.

I'm with ya.

Ultimately I am with you too. We have many many a mile to go - and your points about complexity, multiple feedback loops and unknown possible consequences of interventions are all well taken. My hope and intention is for an exciting trip.

[Proconsul]

I agree with Cnorwood here in that it could be the chicken and egg scenario all over again. If there is an aging "gene" or program then it has proved notoriously hard to pin down. The only thing that comes close is telomeres.

Also, from what I can tell it is not an either or proposition.

I think you put it well. For instance the different expression of some genes could affect our repair mechanisms, which in turn protect us against cellular damage. As for telomeres, if they are involved in aging, it's possible that their shortening acts as a signal for some change in the regulation of genes in the peritelomeric region. Actually, several years ago I hold great hopes in the work of Fossel about telomeres, but unfortunately it looks like it is going to be another blind alley.

[Mixter]

How I interpret this: the initial triggers may be inflammaging or even some of
the root causes of aging (cellular junk...) itself, but the process involves a
self-reinforcing cycle of gene activation? Self-reinforcing cycle would be a
possible explanation for the increasing damage from middle age on.
Also very possible that this concerns some but not all of the seven causes,
but probably all but the crosslinks COULD be involved:

http://flyinghigh.or...active-process/

SIRT6 and NF-kB link suggests aging is active process

Posted by Simon on Friday, 9 January 2009; This entry is filed under Aging,
NF-kB, SIRT6.

Stanford researchers have revealed a link between two aging-related pathways,
which will be published in the 9 January 2009 issue of Cell .

Researchers from Stanford University revealed today that they have found a
link between SIRT6 and NF-kB – that the aging-related processes influenced by
NF-kB are under the control of SIRT6, suggesting that aging is a deliberate,
active process as opposed to the idea that it’s simply the accumulation of
wear and tear over time.

“There is a genetic process that has to be on, and enforced, in order for
aging to happen. It’s possible that those rare individuals who live beyond
100 years have a less-efficient version of this master pathway, just as
children with progeria — a genetic aging disease — may have components of
this pathway that are more active,” said Howard Chang, MD, PhD, associate
professor of dermatology at the school and a member of Stanford’s Cancer
Center.

SIRT6 is a member of the Silent Information Regulator proteins known as
sirtuins that have been a major focus of life-extension efforts in recent
years due to their enhanced expression in proven anti-aging modalities like
caloric restriction. Little is mentioned about SIRT6 in anti-aging circles,
however, with most of the attention focused on SIRT1, which is thought to be
stimulated by chemicals like resveratrol.

Little is known about SIRT6, but Dr Katrin Chua, assistant professor of
endocrinology, gerontology and metabolism at Stanford, has been studying it
for several years. Sirtuins are involved in keeping the genome stable, making
sure the correct genes are being expressed and unnecessary genes suppressed.
A breakdown in this function is thought to be one of the root causes of
aging, as increasing genetic dysregulation is thought to be the cause of the
pathological effects of age.

Now, in addition to this function, Chang and Chua have found that SIRT6
regulates gene expression itself by binding to and inhibiting the ability of
another protein, NF-kB, to stimulate the expression of genes that make cells
age.

It’s been well established that NF-kB is strongly implicated in the aging
process, and in searching for therapies to retard aging, the ability to
inhibit NF-kB is a good sign. Blocking NF-kB in the skin cells of elderly
mice causes these cells to behave as if they were young.

“It seems that an important job of SIRT6 is to restrain NF-kB and limit the
expression of genes associated with aging. We’ve been interested in the
activity of regulatory genes such as NF-kB during aging for several years
now, and we were quite happy to find this very clear biochemical connection
between these two pathways,” said Dr Chang.

Mice lacking SIRT6 die young, experiencing a rapid degeneration at about 4
weeks of age that coincides with elevated levels of NF-kB. When NF-KB is
simultaneously blocked, the mice are able to live somewhat longer.

So, it seems that SIRT6 might be part of our aging-clock and NF-kB its
instrument of death. Obviously, the story is much more complicated, but this
seems to be an extremely exciting new lead in the search for what controls
the aging process. I’m going to go and do some reading about SIRT6!

Refs:

* Stanford researchers uncover link between two aging pathways in mice

* SIRT6 Links Histone H3 Lysine 9 Deacetylation to NF-kB-Dependent Gene
Expression and Organismal Life Span

* Eurekalert! - Stanford researchers uncover link between 2 aging
pathways in mice

[Mind]

Standford researchers again hint at program theory of aging, and link SIRT6 with NF-kappaB.

The researchers focused their investigation on two seemingly separate pathways linked to aging. One involved a molecule known as SIRT6 — a member of the sirtuin family of proteins that modulate life span in organisms such as yeast and worms — that Chua's laboratory has been studying for several years. She and her lab members have previously shown that SIRT6 is involved in genomic stability and the protection of chromosomal ends called telomeres. Telomeres, which grow shorter with each cell division, are thought to function as a kind of internal molecular clock associated with aging. Furthermore, mice lacking SIRT6 are born normally but die within a few weeks because of a rapid, multi-organ degeneration that somewhat resembles premature aging.

"Sirtuin family members have been implicated in aging and age-related diseases," said Chua, "but very little was known about how SIRT6 worked on a molecular level until recently. Our new study reveals that SIRT6, in addition to its role in genomic stability and telomere protection, also regulates gene expression."

The other pathway involved a more well-known protein called NF-kappa B, or NF-kB, that binds to and regulates the expression of many genes, including those involved in aging. The expression of many of these genes increases with age, and blocking the activity of NF-kB in the skin cells of elderly mice causes them to look and act like younger cells.

The researchers wondered if NF-kB and SIRT6 somehow work together to help cells age appropriately. They found that, in human and mouse cells, SIRT6 binds to a subunit of NF-kB and modifies components of a nearby DNA packaging center, called histones. This modification makes it more difficult for NF-kB to trigger the expression of the downstream gene — perhaps by causing the DNA to twist in such a way to boot off the protein.

Reason responds with the "chicken and egg" argument.

I suspect that one
reason that theories of programmed aging remain somewhat popular is that
the reactions of our cells to a slow stochastic accumulation of biochemical
wear and tear do look something like the unfolding of a program. Gene
expression steadily changes as the damage mounts. So you see research like
this, said to support programmed aging but which could just as well support
aging as an accumulation of damage. Researchers are linking changes in gene
expression previously noted to be important to aging and longevity, but
without evidence of the root cause of these changes, it's premature to
declare aging programmed.

[Prometheus]

Why such resistance to the notion that aging is programmed?

There is more evidence for than against.

The new study linking SIRT6 to NF-kappaB supports the 'for' argument. One has to carefully examine the network of regulatory interactions to appreciate why this looks more like a program that mirrors developmental processes rather than a desperate effort of a cell to address an accumulation of 'stochastic damage'.

Personally, I think each of these revelations should be cause for celebration rather than sour skepticism from a community that feels very comfortable entertaining extraordinary optimism in notions such as 'singularity', 'cryogenics', etc, for which a valid technological substrate is presently lacking.


Yoohoo! Aging is programmed! The solution is near!

[astrout]

Why such resistance to the notion that aging is programmed?

There is more evidence for than against.

The new study linking SIRT6 to NF-kappaB supports the 'for' argument. One has to carefully examine the network of regulatory interactions to appreciate why this looks more like a program that mirrors developmental processes rather than a desperate effort of a cell to address an accumulation of 'stochastic damage'.

Personally, I think each of these revelations should be cause for celebration rather than sour skepticism from a community that feels very comfortable entertaining extraordinary optimism in notions such as 'singularity', 'cryogenics', etc, for which a valid technological substrate is presently lacking.


Yoohoo! Aging is programmed! The solution is near!

I have to agree with you here Dr.
The evidence (and almost some common sense) says that aging is a genetic function. For example, look at a baby and look at a full grown adult. The expression of their genetics is entirely different, and not in the way one would expect from wear and tear which is basically what the proponents of aging as "rust" are saying. If that were the case we should all look like really gross infants when we die, but we do not, we move through several life stages, and once those stages have run their course, our bodies eventually break down. In my honest opinion it is less a matter of the body having a "death" stage built in, and more that it doesn't have another stage of life programmed in. If a bone is growing strong in a twenty year old human, there is no reason for it eventually to become brittle other than that the functions which keep it growing healthy for several years eventually stop functioning at an optimal level. If the body kept maintaining itself at 50 and on the same as it did at 20, the human life span would be near endless. If anything I see the "rust" research as a great way to find what things do end up causing our death by accumulation. This will extend life, but it will not immortalize us. We will only be a semi-immortal biology when we have created a way to halt the progress of our bodies through their life stages after the age of 25 or so. That is not to say that the "rust" branch of research isn't important, because it is very important, it may be the most impact-full in the near term, but it can never be an aging cure, only a way to help people remain healthier as they age.

Cheers!
-Arne

[Mind]

As mentioned in a couple other threads, both avenues of research will likely bear fruit. It seems doubtful either could be a "silver bullet" or be ignored. I have also come to realize that sufficiently advanced interventions (whether based on SENS or genomics) are really going to look quite similar. In both cases we will need some powerful tools to change the course of aging and/or rejuvenate the body.