15 replies to this topic

[opales]

The following paper [2] discusses the Metabolic Stability-Longevity Hypothesis [1], a model for aging that has been consistent thus far encountered experimental observations, and more importantly, explains some anomalies that have plagued the Free Radical Theory of Aging (or its variations), the dominating mechanistic aging theory for the past 40 years.

http://www.sureshrat...attBgen2005.pdf

See also [3]:
http://www.sureshrat...ttanDiscMed.pdf

If the hypothesis holds out, it will have implications to wide range aging related issues, starting from research to SENS to CR (won't do much for humans) to supplements (reducing ROS production won't probably work, as is consistent with observations from rodent studies on ALA).

[1]Demetrius L. Caloric restriction, metabolic rate, and entropy. J Gerontol A Biol Sci Med Sci. 2004 Sep;59(9):B902-15.
PMID: 15472153 [PubMed - indexed for MEDLINE]
http://biomed.geront...tract/59/9/B902

[2]Olshansky SJ, Rattan SI. At the heart of aging: is it metabolic rate or stability?
Biogerontology. 2005;6(4):291-5. PMID: 16333763 [PubMed - in process]

[3] Olshansky, S.J. and Rattan, S.I.S. What determines longevity: metabolic rate or stability? Discovery Medicine, 5, 359-362, 2005.

Edited by opales, 06 June 2006 - 08:05 AM.

[opales]

I am going to have to make an immidiate bump, so this won't ignored because it was made in the boring aging theories forum that no one actually seems to be reading [tung] . The mentioned papers have profound implications for EVERY life extensionist whether they be researchers or just trying to maximize health. I just posted [3] in the CR forum but it would be probably more relevant here as it is a good primer on both the Metabolic Stability-Longevity Hypothesis and the Directionality theory, two important and related new models that could become the new paradigms in gerontology.

[3]Braeckman BP, Demetrius L, Vanfleteren JR. The dietary restriction effect in C. elegans and humans: is the worm a one-millimeter human? Biogerontology. 2006 May 27; [Epub ahead of print]
PMID: 16732407 [PubMed - as supplied by publisher]

http://www.springerl...ults,1:104841,1

[opales]

Additional but related papers

A very rigorous and technical paper on the Directionality Theory:
Demetrius L (1997) Directionality principles in thermodynamics
and evolution. Proc Natl Acad Sci USA
94:3491–3498

http://www.pnas.org/...print/94/8/3491

And a newer one:
Ziehe M, Demetrius L. Directionality theory: an empirical study of an entropic principle in life-history evolution.
Proc Biol Sci. 2005 Jun 7;272(1568):1185-94.
http://www.journals....83qptqjt2u5.pdf

Article on metbaolic stability hypothesis, but could not get my hands on it
Demetrius L (2005) Of mice and men. EMBO Rep 6: S39–S44

Less scientifically loaded pop press account:

A New Theory on Longevity
http://www.harvardma...ine/110474.html

CR society discussion on the subject (search with words metabolic + stability)
http://lists.milepos...ity&s=&f=&a=&b=

Edited by opales, 05 June 2006 - 09:56 PM.

[ag24]

Demetrius's model has not been discussed much within the field, even though he's presented it a few times at relevant meetings. It is one of three recent hypotheses suggesting that long-lived species won't gain as much as short-lived ones, if anything, from CR: the others are due to me (Gerontology 51:73) and Phelan and Rose (Agein Research Reviews 4:339). Debate on these models will get going in the fullness of time, maybe, but as usual, most gerontologists are keener to wait for direct evidence one way or the other (such as from the ongoing monker CR studies) than to discuss theories :-( Luckily, Michael Rae has written a critique of my model that has just come out in AGE (the journal of the American Aging Association) - this should be online soon - so that debate has begin in earnest. Maybe the other models will get corresponding treatment soon.

[Athanasios]

  profound implications for EVERY life extensionist whether they be researchers or just trying to maximize health.

Actually, I dont think this has very profound implications for me. I don't see how this theory of aging would change the squaring of the curve that I am expecting supplements and a healthy lifestyle will give. No?

For CR people, it is one more argument against.

[maestro949]

Hot off the presses...

Demetrius L
Ann. N.Y. Acad. Sci. 1067: 66–82 (2006). C 2006 New York Academy of Sciences.
doi: 10.1196/annals.1354.010

ABSTRACT: This article discusses the significance of mouse models as a
basis for elucidating the aging process in humans. We identify certain
parallels between mouse and human systems and review the theoretical
and empirical support for the claim that the large divergence in the
rate of aging between the two species resides in differences in the stability
of their metabolic networks. We will show that these differences in
metabolic stability have their origin in the different ecological constraints
the species experience during their evolutionary history.We exploit these
ideas to compare the effect of caloric restriction on murine and human
systems. The studies predict that the large increases in mean life span
and maximum life-span potential observed in laboratory rodents subject
to caloric restriction will not obtain in human populations. We predict
that, in viewof the different metabolic stability of the two systems, caloric
restriction will have no effect on the maximum life-span potential of humans,
and a relatively minor effect on the mean life span of nonobese
populations. This article thus points to certain intrinsic limitations in
the use of mouse models in elucidating the aging process in humans.We
furthermore contend the view that these limitations can be mitigated by
considering the metabolic stability of the two species.

Attached Files

•  aging_in_mouse_and_human_systems.pdf   93.41KB   38 downloads

[maestro949]

My ignorant question of the day: What causes mice to die at the age of 4? Is their DNA, lipids and proteins so damaged by then that they succeptibe to one of many diseases or cancer?

[Athanasios]

I have heard from multiple sources that cancer was a huge limiter, as in majority, when doing longevity research with supplements. So cancer resistant mice will be very good for these studies.

[opales]

Actually, I dont think this has very profound implications for me. I don't see how this theory of aging would change the squaring of the curve that I am expecting supplements and a healthy lifestyle will give. No?

For CR people, it is one more argument against.

Well it does imply ROS production is not the crux, thus reducing it (through say R-ALA) or counteracting it (through antioxidants) should not have much effect, which is very consistent with existing data I think. You are right in the sense that from the outset these particular supplements are directed at treating *secondary aging* traits (i.e. diseases that come about with aging) thus squaring the curve, however, their theoretical rationale is based on attacking primary aging through ROS minimization no matter how you look at it IMO.

[opales]

Actually, I dont think this has very profound implications for me. I don't see how this theory of aging would change the squaring of the curve that I am expecting supplements and a healthy lifestyle will give. No?

For CR people, it is one more argument against.

In addition it gives a theoretical foundation on something that was widely ignored, i.e. why certain surrogate endpoints used in marketing (IT'S POTENT ANTIOXIDANT) or promoting relevance of some result (IT REDUCES OXIDATIVE STRESS) are not very relevant after all.

I have discussed this here:
http://www.imminst.o...f=175&t=8394&s=

Note BTW that while the above thread is named "*Theory*:ROS may be an essential biological compound", the above paper by Olshansky and Rattan IMO introduces the position of ROS being valuable as a given fact instead of mere theoretical plausibility as my thread title might imply.

[Athanasios]

Well it does imply ROS production is not the crux, thus reducing it (through say R-ALA) or counteracting it (through antioxidants) should not have much effect, which is very consistent with existing data I think. You are right in the sense that from the outset these particular supplements are directed at treating *secondary aging* traits (i.e. diseases that come about with aging) thus squaring the curve, however, their theoretical rationale is based on attacking primary aging through ROS minimization no matter how you look at it IMO.

If taking supplements didn't square the curve, I wouldnt take them based on theory alone.

"Well it does imply ROS production is not the crux"
Only in that it is another theory. One that fits observable evidence, but has not been tested and discussed as much.

"thus reducing it (through say R-ALA) or counteracting it (through antioxidants) should not have much effect, which is very consistent with existing data I think. "
We are talking about extending possible lifespan. It is possible that reducing ROS just squares the curve, and not extend lifespan. It could also mean that it does extend life, but does not cure/prevent cancer. What if it were cog number two in the wheel? The second jump to extend life after the first? Weakest link in the chain will break us, so if it doesnt fix the cancer link, it wont go much further no? That is why cancer resistant mice can help test a theory such as this.

"their theoretical rationale is based on attacking primary aging through ROS minimization no matter how you look at it "
They seem to attack the ROS theory, but in no way is it needed to submit their own. My guess is that they "attack" it because they want to show it is not PROVEN, so another theory, like theirs, might be given more attention/thought.

[geert]

Hi!

i stumbled upon this forum by a google search.

i'm a Phd student in Belgium and work in the C.elegans gerontology lab.

as a matter of fact we are working closely 'together' (the man is a mathematician/biologist) with Lloyd Demetrius in an attempt to validate some of the specific predictions his theory produces.

it must be said that the idea and also the evolutinary rationale put forward by Demetrius is a very interesting one, because it seems to offer a concrete mechanism/answer for most of the 'problems' or inconsistencies that are accumulating and haunting the 'rate of living' theory.

i do not know what 'ROS theory' means to you cnorwood19? because there is no such thing that is called the 'ROS theory'??...(maybe Harman??)
but i would like to say that nobody doubts the crucial role of ROS production in the aging process here...right?

it's the rate of living theory (a combination of Harman and Pearl) that seems not to be consistent with a lot of experimental data...

always like to discuss some insights or questions about this theory...because that would help me too, searching in the literature and stuff.

keep on thinkering!

ps. writing in english is kinda new for me, so excuse archaic writing and stuff...

[FunkOdyssey]

Unfortunately, your English spelling and grammar are better than most Americans. Welcome to ImmInst geert, hope you stick around.

[opales]

Hi!

i stumbled upon this forum by a google search.

i'm a Phd student in Belgium and work in the C.elegans gerontology lab.

as a matter of fact we are working closely 'together' (the man is a mathematician/biologist) with Lloyd Demetrius in an attempt to validate some of the specific predictions his theory produces.

it must be said that the idea and also the evolutinary rationale put forward by Demetrius is a very interesting one, because it seems to offer a concrete mechanism/answer for most of the 'problems' or inconsistencies that are accumulating and haunting the 'rate of living' theory.

i do not know what 'ROS theory' means to you cnorwood19? because there is no such thing that is called the 'ROS theory'??...(maybe Harman??)
but i would like to say that nobody doubts the crucial role of ROS production in the aging process here...right?

it's the rate of living theory (a combination of Harman and Pearl) that seems not to be consistent with a lot of experimental data...

always like to discuss some insights or questions about this theory...because that would help me too, searching in the literature and stuff.

keep on thinkering!

ps. writing in english is kinda new for me, so excuse archaic writing and stuff...

Only time for quick comment... ROS theory was reference to any of the Free Radical Theories of Aging (original theory presented by Harman), which really are mechanistic explanations (i.e. how does it ACTUALLY happen) to the rate of living hypothesis. If you look at Rattan's and Olshansky's interpretation of the Metabolic Stability hypothesis (for example last two paragraph in paper [3] in the first post), yes indeed they seem think that ROS production might not be the culprit, at least from intervention standpoint (I can't copy&paste the text here so you'll have to read it in the original paper).

Geert, if you browse through the papers by Rattan and Olshansky, do you think they misunderstand/misrepresent Demetrius' original argument somehow? I don't think I misrepresented their position, the couple paragraphs seem to be rather straightforward..

BTW, cnorwood19 I will adress your points when I have more time.

Edited by opales, 15 June 2006 - 07:36 AM.

[geert]

hello,

i'm really thinkering on this one...

i would first like o say this:

'we' don't say ROS could't be/isn't the 'culprit' (i don't know this word...means holy grail or something, yes?) of aging.

no, its important to see that it's not ROS production per se[I] that determines longevity.

you see, rate of living theory is appealing and logic: more ROS = higher metabolic rate --> faster aging.

but this simply does not seem to be the case!

indeed a lot of animals with similar body size that live longer have a HIGHER standard metabolic rate.

another: CR: does NOT result in a clear decrease of metabolic rate. sometimes it even increases it.

so the predictions made by rate of living theory simply aren't correct. maybe, in the best case, ROS producton vs maintenance mechanisms can explain aging and aging rates...

but.......... now there is tis demetrius guy with a radical different view...

for me, demetrius hypothesis is actually difficult to really grasp just yet( i mainly focus on protein turnover and aging...cause my personal feeling is that protein tunover and lysosomal/proteasomal maintenance is the key to aging)...so the only thing i do, is test some of his specific predictions...

as to Olshansky and Rattan...

seems t me that they assume that lowering ROS production has no effect on metabolic stability... i'm not sure if Demetrius would agree...
i also don't know if demetrius thinks that lowering ROS production or elevating ROS production artificially has no effect on life span.

i'll ask him if i ever got the chance

he doesn't talk about that directly. all he says is that it is the metabolic stability that matters, end NOT ROS production rates per se...and that metabolic speed is NOT the determinant of longevity (thus, there is NO fixed absolue value of energy that can be consumed during the lifetime of different species.... this value varies. and thus... rate of living isn't correct ...among other arguments...

please, correct me, if you think some of these statements are not correct...

Edited by geert, 15 June 2006 - 11:24 AM.

[opales]

hello,

i'm really thinkering on this one...

i would first like o say this:

'we' don't say ROS could't be/isn't the 'culprit' (i don't know this word...means holy grail or something, yes?) of aging.

no, its important to see that it's not ROS production per se[I] that  determines longevity.

you see, rate of living theory is appealing and logic: more ROS = higher metabolic rate --> faster aging.

but this simply does not seem to be the case!

indeed a lot of animals with similar body size that live longer have a HIGHER standard metabolic rate.

another: CR: does NOT result in a clear decrease of metabolic rate. sometimes it even increases it.

so the predictions made by rate of living theory simply aren't correct. maybe, in the best case, ROS producton vs maintenance mechanisms can explain aging and aging rates...

but.......... now there is tis demetrius guy with a radical different view...

for me, demetrius hypothesis is actually difficult to really grasp just yet( i mainly focus on protein turnover and aging...cause my personal feeling is that protein tunover and lysosomal/proteasomal maintenance is the key to aging)...so the only thing i do, is test his specific predictions:

i give animals a sublethal stress pulse: for example, sodium azide. so ADP/ATP ratio goes way up (sort of suffication) and measure the recovery to the  normal ADP/ATP ratio. my preliminary data indeed shows that long lived mutants recover much faster to the steady state ADP/ATP ratio than does the wild type, which is, for now, in accordance with the  stability/longevity hypotesis.

as to Olshansky and Rattan...

seems t me that they assume that lowering ROS production has no effect on metabolic stability... i'm not sure if Demetrius would agree...
i also don't know if demetrius thinks that lowering ROS production or elevating ROS production artificially has no effect on life span.

i'll ask him if i ever got the chance

he doesn't talk about that directly. all he says is that it is the metabolic stability that matters, end NOT ROS production rates per se...and that metabolic speed is NOT the determinant of longevity (thus, there is NO fixed absolue value of energy that can be consumed during the lifetime of different species.... this value varies. and thus... rate of living isn't correct ...among other arguments...

please, correct me, if you think some of these statements are not correct...

Ok. I do think that Demetrius himself implied the insignificance of ROS production. I will have to check whether it was him or rather the interpretation by Rattan and Olshansky. Olshansky is a contributor here at ImmInst by the way (his nick is sjayo), perhaps we will just have to ask him for comments.

Anywhoo, have you read De Grey's argument on CR not working [1]? The paper has good synopsis of what we know about the evidence (and outliers) regarding Rate of Living hypothesis and Free Radical Theory of Aging, might be of help to your guys' research.

http://www.sens.org/weatherPP.pdf

[1] Gerontology 2005;51:73-82, The Unfortunate Influence of the Weather on the Rate of Ageing: Why Human Caloric Restriction or Its Emulation May Only Extend Life Expectancy by 2-3 Years, Aubrey D.N.J. de Grey, Department of Genetics, University of Cambridge, Cambridge, UK

Edited by opales, 15 June 2006 - 01:12 PM.