20 replies to this topic

[Logic]

Life Span Extension by Calorie Restriction Depends on Rim15 and Transcription Factors Downstream of Ras/PKA, Tor, and Sch9

Calorie restriction (CR), the only non-genetic intervention known to slow aging and extend life span in organisms ranging from yeast to mice, has been linked to the down-regulation of Tor, Akt, and Ras signaling. In this study, we demonstrate that the serine/threonine kinase Rim15 is required for yeast chronological life span extension caused by deficiencies in Ras2, Tor1, and Sch9, and by calorie restriction. Deletion of stress resistance transcription factors Gis1 and Msn2/4, which are positively regulated by Rim15, also caused a major although not complete reversion of the effect of calorie restriction on life span. The deletion of both RAS2 and the Akt and S6 kinase homolog SCH9 in combination with calorie restriction caused a remarkable 10-fold life span extension, which, surprisingly, was only partially reversed by the lack of Rim15. These results indicate that the Ras/cAMP/PKA/Rim15/Msn2/4 and the Tor/Sch9/Rim15/Gis1 pathways are major mediators of the calorie restriction-dependent stress resistance and life span extension, although additional mediators are involved. Notably, the anti-aging effect caused by the inactivation of both pathways is much more potent than that caused by CR.

http://www.plosgenet...al.pgen.0040013

[Mind]

Why are these pathways such large regulators of lifespan in yeast? What do we know about these pathways in relation to cell maintenance and various metabolic mechanisms?

Edited by Mind, 30 January 2013 - 06:22 PM.

[Logic]

An equivalent extension in humans would give a lifespan of around 800 years!
So I agree that this worth looking into Mind.

[nowayout]

An equivalent extension in humans would give a lifespan of around 800 years!
So I agree that this worth looking into Mind.

Yeah, but these effects unfortunately tend to become less and less significant as we climb the chain to organisms that are already relatively long-lived. For example, in rodents the effects of CR are much more modest than in yeast, and in longer lived primates recent research has cast questions on whether CR even works at all for them.

Aging experiments are commonly done in yeasts because they are easy to manipulate and have short lifespans, but I wonder if one might not make more progress by investing more in studying organisms that are known to be extraordinarily resistant to senility, such as turtles.

Edited by viveutvivas, 29 January 2013 - 08:42 PM.

[niner]

The best way to deal with in vitro experiments? Ignore them.

[Logic]

Thx guys.
You both make good points and I know that this study is of no practicle use. (more-so now )
I still hope that that this research leads to bigger and better things in the future as its such a huge leap for yeast..?

[Musli]

Yeast, fruit flies? Not even bothering to read ;p

[nowayout]

The best way to deal with in vitro experiments? Ignore them.

Well, to be fair, these are whole organisms (though unicellular) that are only coincidentally housed in vitro, so your objection might equally be taken to apply to rodents housed in glass cages.

[Logic]

..Interesting points of view and a good point viveutvives.

Is it worth looking at research on the same or equivalent genes in rats and higher?
As usual I'm way out of my depth...

[Mind]

I am aware that yeast, fruit flies, and even (most times) mice are poor substitutes for human longevity mechanisms/experiments, but there are many analogous genetic pathways between humans and lower organisms. Understanding why it works in yeast, at least gives us some new things to investigate in higher animals.

[niner]

The best way to deal with in vitro experiments? Ignore them.

Well, to be fair, these are whole organisms (though unicellular) that are only coincidentally housed in vitro, so your objection might equally be taken to apply to rodents housed in glass cages.

That's ridiculous. They're freaking single cells. Single cell != rat.

[nowayout]

The best way to deal with in vitro experiments? Ignore them.

Well, to be fair, these are whole organisms (though unicellular) that are only coincidentally housed in vitro, so your objection might equally be taken to apply to rodents housed in glass cages.

That's ridiculous. They're freaking single cells. Single cell != rat.

Yes, but the reason we distrust in vitro experiments is because for most people the term refers to cultures of part of an organism, which are not necessarily expected to reflect their behavior in the organism. Yeast cells growing, even in a lab, are in vivo. I think your apparent claim that we can learn nothing about aging pathways in humans from yeast is very strong, and I don't know how you can confidently support that claim unless you understand more about aging than anyone else in the field. By the way, most rodent experiments are arguably no more useful than yeast experiments for their application to humans - in fact the vast majority of rodent medical studies turn out to be demonstrably inapplicable to humans.

[niner]

The best way to deal with in vitro experiments? Ignore them.

Well, to be fair, these are whole organisms (though unicellular) that are only coincidentally housed in vitro, so your objection might equally be taken to apply to rodents housed in glass cages.

That's ridiculous. They're freaking single cells. Single cell != rat.

Yes, but the reason we distrust in vitro experiments is because for most people the term refers to cultures of part of an organism, which are not necessarily expected to reflect their behavior in the organism. Yeast cells growing, even in a lab, are in vivo. I think your apparent claim that we can learn nothing about aging pathways in humans from yeast is very strong, and I don't know how you can confidently support that claim unless you understand more about aging than anyone else in the field. By the way, most rodent experiments are arguably no more useful than yeast experiments for their application to humans - in fact the vast majority of rodent medical studies turn out to be demonstrably inapplicable to humans.

In vitro experiments, whether with isolated cells of a multicellular organism or with free-living single celled organisms are the number one time-waste around here. Every time you turn around, someone is claiming that supplement X causes effect Y (in humans, of course) because of an experiment where cells were soaked in ridiculously high concentrations of a compound for ridiculously long periods of time, neither of which could be obtained in a human or even in an animal. If you want to argue that an experiment in a mammal, using the same dosing protocol proposed for the human is no more useful than an in vitro experiment, then: a) You're wrong. b) I think you are arguing just for the sake of arguing.

I never said that scientists can learn nothing about aging pathways from yeast. Of course they can. Why do you think S. Cerevisiae is such a popular model organism? What I will say is that the typical Longecity user can't learn crap about how to alter their own health, rate of aging, or much else from an in vitro paper. We would waste a lot less time if we didn't have so much in vitro nonsense to wade through in these fora.

[xEva]

whoa I think if we could figure out yeast completely, that would be a great advance in our understanding. And I hope we are getting closer to this goal. Otherwise, in all models, we are hopelessly lost in details of particular pathways and are unable to zoom out and see the organism as a whole.

I side with Mind and viveutvivas here, but I also understand niner's frustration. We are still very, very far from being able to manipulate physiology of a simple, unicellular eukaryote. And until this happens, there is no way in hell that we could do anything meaningful about our own aging (but we still can get lucky and stumble onto something by chance )

[niner]

whoa I think if we could figure out yeast completely, that would be a great advance in our understanding. And I hope we are getting closer to this goal. Otherwise, in all models, we are hopelessly lost in details of particular pathways and are unable to zoom out and see the organism as a whole.

I side with Mind and viveutvivas here, but I also understand niner's frustration. We are still very, very far from being able to manipulate physiology of a simple, unicellular eukaryote. And until this happens, there is no way in hell that we could do anything meaningful about our own aging (but we still can get lucky and stumble onto something by chance )

If by siding with Mind and viveutvivas, you mean that you understand there to be evolutionarily related pathways in yeast, fruitflies, mice and humans, and that someone with a good understanding of molecular biology could learn something from a lower organism that could help them find or understand the analogous mechanism in a human, then you're siding with me too. There's no disagreement about that. I don't think we are far at all from manipulating the physiology of either unicellular or multicellular organisms- we do it all the time. That's what drugs, supplements, and various other interventions do. I suppose it depends what you mean by "meaningful", but I think we are already having modest impacts on human aging.

On the usefulness of yeast, fly, and worm papers to the average person? I side with Musli on that. I say that as a person who has the training to understand such papers, and spends an inordinate amount of time explaining why a given in vitro experiment is not relevant to their supplementation routine, or is not a cause for alarm.

[xEva]

... I don't think we are far at all from manipulating the physiology of either unicellular or multicellular organisms- we do it all the time. That's what drugs, supplements, and various other interventions do. I suppose it depends what you mean by "meaningful", but I think we are already having modest impacts on human aging.

Yes we can manipulate the physiology of either unicellular or multicellular organisms -- it's enough to simply change their environment or add this or that chemical to the feed. But at the moment, these manipulations mostly amount to poking at random without much understanding ..like pressing random keys of a complex instrument trying to come up with a melody. . That's what I meant by meaningful.

We are ages away from manipulating an eukaryote as if playing a melody. We are still at the stage of gathering info on what pressing a specific key does and what other keys need to be pressed so that the resulting accord sounds harmoniously. And imo we are inordinately fixated on particular metabolic pathways while disregarding the context in which they are active.

If we take a symphony as an analogy to life then we could say that the environment dictates the key and an organism's metabolic response must be a melody in the given key. Looked from this perspective, our attempts to provoke a certain metabolic response in a different environment (ex. 'CR in a pill' = 'eat all you want but have the metabolism of a faster') is equivalent to playing a 'right' melody in the 'wrong' from the rest of the orchestra key. In other words, it will never work and imo, trying to get it to work is a waste of time (other than learning the specifics of this or that pathway in the process).

The right way to go is to work with nature, not in spite of it; i.e. make periodic fasting easy, 'cause the main objection to it is that it is hard, right?

On the usefulness of yeast, fly, and worm papers to the average person? I side with Musli on that. I say that as a person who has the training to understand such papers, and spends an inordinate amount of time explaining why a given in vitro experiment is not relevant to their supplementation routine, or is not a cause for alarm.

well said

Edited by xEva, 31 January 2013 - 07:09 PM.

[nowayout]

We would waste a lot less time if we didn't have so much in vitro nonsense to wade through in these fora.

I am disappointed that you would discourage discussion of this kind of work. I think there is little enough of it and I wish there were more threads to do with actual aging in any organisms, such as this very interesting one, as opposed to all the "nootropic" nonsense these forums are being absolutely overwhelmingly swamped with (which are mostly about recreational drug (ab)use or lazy people who want shortcuts to doing the actual work of studying, making friends, etc., etc.).

[niner]

We would waste a lot less time if we didn't have so much in vitro nonsense to wade through in these fora.

I am disappointed that you would discourage discussion of this kind of work. I think there is little enough of it and I wish there were more threads to do with actual aging in any organisms, such as this very interesting one, as opposed to all the "nootropic" nonsense these forums are being absolutely overwhelmingly swamped with (which are mostly about recreational drug (ab)use or lazy people who want shortcuts to doing the actual work of studying, making friends, etc., etc.).

Well, please don't let me stop you or anyone else from discussing this paper or aging theories or anything, but my rant about in vitro papers has to do with the usual use to which they are put in these fora, which is not productive.

I use the active topics filters (best forum tool ever) to filter out the noot forums. It's just too much to keep up with and I'm mostly not interested in it anyway.

Let us proceed to a discussion of Ras/cAMP/PKA/Rim15/Msn2/4/Tor/Sch9/Rim15/Gis1.

[Logic]

Let us proceed to a discussion of Ras/cAMP/PKA/Rim15/Msn2/4/Tor/Sch9/Rim15/Gis1.

+1
Sadly I am not qualified enough to be of help..?

[xEva]

Let us proceed to a discussion of Ras/cAMP/PKA/Rim15/Msn2/4/Tor/Sch9/Rim15/Gis1.

+1
Sadly I am not qualified enough to be of help..?

That was a joke

[Logic]

This link has new info on mouse trials that I am reminding myself to follow as well as info on humans with the above genetic 'defects'.
http://io9.com/34572...ns-to-800-years

A thought:
Apparently the 'defect' results in smaller people.
IMHO if we were all smaller; there would be more space and resources for everyone.
Due to our level of technology; there is no reason for us to be as large as we are anymore..?
Mayhaps smaller, long lived humans is the future!?