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Can SENS produce an immortal yeast ?


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#31 ag24

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Posted 04 January 2006 - 04:27 PM

Nice idea wolfram. But we must also explain why most fish don't do this.

#32 JonesGuy

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Posted 04 January 2006 - 05:18 PM

What about just isolating the parent yeast cell after each division, and see how long it lives? Or is the distinction parent/offspring meaningless in yeast. (as you can tell, I am not a yeast expert)


The distinction is very important, it's what makes us think of yeast as being different than bacteria in a very important way. It's also why we think that sexual reproduction is a 'cause' of aging.

There is a definite 'daugher' with yeast, the bud is smaller. As well, the number of replications done by the mother cell is heavily connected with the maximum lifespan of the mother. Much like other populations, the colony of yeast can be immortal, but the mother cells die after a set number of buddings.

#33 olaf.larsson

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Posted 04 January 2006 - 05:25 PM

But we must also explain why most fish don't do this.


Here are some more ideas got when thinking about this subject, maybee some of them contain some trouth:

*Salomons have a habbit to mate in streams, where the chance of returning to see is almost zero. If the chance of mating a second time is very low it will suit gene propagation better to die in the place of mating then to try to mate again.

*The difference between living in a lake and living in a steam could for a fish be that if the fish moves down the streem and dies, the biomass in its body will be lost as resource for the ofspring which is located up the stream.

*The salomons in a stream compeete geneticaly with salomons in other streams, since they all meet in the see. Fish in a lake compete only geneticaly with those fish in the same lake. To die after mating in a lake will therefore not be an evolutionary advantage agaist fish in other lakes or for an individual agaist other fish in the same lake.
Whereas to die after mating in a steam, will give evolutionary advantage against non-dying salomon in other steams, even if only a few individuals of the population are dying salomons.

*A lake/see harbors many other organisms. The biomass of the parrents should therefore very small compaired to the biomass of other organisms, the benefit of phenoptosis after mating should therefore go agaist zero.

..I guess I have to learn some marine ecology to discuss this subject further.. [tung]

#34 noam

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Posted 04 January 2006 - 05:59 PM

John,
Thanks again for your explanation of the relation between cancer and DNA repair. Believe me, I wasn't even close to figuring this out from the things Aubrey said yesterday (maybe he thought I already knew that from his website...).

So, let's see if I understand (it's a new concept for me, and I want to make sure I'm not doing it injustice):

1. For an organism in nature, the function of DNA repair/replication mechanisms, is to be good enough to allow the organism to die just from extrinsic death factors. Not sooner or later.

2. A multicellular organism that is consisted from X cells, has the ability to "lose" up to a certain fraction of its cells ( "lose" = complete death of the cell, or a dysfunction in the cell that keeps it from doing its job), before the organism faces dysfunctional problems.

3. The consequence of #2, in theory, is that the DNA repair/replication mechanisms can allow themeselves to be relatively "sloppy", and make mistakes that will damage some of the genes, and hence kill/damage some cells, during the extrinsic-governed lifespan.

4. In a vertebrate's genome, because we have genes that can cause cancer when mutated and kill the entire organism, it means that the organism must maintain an intact genome (if, like I said at the beginning, he usually dies from extrinsic factors), and the consequence will be that it will not lose cells due to DNA mutations, during the extrinsic-governed life expectancy period.

In order to do this, the DNA repair/replication mechanisms will be upregulated by a large factor, in relation to an organism which doesn't develop cancer (and can allow itself to lose some fraction of its cells during the extrinsic-governed life expectancy period).

5. In consequence of the above, if we: 1. Remove extrinsic death factors for a vertebrate, and 2. Remove its ability to die of cancer, then the amount of time (after its old extrisic life expectancy period) that will take him to lose that certain amount of cells which will make it dysfunctional, will be relatively very long.

Why ?, because up to the limit of its extrinsic lifespan, he did not accumulate much genomic damage, and so didn't lose cells for this reason. He will indeed start to gradually lose cells from now, but he begins this "past extrinsic-goverened lifespan" from a "fresh start" in relation to viable cell number, and still with the slow enough mutation accumulation that allowed him to reach this point in this condition. (So, this will theoretically what ?, allow him to treble its extrinsic-governed life span in relation to just this category of damage ?).


Am I close ?.

Edited by noam, 04 January 2006 - 06:27 PM.


#35 noam

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Posted 04 January 2006 - 06:50 PM

Ok, I'll assume I didn't misrepresent the model above too much, and continue to the next argument:

I'd like to qualify that: If there is no class of genes in yeast, the deletion of which has no greater negative effect than the loss of the cell in which it occurs, then the argument does not hold. However, I would suggest that there are such genes, namely those that create cells which continue to expand and consume resources, but are not optimally competitive (like cancer cells in us)


Maybe I'm wrong, but according to my understanding of things, the yeast cell can be regarded as a cell with a huge amount of "cancerous" genes, that should be protected at all cost.

The yeast don't have the luxury of the Nematode or Drosophila, to lose some cells and go on. A mutation in one important gene, means the loss of the single cell, ie. death of the yeast.

Now, if the DNA repair/replication mechanisms are to allow the yeast to die from extrinsic forces, there is no way they can allow high DNA damage during the extrinsic-governed life span.

If this is correct, then in regard to the nDNA mutation category, yeast which are raised without extrinsic death factors, should see the same proportional gain over extrinsic life expectancy, as mammals cells will see with WILT.

#36 noam

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Posted 04 January 2006 - 08:18 PM

Nope, my logic flaw is that we also have to do the comparable of "WILT" for the yeast, i.e remove the deleterious effects of its possibly many "cancerous genes"... (only here "cancer" may mean many things, all at once).

Maybe if we can come to a certain number of very deadly-if-mutated genes, that the yeast is carrying, it will be possible to intervene late in its life, by inserting a plasmid with a fresh copy of those genes ?. Sort of like moving the nDNA to the "c"DNA (cytoplasmic DNA)... It probably won't last long, but it's a yeast, every day counts (and of course this could only be done for "chronological life span", but for chronological life span, if the cell is not dividing in the first place, maybe nDNA mutations are not that much of a problem to begin with ?. On the other hand, maybe we can use a centromer for the plasmid, which will allow it go into the daughter cell with equal segregation, this way it might be possible to use replicative life span).

I read that some company has a prototype of recombinant Zinc Finger for gene therapy with very high accuracy, but their current problem is that it doesn't work for large segments of DNA to be very useful for humans. But what about yeast ?.

http://www.sangamo.c...ur_tech_ex.html

If we can use this to replace large chunks of the entire nDNA, say after 80% of the extrinsic governed life span...

Edited by noam, 04 January 2006 - 09:07 PM.


#37 jaydfox

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Posted 04 January 2006 - 08:31 PM

Nope, my logic flaw is that we also have to do the comparable of "WILT" for the yeast, i.e remove the deleterious effects of its possibly many "cancerous genes"... (only here "cancer" may mean many things, all at once).

Actually, assuming cancer has given vertebrates the free ride of safe nDNA, then in yeast, the comparable gene for a yeast "WILT" target would be a gene that is hundreds or thousands or millions of times worse to get mutated than any other typical gene. The problem is, there are probably hundreds of such mission critical genes, if not thousands, as opposed to just a handful in the case of telomerase and the vaguely understood ALT pathway. And indeed, with WILT, the procedure is to remove a gene that's not mission critical (other than the need for stem cell reseedings), but which is deadly if mutated.

I really don't see how we could find an equivalent to a WILT-target gene in yeast.

#38 jaydfox

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Posted 04 January 2006 - 08:39 PM

4. In a vertebrate's genome, because we have genes that can cause cancer when mutated and kill the entire organism, it means that the organism must maintain an intact genome (if, like I said at the beginning, he usually dies from extrinsic factors), and the consequence will be that it will not lose cells due to DNA mutations, during the extrinsic-governed life expectancy period.

In order to do this, the DNA repair/replication mechanisms will be upregulated by a large factor, in relation to an organism which doesn't develop cancer (and can allow itself to lose some fraction of its cells during the extrinsic-governed life expectancy period).

5. In consequence of the above, if we: 1. Remove extrinsic death factors for a vertebrate, and 2. Remove its ability to die of cancer, then the amount of time (after its old extrisic life expectancy period) that will take him to lose that certain amount of cells which will make it dysfunctional, will be relatively very long.

This comment sparked some thought on my part (no jokes, please), and I decided to write up a rough and hasty post. It's probably way off, but I wanted to write the thought down while I still had the details fresh, so it could be picked apart.

#39 noam

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Posted 04 January 2006 - 08:48 PM

Actually, assuming cancer has given vertebrates the free ride of safe nDNA, then in yeast, the comparable gene for a yeast "WILT" target would be a gene that is hundreds or thousands or millions of times worse to get mutated than any other typical gene.

Sure it's the best target, I just don't believe we're that lucky that such a gene (few genes) actually exist. And if we're indeed not that lucky, we're as you said stuck with a huge bunch of genes... and in order to resolve this, we have to use a notion from the second generation of SENS treatments (treating nDNA mutations). Then again, it's just a single celled yeast, maybe it's possible somehow.

#40 veronica

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Posted 08 January 2006 - 05:59 AM

Do you think that inhibition of ADH2 in yeast or increased activity of PDK4 could lead to incresed lifespan?

#41 veronica

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Posted 08 January 2006 - 06:19 AM

Ok. I just see it was already done in yeast. But how about silencing or inhibiting Sirt1 together with activation of PDK4 in mammals?

#42 noam

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Posted 08 January 2006 - 04:24 PM

I thought basic science approaches are considered blasphemy in this forum...

#43 John Schloendorn

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Posted 08 January 2006 - 07:34 PM

I'm happy with any "blasphemy" if it gives me more time to work on fixing things the SENS way (or even better, makes it unnecessary)... The problem is that we simply don't know the answer to Veronica's question in humans, and there is no way to find out other than to first age mice, then age monkeys, and then age humans that get the intervention. And for now, it is not even known if this type of thing works in yeast at "adult" onset, is it?

#44 veronica

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Posted 10 January 2006 - 11:14 AM

Yes I know, it will take a time before we find something that will work for us. I just think it is interesting. Based on genomic profiles of various aging postmitotic tissues, they all share decreased PDK4 activity. This is reversible by CR. And decreased PDK4 activity is associated with shift towards carbohydrate metabolism. It almost resembles yeast. When they start to age chronologically, they shift from fermentation to oxidative phosphorylation in mitochondria. It seems like all aging pathways leads towards mitochondria and ATP production:)

#45

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Posted 10 January 2006 - 12:47 PM

I thought basic science approaches are considered blasphemy in this forum...


I'm sorry if you have obtained that impression Noam.. Particularly if it was from me. On the contrary, I'm sure that I speak for most of us here that without basic science there can be no solution to the aging problem. Don't hesitate to raise something specific for us to explore.

PDK4 is a kinase that phosphorylates (activates) pyruvate dehydrogenase which is associated with ATP production via glycolysis. If we could reduce PDK4 activity we would reduce ATP production from glucose, effectively simulating CR. As Veronika mentioned increased PDK4 expression occurs during CR and abnormal PDK4 overactivity is associated with obesity. There are a few SNPs in the human PDK4 gene and it would be interesting to see if there are mutations that confer longevity based on reduced PDK4 activity.

#46 noam

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Posted 10 January 2006 - 08:59 PM

I'm sorry if you have obtained that impression Noam.. Particularly if it was from me.

Nope, it wasn't from you.

I just thought SENS was geared toward removing the molecular damage after it already occurred, and not trying to prevent it from occuring in the first place, by upregulating/downregulating one or two of our ~30,000 complexly regulated genes...

According to Hormesis (and assuming CR is a hormetic effect, and according to experiments with low organisms, it is), it is possible that the constant psychological stress most humans are subjected to by living in modern society, acts on the same pathway that CR acts, and hence we'll gain nothing by doing CR, or mimicking it in any other way. (we are also subjected to a constant chemical stress, with all the poison we introduce to our body by eating industrialized food. I can think of more stressors we are subjected to, like constant air pollution, UV radiation, etc. If a minimal level of stress was beneficial to a cell's life, it seems that we [humans] are already way past that minimal level already).

Edited by noam, 10 January 2006 - 09:41 PM.


#47

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Posted 10 January 2006 - 10:13 PM

I just thought SENS was geared toward removing the molecular damage after it already occurred, and not trying to prevent it from occuring in the first place, by upregulating/downregulating one or two of our ~30,000 complexly regulated genes...


Quite right. The rationale behind SENS is to ignore the complexity altogether. Not everyone (such as Jay Fox or myself) agrees with this approach or even that it is technically feasible to implement in reality. At Imminst, however, the purpose of debating SENS is to improve its theoretical framework and thus increase the likelihood of its success when the opportunity arises in a research scenario such as is unfolding with LysoSENS and John Schloendorn.

#48 noam

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Posted 10 January 2006 - 10:36 PM

To me it seems that a full implementation of a working SENS therapy, is a small but very important first step in figuring out the basic science behind aging. It will be a "proof of concept" that we really know what contributes to aging.

#49 veronica

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Posted 10 January 2006 - 10:41 PM

"There are a few SNPs in the human PDK4 gene and it would be interesting to see if there are mutations that confer longevity based on reduced PDK4 activity. "

Yes, it is very interesting. It looks like if we find the right SNP we could control all three systems: CR, Sirt1 and IGF-I signaling. And maybe Ras too. A simple approach but effective.

#50 veronica

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Posted 10 January 2006 - 10:47 PM

It could also lead to increased resistance to oxidative stress etc. IGF-I signaling mutants are very resistant to stress.




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