45 replies to this topic

[John Schloendorn]

SIRT1-deficient cells fail to normally upregulate either the p19ARF senescence regulator or its downstream target p53

And there goes another longevity therapy...

(Sorry, can't get full text either)

[manofsan]

Hmm, not sure exactly what you mean by that, John.

Likewise, Spiritus' cut-n-paste quote said that the Sirt1 knockout also knocked out a couple of other genes, or affected them in some way, but I don't understand how that resulted in the 'artificial medium' mentioned. How could such an 'artificial medium' have been achieved by Sirt1 knockout, and how could this artificial medium then extend the lifespan by so much?

John, regarding your own quote about the p19ARF regulator, what does it imply? That the Sirt1 knockout conclusions are invalid due to some follow-on impact on this p19ARF regulator and its target p53?
Or are we saying that p19ARF regulator is the real point of interest for longevity purposes?

[John Schloendorn]

p19ARF / p53 is one, if not the, major tumor suppressor pathway in humans. I'm sure you've heard p53 before. If cells "fail to normally upregulate it", I fail to see how this can be desirable to induce in living humans.

[veronica]

I think increased expression of p53 leads to more effective tumor supression but shortens lifespan in animals.

[manofsan]

Hi John, thanks for the info. Well, I'd have to know more about about how the p19ARF / p53 tumor suppression pathway works, and also how the Sirt1 life-extension actually works. These are just switched to activate/inactivate a pathway, but we would really have to know what's happening at the end of the pathway to give the longer life, rather than merely knowing the empiral result of how much life is lengthened.

My point is that the adverse effects on p19ARF / p53 tumor suppression may not necessarily be unavoidable. Perhaps they can be offset, or counter-acted.

[spiritus]

I do not think we should merely avoid research on this, what I would call a dramatic find. Right here we have something that extends lifespans but can be a cancer creator.

Now people are trying to find the cure for cancer, which is also very desirable in the persuit of life everlasting in its current form.

What we have here are questions needings awnsers, and those awnsers could be huge steps in the field of cancer research as well as immortality, because we all know that cancer is eventually one of the big problems that will come up to new immortals.

[manofsan]

Likewise, when some call for permanent full expression of telomerase, to keep the telomere counters from ever running down, that could likewise increase the risk of cancer. It would seem that many proscriptions for lifespan extension inherently have that tradeoff with cancer risk. Perhaps then the key is to specialize in counteracting specific types of cancer caused by specific types of oncogenous activity, while reaping the associated life-extension benefits.

[veronica]

Yes, it would be interesting. Especially since worms are composed of postmitotic cells. I think it should be done in combination with deletion of Akt or other gene in IGF-1 signaling. And put the worms on caloric restriction:)
I think that the article also mentioned that deletion of Sir2 actually caused the decrease in amount of mutation with time. Should this be possible cancer prevention?

[veronica]

I meant inhibition of Sir2 otholog in worms would be interesting experiment:). Or in human postmitotic cells like neurons.

[John Schloendorn]

Well, I'd have to know more about about how the p19ARF / p53 tumor suppression pathway works

Well, there's a mountain of knowledge out there... p53 is a DNA damage signal integrator, that has three main outcomes, increased DNA repair, senescence or apoptosis. The latter two can shorten life-span, possibly mainly by senescent cell signaling and stem cell depletion, if they occur excessively.

I think increased expression of p53 leads to more effective tumor supression but shortens lifespan in animals.

Yes... There is one very interesting mutant called super p53, which effects increased tumor suppression, without the life span shortening. It is tempting to speculate that this might be by shifting the outcome towards DNA repair (see the SENS2 talk by Serrano). Anyway, this has no implication for how not to downregulate tumor suppression with sir1 silencing.

My point is that the adverse effects on p19ARF / p53 tumor suppression may not necessarily be unavoidable. Perhaps they can be offset, or counter-acted.

And that would be a great point, if it was joined by some ideas of how this might be possible in prinicple...

I do not think we should merely avoid research on this

Depends on who "we" is. Sirtuin researchers should and sure will continue to do this. But for immortalists, I do not think the evidence warrants placing a top priority on this just yet.

Perhaps then the key is to specialize in counteracting specific types of cancer caused by specific types of oncogenous activity, while reaping the associated life-extension benefits.

It's too crazy hard to do. I know I'm repeating myself, but the key is to target the damage, because damage is so way simpler than the metabolism that causes it, and targeting metabolism cannot reverse pre-existing types of damage that it is not equiped to handle.

done in combination with deletion of Akt or other gene in IGF-1 signaling. And put the worms on caloric restriction:)

Heh, that should give us some good PR [thumb]

I think that the article also mentioned that deletion of Sir2 actually caused the decrease in amount of mutation with time. Should this be possible cancer prevention?

I see, here comes the how-to. Well, I don't know. Veronica are you dreaming this, or are you in some position to acutally play with these things?

in human postmitotic cells like neurons.

Interesting, very interesting!

[veronica]

Just dreaming but hope to work on it one day:)

[veronica]

http://www.biologyne..._and_aging.html

[John Schloendorn]

What do you do that makes you dream like this? No introduction and already a full member? ;-)

[veronica]

Sorry I did not introduce myself properly. I am a student of molecular biology.

[John Schloendorn]

No worries at all, great to to have you here!

[veronica]

I love this forum!!! So many great people share the same ideas!!!