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In this post, CRON4healthylife, in his usual down-to-earth style, paints what seems like a reasonably clear picture of what *may* be going on w/ all this SIRT1/SIRT2 stuff. In mammals, SIRT1, the equivalent of the yeast "longevity gene," downregulates p53. P53 serves a "quality control" function in our cells, killing off those that don't make the grade - and thereby preventing cancer. So it would seem downregulating p53 via SIRT1 would not be such a good idea from a longevity perspective. Hence the befuddlement MR expressed in the previous post on the topic - SIRT2 good in yeast, but SIRT1 bad in mammals.

CRON4healthyfuture suggests in this post that the downregulation of p53 may not be such a bad thing in CR'ed mammals. In CRON4healthyfuture's words: "By eating so much less, you are creating, artificially, a "metabolic, barren wasteland" upon which no cancer cells have a chance anyways!" The complete article from 2004-02-06 appears below:

Human Sirtuin (Yeast CR Gene) DEPRESSES Human Foxos (Worm)

Wow, that is fascinating stuff. I think there are a couple of things
that stick out in my mind.

Evolutionary drift --
1) Yeast are particularly primitive and unicellular, and worms are
quintessential r-strategists. The challenge facing them is simply
ramping up their stress resistance by any means necessary, and stress
itself is one such way of doing that. The forkhead stuff in worms
triggers all sorts of antioxidant enzyme goodies and other things.
By mammalian standards, these things are pea-shooters, but they are a
*big* deal to the yeasties and wormies.

The lifespan of these organisms is inconsequential, so cancer is not
even "on the radar screen" for these guys, and so triggering
forkhead-related enzymes extends their lifespan. Stress is the best
way of doing this. Notice something weird going on here.....nature
could make these guys live longer if she wanted to by ramping up
their antioxidant activity constitutively, but she didn't.....is this
to promote evolution? You be the judge.

2) In mammals, the SIRT1 protein de-acetylates p53 and inhibits
forkhead activity. The net effect of this is to make p53 "not such
of a hardass" in terms of quality control. Why is this important?
Because the exquisite multicelluar organs of higher primates are
populated by stem cells that are slowly senescing, and everytime you
lose a couple of these guys, you have had it. p53 in a
hyperacetylated state will kill off of your stem cells faster than
you can say "Shut the heck up, forkhead"!

[12960381] http://www.nature.com/nsu/020101/020101-2.html

So, if you are essentially taking away p53, won't that cause cancer?
Heck no, because you AREN'T eating as much, are you?!? ;P

By eating so much less, you are creating, artifically, a "metabolic,
barren wasteland" upon which no cancer cells have a chance anyways!
With no food, no insulin, no IGF-1, and cortisol bearing down on your
multicellular wonderland, *even* with attenuated p53 quality control,
cancer cells don't have a snowball's chance in Jamaica.

But the simple fact is, nature *assumes* you are going to be eating
ad lib, so p53 activity is racheted up high. But in "stress
conditions", your body will rachet it down with SIRT1. You don't
need those antioxidant goodies lying underneath the forkhead genes
anyways, our higher primate cells are tough. 12890857 14660625

In contrast, in lower organisms, you are essentially *trying* turn
them into walking, talking cancer cells by inducing forkhead activity
and giving them all the stress resistance they need.

And that p66shc business is just the same thing as p53
hyperacetylation......when turned on, it makes a cell a "hardass"
about quality control by frying the cell oxidatively whenever p53
"thinks" there is too much damage. By removing it, whenever stem
cells make a little mistake, they won't get nuked by the p53-p66shc
axis.

That is my take on things, basically I look at it from the view of
the stem cells. Less quality control in the midst of a
nutritionally-induced antimitogenic environment will mean less stuff
(stem cells) will get tossed in the "rejected" bin.

I hope this helps. I know, biology is nuts, isn't it?