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[MR]

All:


A CRONie recently mentioned:

> Sirt1, the mammalian sirtuin and stripper of acetyl groups from DNA, is
> purported to be involved in the mechanism whereby CR promotes
> longevity.

... by a small number of scientists, most of them the primary
researchers in yeasts or biochemists, and few of them actually working
ing biogerontology.

> CR
> and Sirt1 also can counter cancer.

This latter is not clear at all, at all; in particular, there is already
ambiguity about SIRT1's effects on the tumor suppressor p53, which ARE
complex but certainly have the capacity to be supupressive. Now this new
study comes out:

> How may Sirt1 effectuate counter-cancer
> actions? It may be that by removing acetyl groups from the DNA of tumor
> suppressor genes that are inactive become activated by Sirt1 and become
> anti-cancer agents. A new paper [1] suggests that new enzymology studies show
> that the Sirt1 histone deacetylase can confer the expression of acetyl
> group silenced tumor suppressor genes.

Importantly, this stuidy suggests the exact opposite. It finds, in fact,
that "*Inhibition* of SIRT1 *Reactivates* Silenced Cancer Genes" in
breast and colon cancer cell lines; ie, these cancer cell lines have
their tumor-suppressing genes turned OFF (as you'd expect), and turning
down the activity of SIRT1 in them turns them back ON.

In a bit more detail: "In virtually every form of cancer, tumor
suppressor genes (TSGs)... are epigenetically altered [ie, functionally
changed through reversible alterations in the structures that help to
control DNA expression, without changing DNA structure -- methylation
and acetylation are heavily studied epigenetic changes -MR] such that
[they no longer function]. ... Here, the authors show SIRT1 is involved
in epigenetic silencing of DNA-hypermethylated TSGs in cancer cells.
*Inhibition* of SIRT1 by multiple approaches leads to TSG
*re-expression* [ie, the *reactivation* of previously-DEactivated
tumor-suppressor genes] and a block in tumor-causing networks of cell
signaling that are activated by loss of the TSGs in a wide range of
cancers." "Furthermore, SIRT1 inhibition affects key phenotypic aspects
of cancer cells. " "Our findings then suggest new directions for
targeting reversal of abnormal gene silencing and demonstrate the
importance of continued study, which may lead to the eventual
translation into the clinic" -- ie, drugs that would turn down SIRT1
activity in order to restore tumor supporssor genes in cancer cells,
turning them healthy (particularly in concert with other agents that
would deal with methylation or other acetylation silencing).

This doesn't exactly mean that SIRT1 "caused" cancer in these cells --
although this is slippery ground on the concept of "causation" -- but if
you have a cell that has gone into a cancer mode, part of that will
often be the silencing of these TSGs, and SIRT1 will be keeping those
suckers turned off. In those cases, activating SIRT1 pharmacologically
(as resveratrol, eg, is alleged (controversially (2-4) to do) or thru'
changes in lifestyle thought by some to activate it, may well keep a
cancer cell in a cancerous state.

> 1. Pruitt K, Zinn RL, Ohm JE, McGarvey KM, Kang SH, Watkins DN, Herman JG,
> Baylin SB.
> Inhibition of SIRT1 Reactivates Silenced Cancer Genes without Loss of
> Promoter DNA Hypermethylation.
> PLoS Genet. 2006 Mar;2(3):e40. Epub 2006 Mar 31.
> PMID: 16596166
http://genetics.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pgen.0020040

2: Borra MT, Smith BC, Denu JM. Mechanism of human SIRT1 activation by
resveratrol. J Biol Chem. 2005 Mar 4; [Epub ahead of print] PMID:
15749705 [PubMed - as supplied by publisher]

3. Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell
S, Napper A, Curtis R, Distefano PS, Fields S, Bedalov A, Kennedy BK.
Substrate specific activation fo sirtuins by resveratrol. J Biol Chem.
2005 Jan 31; [Epub ahead of print] PMID: 15684413 [PubMed - as supplied
by publisher]

4.
http://groups.google.com/group/sci.life-extension/msg/93f639b250a431b5?dmode=print